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Hatamipour M, Saremi H, Kesharwani P, Sahebkar A. Identification of potential therapeutic targets for stroke using data mining, network analysis, enrichment, and docking analysis. Comput Biol Chem 2025; 117:108431. [PMID: 40127530 DOI: 10.1016/j.compbiolchem.2025.108431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Revised: 03/12/2025] [Accepted: 03/13/2025] [Indexed: 03/26/2025]
Abstract
Stroke is a leading cause of disability and death worldwide. In this study, we identified potential therapeutic targets for stroke using a data mining, network analysis, enrichment, and docking analysis approach. We first identified 1991 genes associated with stroke from two publicly available databases: GeneCards and DisGeNET. We then constructed a protein-protein interaction (PPI) network using the STRING database and identified 1301 nodes and 5413 edges. We used Metascape to perform GO enrichment analysis and KEGG pathway enrichment analysis. The results of these analyses identified ten hub genes (TNF, IL6, ACTB, AKT1, IL1B, TP53, VEGFA, STAT3, CASP3, and CTNNB1) and five KEGG pathways (cancer, lipid and atherosclerosis, cytokine-cytokine receptor interaction, AGE RAGE signaling pathway in complications, and TNF signaling pathway) that are enriched in stroke genes. We then performed molecular docking analysis to screen potential drug candidates for these targets. The results of this analysis identified several promising drug candidates that could be used to develop new therapeutic strategies for stroke.
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Affiliation(s)
- Mahdi Hatamipour
- Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hossein Saremi
- Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Prashant Kesharwani
- Department of Pharmaceutical Sciences, Dr. Harisingh Gour Vishwavidyalaya, Sagar, Madhya Pradesh 470003, India.
| | - Amirhossein Sahebkar
- Center for Global Health Research, Saveetha Institute of Medical and Technical Sciences, Saveetha Medical College and Hospitals, Saveetha University, Chennai, India; Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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Song YS, Wang S, Park S, Hanna B, Johnson KJ, Darjatmoko SR, Saghiri MA, Saghiri AM, Liu B, Sorenson CM, Sheibani N. Receptor-Interacting Protein Kinase-3 Expression Impacts Ocular Vascular Development and Pathological Neovascularization. Cells 2024; 13:2109. [PMID: 39768199 PMCID: PMC11726843 DOI: 10.3390/cells13242109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Revised: 11/21/2024] [Accepted: 12/18/2024] [Indexed: 01/11/2025] Open
Abstract
Functional cell death pathways are essential for normal ocular vascular development and tissue homeostasis. As our understanding of necrosis-based cell death pathways has expanded, the inclusion of regulated forms, including necroptosis, ferroptosis, and oxytosis, has occurred. Although the existence of these pathways is well described, our understanding of their role during vascular development and pathological neovascularization is very limited. Here, we examined the role of receptor-interacting protein kinase-3 (Ripk3), a key regulator of necroptosis, in postnatal retinal vascularization and retinal and choroidal neovascularization under pathological conditions. Postnatal vascularization of the retinal superficial layer in the absence of Ripk3 (Ripk3-/-) was not significantly different from wild-type mice. However, we noted decreased retinal endothelial cells and pericyte numbers at 3 weeks of age when the formation of the retinal primary vascular plexus was complete. In contrast, choroidal and retinal neovascularization following laser treatment and oxygen-induced ischemic retinopathy increased in the absence of Ripk3 expression, respectively. In addition, the inhibition of RIPK1/3 activity suppressed choroidal neovascularization. Thus, Ripk3 expression and/or activity may have unique roles during normal and pathological ocular vascularization through its interactions with Caspase 8 and modulation of cell death processes.
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Affiliation(s)
- Yong-Seok Song
- Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA; (Y.-S.S.); (S.W.); (S.P.); (S.R.D.)
- McPherson Eye Research Institute, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA
| | - Shoujian Wang
- Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA; (Y.-S.S.); (S.W.); (S.P.); (S.R.D.)
| | - SunYoung Park
- Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA; (Y.-S.S.); (S.W.); (S.P.); (S.R.D.)
| | - Barbara Hanna
- Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA; (B.H.); (K.J.J.)
| | - Kelsey J. Johnson
- Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA; (B.H.); (K.J.J.)
| | - Soesiawati R. Darjatmoko
- Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA; (Y.-S.S.); (S.W.); (S.P.); (S.R.D.)
| | - Mohammad Ali Saghiri
- Department of Restorative Dentistry, Rutgers School of Dental Medicine, Newark, NJ 07103, USA;
| | - Ali Mohammad Saghiri
- Department of Computer Science, William Paterson University, Wayne, NJ 07470, USA;
| | - Bo Liu
- Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA;
| | - Christine M. Sorenson
- McPherson Eye Research Institute, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA
- Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA; (B.H.); (K.J.J.)
| | - Nader Sheibani
- Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA; (Y.-S.S.); (S.W.); (S.P.); (S.R.D.)
- McPherson Eye Research Institute, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA
- Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA;
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Pedrão LFAT, Medeiros POS, Leandro EC, Falquetto B. Parkinson's disease models and death signaling: what do we know until now? Front Neuroanat 2024; 18:1419108. [PMID: 39533977 PMCID: PMC11555652 DOI: 10.3389/fnana.2024.1419108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Accepted: 09/04/2024] [Indexed: 11/16/2024] Open
Abstract
Parkinson's disease (PD) is the second neurodegenerative disorder most prevalent in the world, characterized by the loss of dopaminergic neurons in the Substantia Nigra (SN). It is well known for its motor and non-motor symptoms including bradykinesia, resting tremor, psychiatric, cardiorespiratory, and other dysfunctions. Pathological apoptosis contributes to a wide variety of diseases including PD. Various insults and/or cellular phenotypes have been shown to trigger distinct signaling events leading to cell death in neurons affected by PD. The intrinsic or mitochondrial pathway, inflammatory or oxidative stress-induced extrinsic pathways are the main events associated with apoptosis in PD-related neuronal loss. Although SN is the main brain area studied so far, other brain nuclei are also affected by the disease leading to non-classical motor symptoms as well as non-motor symptoms. Among these, the respiratory symptoms are often overlooked, yet they can cause discomfort and may contribute to patients shortened lifespan after disease diagnosis. While animal and in vitro models are frequently used to investigate the mechanisms involved in the pathogenesis of PD in both the SN and other brain regions, these models provide only a limited understanding of the disease's actual progression. This review offers a comprehensive overview of some of the most studied forms of cell death, including recent research on potential treatment targets for these pathways. It highlights key findings and milestones in the field, shedding light on the potential role of understanding cell death in the prevention and treatment of the PD. Therefore, unraveling the connection between these pathways and the notable pathological mechanisms observed during PD progression could enhance our comprehension of the disease's origin and provide valuable insights into potential molecular targets for the developing therapeutic interventions.
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Affiliation(s)
| | | | | | - Barbara Falquetto
- Department of Pharmacology, Instituto de Ciências Biomédica, Universidade de Sao Paulo, Sao Paulo, Brazil
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Svandova E, Vesela B, Janeckova E, Chai Y, Matalova E. Exploring caspase functions in mouse models. Apoptosis 2024; 29:938-966. [PMID: 38824481 PMCID: PMC11263464 DOI: 10.1007/s10495-024-01976-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/02/2024] [Indexed: 06/03/2024]
Abstract
Caspases are enzymes with protease activity. Despite being known for more than three decades, caspase investigation still yields surprising and fascinating information. Initially associated with cell death and inflammation, their functions have gradually been revealed to extend beyond, targeting pathways such as cell proliferation, migration, and differentiation. These processes are also associated with disease mechanisms, positioning caspases as potential targets for numerous pathologies including inflammatory, neurological, metabolic, or oncological conditions. While in vitro studies play a crucial role in elucidating molecular pathways, they lack the context of the body's complexity. Therefore, laboratory animals are an indispensable part of successfully understanding and applying caspase networks. This paper aims to summarize and discuss recent knowledge, understanding, and challenges in caspase knock-out mice.
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Affiliation(s)
- Eva Svandova
- Laboratory of Odontogenesis and Osteogenesis, Institute of Animal Physiology and Genetic, Brno, Czech Republic.
| | - Barbora Vesela
- Laboratory of Odontogenesis and Osteogenesis, Institute of Animal Physiology and Genetic, Brno, Czech Republic
| | - Eva Janeckova
- Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, USA
| | - Yang Chai
- Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, USA
| | - Eva Matalova
- Laboratory of Odontogenesis and Osteogenesis, Institute of Animal Physiology and Genetic, Brno, Czech Republic
- Department of Physiology, University of Veterinary Sciences, Brno, Czech Republic
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Zhu C, Fan F, Li CY, Xiong Y, Liu X. Caspase-3 promotes oncogene-induced malignant transformation via EndoG-dependent Src-STAT3 phosphorylation. Cell Death Dis 2024; 15:486. [PMID: 38977663 PMCID: PMC11231138 DOI: 10.1038/s41419-024-06884-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 06/26/2024] [Accepted: 07/02/2024] [Indexed: 07/10/2024]
Abstract
Accumulating evidence suggests that caspase-3 plays critical roles beyond apoptosis, serving pro-survival functions in malignant transformation and tumorigenesis. However, the mechanism of non-apoptotic action of caspase-3 in oncogenic transformation remains unclear. In the present study, we show that caspase-3 is consistently activated in malignant transformation induced by exogenous expression of oncogenic cocktail (c-Myc, p53DD, Oct-4, and H-Ras) in vitro as well as in the mouse mammary tumor virus-polyomavirus middle T antigen (MMTV-PyMT) mouse model of breast cancer. Genetic ablation of caspase-3 significantly attenuated oncogene-induced transformation of mammalian cells and delayed breast cancer progression in MMTV-PyMT transgenic mice. Mechanistically, active caspase-3 triggers the translocation of endonuclease G (EndoG) from mitochondria, which migrates to the nucleus, thereby induces phosphorylation of Src-STAT3 signaling pathway to facilitate oncogenic transformation. Taken together, our data suggest that caspase-3 plays pivotal role in facilitating rather than suppressing oncogene-induced malignant transformation of mammalian cells.
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Affiliation(s)
- Chenchen Zhu
- Department of Biochemistry, School of Medicine, Shenzhen Campus of Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Fushun Fan
- BeBetter Med Inc., Guangzhou, Guangdong, China
| | - Chuan-Yuan Li
- Department of Dermatology, Duke University Medical Center, Durham, NC, USA
| | - Yan Xiong
- Guangzhou Consen Pharmaceutical Technology Co. Ltd, Guangzhou, Guangdong, China.
| | - Xinjian Liu
- Department of Biochemistry, School of Medicine, Shenzhen Campus of Sun Yat-sen University, Shenzhen, Guangdong, China.
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Kantati YT, Kodjo MK, Lefranc B, Basille-Dugay M, Hupin S, Schmitz I, Leprince J, Gbeassor M, Vaudry D. Neuroprotective Effect of Sterculia setigera Leaves Hydroethanolic Extract. J Mol Neurosci 2024; 74:44. [PMID: 38630337 DOI: 10.1007/s12031-024-02222-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2023] [Accepted: 04/06/2024] [Indexed: 04/19/2024]
Abstract
Plants are a valuable source of information for pharmacological research and new drug discovery. The present study aimed to evaluate the neuroprotective potential of the leaves of the medicinal plant Sterculia setigera. In vitro, the effect of Sterculia setigera leaves dry hydroethanolic extract (SSE) was tested on cultured cerebellar granule neurons (CGN) survival when exposed to hydrogen peroxide (H2O2) or 6-hydroxydopamine (6-OHDA), using the viability probe fluorescein diacetate (FDA), a lactate dehydrogenase (LDH) activity assay, an immunocytochemical staining against Gap 43, and the quantification of the expression of genes involved in apoptosis, necrosis, or oxidative stress. In vivo, the effect of intraperitoneal (ip) injection of SSE was assessed on the developing brain of 8-day-old Wistar rats exposed to ethanol neurotoxicity by measuring caspase-3 activity on cerebellum homogenates, the expression of some genes in tissue extracts, the thickness of cerebellar cortical layers and motor coordination. In vitro, SSE protected CGN against H2O2 and 6-OHDA-induced cell death at a dose of 10 µg/mL, inhibited the expression of genes Casp3 and Bad, and upregulated the expression of Cat and Gpx7. In vivo, SSE significantly blocked the deleterious effect of ethanol by reducing the activity of caspase-3, inhibiting the expression of Bax and Tp53, preventing the reduction of the thickness of the internal granule cell layer of the cerebellar cortex, and restoring motor functions. Sterculia setigera exerts neuroactive functions as claimed by traditional medicine and should be a good candidate for the development of a neuroprotective treatment against neurodegenerative diseases.
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Affiliation(s)
- Yendubé T Kantati
- Univ Rouen Normandie, Normandie Univ, NorDiC UMR 1239, 76000, Inserm, Rouen, France
- Laboratory of Physiology/Pharmacology, Physiopathology Bioactive Substances and Innocuity Research Unit (PBSI), Faculty of Sciences, of Lomé, Lomé, Togo, 01BP 1515
| | - Magloire K Kodjo
- Laboratory of Physiology/Pharmacology, Physiopathology Bioactive Substances and Innocuity Research Unit (PBSI), Faculty of Sciences, of Lomé, Lomé, Togo, 01BP 1515
| | - Benjamin Lefranc
- Univ Rouen Normandie, Normandie Univ, NorDiC UMR 1239, 76000, Inserm, Rouen, France
- Univ Rouen Normandie, CNRS, Normandie Univ, HeRacLeS US 51 UAR 2026, 76000, Inserm, Rouen, France
| | - Magali Basille-Dugay
- Univ Rouen Normandie, Normandie Univ, NorDiC UMR 1239, 76000, Inserm, Rouen, France
| | - Sébastien Hupin
- UMR 6014, Normandie Université, COBRA, Université de Rouen, INSA de Rouen-Normandie, CNRS, IRCOF, 3038, Mont Saint Aignan Cedex, FR, France
| | - Isabelle Schmitz
- UMR 6014, Normandie Université, COBRA, Université de Rouen, INSA de Rouen-Normandie, CNRS, IRCOF, 3038, Mont Saint Aignan Cedex, FR, France
- UMR 6270, Univ Rouen Normandie, INSA Rouen Normandie, CNRS, Normandie Univ, 76000, Rouen, France
| | - Jérôme Leprince
- Univ Rouen Normandie, Normandie Univ, NorDiC UMR 1239, 76000, Inserm, Rouen, France
- Univ Rouen Normandie, CNRS, Normandie Univ, HeRacLeS US 51 UAR 2026, 76000, Inserm, Rouen, France
| | - Messanvi Gbeassor
- Laboratory of Physiology/Pharmacology, Physiopathology Bioactive Substances and Innocuity Research Unit (PBSI), Faculty of Sciences, of Lomé, Lomé, Togo, 01BP 1515
| | - David Vaudry
- Univ Rouen Normandie, CNRS, Normandie Univ, HeRacLeS US 51 UAR 2026, 76000, Inserm, Rouen, France.
- UMR 1245, Laboratory of Cancer and Brain Genomics, Univ Rouen Normandie, Normandie Univ, 76000, Inserm, Rouen, France.
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Chesnokov MS, Mamedova AR, Zhivotovsky B, Kopeina GS. A matter of new life and cell death: programmed cell death in the mammalian ovary. J Biomed Sci 2024; 31:31. [PMID: 38509545 PMCID: PMC10956231 DOI: 10.1186/s12929-024-01017-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Accepted: 02/27/2024] [Indexed: 03/22/2024] Open
Abstract
BACKGROUND The mammalian ovary is a unique organ that displays a distinctive feature of cyclic changes throughout the entire reproductive period. The estrous/menstrual cycles are associated with drastic functional and morphological rearrangements of ovarian tissue, including follicular development and degeneration, and the formation and subsequent atrophy of the corpus luteum. The flawless execution of these reiterative processes is impossible without the involvement of programmed cell death (PCD). MAIN TEXT PCD is crucial for efficient and careful clearance of excessive, depleted, or obsolete ovarian structures for ovarian cycling. Moreover, PCD facilitates selection of high-quality oocytes and formation of the ovarian reserve during embryonic and juvenile development. Disruption of PCD regulation can heavily impact the ovarian functions and is associated with various pathologies, from a moderate decrease in fertility to severe hormonal disturbance, complete loss of reproductive function, and tumorigenesis. This comprehensive review aims to provide updated information on the role of PCD in various processes occurring in normal and pathologic ovaries. Three major events of PCD in the ovary-progenitor germ cell depletion, follicular atresia, and corpus luteum degradation-are described, alongside the detailed information on molecular regulation of these processes, highlighting the contribution of apoptosis, autophagy, necroptosis, and ferroptosis. Ultimately, the current knowledge of PCD aberrations associated with pathologies, such as polycystic ovarian syndrome, premature ovarian insufficiency, and tumors of ovarian origin, is outlined. CONCLUSION PCD is an essential element in ovarian development, functions and pathologies. A thorough understanding of molecular mechanisms regulating PCD events is required for future advances in the diagnosis and management of various disorders of the ovary and the female reproductive system in general.
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Affiliation(s)
- Mikhail S Chesnokov
- Faculty of Medicine, MV Lomonosov Moscow State University, Moscow, Russia
- Centro Nacional de Investigaciones Oncológicas, Madrid, Spain
| | - Aygun R Mamedova
- Faculty of Medicine, MV Lomonosov Moscow State University, Moscow, Russia
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia
| | - Boris Zhivotovsky
- Faculty of Medicine, MV Lomonosov Moscow State University, Moscow, Russia.
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia.
- Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden.
| | - Gelina S Kopeina
- Faculty of Medicine, MV Lomonosov Moscow State University, Moscow, Russia.
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia.
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Hernandez M, Ghislin S, Lalonde R, Strazielle C. Corticosterone effects on postnatal cerebellar development in mice. Neurochem Int 2023; 171:105611. [PMID: 37704081 DOI: 10.1016/j.neuint.2023.105611] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Revised: 08/23/2023] [Accepted: 09/06/2023] [Indexed: 09/15/2023]
Abstract
Glucocorticoids administered early in infancy can affect the architectonic organization of brain structures, particularly those with a postnatal development and resulting in long-term deficits of neuromotor function and cognition. The present study was undertaken to study the effects of daily corticosterone (CORT) injections at a pharmacological dose from postnatal days 8-15 on cerebellar and hippocampal development in mouse pups. Gene expression status for trophic factors involved in synaptic development and function as well as measures of layer thickness associated with cytochrome oxidase labelling were analyzed in the hippocampus, hypothalamus, and specific cerebellar lobules involved in motor control. Repeated CORT injections dysregulated the HPA axis with increased Crh and Nr3c1 mRNA levels in the hypothalamus and a resulting higher serum corticosterone level. The CORT treatment altered the morphology of the hippocampus and down-regulated gene transcription for corticotropin-releasing hormone (Crh) and its type-1 receptor (Crhr1), glucocorticoid receptor (Nr3c1), and brain-derived neurotrophic factor Bdnf and its receptor Ntrk2 (neurotrophic receptor tyrosine kinase 2). Similar mRNA expression decreases were found in the cerebellum for Crhr1, Crhr2, Nr3c1, and Grid2 (glutamatergic δ2 receptor). Morphological alterations and metabolic activity variations were observed in specific cerebellar lobules involved in motor control. The paramedian lobule, normally characterized by mitotic activity in the external germinative layer during the second postnatal week, was atrophic but metabolically hyperactive in its granule cell and molecular layers. On the contrary, lobules with an earlier cell proliferation displayed neurogenesis but a hypoactivated granule cell layer, suggesting a developmental delay in synaptogenesis. The results indicate that glucocorticoid, administered daily during the second postnatal week modulated the developmental programming of the hippocampus and cerebellum. These growth and metabolic alterations may lead possibly to morphological and functional changes later in life.
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Affiliation(s)
- M Hernandez
- Laboratory of Stress, Immunity, Pathogens (EA 7300), Medical School, University of Lorraine, 54500 Vandœuvre-les-Nancy, France; CHRU Nancy, Vandœuvre-les-Nancy, France
| | - S Ghislin
- Laboratory of Stress, Immunity, Pathogens (EA 7300), Medical School, University of Lorraine, 54500 Vandœuvre-les-Nancy, France
| | - R Lalonde
- Laboratory of Stress, Immunity, Pathogens (EA 7300), Medical School, University of Lorraine, 54500 Vandœuvre-les-Nancy, France
| | - C Strazielle
- Laboratory of Stress, Immunity, Pathogens (EA 7300), Medical School, University of Lorraine, 54500 Vandœuvre-les-Nancy, France; CHRU Nancy, Vandœuvre-les-Nancy, France.
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Sahoo G, Samal D, Khandayataray P, Murthy MK. A Review on Caspases: Key Regulators of Biological Activities and Apoptosis. Mol Neurobiol 2023; 60:5805-5837. [PMID: 37349620 DOI: 10.1007/s12035-023-03433-5] [Citation(s) in RCA: 87] [Impact Index Per Article: 43.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2021] [Accepted: 06/06/2023] [Indexed: 06/24/2023]
Abstract
Caspases are proteolytic enzymes that belong to the cysteine protease family and play a crucial role in homeostasis and programmed cell death. Caspases have been broadly classified by their known roles in apoptosis (caspase-3, caspase-6, caspase-7, caspase-8, and caspase-9 in mammals) and in inflammation (caspase-1, caspase-4, caspase-5, and caspase-12 in humans, and caspase-1, caspase-11, and caspase-12 in mice). Caspases involved in apoptosis have been subclassified by their mechanism of action as either initiator caspases (caspase-8 and caspase-9) or executioner caspases (caspase-3, caspase-6, and caspase-7). Caspases that participate in apoptosis are inhibited by proteins known as inhibitors of apoptosis (IAPs). In addition to apoptosis, caspases play a role in necroptosis, pyroptosis, and autophagy, which are non-apoptotic cell death processes. Dysregulation of caspases features prominently in many human diseases, including cancer, autoimmunity, and neurodegenerative disorders, and increasing evidence shows that altering caspase activity can confer therapeutic benefits. This review covers the different types of caspases, their functions, and their physiological and biological activities and roles in different organisms.
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Affiliation(s)
- Gayatri Sahoo
- Department of Zoology, PSSJ College, Banarpal, 759128, Odisha, India
| | - Dibyaranjan Samal
- Department of Biotechnology, Academy of Management and Information Technology (AMIT, affiliated to Utkal University), Khurda, 752057, Odisha, India
| | | | - Meesala Krishna Murthy
- Department of Allied Health Sciences, Chitkara School of Health Sciences, Chitkara University, Rajpura, Punjab, 140401, India.
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Nozaki K, Miao EA. Bucket lists must be completed during cell death. Trends Cell Biol 2023; 33:803-815. [PMID: 36958996 PMCID: PMC10440244 DOI: 10.1016/j.tcb.2023.02.008] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 02/23/2023] [Accepted: 02/24/2023] [Indexed: 03/25/2023]
Abstract
Regulated cell death occurs in many forms, including apoptosis, pyroptosis, necroptosis, and NETosis. Most obviously, the purpose of these pathways is to kill the cell. However, many cells need to complete a set of effector programs before they die, which we define as a cellular 'bucket list'. These effector programs are specific to the cell type, and mode and circumstances of death. For example, intestinal epithelial cells need to complete the process of extrusion before they die. Cells use regulatory mechanisms to temporarily prolong their life, including endosomal sorting complex required for transport (ESCRT)- and acid sphingomyelinase (ASM)-driven membrane repair. These allow cells to complete their bucket lists before they die.
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Affiliation(s)
- Kengo Nozaki
- Department of Immunology, Duke University School of Medicine, Durham, NC, USA; Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, USA; Department of Cell Biology, Duke University School of Medicine, Durham, NC, USA.
| | - Edward A Miao
- Department of Immunology, Duke University School of Medicine, Durham, NC, USA; Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, USA; Department of Cell Biology, Duke University School of Medicine, Durham, NC, USA.
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11
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Matsui Y, Djekidel MN, Lindsay K, Samir P, Connolly N, Wu G, Yang X, Fan Y, Xu B, Peng JC. SNIP1 and PRC2 coordinate cell fates of neural progenitors during brain development. Nat Commun 2023; 14:4754. [PMID: 37553330 PMCID: PMC10409800 DOI: 10.1038/s41467-023-40487-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 07/28/2023] [Indexed: 08/10/2023] Open
Abstract
Stem cell survival versus death is a developmentally programmed process essential for morphogenesis, sizing, and quality control of genome integrity and cell fates. Cell death is pervasive during development, but its programming is little known. Here, we report that Smad nuclear interacting protein 1 (SNIP1) promotes neural progenitor cell survival and neurogenesis and is, therefore, integral to brain development. The SNIP1-depleted brain exhibits dysplasia with robust induction of caspase 9-dependent apoptosis. Mechanistically, SNIP1 regulates target genes that promote cell survival and neurogenesis, and its activities are influenced by TGFβ and NFκB signaling pathways. Further, SNIP1 facilitates the genomic occupancy of Polycomb complex PRC2 and instructs H3K27me3 turnover at target genes. Depletion of PRC2 is sufficient to reduce apoptosis and brain dysplasia and to partially restore genetic programs in the SNIP1-depleted brain in vivo. These findings suggest a loci-specific regulation of PRC2 and H3K27 marks to toggle cell survival and death in the developing brain.
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Affiliation(s)
- Yurika Matsui
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - Mohamed Nadhir Djekidel
- Center for Applied Bioinformatics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - Katherine Lindsay
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - Parimal Samir
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
- Department of Microbiology and Immunology, University of Texas Medical Branch, 301 University Blvd, Medical Research Building, Room 7, 138E, Galveston, TX, 77550, USA
| | - Nina Connolly
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - Gang Wu
- Center for Applied Bioinformatics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - Xiaoyang Yang
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - Yiping Fan
- Center for Applied Bioinformatics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - Beisi Xu
- Center for Applied Bioinformatics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - Jamy C Peng
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.
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12
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Petry P, Oschwald A, Kierdorf K. Microglial tissue surveillance: The never-resting gardener in the developing and adult CNS. Eur J Immunol 2023; 53:e2250232. [PMID: 37042800 DOI: 10.1002/eji.202250232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 03/24/2023] [Accepted: 04/11/2023] [Indexed: 04/13/2023]
Abstract
Immunosurveillance by microglia is a dynamic process in the central nervous system (CNS) with versatile functions to maintain tissue homeostasis and provide immune defense. A tightly controlled microglia network throughout the CNS parenchyma facilitates efficient immunosurveillance, where each cell guards a certain tissue territory. Each cell is constantly surveilling its environment and the surrounding cells, screening for pathogens but also removing cell debris and metabolites, grooming neighboring cells and facilitating cellular crosstalk. In the absence of inflammation, this "tissue surveillance" by microglia presents an essential process for CNS homeostasis and development. In this review, we provide a summary on different tissue surveillance functions mediated by microglia, the underlying molecular machineries, and how defects, such as genetic mutations, can alter these surveillance mechanisms and cause disease onset.
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Affiliation(s)
- Philippe Petry
- Institute of Neuropathology, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Faculty of Biology, University of Freiburg, Freiburg, Germany
| | - Alexander Oschwald
- Institute of Neuropathology, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Faculty of Biology, University of Freiburg, Freiburg, Germany
| | - Katrin Kierdorf
- Institute of Neuropathology, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Center for Basics in NeuroModulation (NeuroModulBasics), Faculty of Medicine, University of Freiburg, Freiburg, Germany
- CIBSS-Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany
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13
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Sell T, Klotz C, Fischer MM, Astaburuaga-García R, Krug S, Drost J, Clevers H, Sers C, Morkel M, Blüthgen N. Oncogenic signaling is coupled to colorectal cancer cell differentiation state. J Cell Biol 2023; 222:e202204001. [PMID: 37017636 PMCID: PMC10082329 DOI: 10.1083/jcb.202204001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 12/23/2022] [Accepted: 03/17/2023] [Indexed: 04/06/2023] Open
Abstract
Colorectal cancer progression is intrinsically linked to stepwise deregulation of the intestinal differentiation trajectory. In this process, sequential mutations of APC, KRAS, TP53, and SMAD4 enable oncogenic signaling and establish the hallmarks of cancer. Here, we use mass cytometry of isogenic human colon organoids and patient-derived cancer organoids to capture oncogenic signaling, cell phenotypes, and differentiation states in a high-dimensional single-cell map. We define a differentiation axis in all tumor progression states from normal to cancer. Our data show that colorectal cancer driver mutations shape the distribution of cells along the differentiation axis. In this regard, subsequent mutations can have stem cell promoting or restricting effects. Individual nodes of the cancer cell signaling network remain coupled to the differentiation state, regardless of the presence of driver mutations. We use single-cell RNA sequencing to link the (phospho-)protein signaling network to transcriptomic states with biological and clinical relevance. Our work highlights how oncogenes gradually shape signaling and transcriptomes during tumor progression.
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Affiliation(s)
- Thomas Sell
- Institute of Pathology, Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Institute of Biology, Humboldt University of Berlin, Berlin, Germany
| | - Christian Klotz
- Department of Infectious Diseases, Robert Koch-Institute, Unit 16 Mycotic and Parasitic Agents and Mycobacteria, Berlin, Germany
| | - Matthias M. Fischer
- Institute of Pathology, Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Institute of Biology, Humboldt University of Berlin, Berlin, Germany
| | - Rosario Astaburuaga-García
- Institute of Pathology, Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Institute of Biology, Humboldt University of Berlin, Berlin, Germany
| | - Susanne Krug
- Department of Gastroenterology, Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Rheumatology and Infectious Diseases, Clinical Physiology/Nutritional Medicine, Berlin, Germany
| | - Jarno Drost
- Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
- Oncode Institute, Utrecht, Netherlands
| | - Hans Clevers
- Oncode Institute, Utrecht, Netherlands
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center Utrecht, Utrecht, Netherlands
| | - Christine Sers
- Institute of Pathology, Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Institute of Biology, Humboldt University of Berlin, Berlin, Germany
- German Cancer Consortium Partner Site Berlin, German Cancer Research Center, Heidelberg, Germany
| | - Markus Morkel
- Institute of Pathology, Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- German Cancer Consortium Partner Site Berlin, German Cancer Research Center, Heidelberg, Germany
- Berlin Institute of Health at Charité—Universitätsmedizin Berlin, Bioportal Single Cells, Berlin, Germany
| | - Nils Blüthgen
- Institute of Pathology, Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Institute of Biology, Humboldt University of Berlin, Berlin, Germany
- German Cancer Consortium Partner Site Berlin, German Cancer Research Center, Heidelberg, Germany
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14
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Vitale I, Pietrocola F, Guilbaud E, Aaronson SA, Abrams JM, Adam D, Agostini M, Agostinis P, Alnemri ES, Altucci L, Amelio I, Andrews DW, Aqeilan RI, Arama E, Baehrecke EH, Balachandran S, Bano D, Barlev NA, Bartek J, Bazan NG, Becker C, Bernassola F, Bertrand MJM, Bianchi ME, Blagosklonny MV, Blander JM, Blandino G, Blomgren K, Borner C, Bortner CD, Bove P, Boya P, Brenner C, Broz P, Brunner T, Damgaard RB, Calin GA, Campanella M, Candi E, Carbone M, Carmona-Gutierrez D, Cecconi F, Chan FKM, Chen GQ, Chen Q, Chen YH, Cheng EH, Chipuk JE, Cidlowski JA, Ciechanover A, Ciliberto G, Conrad M, Cubillos-Ruiz JR, Czabotar PE, D'Angiolella V, Daugaard M, Dawson TM, Dawson VL, De Maria R, De Strooper B, Debatin KM, Deberardinis RJ, Degterev A, Del Sal G, Deshmukh M, Di Virgilio F, Diederich M, Dixon SJ, Dynlacht BD, El-Deiry WS, Elrod JW, Engeland K, Fimia GM, Galassi C, Ganini C, Garcia-Saez AJ, Garg AD, Garrido C, Gavathiotis E, Gerlic M, Ghosh S, Green DR, Greene LA, Gronemeyer H, Häcker G, Hajnóczky G, Hardwick JM, Haupt Y, He S, Heery DM, Hengartner MO, Hetz C, Hildeman DA, Ichijo H, Inoue S, Jäättelä M, Janic A, Joseph B, Jost PJ, Kanneganti TD, et alVitale I, Pietrocola F, Guilbaud E, Aaronson SA, Abrams JM, Adam D, Agostini M, Agostinis P, Alnemri ES, Altucci L, Amelio I, Andrews DW, Aqeilan RI, Arama E, Baehrecke EH, Balachandran S, Bano D, Barlev NA, Bartek J, Bazan NG, Becker C, Bernassola F, Bertrand MJM, Bianchi ME, Blagosklonny MV, Blander JM, Blandino G, Blomgren K, Borner C, Bortner CD, Bove P, Boya P, Brenner C, Broz P, Brunner T, Damgaard RB, Calin GA, Campanella M, Candi E, Carbone M, Carmona-Gutierrez D, Cecconi F, Chan FKM, Chen GQ, Chen Q, Chen YH, Cheng EH, Chipuk JE, Cidlowski JA, Ciechanover A, Ciliberto G, Conrad M, Cubillos-Ruiz JR, Czabotar PE, D'Angiolella V, Daugaard M, Dawson TM, Dawson VL, De Maria R, De Strooper B, Debatin KM, Deberardinis RJ, Degterev A, Del Sal G, Deshmukh M, Di Virgilio F, Diederich M, Dixon SJ, Dynlacht BD, El-Deiry WS, Elrod JW, Engeland K, Fimia GM, Galassi C, Ganini C, Garcia-Saez AJ, Garg AD, Garrido C, Gavathiotis E, Gerlic M, Ghosh S, Green DR, Greene LA, Gronemeyer H, Häcker G, Hajnóczky G, Hardwick JM, Haupt Y, He S, Heery DM, Hengartner MO, Hetz C, Hildeman DA, Ichijo H, Inoue S, Jäättelä M, Janic A, Joseph B, Jost PJ, Kanneganti TD, Karin M, Kashkar H, Kaufmann T, Kelly GL, Kepp O, Kimchi A, Kitsis RN, Klionsky DJ, Kluck R, Krysko DV, Kulms D, Kumar S, Lavandero S, Lavrik IN, Lemasters JJ, Liccardi G, Linkermann A, Lipton SA, Lockshin RA, López-Otín C, Luedde T, MacFarlane M, Madeo F, Malorni W, Manic G, Mantovani R, Marchi S, Marine JC, Martin SJ, Martinou JC, Mastroberardino PG, Medema JP, Mehlen P, Meier P, Melino G, Melino S, Miao EA, Moll UM, Muñoz-Pinedo C, Murphy DJ, Niklison-Chirou MV, Novelli F, Núñez G, Oberst A, Ofengeim D, Opferman JT, Oren M, Pagano M, Panaretakis T, Pasparakis M, Penninger JM, Pentimalli F, Pereira DM, Pervaiz S, Peter ME, Pinton P, Porta G, Prehn JHM, Puthalakath H, Rabinovich GA, Rajalingam K, Ravichandran KS, Rehm M, Ricci JE, Rizzuto R, Robinson N, Rodrigues CMP, Rotblat B, Rothlin CV, Rubinsztein DC, Rudel T, Rufini A, Ryan KM, Sarosiek KA, Sawa A, Sayan E, Schroder K, Scorrano L, Sesti F, Shao F, Shi Y, Sica GS, Silke J, Simon HU, Sistigu A, Stephanou A, Stockwell BR, Strapazzon F, Strasser A, Sun L, Sun E, Sun Q, Szabadkai G, Tait SWG, Tang D, Tavernarakis N, Troy CM, Turk B, Urbano N, Vandenabeele P, Vanden Berghe T, Vander Heiden MG, Vanderluit JL, Verkhratsky A, Villunger A, von Karstedt S, Voss AK, Vousden KH, Vucic D, Vuri D, Wagner EF, Walczak H, Wallach D, Wang R, Wang Y, Weber A, Wood W, Yamazaki T, Yang HT, Zakeri Z, Zawacka-Pankau JE, Zhang L, Zhang H, Zhivotovsky B, Zhou W, Piacentini M, Kroemer G, Galluzzi L. Apoptotic cell death in disease-Current understanding of the NCCD 2023. Cell Death Differ 2023; 30:1097-1154. [PMID: 37100955 PMCID: PMC10130819 DOI: 10.1038/s41418-023-01153-w] [Show More Authors] [Citation(s) in RCA: 164] [Impact Index Per Article: 82.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 03/10/2023] [Accepted: 03/17/2023] [Indexed: 04/28/2023] Open
Abstract
Apoptosis is a form of regulated cell death (RCD) that involves proteases of the caspase family. Pharmacological and genetic strategies that experimentally inhibit or delay apoptosis in mammalian systems have elucidated the key contribution of this process not only to (post-)embryonic development and adult tissue homeostasis, but also to the etiology of multiple human disorders. Consistent with this notion, while defects in the molecular machinery for apoptotic cell death impair organismal development and promote oncogenesis, the unwarranted activation of apoptosis promotes cell loss and tissue damage in the context of various neurological, cardiovascular, renal, hepatic, infectious, neoplastic and inflammatory conditions. Here, the Nomenclature Committee on Cell Death (NCCD) gathered to critically summarize an abundant pre-clinical literature mechanistically linking the core apoptotic apparatus to organismal homeostasis in the context of disease.
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Affiliation(s)
- Ilio Vitale
- IIGM - Italian Institute for Genomic Medicine, c/o IRCSS Candiolo, Torino, Italy.
- Candiolo Cancer Institute, FPO -IRCCS, Candiolo, Italy.
| | - Federico Pietrocola
- Department of Biosciences and Nutrition, Karolinska Institute, Huddinge, Sweden
| | - Emma Guilbaud
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA
| | - Stuart A Aaronson
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York City, NY, USA
| | - John M Abrams
- Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Dieter Adam
- Institut für Immunologie, Kiel University, Kiel, Germany
| | - Massimiliano Agostini
- Department of Experimental Medicine, University of Rome Tor Vergata, TOR, Rome, Italy
| | - Patrizia Agostinis
- Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
- VIB Center for Cancer Biology, Leuven, Belgium
| | - Emad S Alnemri
- Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Lucia Altucci
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
- BIOGEM, Avellino, Italy
| | - Ivano Amelio
- Division of Systems Toxicology, Department of Biology, University of Konstanz, Konstanz, Germany
| | - David W Andrews
- Sunnybrook Research Institute, Toronto, ON, Canada
- Departments of Biochemistry and Medical Biophysics, University of Toronto, Toronto, ON, Canada
| | - Rami I Aqeilan
- Hebrew University of Jerusalem, Lautenberg Center for Immunology & Cancer Research, Institute for Medical Research Israel-Canada (IMRIC), Faculty of Medicine, Jerusalem, Israel
| | - Eli Arama
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
| | - Eric H Baehrecke
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Siddharth Balachandran
- Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Daniele Bano
- Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Bonn, Germany
| | - Nickolai A Barlev
- Department of Biomedicine, Nazarbayev University School of Medicine, Astana, Kazakhstan
| | - Jiri Bartek
- Department of Medical Biochemistry and Biophysics, Science for Life Laboratory, Karolinska Institute, Stockholm, Sweden
- Danish Cancer Society Research Center, Copenhagen, Denmark
| | - Nicolas G Bazan
- Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health New Orleans, New Orleans, LA, USA
| | - Christoph Becker
- Department of Medicine 1, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
| | - Francesca Bernassola
- Department of Experimental Medicine, University of Rome Tor Vergata, TOR, Rome, Italy
| | - Mathieu J M Bertrand
- VIB-UGent Center for Inflammation Research, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Marco E Bianchi
- Università Vita-Salute San Raffaele, School of Medicine, Milan, Italy and Ospedale San Raffaele IRCSS, Milan, Italy
| | | | - J Magarian Blander
- Department of Medicine, Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, New York, NY, USA
- Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY, USA
- Sandra and Edward Meyer Cancer Center, New York, NY, USA
| | | | - Klas Blomgren
- Department of Women's and Children's Health, Karolinska Institute, Stockholm, Sweden
- Pediatric Hematology and Oncology, Karolinska University Hospital, Stockholm, Sweden
| | - Christoph Borner
- Institute of Molecular Medicine and Cell Research, Medical Faculty, Albert Ludwigs University of Freiburg, Freiburg, Germany
| | - Carl D Bortner
- Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, Durham, NC, USA
| | - Pierluigi Bove
- Department of Experimental Medicine, University of Rome Tor Vergata, TOR, Rome, Italy
| | - Patricia Boya
- Centro de Investigaciones Biologicas Margarita Salas, CSIC, Madrid, Spain
| | - Catherine Brenner
- Université Paris-Saclay, CNRS, Institut Gustave Roussy, Aspects métaboliques et systémiques de l'oncogénèse pour de nouvelles approches thérapeutiques, Villejuif, France
| | - Petr Broz
- Department of Immunobiology, University of Lausanne, Epalinges, Vaud, Switzerland
| | - Thomas Brunner
- Department of Biology, University of Konstanz, Konstanz, Germany
| | - Rune Busk Damgaard
- Department of Biotechnology and Biomedicine, Technical University of Denmark, Kongens Lyngby, Denmark
| | - George A Calin
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Michelangelo Campanella
- Department of Comparative Biomedical Sciences, The Royal Veterinary College, University of London, London, UK
- UCL Consortium for Mitochondrial Research, London, UK
- Department of Biology, University of Rome Tor Vergata, Rome, Italy
| | - Eleonora Candi
- Department of Experimental Medicine, University of Rome Tor Vergata, TOR, Rome, Italy
| | - Michele Carbone
- Thoracic Oncology, University of Hawaii Cancer Center, Honolulu, HI, USA
| | | | - Francesco Cecconi
- Cell Stress and Survival Unit, Center for Autophagy, Recycling and Disease (CARD), Danish Cancer Society Research Center, Copenhagen, Denmark
- Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
- Università Cattolica del Sacro Cuore, Rome, Italy
| | - Francis K-M Chan
- Department of Immunology, Duke University School of Medicine, Durham, NC, USA
| | - Guo-Qiang Chen
- State Key Lab of Oncogene and its related gene, Ren-Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Quan Chen
- College of Life Sciences, Nankai University, Tianjin, China
| | - Youhai H Chen
- Shenzhen Institute of Advanced Technology (SIAT), Shenzhen, Guangdong, China
| | - Emily H Cheng
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jerry E Chipuk
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - John A Cidlowski
- Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, Durham, NC, USA
| | - Aaron Ciechanover
- The Technion-Integrated Cancer Center, The Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
| | | | - Marcus Conrad
- Helmholtz Munich, Institute of Metabolism and Cell Death, Neuherberg, Germany
| | - Juan R Cubillos-Ruiz
- Department of Obstetrics and Gynecology, Weill Cornell Medical College, New York, NY, USA
| | - Peter E Czabotar
- The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
- Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia
| | | | - Mads Daugaard
- Department of Urologic Sciences, Vancouver Prostate Centre, Vancouver, BC, Canada
| | - Ted M Dawson
- Institute for Cell Engineering and the Departments of Neurology, Neuroscience and Pharmacology & Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Valina L Dawson
- Institute for Cell Engineering and the Departments of Neurology, Neuroscience and Pharmacology & Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ruggero De Maria
- Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
- Università Cattolica del Sacro Cuore, Rome, Italy
| | - Bart De Strooper
- VIB Centre for Brain & Disease Research, Leuven, Belgium
- Department of Neurosciences, Leuven Brain Institute, KU Leuven, Leuven, Belgium
- The Francis Crick Institute, London, UK
- UK Dementia Research Institute at UCL, University College London, London, UK
| | - Klaus-Michael Debatin
- Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany
| | - Ralph J Deberardinis
- Howard Hughes Medical Institute and Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Alexei Degterev
- Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA, USA
| | - Giannino Del Sal
- Department of Life Sciences, University of Trieste, Trieste, Italy
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Area Science Park-Padriciano, Trieste, Italy
- IFOM ETS, the AIRC Institute of Molecular Oncology, Milan, Italy
| | - Mohanish Deshmukh
- Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC, USA
| | | | - Marc Diederich
- College of Pharmacy, Seoul National University, Seoul, South Korea
| | - Scott J Dixon
- Department of Biology, Stanford University, Stanford, CA, USA
| | - Brian D Dynlacht
- Department of Pathology, New York University Cancer Institute, New York University School of Medicine, New York, NY, USA
| | - Wafik S El-Deiry
- Division of Hematology/Oncology, Brown University and the Lifespan Cancer Institute, Providence, RI, USA
- Legorreta Cancer Center at Brown University, The Warren Alpert Medical School, Brown University, Providence, RI, USA
- Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School, Brown University, Providence, RI, USA
| | - John W Elrod
- Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA
| | - Kurt Engeland
- Molecular Oncology, University of Leipzig, Leipzig, Germany
| | - Gian Maria Fimia
- Department of Epidemiology, Preclinical Research and Advanced Diagnostics, National Institute for Infectious Diseases 'L. Spallanzani' IRCCS, Rome, Italy
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Claudia Galassi
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA
| | - Carlo Ganini
- Department of Experimental Medicine, University of Rome Tor Vergata, TOR, Rome, Italy
- Biochemistry Laboratory, Dermopatic Institute of Immaculate (IDI) IRCCS, Rome, Italy
| | - Ana J Garcia-Saez
- CECAD, Institute of Genetics, University of Cologne, Cologne, Germany
| | - Abhishek D Garg
- Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
| | - Carmen Garrido
- INSERM, UMR, 1231, Dijon, France
- Faculty of Medicine, Université de Bourgogne Franche-Comté, Dijon, France
- Anti-cancer Center Georges-François Leclerc, Dijon, France
| | - Evripidis Gavathiotis
- Department of Biochemistry, Albert Einstein College of Medicine, New York, NY, USA
- Department of Medicine, Albert Einstein College of Medicine, New York, NY, USA
- Albert Einstein Cancer Center, Albert Einstein College of Medicine, New York, NY, USA
- Institute for Aging Research, Albert Einstein College of Medicine, New York, NY, USA
- Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, New York, NY, USA
| | - Motti Gerlic
- Department of Clinical Microbiology and Immunology, Sackler school of Medicine, Tel Aviv university, Tel Aviv, Israel
| | - Sourav Ghosh
- Department of Neurology and Department of Pharmacology, Yale School of Medicine, New Haven, CT, USA
| | - Douglas R Green
- Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA
| | - Lloyd A Greene
- Department of Pathology and Cell Biology, Columbia University, New York, NY, USA
| | - Hinrich Gronemeyer
- Department of Functional Genomics and Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, France
- Centre National de la Recherche Scientifique, UMR7104, Illkirch, France
- Institut National de la Santé et de la Recherche Médicale, U1258, Illkirch, France
- Université de Strasbourg, Illkirch, France
| | - Georg Häcker
- Faculty of Medicine, Institute of Medical Microbiology and Hygiene, Medical Center, University of Freiburg, Freiburg, Germany
- BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg, Germany
| | - György Hajnóczky
- MitoCare Center, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - J Marie Hardwick
- Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
- Departments of Molecular Microbiology and Immunology, Pharmacology, Oncology and Neurology, Johns Hopkins Bloomberg School of Public Health and School of Medicine, Baltimore, MD, USA
| | - Ygal Haupt
- VITTAIL Ltd, Melbourne, VIC, Australia
- Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
| | - Sudan He
- Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
- Suzhou Institute of Systems Medicine, Suzhou, Jiangsu, China
| | - David M Heery
- School of Pharmacy, University of Nottingham, Nottingham, UK
| | | | - Claudio Hetz
- Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile
- Center for Geroscience, Brain Health and Metabolism, Santiago, Chile
- Center for Molecular Studies of the Cell, Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, University of Chile, Santiago, Chile
- Buck Institute for Research on Aging, Novato, CA, USA
| | - David A Hildeman
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Hidenori Ichijo
- Laboratory of Cell Signaling, The University of Tokyo, Tokyo, Japan
| | - Satoshi Inoue
- National Cancer Center Research Institute, Tokyo, Japan
| | - Marja Jäättelä
- Cell Death and Metabolism, Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center, Copenhagen, Denmark
- Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Ana Janic
- Department of Medicine and Life Sciences, Pompeu Fabra University, Barcelona, Spain
| | - Bertrand Joseph
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Philipp J Jost
- Clinical Division of Oncology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | | | - Michael Karin
- Departments of Pharmacology and Pathology, School of Medicine, University of California San Diego, San Diego, CA, USA
| | - Hamid Kashkar
- CECAD Research Center, Institute for Molecular Immunology, University of Cologne, Cologne, Germany
| | - Thomas Kaufmann
- Institute of Pharmacology, University of Bern, Bern, Switzerland
| | - Gemma L Kelly
- The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
- Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia
| | - Oliver Kepp
- Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Center, Université Paris Saclay, Villejuif, France
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France
| | - Adi Kimchi
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
| | - Richard N Kitsis
- Department of Biochemistry, Albert Einstein College of Medicine, New York, NY, USA
- Department of Medicine, Albert Einstein College of Medicine, New York, NY, USA
- Albert Einstein Cancer Center, Albert Einstein College of Medicine, New York, NY, USA
- Institute for Aging Research, Albert Einstein College of Medicine, New York, NY, USA
- Department of Cell Biology, Albert Einstein College of Medicine, New York, NY, USA
- Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, New York, NY, USA
| | | | - Ruth Kluck
- The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
- Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia
| | - Dmitri V Krysko
- Cell Death Investigation and Therapy Lab, Department of Human Structure and Repair, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Dagmar Kulms
- Department of Dermatology, Experimental Dermatology, TU-Dresden, Dresden, Germany
- National Center for Tumor Diseases Dresden, TU-Dresden, Dresden, Germany
| | - Sharad Kumar
- Centre for Cancer Biology, University of South Australia, Adelaide, SA, Australia
- Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA, Australia
| | - Sergio Lavandero
- Universidad de Chile, Facultad Ciencias Quimicas y Farmaceuticas & Facultad Medicina, Advanced Center for Chronic Diseases (ACCDiS), Santiago, Chile
- Department of Internal Medicine, Cardiology Division, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Inna N Lavrik
- Translational Inflammation Research, Medical Faculty, Otto von Guericke University, Magdeburg, Germany
| | - John J Lemasters
- Departments of Drug Discovery & Biomedical Sciences and Biochemistry & Molecular Biology, Medical University of South Carolina, Charleston, SC, USA
| | - Gianmaria Liccardi
- Center for Biochemistry, Medical Faculty, University of Cologne, Cologne, Germany
| | - Andreas Linkermann
- Division of Nephrology, Department of Internal Medicine 3, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- Biotechnology Center, Technische Universität Dresden, Dresden, Germany
| | - Stuart A Lipton
- Neurodegeneration New Medicines Center and Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA
- Department of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA, USA
- Department of Neurology, Yale School of Medicine, New Haven, CT, USA
| | - Richard A Lockshin
- Department of Biology, Queens College of the City University of New York, Flushing, NY, USA
- St. John's University, Jamaica, NY, USA
| | - Carlos López-Otín
- Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, Oviedo, Spain
| | - Tom Luedde
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Duesseldorf, Heinrich Heine University, Duesseldorf, Germany
| | - Marion MacFarlane
- Medical Research Council Toxicology Unit, University of Cambridge, Cambridge, UK
| | - Frank Madeo
- Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria
- BioTechMed Graz, Graz, Austria
- Field of Excellence BioHealth - University of Graz, Graz, Austria
| | - Walter Malorni
- Center for Global Health, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Gwenola Manic
- IIGM - Italian Institute for Genomic Medicine, c/o IRCSS Candiolo, Torino, Italy
- Candiolo Cancer Institute, FPO -IRCCS, Candiolo, Italy
| | - Roberto Mantovani
- Dipartimento di Bioscienze, Università degli Studi di Milano, Milano, Italy
| | - Saverio Marchi
- Department of Clinical and Molecular Sciences, Marche Polytechnic University, Ancona, Italy
| | - Jean-Christophe Marine
- VIB Center for Cancer Biology, Leuven, Belgium
- Department of Oncology, KU Leuven, Leuven, Belgium
| | | | - Jean-Claude Martinou
- Department of Cell Biology, Faculty of Sciences, University of Geneva, Geneva, Switzerland
| | - Pier G Mastroberardino
- Department of Molecular Genetics, Rotterdam, the Netherlands
- IFOM-ETS The AIRC Institute for Molecular Oncology, Milan, Italy
- Department of Life, Health, and Environmental Sciences, University of L'Aquila, L'Aquila, Italy
| | - Jan Paul Medema
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
- Oncode Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Patrick Mehlen
- Apoptosis, Cancer, and Development Laboratory, Equipe labellisée 'La Ligue', LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Centre Léon Bérard, Université de Lyon, Université Claude Bernard Lyon1, Lyon, France
| | - Pascal Meier
- The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK
| | - Gerry Melino
- Department of Experimental Medicine, University of Rome Tor Vergata, TOR, Rome, Italy
| | - Sonia Melino
- Department of Chemical Science and Technologies, University of Rome Tor Vergata, Rome, Italy
| | - Edward A Miao
- Department of Immunology, Duke University School of Medicine, Durham, NC, USA
| | - Ute M Moll
- Department of Pathology and Stony Brook Cancer Center, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, USA
| | - Cristina Muñoz-Pinedo
- Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Spain
| | - Daniel J Murphy
- School of Cancer Sciences, University of Glasgow, Glasgow, UK
- Cancer Research UK Beatson Institute, Glasgow, UK
| | | | - Flavia Novelli
- Thoracic Oncology, University of Hawaii Cancer Center, Honolulu, HI, USA
| | - Gabriel Núñez
- Department of Pathology and Rogel Cancer Center, The University of Michigan, Ann Arbor, MI, USA
| | - Andrew Oberst
- Department of Immunology, University of Washington, Seattle, WA, USA
| | - Dimitry Ofengeim
- Rare and Neuroscience Therapeutic Area, Sanofi, Cambridge, MA, USA
| | - Joseph T Opferman
- Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Moshe Oren
- Department of Molecular Cell Biology, The Weizmann Institute, Rehovot, Israel
| | - Michele Pagano
- Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine and Howard Hughes Medical Institute, New York, NY, USA
| | - Theocharis Panaretakis
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
- Department of GU Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA
| | | | - Josef M Penninger
- IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria
- Department of Medical Genetics, Life Sciences Institute, University of British Columbia, Vancouver, Canada
| | | | - David M Pereira
- REQUIMTE/LAQV, Laboratório de Farmacognosia, Departamento de Química, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal
| | - Shazib Pervaiz
- Department of Physiology, YLL School of Medicine, National University of Singapore, Singapore, Singapore
- NUS Centre for Cancer Research (N2CR), National University of Singapore, Singapore, Singapore
- National University Cancer Institute, NUHS, Singapore, Singapore
- ISEP, NUS Graduate School, National University of Singapore, Singapore, Singapore
| | - Marcus E Peter
- Department of Medicine, Division Hematology/Oncology, Northwestern University, Chicago, IL, USA
| | - Paolo Pinton
- Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Giovanni Porta
- Center of Genomic Medicine, Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Jochen H M Prehn
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland (RCSI) University of Medicine and Health Sciences, Dublin 2, Ireland
| | - Hamsa Puthalakath
- Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC, Australia
| | - Gabriel A Rabinovich
- Laboratorio de Glicomedicina. Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | | | - Kodi S Ravichandran
- VIB-UGent Center for Inflammation Research, Ghent, Belgium
- Division of Immunobiology, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
- Center for Cell Clearance, Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA, USA
| | - Markus Rehm
- Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany
| | - Jean-Ehrland Ricci
- Université Côte d'Azur, INSERM, C3M, Equipe labellisée Ligue Contre le Cancer, Nice, France
| | - Rosario Rizzuto
- Department of Biomedical Sciences, University of Padua, Padua, Italy
| | - Nirmal Robinson
- Centre for Cancer Biology, University of South Australia, Adelaide, SA, Australia
| | - Cecilia M P Rodrigues
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Barak Rotblat
- Department of Life sciences, Ben Gurion University of the Negev, Beer Sheva, Israel
- The NIBN, Beer Sheva, Israel
| | - Carla V Rothlin
- Department of Immunobiology and Department of Pharmacology, Yale School of Medicine, New Haven, CT, USA
| | - David C Rubinsztein
- Department of Medical Genetics, Cambridge Institute for Medical Research, Cambridge, UK
- UK Dementia Research Institute, University of Cambridge, Cambridge Institute for Medical Research, Cambridge, UK
| | - Thomas Rudel
- Microbiology Biocentre, University of Würzburg, Würzburg, Germany
| | - Alessandro Rufini
- Dipartimento di Bioscienze, Università degli Studi di Milano, Milano, Italy
- University of Leicester, Leicester Cancer Research Centre, Leicester, UK
| | - Kevin M Ryan
- School of Cancer Sciences, University of Glasgow, Glasgow, UK
- Cancer Research UK Beatson Institute, Glasgow, UK
| | - Kristopher A Sarosiek
- John B. Little Center for Radiation Sciences, Harvard School of Public Health, Boston, MA, USA
- Department of Systems Biology, Lab of Systems Pharmacology, Harvard Program in Therapeutics Science, Harvard Medical School, Boston, MA, USA
- Department of Environmental Health, Molecular and Integrative Physiological Sciences Program, Harvard School of Public Health, Boston, MA, USA
| | - Akira Sawa
- Johns Hopkins Schizophrenia Center, Johns Hopkins University, Baltimore, MD, USA
| | - Emre Sayan
- Faculty of Medicine, Cancer Sciences Unit, University of Southampton, Southampton, UK
| | - Kate Schroder
- Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia
| | - Luca Scorrano
- Department of Biology, University of Padua, Padua, Italy
- Veneto Institute of Molecular Medicine, Padua, Italy
| | - Federico Sesti
- Department of Neuroscience and Cell Biology, Robert Wood Johnson Medical School, Rutgers University, NJ, USA
| | - Feng Shao
- National Institute of Biological Sciences, Beijing, PR China
| | - Yufang Shi
- Department of Experimental Medicine, University of Rome Tor Vergata, TOR, Rome, Italy
- The Third Affiliated Hospital of Soochow University and State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University, Suzhou, Jiangsu, China
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China
| | - Giuseppe S Sica
- Department of Surgical Science, University Tor Vergata, Rome, Italy
| | - John Silke
- The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
- Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia
| | - Hans-Uwe Simon
- Institute of Pharmacology, University of Bern, Bern, Switzerland
- Institute of Biochemistry, Brandenburg Medical School, Neuruppin, Germany
| | - Antonella Sistigu
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | | | - Brent R Stockwell
- Department of Biological Sciences and Department of Chemistry, Columbia University, New York, NY, USA
| | - Flavie Strapazzon
- IRCCS Fondazione Santa Lucia, Rome, Italy
- Univ Lyon, Univ Lyon 1, Physiopathologie et Génétique du Neurone et du Muscle, UMR5261, U1315, Institut NeuroMyogène CNRS, INSERM, Lyon, France
| | - Andreas Strasser
- The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
- Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia
| | - Liming Sun
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
| | - Erwei Sun
- Department of Rheumatology and Immunology, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China
| | - Qiang Sun
- Laboratory of Cell Engineering, Institute of Biotechnology, Beijing, China
- Research Unit of Cell Death Mechanism, 2021RU008, Chinese Academy of Medical Science, Beijing, China
| | - Gyorgy Szabadkai
- Department of Biomedical Sciences, University of Padua, Padua, Italy
- Department of Cell and Developmental Biology, Consortium for Mitochondrial Research, University College London, London, UK
| | - Stephen W G Tait
- School of Cancer Sciences, University of Glasgow, Glasgow, UK
- Cancer Research UK Beatson Institute, Glasgow, UK
| | - Daolin Tang
- Department of Surgery, The University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Nektarios Tavernarakis
- Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Heraklion, Crete, Greece
- Department of Basic Sciences, School of Medicine, University of Crete, Heraklion, Crete, Greece
| | - Carol M Troy
- Departments of Pathology & Cell Biology and Neurology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY, USA
| | - Boris Turk
- Department of Biochemistry and Molecular and Structural Biology, J. Stefan Institute, Ljubljana, Slovenia
- Faculty of Chemistry and Chemical Technology, University of Ljubljana, Ljubljana, Slovenia
| | - Nicoletta Urbano
- Department of Oncohaematology, University of Rome Tor Vergata, TOR, Rome, Italy
| | - Peter Vandenabeele
- VIB-UGent Center for Inflammation Research, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
- Methusalem Program, Ghent University, Ghent, Belgium
| | - Tom Vanden Berghe
- VIB-UGent Center for Inflammation Research, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
- Infla-Med Centre of Excellence, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium
| | - Matthew G Vander Heiden
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
- Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA
- Dana-Farber Cancer Institute, Boston, MA, USA
| | | | - Alexei Verkhratsky
- Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
- Achucarro Center for Neuroscience, IKERBASQUE, Bilbao, Spain
- School of Forensic Medicine, China Medical University, Shenyang, China
- State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania
| | - Andreas Villunger
- Institute for Developmental Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria
- The Research Center for Molecular Medicine (CeMM) of the Austrian Academy of Sciences (OeAW), Vienna, Austria
- The Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI-RUD), Vienna, Austria
| | - Silvia von Karstedt
- Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
- CECAD Cluster of Excellence, University of Cologne, Cologne, Germany
- Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| | - Anne K Voss
- The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
- Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia
| | | | - Domagoj Vucic
- Department of Early Discovery Biochemistry, Genentech, South San Francisco, CA, USA
| | - Daniela Vuri
- Department of Experimental Medicine, University of Rome Tor Vergata, TOR, Rome, Italy
| | - Erwin F Wagner
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Henning Walczak
- Center for Biochemistry, Medical Faculty, University of Cologne, Cologne, Germany
- CECAD Cluster of Excellence, University of Cologne, Cologne, Germany
- Centre for Cell Death, Cancer and Inflammation, UCL Cancer Institute, University College London, London, UK
| | - David Wallach
- Department of Biomolecular Sciences, The Weizmann Institute of Science, Rehovot, Israel
| | - Ruoning Wang
- Center for Childhood Cancer and Blood Diseases, Abigail Wexner Research Institute at Nationwide Children's Hospital, The Ohio State University, Columbus, OH, USA
| | - Ying Wang
- Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China
| | - Achim Weber
- University of Zurich and University Hospital Zurich, Department of Pathology and Molecular Pathology, Zurich, Switzerland
- University of Zurich, Institute of Molecular Cancer Research, Zurich, Switzerland
| | - Will Wood
- Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Takahiro Yamazaki
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA
| | - Huang-Tian Yang
- Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China
| | - Zahra Zakeri
- Queens College and Graduate Center, City University of New York, Flushing, NY, USA
| | - Joanna E Zawacka-Pankau
- Department of Medicine Huddinge, Karolinska Institute, Stockholm, Sweden
- Department of Biochemistry, Laboratory of Biophysics and p53 protein biology, Medical University of Warsaw, Warsaw, Poland
| | - Lin Zhang
- Department of Pharmacology & Chemical Biology, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Haibing Zhang
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China
| | - Boris Zhivotovsky
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
- Faculty of Medicine, Lomonosov Moscow State University, Moscow, Russia
| | - Wenzhao Zhou
- Laboratory of Cell Engineering, Institute of Biotechnology, Beijing, China
- Research Unit of Cell Death Mechanism, 2021RU008, Chinese Academy of Medical Science, Beijing, China
| | - Mauro Piacentini
- Department of Biology, University of Rome Tor Vergata, Rome, Italy
- National Institute for Infectious Diseases IRCCS "Lazzaro Spallanzani", Rome, Italy
| | - Guido Kroemer
- Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Center, Université Paris Saclay, Villejuif, France
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France
- Institut du Cancer Paris CARPEM, Department of Biology, Hôpital Européen Georges Pompidou, AP-HP, Paris, France
| | - Lorenzo Galluzzi
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA.
- Sandra and Edward Meyer Cancer Center, New York, NY, USA.
- Caryl and Israel Englander Institute for Precision Medicine, New York, NY, USA.
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15
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Jacquemin V, Versbraegen N, Duerinckx S, Massart A, Soblet J, Perazzolo C, Deconinck N, Brischoux-Boucher E, De Leener A, Revencu N, Janssens S, Moorgat S, Blaumeiser B, Avela K, Touraine R, Abou Jaoude I, Keymolen K, Saugier-Veber P, Lenaerts T, Abramowicz M, Pirson I. Congenital hydrocephalus: new Mendelian mutations and evidence for oligogenic inheritance. Hum Genomics 2023; 17:16. [PMID: 36859317 PMCID: PMC9979489 DOI: 10.1186/s40246-023-00464-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Accepted: 02/22/2023] [Indexed: 03/03/2023] Open
Abstract
BACKGROUND Congenital hydrocephalus is characterized by ventriculomegaly, defined as a dilatation of cerebral ventricles, and thought to be due to impaired cerebrospinal fluid (CSF) homeostasis. Primary congenital hydrocephalus is a subset of cases with prenatal onset and absence of another primary cause, e.g., brain hemorrhage. Published series report a Mendelian cause in only a minority of cases. In this study, we analyzed exome data of PCH patients in search of novel causal genes and addressed the possibility of an underlying oligogenic mode of inheritance for PCH. MATERIALS AND METHODS We sequenced the exome in 28 unrelated probands with PCH, 12 of whom from families with at least two affected siblings and 9 of whom consanguineous, thereby increasing the contribution of genetic causes. Patient exome data were first analyzed for rare (MAF < 0.005) transmitted or de novo variants. Population stratification of unrelated PCH patients and controls was determined by principle component analysis, and outliers identified using Mahalanobis distance 5% as cutoff. Patient and control exome data for genes biologically related to cilia (SYScilia database) were analyzed by mutation burden test. RESULTS In 18% of probands, we identify a causal (pathogenic or likely pathogenic) variant of a known hydrocephalus gene, including genes for postnatal, syndromic hydrocephalus, not previously reported in isolated PCH. In a further 11%, we identify mutations in novel candidate genes. Through mutation burden tests, we demonstrate a significant burden of genetic variants in genes coding for proteins of the primary cilium in PCH patients compared to controls. CONCLUSION Our study confirms the low contribution of Mendelian mutations in PCH and reports PCH as a phenotypic presentation of some known genes known for syndromic, postnatal hydrocephalus. Furthermore, this study identifies novel Mendelian candidate genes, and provides evidence for oligogenic inheritance implicating primary cilia in PCH.
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Affiliation(s)
- Valerie Jacquemin
- Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Université Libre de Bruxelles, Brussels, Belgium.
| | - Nassim Versbraegen
- grid.4989.c0000 0001 2348 0746Interuniversity Institute of Bioinformatics in Brussels, Université Libre de Bruxelles-Vrije Universiteit Brussel, Brussels, Belgium ,grid.4989.c0000 0001 2348 0746Machine Learning Group, Université Libre de Bruxelles, Brussels, Belgium
| | - Sarah Duerinckx
- grid.4989.c0000 0001 2348 0746Service de Neuropédiatrie, Hôpital Universitaire de Bruxelles and CUB Hôpital Erasme and Université Libre de Bruxelles, Brussels, Belgium
| | - Annick Massart
- grid.4989.c0000 0001 2348 0746Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Université Libre de Bruxelles, Brussels, Belgium ,grid.411414.50000 0004 0626 3418Department of Nephrology, University Hospital of Antwerp, Edegem, Belgium
| | - Julie Soblet
- grid.412157.40000 0000 8571 829XHuman Genetics Department, CUB Hôpital Erasme, Brussels, Belgium
| | - Camille Perazzolo
- grid.4989.c0000 0001 2348 0746Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Université Libre de Bruxelles, Brussels, Belgium
| | - Nicolas Deconinck
- grid.412209.c0000 0004 0578 1002Hopital Universitaire des Enfants Reine Fabiola and Hopital Universitaire de Bruxelles and Université Libre de Bruxelles, Brussels, Belgium
| | - Elise Brischoux-Boucher
- grid.493090.70000 0004 4910 6615Centre de génétique humaine - CHU de Besançon, Université de Bourgogne-Franche-Comté, Besançon, France
| | - Anne De Leener
- grid.48769.340000 0004 0461 6320Centre de Génétique Humaine, Cliniques Universitaires Saint-Luc et Université Catholique de Louvain, Brussels, Belgium
| | - Nicole Revencu
- grid.48769.340000 0004 0461 6320Centre de Génétique Humaine, Cliniques Universitaires Saint-Luc et Université Catholique de Louvain, Brussels, Belgium
| | - Sandra Janssens
- grid.410566.00000 0004 0626 3303Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium
| | - Stèphanie Moorgat
- grid.452439.d0000 0004 0578 0894Centre de Génétique Humaine, Institut de Pathologie et de Génétique, Gosselies, Belgium
| | - Bettina Blaumeiser
- grid.411414.50000 0004 0626 3418Center of Medical Genetics, Antwerp University and Antwerp University Hospital, Edegem, Belgium
| | - Kristiina Avela
- grid.15485.3d0000 0000 9950 5666Department of Clinical Genetics, Helsinki University Hospital, Helsinki, Finland
| | - Renaud Touraine
- grid.412954.f0000 0004 1765 1491Génétique Clinique Chromosomique et Moléculaire, CHU de Saint-Etienne, St-Priest-en-Jarez, France
| | - Imad Abou Jaoude
- Department of Gynecology and Obstetrics, Abou Jaoude Hospital, Jal El Dib, Lebanon
| | - Kathelijn Keymolen
- grid.411326.30000 0004 0626 3362Center for Medical Genetics, UZ Brussels, Jette, Belgium
| | - Pascale Saugier-Veber
- grid.10400.350000 0001 2108 3034Department of Genetics and Reference Center for Developmental Disorders, Université Rouen Normandie, Inserm U1245 and CHU Rouen, Rouen, France
| | - Tom Lenaerts
- grid.4989.c0000 0001 2348 0746Interuniversity Institute of Bioinformatics in Brussels, Université Libre de Bruxelles-Vrije Universiteit Brussel, Brussels, Belgium ,grid.4989.c0000 0001 2348 0746Machine Learning Group, Université Libre de Bruxelles, Brussels, Belgium ,grid.8767.e0000 0001 2290 8069Artificial Intelligence Lab, Vrije Universiteit Brussel, Brussels, Belgium
| | - Marc Abramowicz
- Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Université Libre de Bruxelles, Brussels, Belgium. .,Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland.
| | - Isabelle Pirson
- grid.4989.c0000 0001 2348 0746Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Université Libre de Bruxelles, Brussels, Belgium
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16
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Mitochondrial DNA in cell death and inflammation. Biochem Soc Trans 2023; 51:457-472. [PMID: 36815695 PMCID: PMC9988000 DOI: 10.1042/bst20221525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 02/02/2023] [Accepted: 02/03/2023] [Indexed: 02/24/2023]
Abstract
Cytosolic DNA is recognized by the innate immune system as a potential threat. During apoptotic cell death, mitochondrial DNA (mtDNA) release activates the DNA sensor cyclic GMP-AMP synthase (cGAS) to promote a pro-inflammatory type I interferon response. Inflammation following mtDNA release during apoptotic cell death can be exploited to engage anti-tumor immunity and represents a potential avenue for cancer therapy. Additionally, various studies have described leakage of mtDNA, independent of cell death, with different underlying cues such as pathogenic infections, changes in mtDNA packaging, mtDNA stress or reduced mitochondrial clearance. The interferon response in these scenarios can be beneficial but also potentially disadvantageous, as suggested by a variety of disease phenotypes. In this review, we discuss mechanisms underlying mtDNA release governed by cell death pathways and summarize release mechanisms independent of cell death. We further highlight the similarities and differences in mtDNA release pathways, outlining gaps in our knowledge and questions for further research. Together, a deeper understanding of how and when mtDNA is released may enable the development of drugs to specifically target or inhibit mtDNA release in different disease settings.
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17
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Moriizumi H, Kubota Y, Tsuchiya T, Naka R, Takekawa M. Caspase 3-specific cleavage of MEK1 suppresses ERK signaling and sensitizes cells to stress-induced apoptosis. FEBS Open Bio 2023; 13:684-700. [PMID: 36776127 PMCID: PMC10068311 DOI: 10.1002/2211-5463.13574] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 01/30/2023] [Accepted: 02/10/2023] [Indexed: 02/14/2023] Open
Abstract
Proper regulation of apoptotic cell death is crucial for normal development and homeostasis in multicellular organisms and is achieved by the balance between pro-apoptotic processes, such as caspase activation, and pro-survival signaling, such as extracellular signal-regulated kinase (ERK) activation. However, the functional interplay between these opposing signaling pathways remains incompletely understood. Here, we identified MAPK/ERK kinase (MEK) 1, a central component of the ERK pathway, as a specific substrate for the executioner caspase-3. During apoptosis, MEK1 is cleaved at an evolutionarily conserved Asp282 residue in the kinase domain, thereby losing its catalytic activity. Gene knockout experiments showed that MEK1 cleavage was mediated by caspase-3, but not by the other executioner caspases, caspase-6 or -7. Following exposure of cells to osmotic stress, elevated ERK activity gradually decreased, and this was accompanied by increased cleavage of MEK1. In contrast, the expression of a caspase-uncleavable MEK1(D282N) mutant in cells maintained stress-induced ERK activity and thereby attenuated apoptotic cell death. Thus, caspase-3-mediated, proteolytic inhibition of MEK1 sensitizes cells to apoptosis by suppressing pro-survival ERK signaling. Furthermore, we found that a RASopathy-associated MEK1(Y130C) mutation prevented this caspase-3-mediated proteolytic inactivation of MEK1 and efficiently protected cells from stress-induced apoptosis. Our data reveal the functional crosstalk between ERK-mediated cell survival and caspase-mediated cell death pathways and suggest that its dysregulation by a disease-associated MEK1 mutation is at least partly involved in the pathophysiology of congenital RASopathies.
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Affiliation(s)
- Hisashi Moriizumi
- Division of Cell Signaling and Molecular Medicine, Institute of Medical Science, The University of Tokyo, Japan.,Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan
| | - Yuji Kubota
- Division of Cell Signaling and Molecular Medicine, Institute of Medical Science, The University of Tokyo, Japan
| | - Tomoyuki Tsuchiya
- Division of Cell Signaling and Molecular Medicine, Institute of Medical Science, The University of Tokyo, Japan
| | - Ryosuke Naka
- Division of Cell Signaling and Molecular Medicine, Institute of Medical Science, The University of Tokyo, Japan
| | - Mutsuhiro Takekawa
- Division of Cell Signaling and Molecular Medicine, Institute of Medical Science, The University of Tokyo, Japan.,Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan
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18
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Sener EF, Dana H, Tahtasakal R, Hamurcu Z, Guler A, Tufan E, Doganyigit Z, Rassoulzadegan M. Partial changes in apoptotic pathways in hippocampus and hypothalamus of Cc2d1a heterozygous. Metab Brain Dis 2023; 38:531-541. [PMID: 36454503 DOI: 10.1007/s11011-022-01125-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Accepted: 11/10/2022] [Indexed: 12/02/2022]
Abstract
Alterations in the apoptosis pathway have been linked to changes in serotonin levels seen in autistic patients. Cc2d1a is a repressor of the HTR1A gene involved in the serotonin pathway. The hippocampus and hypothalamus of Cc2d1a ± mice were analyzed for the expression of apoptosis markers (caspase 3, 8 and 9). Gender differences were observed in the expression levels of the three caspases consistent with some altered activity in the open-field assay. The number of apoptotic cells was significantly increased. We concluded that apoptotic pathways are only partially affected in the pathogenesis of the Cc2d1a heterozygous mouse model. A) Apoptosis is suppressed because the cell does not receive a death signal, or the receptor cannot activate the caspase 8 pathway despite the death signal. B) Since Caspase 8 and Caspase 3 expression is downregulated in our mouse model, the mechanism of apoptosis is not activated.
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Affiliation(s)
- Elif Funda Sener
- Department of Medical Biology, Erciyes University Medical Faculty, 38039, Kayseri, Turkey.
- Erciyes University Genome and Stem Cell Center (GENKOK), Kayseri, Turkey.
| | - Halime Dana
- Department of Medical Biology, Erciyes University Medical Faculty, 38039, Kayseri, Turkey
- Erciyes University Genome and Stem Cell Center (GENKOK), Kayseri, Turkey
| | - Reyhan Tahtasakal
- Department of Medical Biology, Erciyes University Medical Faculty, 38039, Kayseri, Turkey
- Erciyes University Genome and Stem Cell Center (GENKOK), Kayseri, Turkey
| | - Zuhal Hamurcu
- Department of Medical Biology, Erciyes University Medical Faculty, 38039, Kayseri, Turkey
- Erciyes University Genome and Stem Cell Center (GENKOK), Kayseri, Turkey
| | - Ahsen Guler
- Department of Medical Biology, Erciyes University Medical Faculty, 38039, Kayseri, Turkey
- Erciyes University Genome and Stem Cell Center (GENKOK), Kayseri, Turkey
| | - Esra Tufan
- Erciyes University Genome and Stem Cell Center (GENKOK), Kayseri, Turkey
| | - Zuleyha Doganyigit
- Department of Histology and Embryology, Bozok University Medical Faculty, 66100, Yozgat, Turkey
| | - Minoo Rassoulzadegan
- Erciyes University Genome and Stem Cell Center (GENKOK), Kayseri, Turkey
- INSERM-CNRS, IRCAN, Universite Cote d'Azur (UCA), 06107, Nice, France
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19
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Svandova E, Lesot H, Sharpe P, Matalova E. Making the head: Caspases in life and death. Front Cell Dev Biol 2023; 10:1075751. [PMID: 36712975 PMCID: PMC9880857 DOI: 10.3389/fcell.2022.1075751] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Accepted: 12/29/2022] [Indexed: 01/14/2023] Open
Abstract
The term apoptosis, as a way of programmed cell death, was coined a half century ago and since its discovery the process has been extensively investigated. The anatomy and physiology of the head are complex and thus apoptosis has mostly been followed in separate structures, tissues or cell types. This review aims to provide a comprehensive overview of recent knowledge concerning apoptosis-related molecules involved in the development of structures of head with a particular focus on caspases, cysteine proteases having a key position in apoptotic pathways. Since many classical apoptosis-related molecules, including caspases, are emerging in several non-apoptotic processes, these were also considered. The largest organ of the head region is the brain and its development has been extensively investigated, including the roles of apoptosis and related molecules. Neurogenesis research also includes sensory organs such as the eye and ear, efferent nervous system and associated muscles and glands. Caspases have been also associated with normal function of the skin and hair follicles. Regarding mineralised tissues within craniofacial morphogenesis, apoptosis in bones has been of interest along with palate fusion and tooth development. Finally, the role of apoptosis and caspases in angiogenesis, necessary for any tissue/organ development and maintenance/homeostasis, are discussed. Additionally, this review points to abnormalities of development resulting from improper expression/activation of apoptosis-related molecules.
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Affiliation(s)
- Eva Svandova
- Faculty of Medicine, Masaryk University, Brno, Czechia
| | - Herve Lesot
- Institute of Animal Physiology and Genetics, Czech Academy of Sciences, Brno, Czechia
| | - Paul Sharpe
- Institute of Animal Physiology and Genetics, Czech Academy of Sciences, Brno, Czechia
- Centre for Craniofacial and Regenerative Biology, Faculty of Dentistry, Oral, and Craniofacial Sciences, King’s College London, London, United Kingdom
| | - Eva Matalova
- Department of Physiology, University of Veterinary Sciences, Brno, Czechia
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20
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Unnisa A, Greig NH, Kamal MA. Inhibition of Caspase 3 and Caspase 9 Mediated Apoptosis: A Multimodal Therapeutic Target in Traumatic Brain Injury. Curr Neuropharmacol 2023; 21:1001-1012. [PMID: 35339178 PMCID: PMC10227914 DOI: 10.2174/1570159x20666220327222921] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 02/17/2022] [Accepted: 03/23/2022] [Indexed: 02/08/2023] Open
Abstract
Traumatic brain injury (TBI) is one of the significant causes of death and morbidity, and it is hence a focus of translational research. Apoptosis plays an essential part in the pathophysiology of TBI, and its inhibition may help overcome TBI's negative consequences and improve functional recovery. Although physiological neuronal death is necessary for appropriate embryologic development and adult cell turnover, it can also drive neurodegeneration. Caspases are principal mediators of cell death due to apoptosis and are critical for the required cleavage of intracellular proteins of cells committed to die. Caspase-3 is the major executioner Caspase of apoptosis and is regulated by a range of cellular components during physiological and pathological conditions. Activation of Caspase-3 causes proteolyzation of DNA repair proteins, cytoskeletal proteins, and the inhibitor of Caspase-activated DNase (ICAD) during programmed cell death, resulting in morphological alterations and DNA damage that define apoptosis. Caspase-9 is an additional crucial part of the intrinsic pathway, activated in response to several stimuli. Caspases can be altered post-translationally or by modulatory elements interacting with the zymogenic or active form of a Caspase, preventing their activation. The necessity of Caspase-9 and -3 in diverse apoptotic situations suggests that mammalian cells have at least four distinct apoptotic pathways. Continued investigation of these processes is anticipated to disclose new Caspase regulatory mechanisms with consequences far beyond apoptotic cell death control. The present review discusses various Caspase-dependent apoptotic pathways and the treatment strategies to inhibit the Caspases potentially.
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Affiliation(s)
- Aziz Unnisa
- Department of Pharmacology, College of Pharmacy, University of Hail, Hail, KSA;
| | - Nigel H. Greig
- Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
| | - Mohammad Amjad Kamal
- Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
- King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka, Bangladesh
- Enzymoics, 7 Peterlee Place, Hebersham, NSW 2770; Novel Global Community Educational Foundation, NSW, Australia
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21
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Wiegreffe C, Wahl T, Joos NS, Bonnefont J, Liu P, Britsch S. Developmental cell death of cortical projection neurons is controlled by a Bcl11a/Bcl6‐dependent pathway. EMBO Rep 2022; 23:e54104. [PMID: 35766181 PMCID: PMC9346488 DOI: 10.15252/embr.202154104] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Revised: 05/31/2022] [Accepted: 06/08/2022] [Indexed: 12/05/2022] Open
Abstract
Developmental neuron death plays a pivotal role in refining organization and wiring during neocortex formation. Aberrant regulation of this process results in neurodevelopmental disorders including impaired learning and memory. Underlying molecular pathways are incompletely determined. Loss of Bcl11a in cortical projection neurons induces pronounced cell death in upper‐layer cortical projection neurons during postnatal corticogenesis. We use this genetic model to explore genetic mechanisms by which developmental neuron death is controlled. Unexpectedly, we find Bcl6, previously shown to be involved in the transition of cortical neurons from progenitor to postmitotic differentiation state to provide a major checkpoint regulating neuron survival during late cortical development. We show that Bcl11a is a direct transcriptional regulator of Bcl6. Deletion of Bcl6 exerts death of cortical projection neurons. In turn, reintroduction of Bcl6 into Bcl11a mutants prevents induction of cell death in these neurons. Together, our data identify a novel Bcl11a/Bcl6‐dependent molecular pathway in regulation of developmental cell death during corticogenesis.
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Affiliation(s)
| | - Tobias Wahl
- Institute of Molecular and Cellular Anatomy Ulm University Ulm Germany
| | | | - Jerome Bonnefont
- Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), and ULB Neuroscience Institute (UNI) Université Libre de Bruxelles (ULB) Brussels Belgium
- VIB‐KU Leuven Center for Brain & Disease Research, KU Leuven Department of Neuroscience Leuven Brain Institute Leuven Belgium
| | - Pentao Liu
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine The University of Hong Kong Hong Kong China
| | - Stefan Britsch
- Institute of Molecular and Cellular Anatomy Ulm University Ulm Germany
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22
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Nozaki K, Maltez VI, Rayamajhi M, Tubbs AL, Mitchell JE, Lacey CA, Harvest CK, Li L, Nash WT, Larson HN, McGlaughon BD, Moorman NJ, Brown MG, Whitmire JK, Miao EA. Caspase-7 activates ASM to repair gasdermin and perforin pores. Nature 2022; 606:960-967. [PMID: 35705808 PMCID: PMC9247046 DOI: 10.1038/s41586-022-04825-8] [Citation(s) in RCA: 77] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Accepted: 04/29/2022] [Indexed: 12/15/2022]
Abstract
Among the caspases that cause regulated cell death, a unique function for caspase-7 has remained elusive. Caspase-3 performs apoptosis, whereas caspase-7 is typically considered an inefficient back-up. Caspase-1 activates gasdermin D pores to lyse the cell; however, caspase-1 also activates caspase-7 for unknown reasons1. Caspases can also trigger cell-type-specific death responses; for example, caspase-1 causes the extrusion of intestinal epithelial cell (IECs) in response to infection with Salmonella enterica subsp. enterica serovar Typhimurium (S. Typhimurium)2,3. Here we show in both organoids and mice that caspase-7-deficient IECs do not complete extrusion. Mechanistically, caspase-7 counteracts gasdermin D pores and preserves cell integrity by cleaving and activating acid sphingomyelinase (ASM), which thereby generates copious amounts of ceramide to enable enhanced membrane repair. This provides time to complete the process of IEC extrusion. In parallel, we also show that caspase-7 and ASM cleavage are required to clear Chromobacterium violaceum and Listeria monocytogenes after perforin-pore-mediated attack by natural killer cells or cytotoxic T lymphocytes, which normally causes apoptosis in infected hepatocytes. Therefore, caspase-7 is not a conventional executioner but instead is a death facilitator that delays pore-driven lysis so that more-specialized processes, such as extrusion or apoptosis, can be completed before cell death. Cells must put their affairs in order before they die.
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Affiliation(s)
- Kengo Nozaki
- Department of Immunology, Duke University School of Medicine, Durham, NC, USA
- Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, USA
| | - Vivien I Maltez
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Manira Rayamajhi
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Alan L Tubbs
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Joseph E Mitchell
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Carolyn A Lacey
- Department of Immunology, Duke University School of Medicine, Durham, NC, USA
- Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, USA
| | - Carissa K Harvest
- Department of Immunology, Duke University School of Medicine, Durham, NC, USA
- Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, USA
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Lupeng Li
- Department of Immunology, Duke University School of Medicine, Durham, NC, USA
- Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, USA
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - William T Nash
- Department of Medicine, Division of Nephrology and the Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, USA
| | - Heather N Larson
- Department of Immunology, Duke University School of Medicine, Durham, NC, USA
- Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, USA
| | - Benjamin D McGlaughon
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Nathaniel J Moorman
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Michael G Brown
- Department of Medicine, Division of Nephrology and the Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, USA
| | - Jason K Whitmire
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Edward A Miao
- Department of Immunology, Duke University School of Medicine, Durham, NC, USA.
- Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, USA.
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23
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Activation of TGR5 Ameliorates Streptozotocin-Induced Cognitive Impairment by Modulating Apoptosis, Neurogenesis, and Neuronal Firing. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:3716609. [PMID: 35464765 PMCID: PMC9033389 DOI: 10.1155/2022/3716609] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 01/03/2022] [Accepted: 03/08/2022] [Indexed: 12/15/2022]
Abstract
Takeda G protein-coupled receptor 5 (TGR5) is the first known G protein-coupled receptor specific for bile acids and is recognized as a new and critical target for type 2 diabetes and metabolic syndrome. It is expressed in many brain regions associated with memory such as the hippocampus and frontal cortex. Here, we hypothesize that activation of TGR5 may ameliorate streptozotocin- (STZ-) induced cognitive impairment. The mouse model of cognitive impairment was established by a single intracerebroventricular (ICV) injection of STZ (3.0 mg/kg), and we found that TGR5 activation by its agonist INT-777 (1.5 or 3.0 μg/mouse, ICV injection) ameliorated spatial memory impairment in the Morris water maze and Y-maze tests. Importantly, INT-777 reversed STZ-induced downregulation of TGR5 and glucose usage deficits. Our results further showed that INT-777 suppressed neuronal apoptosis and improved neurogenesis which were involved in tau phosphorylation and CREB-BDNF signaling. Moreover, INT-777 increased action potential firing of excitatory pyramidal neurons in the hippocampal CA3 and medial prefrontal cortex of ICV-STZ groups. Taken together, these findings reveal that activation of TGR5 has a neuroprotective effect against STZ-induced cognitive impairment by modulating apoptosis, neurogenesis, and neuronal firing in the brain and TGR5 might be a novel and potential target for Alzheimer's disease.
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24
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Iberg CA, Bourque J, Fallahee I, Son S, Hawiger D. TNF-α sculpts a maturation process in vivo by pruning tolerogenic dendritic cells. Cell Rep 2022; 39:110657. [PMID: 35417681 PMCID: PMC9113652 DOI: 10.1016/j.celrep.2022.110657] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 02/16/2022] [Accepted: 03/18/2022] [Indexed: 12/12/2022] Open
Abstract
It remains unclear how the pro-immunogenic maturation of conventional dendritic cells (cDCs) abrogates their tolerogenic functions. Here, we report that the loss of tolerogenic functions depends on the rapid death of BTLAhi cDC1s, which, in the steady state, are present in systemic peripheral lymphoid organs and promote tolerance that limits subsequent immune responses. A canonical inducer of maturation, lipopolysaccharide (LPS), initiates a burst of tumor necrosis factor alpha (TNF-α) production and the resultant acute death of BTLAhi cDC1s mediated by tumor necrosis factor receptor 1. The ablation of these individual tolerogenic cDCs is amplified by TNF-α produced by neighboring cells. This loss of tolerogenic cDCs is transient, accentuating the restoration of homeostatic conditions through biological turnover of cDCs in vivo. Therefore, our results reveal that the abrogation of tolerogenic functions during an acute immunogenic maturation depends on an ablation of the tolerogenic cDC population, resulting in a dynamic remodeling of the cDC functional landscape.
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Affiliation(s)
- Courtney A Iberg
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO, USA
| | - Jessica Bourque
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO, USA
| | - Ian Fallahee
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO, USA
| | - Sungho Son
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO, USA
| | - Daniel Hawiger
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO, USA.
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25
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Wang Q, Li Y, Tan H, Wang Y. Sevoflurane-Induced Apoptosis in the Mouse Cerebral Cortex Follows Similar Characteristics of Physiological Apoptosis. Front Mol Neurosci 2022; 15:873658. [PMID: 35465098 PMCID: PMC9024292 DOI: 10.3389/fnmol.2022.873658] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Accepted: 03/17/2022] [Indexed: 11/13/2022] Open
Abstract
General anesthetics are capable of inducing neuronal apoptosis during the rapid synaptogenesis of immature mammalian brains. In this vulnerable time window, physiological apoptosis also occurs to eliminate excess and inappropriately integrated neurons. We previously showed that physiological and ketamine-induced apoptosis in mouse primary somatosensory cortex (S1) followed similar developmental patterns. However, since sevoflurane is more widely used in pediatric anesthesia, and targets mainly on different receptors, as compared with ketamine, it is important to determine whether sevoflurane-induced apoptosis also follows similar developmental patterns as physiological apoptosis or not. Mice at postnatal days 5 (P5) and P9 were anesthetized with 1.5% sevoflurane for 4 h, and the apoptotic neurons in S1 were quantitated by immunohistochemistry. The results showed that sevoflurane raised the levels of apoptosis in S1 without interfering with the developmental patterns of physiological apoptosis. The cells more vulnerable to both physiological and sevoflurane-induced apoptosis shifted from layer V pyramidal neurons at P5 to layers II–IV GABAergic neurons by P9. The magnitude of both sevoflurane-induced and physiological apoptosis was more attenuated at P9 than P5. To determine whether the Akt-FoxO1-PUMA pathway contributes to the developmental decrease in magnitude of both physiological and sevoflurane-induced apoptosis, Western blot was used to measure the levels of related proteins in S1 of P5 and P9 mice. We observed higher levels of antiapoptotic phosphorylated Akt (p-Akt) and phosphorylated FoxO1 (p-FoxO1), and lower levels of the downstream proapoptotic factor PUMA in control and anesthetized mice at P9 than P5. In addition, the Akt-FoxO1-PUMA pathway may also be responsible for sevoflurane-induced apoptosis. Together, these results suggest that magnitude, lamination pattern and cell-type specificity to sevoflurane-induced apoptosis are age-dependent and follow physiological apoptosis pattern. Moreover, The Akt-FoxO1-PUMA pathway may mediate the developmental decreases in magnitude of both physiological and sevoflurane-induced apoptosis in neonatal mouse S1.
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26
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Qiu R, Sasselli IR, Álvarez Z, Sai H, Ji W, Palmer LC, Stupp SI. Supramolecular Copolymers of Peptides and Lipidated Peptides and Their Therapeutic Potential. J Am Chem Soc 2022; 144:5562-5574. [PMID: 35296133 DOI: 10.1021/jacs.2c00433] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Supramolecular peptide chemistry offers a versatile strategy to create chemical systems useful as new biomaterials with potential to deliver nearly 1000 known candidate peptide therapeutics or integrate other types of bioactivity. We report here on the co-assembly of lipidated β-sheet-forming peptides with soluble short peptides, yielding supramolecular copolymers with various degrees of internal order. At low peptide concentrations, the co-monomer is protected by lodging within internal aqueous compartments and stabilizing internal β-sheets formed by the lipidated peptides. At higher concentrations, the peptide copolymerizes with the lipidated peptide and disrupts the β-sheet secondary structure. The thermodynamic metastability of the co-assembly in turn leads to the spontaneous release of peptide monomers and thus serves as a potential mechanism for drug delivery. We demonstrated the function of these supramolecular systems using a drug candidate for Alzheimer's disease and found that the copolymers enhance neuronal cell viability when the soluble peptide is released from the assemblies.
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Affiliation(s)
- Ruomeng Qiu
- Department of Chemistry, Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208, United States
| | - Ivan R Sasselli
- Department of Chemistry, Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208, United States.,Simpson Querrey Institute for BioNanotechnology, Northwestern University, 303 E. Superior Street, Chicago, Illinois 60611, United States
| | - Zaida Álvarez
- Simpson Querrey Institute for BioNanotechnology, Northwestern University, 303 E. Superior Street, Chicago, Illinois 60611, United States.,Department of Medicine, Northwestern University, 676 N. St. Clair Street, Chicago, Illinois 60611, United States
| | - Hiroaki Sai
- Simpson Querrey Institute for BioNanotechnology, Northwestern University, 303 E. Superior Street, Chicago, Illinois 60611, United States.,Department of Materials Science and Engineering, Northwestern University, 2220 Campus Drive, Evanston, Illinois 60208, United States
| | - Wei Ji
- Simpson Querrey Institute for BioNanotechnology, Northwestern University, 303 E. Superior Street, Chicago, Illinois 60611, United States
| | - Liam C Palmer
- Department of Chemistry, Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208, United States.,Simpson Querrey Institute for BioNanotechnology, Northwestern University, 303 E. Superior Street, Chicago, Illinois 60611, United States
| | - Samuel I Stupp
- Department of Chemistry, Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208, United States.,Simpson Querrey Institute for BioNanotechnology, Northwestern University, 303 E. Superior Street, Chicago, Illinois 60611, United States.,Department of Medicine, Northwestern University, 676 N. St. Clair Street, Chicago, Illinois 60611, United States.,Department of Materials Science and Engineering, Northwestern University, 2220 Campus Drive, Evanston, Illinois 60208, United States.,Department of Biomedical Engineering, Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208, United States
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27
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Roellig D, Theis S, Proag A, Allio G, Bénazéraf B, Gros J, Suzanne M. Force-generating apoptotic cells orchestrate avian neural tube bending. Dev Cell 2022; 57:707-718.e6. [PMID: 35303434 PMCID: PMC8967407 DOI: 10.1016/j.devcel.2022.02.020] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 11/15/2021] [Accepted: 02/22/2022] [Indexed: 12/16/2022]
Abstract
Apoptosis plays an important role in morphogenesis, and the notion that apoptotic cells can impact their surroundings came to light recently. However, how this applies to vertebrate morphogenesis remains unknown. Here, we use the formation of the neural tube to determine how apoptosis contributes to morphogenesis in vertebrates. Neural tube closure defects have been reported when apoptosis is impaired in vertebrates, although the cellular mechanisms involved are unknown. Using avian embryos, we found that apoptotic cells generate an apico-basal force before being extruded from the neuro-epithelium. This force, which relies on a contractile actomyosin cable that extends along the apico-basal axis of the cell, drives nuclear fragmentation and influences the neighboring tissue. Together with the morphological defects observed when apoptosis is prevented, these data strongly suggest that the neuroepithelium keeps track of the mechanical impact of apoptotic cells and that the apoptotic forces, cumulatively, contribute actively to neural tube bending.
Apoptotic cells are force-generating cells in the avian neural tube Apoptotic force drives the upward movement of the nucleus and nuclear fragmentation Apoptotic cells cumulatively impact the neighboring tissue Apoptotic force mechanical impact participates in progressive bending of the neural tube
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Affiliation(s)
- Daniela Roellig
- Centre de Biologie Intégrative, CNRS/UMR 5088, Université Toulouse III, Toulouse, France
| | - Sophie Theis
- Centre de Biologie Intégrative, CNRS/UMR 5088, Université Toulouse III, Toulouse, France; Morphogénie Logiciels, 32110 St Martin d'Armagnac, France
| | - Amsha Proag
- Centre de Biologie Intégrative, CNRS/UMR 5088, Université Toulouse III, Toulouse, France
| | - Guillaume Allio
- Centre de Biologie Intégrative, CNRS/UMR 5088, Université Toulouse III, Toulouse, France
| | - Bertrand Bénazéraf
- Centre de Biologie Intégrative, CNRS/UMR 5088, Université Toulouse III, Toulouse, France
| | - Jérôme Gros
- Institut Pasteur, CNRS/UMR 3738, Paris, France
| | - Magali Suzanne
- Centre de Biologie Intégrative, CNRS/UMR 5088, Université Toulouse III, Toulouse, France.
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28
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Affiliation(s)
- Douglas R Green
- St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA
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29
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Akiyama S, Madan N, Graham G, Samura O, Kitano R, Yun HJ, Craig A, Nakamura T, Hozawa A, Grant E, Im K, Tarui T. Regional brain development in fetuses with Dandy-Walker malformation: A volumetric fetal brain magnetic resonance imaging study. PLoS One 2022; 17:e0263535. [PMID: 35202430 PMCID: PMC8870580 DOI: 10.1371/journal.pone.0263535] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 01/20/2022] [Indexed: 11/18/2022] Open
Abstract
Dandy-Walker malformation (DWM) is a common prenatally diagnosed cerebellar malformation, characterized by cystic dilatation of the fourth ventricle, upward rotation of the hypoplastic vermis, and posterior fossa enlargement with torcular elevation. DWM is associated with a broad spectrum of neurodevelopmental abnormalities such as cognitive, motor, and behavioral impairments, which cannot be explained solely by cerebellar malformations. Notably, the pathogenesis of these symptoms remains poorly understood. This study investigated whether fetal structural developmental abnormalities in DWM extended beyond the posterior fossa to the cerebrum even in fetuses without apparent cerebral anomalies. Post-acquisition volumetric fetal magnetic resonance imaging (MRI) analysis was performed in 12 fetuses with DWM and 14 control fetuses. Growth trajectories of the volumes of the cortical plate, subcortical parenchyma, cerebellar hemispheres, and vermis between 18 and 33 weeks of gestation were compared. The median (interquartile range) gestational ages at the time of MRI were 22.4 (19.4-24.0) and 23.9 (20.6-29.2) weeks in the DWM and control groups, respectively (p = 0.269). Eight of the 12 fetuses with DWM presented with associated cerebral anomalies, including hydrocephalus (n = 3), cerebral ventriculomegaly (n = 3), and complete (n = 2) and partial (n = 2) agenesis of the corpus callosum (ACC); 7 presented with extracerebral abnormalities. Chromosomal abnormalities were detected by microarray analysis in 4 of 11 fetuses with DWM, using amniocentesis. Volumetric analysis revealed that the cortical plate was significantly larger in fetuses with DWM than in controls (p = 0.040). Even without ACC, the subcortical parenchyma, whole cerebrum, cerebellar hemispheres, and whole brain were significantly larger in fetuses with DWM (n = 8) than in controls (p = 0.004, 0.025, 0.033, and 0.026, respectively). In conclusion, volumetric fetal MRI analysis demonstrated that the development of DWM extends throughout the brain during the fetal period, even without apparent cerebral anomalies.
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Affiliation(s)
- Shizuko Akiyama
- Mother Infant Research Institute, Tufts Medical Center, Boston, Massachusetts, United States of America
| | - Neel Madan
- Radiology, Tufts Medical Center, Boston, Massachusetts, United States of America
| | - George Graham
- Obstetrics and Gynecology, Tufts Medical Center, Boston, Massachusetts, United States of America
| | - Osamu Samura
- Obstetrics and Gynecology, Jikei University School of Medicine, Tokyo, Japan
| | - Rie Kitano
- Mother Infant Research Institute, Tufts Medical Center, Boston, Massachusetts, United States of America
| | - Hyuk Jin Yun
- Fetal-Neonatal Neuroimaging and Developmental Science Center, Boston Children’s Hospital, Boston, Massachusetts, United States of America
| | - Alexa Craig
- Pediatric Neurology, Maine Medical Center, Portland, Oregan, United States of America
| | - Tomohiro Nakamura
- Department of Preventive Medicine and Epidemiology, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
| | - Atsushi Hozawa
- Department of Preventive Medicine and Epidemiology, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
| | - Ellen Grant
- Fetal-Neonatal Neuroimaging and Developmental Science Center, Boston Children’s Hospital, Boston, Massachusetts, United States of America
| | - Kiho Im
- Fetal-Neonatal Neuroimaging and Developmental Science Center, Boston Children’s Hospital, Boston, Massachusetts, United States of America
| | - Tomo Tarui
- Mother Infant Research Institute, Tufts Medical Center, Boston, Massachusetts, United States of America
- Pediatric Neurology, Tufts Children’s Hospital, Boston, Massachusetts, United States of America
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30
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Cisplatin toxicity in the developing brain displays an absolute requirement for caspase-3. Exp Neurol 2022; 351:114010. [DOI: 10.1016/j.expneurol.2022.114010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 01/26/2022] [Accepted: 02/08/2022] [Indexed: 11/19/2022]
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31
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Ossola C, Kalebic N. Roots of the Malformations of Cortical Development in the Cell Biology of Neural Progenitor Cells. Front Neurosci 2022; 15:817218. [PMID: 35069108 PMCID: PMC8766818 DOI: 10.3389/fnins.2021.817218] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 12/14/2021] [Indexed: 12/13/2022] Open
Abstract
The cerebral cortex is a structure that underlies various brain functions, including cognition and language. Mammalian cerebral cortex starts developing during the embryonic period with the neural progenitor cells generating neurons. Newborn neurons migrate along progenitors’ radial processes from the site of their origin in the germinal zones to the cortical plate, where they mature and integrate in the forming circuitry. Cell biological features of neural progenitors, such as the location and timing of their mitoses, together with their characteristic morphologies, can directly or indirectly regulate the abundance and the identity of their neuronal progeny. Alterations in the complex and delicate process of cerebral cortex development can lead to malformations of cortical development (MCDs). They include various structural abnormalities that affect the size, thickness and/or folding pattern of the developing cortex. Their clinical manifestations can entail a neurodevelopmental disorder, such as epilepsy, developmental delay, intellectual disability, or autism spectrum disorder. The recent advancements of molecular and neuroimaging techniques, along with the development of appropriate in vitro and in vivo model systems, have enabled the assessment of the genetic and environmental causes of MCDs. Here we broadly review the cell biological characteristics of neural progenitor cells and focus on those features whose perturbations have been linked to MCDs.
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Ma Y, Wang C, Elmhadi M, Zhang H, Liu F, Gao X, Wang H. Dietary supplementation of thiamine enhances colonic integrity and modulates mucosal inflammation injury in goats challenged by lipopolysaccharide and low pH. Br J Nutr 2022; 128:1-11. [PMID: 35057872 DOI: 10.1017/s0007114522000174] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
The current study aimed to investigate the protective effects of dietary thiamine supplementation on the regulation of colonic integrity and mucosal inflammation in goats fed a high-concentrate (HC) diet. Twenty-four Boer goats (live weight of 35·62 (sem 2·4) kg) were allocated to three groups (CON: concentrate/forage = 30:70; HC; concentrate/forage = 70:30 and HCT: concentrate/forage = 70:30 with 200 mg thiamine/kg DMI) for 12 weeks. Results showed that compared with the HC treatment, the HCT group had a significantly higher ruminal pH value from 0 to 12 h after the feeding. The haematoxylin-eosin staining showed that desquamation and severe cellular damage were observed in the colon epithelium of the HC group, whereas the HCT group exhibited more structural integrity of the epithelial cell morphology. Compared with the HC treatment, the HCT group showed a markedly increase in pyruvate dehydrogenase and α-ketoglutarate dehydrogenase enzymes activity. The mRNA expressions in the colonic epithelium of SLC19A2, SLC19A3, SLC25A19, Bcl-2, occludin, claudin-1, claudin-4 and ZO-1 in the HCT group were significantly increased in comparison with the HC diet treatment. Compared with the HC treatment, the HCT diet significantly increased the protein expression of claudin-1 and significantly decreased the protein expression of NF-κB-related proteins p65. The results show that dietary thiamine supplementation could improve the colon epithelial barrier function and alleviate mucosal inflammation injury in goats after lipopolysaccharide and low pH challenge.
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Affiliation(s)
- Yi Ma
- Laboratory of Metabolic Manipulation of Herbivorous Animal Nutrition, College of Animal Science and Technology, Yangzhou University, Yangzhou, 225009, People's Republic of China
- Queen Elizabeth II Medical Centre, School of Biomedical Sciences, The University of Western Australia, Nedlands, WA, Australia
| | - Chao Wang
- Queen Elizabeth II Medical Centre, School of Biomedical Sciences, The University of Western Australia, Nedlands, WA, Australia
| | - Mawda Elmhadi
- Laboratory of Metabolic Manipulation of Herbivorous Animal Nutrition, College of Animal Science and Technology, Yangzhou University, Yangzhou, 225009, People's Republic of China
| | - Hao Zhang
- Laboratory of Metabolic Manipulation of Herbivorous Animal Nutrition, College of Animal Science and Technology, Yangzhou University, Yangzhou, 225009, People's Republic of China
| | - Fuyuan Liu
- State Key Laboratory of Sheep Genetic Improvement and Healthy Production, Xinjiang Academy of Agricultural and Reclamation Sciences, Shihezi, People's Republic of China
| | - Xingliang Gao
- State Key Laboratory of Sheep Genetic Improvement and Healthy Production, Xinjiang Academy of Agricultural and Reclamation Sciences, Shihezi, People's Republic of China
| | - Hongrong Wang
- Laboratory of Metabolic Manipulation of Herbivorous Animal Nutrition, College of Animal Science and Technology, Yangzhou University, Yangzhou, 225009, People's Republic of China
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33
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Borse V, Kaur T, Hinton A, Ohlemiller K, Warchol ME. Programmed Cell Death Recruits Macrophages Into the Developing Mouse Cochlea. Front Cell Dev Biol 2021; 9:777836. [PMID: 34957108 PMCID: PMC8696258 DOI: 10.3389/fcell.2021.777836] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 11/19/2021] [Indexed: 12/31/2022] Open
Abstract
Programmed cell death (PCD) plays a critical role in the development and maturation of the cochlea. Significant remodeling occurs among cells of the greater epithelial ridge (GER) of Kölliker’s organ, leading to tissue regression and formation of the inner sulcus. In mice, this event normally occurs between postnatal days 5–15 (P5-15) and is regulated by thyroid hormone (T3). During this developmental time period, the cochlea also contains a large population of macrophages. Macrophages are frequently involved in the phagocytic clearance of dead cells, both during development and after injury, but the role of macrophages in the developing cochlea is unknown. This study examined the link between developmental cell death in the GER and the recruitment of macrophages into this region. Cell death in the basal GER begins at P5 and enhanced numbers of macrophages were observed at P7. This pattern of macrophage recruitment was unchanged in mice that were genetically deficient for CX3CR1, the receptor for fractalkine (a known macrophage chemoattractant). We found that injection of T3 at P0 and P1 caused GER cell death to begin at P3, and this premature PCD was accompanied by earlier recruitment of macrophages. We further found that depletion of macrophages from the developing cochlea (using CX3CR1DTR/+ mice and treatment with the CSF1R antagonist BLZ945) had no effect on the pattern of GER regression. Together, these findings suggest that macrophages are recruited into the GER region after initiation of developmental PCD, but that they are not essential for GER regression during cochlear remodeling.
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Affiliation(s)
- Vikrant Borse
- Department of Otolaryngology, Washington University School of Medicine, St. Louis, MO, United States
| | - Tejbeer Kaur
- Department of Biomedical Sciences, School of Medicine, Creighton University, Omaha, NE, United States
| | - Ashley Hinton
- Department of Otolaryngology, Washington University School of Medicine, St. Louis, MO, United States
| | - Kevin Ohlemiller
- Department of Otolaryngology, Washington University School of Medicine, St. Louis, MO, United States
| | - Mark E Warchol
- Department of Otolaryngology, Washington University School of Medicine, St. Louis, MO, United States
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Abstract
DNA mutation is a common event in the human body, but in most situations, it is fixed right away by the DNA damage response program. In case the damage is too severe to repair, the programmed cell death system will be activated to get rid of the cell. However, if the damage affects some critical components of this system, the genetic scars are kept and multiply through mitosis, possibly leading to cancer someday. There are many forms of programmed cell death, but apoptosis and necroptosis represent the default and backup strategy, respectively, in the maintenance of optimal cell population as well as in cancer prevention. For the same reason, the ideal approach for cancer treatment is to induce apoptosis in the cancer cells because it proceeds 20 times faster than tumor cell proliferation and leaves no mess behind. Induction of necroptosis can be the second choice in case apoptosis becomes hard to achieve, however, necroptosis finishes the job at a cost-inflammation.
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Affiliation(s)
- Xianmei Meng
- Inner Mongolia Institute of Digestive Diseases, Inner Mongolia Engineering Research Center for Prevention and Treatment of Digestive Diseases, Inner Mongolia University of Science and Technology, 74506The Second Affiliated Hospital of Baotou Medical College, Baotou, China
| | - Tong Dang
- Inner Mongolia Institute of Digestive Diseases, Inner Mongolia Engineering Research Center for Prevention and Treatment of Digestive Diseases, Inner Mongolia University of Science and Technology, 74506The Second Affiliated Hospital of Baotou Medical College, Baotou, China
| | - Jianyuan Chai
- Inner Mongolia Institute of Digestive Diseases, Inner Mongolia Engineering Research Center for Prevention and Treatment of Digestive Diseases, Inner Mongolia University of Science and Technology, 74506The Second Affiliated Hospital of Baotou Medical College, Baotou, China.,Laboratory of Gastrointestinal Injury and Cancer, VA Long Beach Healthcare System, Long Beach, CA, USA.,College of Medicine, University of California, Irvine, CA, USA
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35
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Zhang J, Chen Y, Yin D, Feng F, An Q, Liu Z, An N, Xu J, Yi J, Gu S, Yin W, Wang Y, Hu X. Caspase-3/NLRP3 signaling in the mesenchymal stromal niche regulates myeloid-biased hematopoiesis. Stem Cell Res Ther 2021; 12:579. [PMID: 34801085 PMCID: PMC8605603 DOI: 10.1186/s13287-021-02640-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Accepted: 10/25/2021] [Indexed: 12/18/2022] Open
Abstract
Background The fate of hematopoietic stem cells (HSCs) is determined by a complex regulatory network that includes both intrinsic and extrinsic signals. In the past decades, many intrinsic key molecules of HSCs have been shown to control hematopoiesis homeostasis. Non-hematopoietic niche cells also contribute to the self-renewal, quiescence, and differentiation of HSCs. Mesenchymal stromal cells (MSCs) have been identified as important components of the niche. However, the regulatory role of MSCs in hematopoiesis has not been fully understood. Methods Caspase-3 and NLRP3 gene knockout mice were generated respectively, and hematopoietic development was evaluated in the peripheral circulation and bone marrow by flow cytometry, colony formation assay, and bone marrow transplantation. Bone-associated MSCs (BA-MSCs) were then isolated from gene knockout mice, and the effect of Caspase-3/NLRP3 deficient BA-MSCs on hematopoiesis regulation was explored in vivo and ex vivo. Results We report that Caspase-3 deficient mice exhibit increased myelopoiesis and an aberrant HSC pool. Ablation of Caspase-3 in BA-MSCs regulates myeloid lineage expansion by altering the expression of hematopoietic retention cytokines, including SCF and CXCL12. Interestingly, NLRP3 gene knockout mice share phenotypic similarities with Caspase-3 deficient mice. Additionally, we found that NLRP3 may play a role in myeloid development by affecting the cell cycle and apoptosis of hematopoietic progenitors. Conclusions Our data demonstrate that the Caspase-3/NLRP3 signaling functions as an important regulator in physiological hematopoiesis, which provides new insights regarding niche signals that influence hematopoiesis regulation in the bone marrow. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-021-02640-y.
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Affiliation(s)
- Jing Zhang
- Department of Transfusion Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Yaozhen Chen
- Department of Transfusion Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Dandan Yin
- Department of Hematology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Fan Feng
- Division of Digestive Surgery, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Qunxing An
- Department of Transfusion Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Zhixin Liu
- Department of Transfusion Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Ning An
- Department of Transfusion Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Jinmei Xu
- Department of Transfusion Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Jing Yi
- Department of Transfusion Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Shunli Gu
- Department of Transfusion Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Wen Yin
- Department of Transfusion Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China.
| | - Yazhou Wang
- Institute of Neuroscience, Fourth Military Medical University, Xi'an, Shaanxi, China.
| | - Xingbin Hu
- Department of Transfusion Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China.
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Emerging immune and cell death mechanisms in stroke: Saponins as therapeutic candidates. Brain Behav Immun Health 2021; 9:100152. [PMID: 34589895 PMCID: PMC8474497 DOI: 10.1016/j.bbih.2020.100152] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Accepted: 09/28/2020] [Indexed: 12/15/2022] Open
Abstract
The complexity of the ischemic cascade is based on the integrated crosstalk of every cell type in the neurovascular unit. Depending on the features of the ischemic insult, several cell death mechanisms are triggered, such as apoptosis, necroptosis, ferroptosis/oxytosis, ETosis or pyroptosis, leading to reactive astrogliosis. However, emerging evidence demonstrates a dual role for the immune system in stroke pathophysiology, where it exerts both detrimental and also beneficial functions. In this review, we discuss the relevance of several cell death modalities and the dual role of the immune system in stroke pathophysiology. We also provide an overview of some emerging immunomodulatory therapeutic strategies, amongst which saponins, which are promising candidates that exert multiple pharmacological effects.
Several cell death mechanisms coexist in stroke pathophysiology. Neurons are more vulnerable to necroptosis than glial cells. Inhibitors of receptor-interacting protein kinases and of ferroptosis induce neuroprotection. Saponins exert modulatory effects on inflammation and neuronal cell death in stroke.
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37
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D-cysteine is an endogenous regulator of neural progenitor cell dynamics in the mammalian brain. Proc Natl Acad Sci U S A 2021; 118:2110610118. [PMID: 34556581 DOI: 10.1073/pnas.2110610118] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/19/2021] [Indexed: 12/19/2022] Open
Abstract
d-amino acids are increasingly recognized as important signaling molecules in the mammalian central nervous system. However, the d-stereoisomer of the amino acid with the fastest spontaneous racemization ratein vitro in vitro, cysteine, has not been examined in mammals. Using chiral high-performance liquid chromatography and a stereospecific luciferase assay, we identify endogenous d-cysteine in the mammalian brain. We identify serine racemase (SR), which generates the N-methyl-d-aspartate (NMDA) glutamate receptor coagonist d-serine, as a candidate biosynthetic enzyme for d-cysteine. d-cysteine is enriched more than 20-fold in the embryonic mouse brain compared with the adult brain. d-cysteine reduces the proliferation of cultured mouse embryonic neural progenitor cells (NPCs) by ∼50%, effects not shared with d-serine or l-cysteine. The antiproliferative effect of d-cysteine is mediated by the transcription factors FoxO1 and FoxO3a. The selective influence of d-cysteine on NPC proliferation is reflected in overgrowth and aberrant lamination of the cerebral cortex in neonatal SR knockout mice. Finally, we perform an unbiased screen for d-cysteine-binding proteins in NPCs by immunoprecipitation with a d-cysteine-specific antibody followed by mass spectrometry. This approach identifies myristoylated alanine-rich C-kinase substrate (MARCKS) as a putative d-cysteine-binding protein. Together, these results establish endogenous mammalian d-cysteine and implicate it as a physiologic regulator of NPC homeostasis in the developing brain.
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Cachia A, Borst G, Jardri R, Raznahan A, Murray GK, Mangin JF, Plaze M. Towards Deciphering the Fetal Foundation of Normal Cognition and Cognitive Symptoms From Sulcation of the Cortex. Front Neuroanat 2021; 15:712862. [PMID: 34650408 PMCID: PMC8505772 DOI: 10.3389/fnana.2021.712862] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 08/31/2021] [Indexed: 01/16/2023] Open
Abstract
Growing evidence supports that prenatal processes play an important role for cognitive ability in normal and clinical conditions. In this context, several neuroimaging studies searched for features in postnatal life that could serve as a proxy for earlier developmental events. A very interesting candidate is the sulcal, or sulco-gyral, patterns, macroscopic features of the cortex anatomy related to the fold topology-e.g., continuous vs. interrupted/broken fold, present vs. absent fold-or their spatial organization. Indeed, as opposed to quantitative features of the cortical sheet (e.g., thickness, surface area or curvature) taking decades to reach the levels measured in adult, the qualitative sulcal patterns are mainly determined before birth and stable across the lifespan. The sulcal patterns therefore offer a window on the fetal constraints on specific brain areas on cognitive abilities and clinical symptoms that manifest later in life. After a global review of the cerebral cortex sulcation, its mechanisms, its ontogenesis along with methodological issues on how to measure the sulcal patterns, we present a selection of studies illustrating that analysis of the sulcal patterns can provide information on prenatal dispositions to cognition (with a focus on cognitive control and academic abilities) and cognitive symptoms (with a focus on schizophrenia and bipolar disorders). Finally, perspectives of sulcal studies are discussed.
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Affiliation(s)
- Arnaud Cachia
- Université de Paris, LaPsyDÉ, CNRS, Paris, France
- Université de Paris, IPNP, INSERM, Paris, France
| | - Grégoire Borst
- Université de Paris, LaPsyDÉ, CNRS, Paris, France
- Institut Universitaire de France, Paris, France
| | - Renaud Jardri
- Univ Lille, INSERM U-1172, CHU Lille, Lille Neuroscience & Cognition Centre, Plasticity & SubjectivitY (PSY) team, Lille, France
| | - Armin Raznahan
- Section on Developmental Neurogenomics, Human Genetics Branch, National Institute of Mental Health, Bethesda, MD, United States
| | - Graham K. Murray
- Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
| | | | - Marion Plaze
- Université de Paris, IPNP, INSERM, Paris, France
- GHU PARIS Psychiatrie & Neurosciences, site Sainte-Anne, Service Hospitalo-Universitaire, Pôle Hospitalo-Universitaire Paris, Paris, France
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Akeret K, Vasella F, Staartjes VE, Velz J, Müller T, Neidert MC, Weller M, Regli L, Serra C, Krayenbühl N. Anatomical phenotyping and staging of brain tumours. Brain 2021; 145:1162-1176. [PMID: 34554211 DOI: 10.1093/brain/awab352] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Revised: 07/25/2021] [Accepted: 08/21/2021] [Indexed: 11/14/2022] Open
Abstract
Unlike other tumors, the anatomical extent of brain tumors is not objectified and quantified through staging. Staging systems are based on understanding the anatomical sequence of tumor progression and its relationship to histopathological dedifferentiation and survival. The aim of this study was to describe the spatiotemporal phenotype of the most frequent brain tumor entities, to assess the association of anatomical tumor features with survival probability and to develop a staging system for WHO grade 2 and 3 gliomas and glioblastoma. Anatomical phenotyping was performed on a consecutive cohort of 1000 patients with first diagnosis of a primary or secondary brain tumor. Tumor probability in different topographic, phylogenetic and ontogenetic parcellation units was assessed on preoperative MRI through normalization of the relative tumor prevalence to the relative volume of the respective structure. We analyzed the spatiotemporal tumor dynamics by cross-referencing preoperative against preceding and subsequent MRIs of the respective patient. The association between anatomical phenotype and outcome defined prognostically critical anatomical tumor features at diagnosis. Based on a hypothesized sequence of anatomical tumor progression, we developed a three-level staging system for WHO grade 2 and 3 gliomas and glioblastoma. This staging system was validated internally in the original cohort and externally in an independent cohort of 300 consecutive patients. While primary central nervous system lymphoma showed highest probability along white matter tracts, metastases enriched along terminal arterial flow areas. Neuroepithelial tumors mapped along all sectors of the ventriculocortical axis, while adjacent units were spared, consistent with a transpallial behavior within phylo-ontogenetic radial units. Their topographic pattern correlated with morphogenetic processes of convergence and divergence of radial units during phylo- and ontogenesis. While a ventriculofugal growth dominated in neuroepithelial tumors, a gradual deviation from this neuroepithelial spatiotemporal behavior was found with progressive histopathological dedifferentiation. The proposed three-level staging system for WHO grade 2 and 3 gliomas and glioblastoma correlated with the degree of histological dedifferentiation and proved accurate in terms of survival upon both internal and external validation. In conclusion, this study identified specific spatiotemporal phenotypes in brain tumors through topographic probability and growth pattern assessment. The association of anatomical tumor features with survival defined critical steps in the anatomical sequence of neuroepithelial tumor progression, based on which a staging system for WHO grade 2 and 3 gliomas and glioblastoma was developed and validated.
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Affiliation(s)
- Kevin Akeret
- Department of Neurosurgery, Clinical Neuroscience Center, University Hospital Zurich and University of Zurich, 8091 Zurich, Switzerland
| | - Flavio Vasella
- Department of Neurosurgery, Clinical Neuroscience Center, University Hospital Zurich and University of Zurich, 8091 Zurich, Switzerland.,Department of Neurology, Clinical Neuroscience Center, University Hospital Zurich and University of Zurich, 8091 Zurich, Switzerland
| | - Victor E Staartjes
- Department of Neurosurgery, Clinical Neuroscience Center, University Hospital Zurich and University of Zurich, 8091 Zurich, Switzerland
| | - Julia Velz
- Department of Neurosurgery, Clinical Neuroscience Center, University Hospital Zurich and University of Zurich, 8091 Zurich, Switzerland
| | - Timothy Müller
- Department of Neurosurgery, Clinical Neuroscience Center, University Hospital Zurich and University of Zurich, 8091 Zurich, Switzerland
| | - Marian Christoph Neidert
- Department of Neurosurgery, Clinical Neuroscience Center, University Hospital Zurich and University of Zurich, 8091 Zurich, Switzerland
| | - Michael Weller
- Department of Neurology, Clinical Neuroscience Center, University Hospital Zurich and University of Zurich, 8091 Zurich, Switzerland
| | - Luca Regli
- Department of Neurosurgery, Clinical Neuroscience Center, University Hospital Zurich and University of Zurich, 8091 Zurich, Switzerland
| | - Carlo Serra
- Department of Neurosurgery, Clinical Neuroscience Center, University Hospital Zurich and University of Zurich, 8091 Zurich, Switzerland
| | - Niklaus Krayenbühl
- Department of Neurosurgery, Clinical Neuroscience Center, University Hospital Zurich and University of Zurich, 8091 Zurich, Switzerland.,Division of Pediatric Neurosurgery, University Children's Hospital, 8032 Zurich, Switzerland
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40
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Li S, Qu L, Wang X, Kong L. Novel insights into RIPK1 as a promising target for future Alzheimer's disease treatment. Pharmacol Ther 2021; 231:107979. [PMID: 34480965 DOI: 10.1016/j.pharmthera.2021.107979] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 06/30/2021] [Accepted: 08/24/2021] [Indexed: 02/06/2023]
Abstract
Alzheimer's disease (AD) is an intractable neurodegenerative disease showing a clinical manifestation with memory loss, cognitive impairment and behavioral dysfunction. The predominant pathological characteristics of AD include neuronal loss, β-amyloid (Aβ) deposition and hyperphosphorylated Tau induced neurofibrillary tangles (NFTs), while considerable studies proved these could be triggered by neuronal death and neuroinflammation. Receptor-interacting protein kinase 1 (RIPK1) is a serine/threonine kinase existed at the cross-point of cell death and inflammatory signaling pathways. Emerging investigations have shed light on RIPK1 for its potential role in AD progression. The present review makes a bird's eye view on the functions of RIPK1 and mainly focus on the underlying linkages between RIPK1 and AD from comprehensive aspects including neuronal death, Aβ and Tau, inflammasome activation, BBB rupture, AMPK/mTOR, mitochondrial dysfunction and O-glcNAcylation. Moreover, the discovery of RIPK1 inhibitors, ongoing clinical trials along with future RIPK1-targeted therapeutics are also reviewed.
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Affiliation(s)
- Shang Li
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, People's Republic of China
| | - Lailiang Qu
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, People's Republic of China
| | - Xiaobing Wang
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, People's Republic of China.
| | - Lingyi Kong
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, People's Republic of China.
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41
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Asadi M, Taghizadeh S, Kaviani E, Vakili O, Taheri-Anganeh M, Tahamtan M, Savardashtaki A. Caspase-3: Structure, function, and biotechnological aspects. Biotechnol Appl Biochem 2021; 69:1633-1645. [PMID: 34342377 DOI: 10.1002/bab.2233] [Citation(s) in RCA: 218] [Impact Index Per Article: 54.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Accepted: 08/01/2021] [Indexed: 12/16/2022]
Abstract
Caspase-3, a cysteine-aspartic acid protease, has recently attracted much attention because of its incredible roles in tissue differentiation, regeneration, and neural development. This enzyme is a key zymogen in cell apoptosis and is not activated until it is cleaved by initiator caspases during apoptotic flux. Since caspase-3 has represented valuable capabilities in the field of medical research, biotechnological aspects of this enzyme, including the production of recombinant type, protein engineering, and designing delivery systems, have been considered as emerging therapeutic strategies in treating the apoptosis-related disorders. To date, several advances have been made in the therapeutic use of caspase-3 in the management of some diseases such as cancers, heart failure, and neurodegenerative disorders. In the current review, we intend to discuss the caspase-3's structure, functions, therapeutic applications, as well as its molecular cloning, protein engineering, and relevant delivery systems.
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Affiliation(s)
- Marzieh Asadi
- Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Saeed Taghizadeh
- Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Elina Kaviani
- Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Omid Vakili
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mortaza Taheri-Anganeh
- Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mahshid Tahamtan
- Department of Neuroscience, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Amir Savardashtaki
- Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
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Nguyen TTM, Gillet G, Popgeorgiev N. Caspases in the Developing Central Nervous System: Apoptosis and Beyond. Front Cell Dev Biol 2021; 9:702404. [PMID: 34336853 PMCID: PMC8322698 DOI: 10.3389/fcell.2021.702404] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 06/23/2021] [Indexed: 12/12/2022] Open
Abstract
The caspase family of cysteine proteases represents the executioners of programmed cell death (PCD) type I or apoptosis. For years, caspases have been known for their critical roles in shaping embryonic structures, including the development of the central nervous system (CNS). Interestingly, recent findings have suggested that aside from their roles in eliminating unnecessary neural cells, caspases are also implicated in other neurodevelopmental processes such as axon guidance, synapse formation, axon pruning, and synaptic functions. These results raise the question as to how neurons regulate this decision-making, leading either to cell death or to proper development and differentiation. This review highlights current knowledge on apoptotic and non-apoptotic functions of caspases in the developing CNS. We also discuss the molecular factors involved in the regulation of caspase-mediated roles, emphasizing the mitochondrial pathway of cell death.
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Affiliation(s)
- Trang Thi Minh Nguyen
- Centre de Recherche en Cancérologie de Lyon, U1052 INSERM, UMR CNRS 5286, Centre Léon Bérard, Université Claude Bernard Lyon 1, Lyon, France
| | - Germain Gillet
- Centre de Recherche en Cancérologie de Lyon, U1052 INSERM, UMR CNRS 5286, Centre Léon Bérard, Université Claude Bernard Lyon 1, Lyon, France.,Hospices Civils de Lyon, Laboratoire d'Anatomie et Cytologie Pathologiques, Centre Hospitalier Lyon Sud, Pierre Bénite, France
| | - Nikolay Popgeorgiev
- Centre de Recherche en Cancérologie de Lyon, U1052 INSERM, UMR CNRS 5286, Centre Léon Bérard, Université Claude Bernard Lyon 1, Lyon, France
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43
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Awazu M, Yamaguchi Y, Nagata M, Miura M, Hida M. Caspase-3 regulates ureteric branching in mice via cell migration. Biochem Biophys Res Commun 2021; 559:28-34. [PMID: 33932897 DOI: 10.1016/j.bbrc.2021.04.081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 04/19/2021] [Indexed: 10/21/2022]
Abstract
Inhibition of caspase-3 (Casp3) reduces ureteric branching in organ culture but the mechanism remains unclear. Since Casp3 has non-apoptotic functions, we examined whether Casp3 regulates ureteric branching by promoting cell migration, using a ureteric bud (UB) cell line and Casp3-deficient (Casp3-/-) mice. Also, we examined whether Casp3 plays a role in the reduced ureteric branching of metanephroi from nutrient restricted mothers, in which Casp3 activity is suppressed. A Casp3 inhibitor Ac-DNLD-CHO reduced FGF2-induced cord formation of UB cells in 3D culture. UB cell migration assessed by Boyden chamber and wound healing assays was inhibited by Ac-DNLD-CHO. Glomerular number was reduced by ≈ 30%, and ureteric tip number was lower in Casp3-/- mice compared with controls. Maternal nutrient restriction decreased ureteric tip number in controls but not in Casp3-/-. In conclusion, Casp3 regulates ureteric branching by promoting UB cell migration. Inhibited ureteric branching by maternal nutrient restriction may be mediated by Casp3.
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Affiliation(s)
- Midori Awazu
- Department of Pediatrics, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
| | - Yoshifumi Yamaguchi
- Department of Genetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; Institute of Low Temperature Science, Hokkaido University, Kita-19, Nishi-8, Kita-ku, Sapporo, 060-0819, Japan.
| | - Michio Nagata
- Kidney and Vascular Pathology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan.
| | - Masayuki Miura
- Department of Genetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
| | - Mariko Hida
- Department of Pediatrics, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
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Ulmke PA, Sakib MS, Ditte P, Sokpor G, Kerimoglu C, Pham L, Xie Y, Mao X, Rosenbusch J, Teichmann U, Nguyen HP, Fischer A, Eichele G, Staiger JF, Tuoc T. Molecular Profiling Reveals Involvement of ESCO2 in Intermediate Progenitor Cell Maintenance in the Developing Mouse Cortex. Stem Cell Reports 2021; 16:968-984. [PMID: 33798452 PMCID: PMC8072132 DOI: 10.1016/j.stemcr.2021.03.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 03/05/2021] [Accepted: 03/08/2021] [Indexed: 12/12/2022] Open
Abstract
Intermediate progenitor cells (IPCs) are neocortical neuronal precursors. Although IPCs play crucial roles in corticogenesis, their molecular features remain largely unknown. In this study, we aimed to characterize the molecular profile of IPCs. We isolated TBR2-positive (+) IPCs and TBR2-negative (-) cell populations in the developing mouse cortex. Comparative genome-wide gene expression analysis of TBR2+ IPCs versus TBR2- cells revealed differences in key factors involved in chromatid segregation, cell-cycle regulation, transcriptional regulation, and cell signaling. Notably, mutation of many IPC genes in human has led to intellectual disability and caused a wide range of cortical malformations, including microcephaly and agenesis of corpus callosum. Loss-of-function experiments in cortex-specific mutants of Esco2, one of the novel IPC genes, demonstrate its critical role in IPC maintenance, and substantiate the identification of a central genetic determinant of IPC biogenesis. Our data provide novel molecular characteristics of IPCs in the developing mouse cortex.
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Affiliation(s)
- Pauline Antonie Ulmke
- Institute for Neuroanatomy, University Medical Center, Georg-August-University, Goettingen, Germany
| | - M Sadman Sakib
- German Center for Neurodegenerative Diseases, Goettingen, Germany
| | - Peter Ditte
- Max-Planck-Institute for Biophysical Chemistry, Goettingen, Germany
| | - Godwin Sokpor
- Institute for Neuroanatomy, University Medical Center, Georg-August-University, Goettingen, Germany; Department of Human Genetics, Ruhr University of Bochum, Bochum, Germany
| | - Cemil Kerimoglu
- German Center for Neurodegenerative Diseases, Goettingen, Germany
| | - Linh Pham
- Institute for Neuroanatomy, University Medical Center, Georg-August-University, Goettingen, Germany; Department of Human Genetics, Ruhr University of Bochum, Bochum, Germany
| | - Yuanbin Xie
- Institute for Neuroanatomy, University Medical Center, Georg-August-University, Goettingen, Germany
| | - Xiaoyi Mao
- Institute for Neuroanatomy, University Medical Center, Georg-August-University, Goettingen, Germany
| | - Joachim Rosenbusch
- Institute for Neuroanatomy, University Medical Center, Georg-August-University, Goettingen, Germany
| | - Ulrike Teichmann
- Max-Planck-Institute for Biophysical Chemistry, Goettingen, Germany
| | - Huu Phuc Nguyen
- Department of Human Genetics, Ruhr University of Bochum, Bochum, Germany
| | - Andre Fischer
- German Center for Neurodegenerative Diseases, Goettingen, Germany; Cluster of Excellence "Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells" (MBExC), Goettingen, Germany
| | - Gregor Eichele
- Max-Planck-Institute for Biophysical Chemistry, Goettingen, Germany
| | - Jochen F Staiger
- Institute for Neuroanatomy, University Medical Center, Georg-August-University, Goettingen, Germany
| | - Tran Tuoc
- Institute for Neuroanatomy, University Medical Center, Georg-August-University, Goettingen, Germany; Department of Human Genetics, Ruhr University of Bochum, Bochum, Germany.
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Ali I, Yang M, Wang Y, Yang C, Shafiq M, Wang G, Li L. Sodium propionate protect the blood-milk barrier integrity, relieve lipopolysaccharide-induced inflammatory injury and cells apoptosis. Life Sci 2021; 270:119138. [PMID: 33524422 DOI: 10.1016/j.lfs.2021.119138] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Revised: 01/02/2021] [Accepted: 01/17/2021] [Indexed: 12/12/2022]
Abstract
AIMS Sodium propionate (SP) has been reported to possess an anti-inflammatory and anti-apoptotic potential by inhibiting certain signaling pathways and helps in reducing the pathological damages of the mammary gland. However, the effects of sodium propionate on attenuating Lipopolysaccharide (LPS)-induced inflammatory condition and cell damage in bovine mammary epithelial cells (bMECs) are not comprehensively studied yet. Therefore, the aim of the current investigation was to evaluate the protective effects of sodium propionate on LPS-induced inflammatory conditions and to clarify the possible underlying molecular mechanism in bMECs. MAIN METHODS The effects of increasing doses of SP on LPS-induced inflammation, oxidative stress and apoptosis was studied in vitro. Furthermore, the underlying protective mechanisms of SP on LPS-stimulated bMECs was investigated under different experimental conditions. KEY FINDINGS The results reveled that increased inflammatory cytokines, chemokines and those of tight junction's mRNA expression was significantly attenuated dose-dependently by propionate. Biochemical analysis revealed that propionate pretreatment modulated the LPS-induced intercellular reactive oxygen species (ROS) accumulation, oxidative and antioxidant factors and apoptosis rate. Furthermore, we investigated that the LPS activated nuclear factor-kB (NF-kB), caspase/Bax apoptotic pathways and Histone deacetylases (HDAC) was significantly attenuated by propionate in bMECs. SIGNIFICANCE Our results suggest that sodium propionate is a potent agent for ameliorating LPS-mediated cellular disruption and limiting detrimental inflammatory responses, partly via maintaining blood milk barrier integrity, inhibiting HDAC activity and NF-kB signaling pathway.
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Affiliation(s)
- Ilyas Ali
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Min Yang
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Yiru Wang
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Caixia Yang
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Muhammad Shafiq
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China
| | - Genlin Wang
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Lian Li
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China.
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Wanner E, Thoppil H, Riabowol K. Senescence and Apoptosis: Architects of Mammalian Development. Front Cell Dev Biol 2021; 8:620089. [PMID: 33537310 PMCID: PMC7848110 DOI: 10.3389/fcell.2020.620089] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Accepted: 12/30/2020] [Indexed: 12/11/2022] Open
Abstract
Mammalian development involves an exquisite choreography of cell division, differentiation, locomotion, programmed cell death, and senescence that directs the transformation of a single cell zygote to a mature organism containing on the order of 40 trillion cells in humans. How a single totipotent zygote undergoes the rapid stages of embryonic development to form over 200 different cell types is complex in the extreme and remains the focus of active research. Processes such as programmed cell death or apoptosis has long been known to occur during development to help sculpt organs and tissue systems. Other processes such as cellular senescence, long thought to only occur in pathologic states such as aging and tumorigenesis have been recently reported to play a vital role in development. In this review, we focus on apoptosis and senescence; the former as an integral mechanism that plays a critical role not only in mature organisms, but that is also essential in shaping mammalian development. The latter as a well-defined feature of aging for which some reports indicate a function in development. We will dissect the dual roles of major gene families, pathways such as Hox, Rb, p53, and epigenetic regulators such as the ING proteins in both early and the late stages and how they play antagonistic roles by increasing fitness and decreasing mortality early in life but contribute to deleterious effects and pathologies later in life.
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Affiliation(s)
- Emma Wanner
- Department of Biology, Faculty of Science, University of Calgary, Calgary, AB, Canada
| | - Harikrishnan Thoppil
- Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Karl Riabowol
- Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.,Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
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García-Domínguez I, Suárez-Pereira I, Santiago M, Pérez-Villegas EM, Bravo L, López-Martín C, Roca-Ceballos MA, García-Revilla J, Espinosa-Oliva AM, Rodríguez-Gómez JA, Joseph B, Berrocoso E, Armengol JÁ, Venero JL, Ruiz R, de Pablos RM. Selective deletion of Caspase-3 gene in the dopaminergic system exhibits autistic-like behaviour. Prog Neuropsychopharmacol Biol Psychiatry 2021; 104:110030. [PMID: 32634539 DOI: 10.1016/j.pnpbp.2020.110030] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 06/09/2020] [Accepted: 06/28/2020] [Indexed: 10/23/2022]
Abstract
Apoptotic caspases are thought to play critical roles in elimination of excessive and non-functional synapses and removal of extra cells during early developmental stages. Hence, an impairment of this process may thus constitute a basis for numerous neurological and psychiatric diseases. This view is especially relevant for dopamine due to its pleiotropic roles in motor control, motivation and reward processing. Here, we have analysed the effect of caspase-3 depletion on the development of catecholaminergic neurons and performed a wide array of neurochemical, ultrastructural and behavioural assays. To achieve this, we performed selective deletion of the Casp3 gene in tyrosine hydroxylase (TH)-expressing cells using Cre-loxP-mediated recombination. Histological evaluation of most relevant catecholaminergic nuclei revealed the ventral mesencephalon as the most affected region. Stereological analysis demonstrated an increase in the number of TH-positive neurons in both the substantia nigra and ventral tegmental area along with enlarged volume of the ventral midbrain. Analysis of main innervating tissues revealed a rather contrasting profile. In striatum, basal extracellular levels and potassium-evoked DA release were significantly reduced in mice lacking Casp3, a clear indication of dopaminergic hypofunction in dopaminergic innervating tissues. This view was sustained by analysis of TH-labelled dopaminergic terminals by confocal and electron microscopy. Remarkably, at a behavioural level, Casp3-deficient mice exhibited impaired social interaction, restrictive interests and repetitive stereotypies, which are considered the core symptoms of autism spectrum disorder (ASD). Our study revitalizes the potential involvement of dopaminergic transmission in ASD and provides an excellent model to get further insights in ASD pathogenesis.
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Affiliation(s)
- Irene García-Domínguez
- Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla, Sevilla, Spain; Instituto de Biomedicina de Sevilla-Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain
| | - Irene Suárez-Pereira
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Spain; Neuropsychopharmacology & Psychobiology Research Group, Department of Neuroscience, University of Cádiz, 11003 Cádiz, Spain; Instituto de Investigación e Innovación en Ciencias Biomédicas de Cádiz, INiBICA, Hospital Universitario Puerta del Mar, Avda. Ana de Viya 21, 11009 Cádiz, Spain
| | - Marti Santiago
- Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla, Sevilla, Spain; Instituto de Biomedicina de Sevilla-Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain
| | - Eva M Pérez-Villegas
- Departamento de Fisiología, Anatomía y Biología Celular, Universidad Pablo de Olavide, Sevilla, Spain
| | - Lidia Bravo
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Spain; Neuropsychopharmacology & Psychobiology Research Group, Department of Neuroscience, University of Cádiz, 11003 Cádiz, Spain; Instituto de Investigación e Innovación en Ciencias Biomédicas de Cádiz, INiBICA, Hospital Universitario Puerta del Mar, Avda. Ana de Viya 21, 11009 Cádiz, Spain
| | - Carolina López-Martín
- Neuropsychopharmacology & Psychobiology Research Group, Department of Neuroscience, University of Cádiz, 11003 Cádiz, Spain; Instituto de Investigación e Innovación en Ciencias Biomédicas de Cádiz, INiBICA, Hospital Universitario Puerta del Mar, Avda. Ana de Viya 21, 11009 Cádiz, Spain; Neuropsychopharmacology and Psychobiology Research Group, Department of Psychology, University of Cádiz, 11510 Puerto Real, Cádiz, Spain
| | - María Angustias Roca-Ceballos
- Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla, Sevilla, Spain; Instituto de Biomedicina de Sevilla-Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain
| | - Juan García-Revilla
- Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla, Sevilla, Spain; Instituto de Biomedicina de Sevilla-Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain
| | - Ana M Espinosa-Oliva
- Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla, Sevilla, Spain; Instituto de Biomedicina de Sevilla-Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain
| | - José A Rodríguez-Gómez
- Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla, Sevilla, Spain; Departament of Medical Physiology and Biophysics, Faculty of Medicine, University of Seville, 41009 Sevilla, Spain; Instituto de Biomedicina de Sevilla-Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain
| | - Bertrand Joseph
- Institute of Environmental Medicine, Toxicology Unit, Karolinska Institutet, Stockholm, Sweden
| | - Esther Berrocoso
- Neuropsychopharmacology & Psychobiology Research Group, Department of Neuroscience, University of Cádiz, 11003 Cádiz, Spain; Instituto de Investigación e Innovación en Ciencias Biomédicas de Cádiz, INiBICA, Hospital Universitario Puerta del Mar, Avda. Ana de Viya 21, 11009 Cádiz, Spain; Neuropsychopharmacology and Psychobiology Research Group, Department of Psychology, University of Cádiz, 11510 Puerto Real, Cádiz, Spain
| | - José Ángel Armengol
- Departamento de Fisiología, Anatomía y Biología Celular, Universidad Pablo de Olavide, Sevilla, Spain
| | - José L Venero
- Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla, Sevilla, Spain; Instituto de Biomedicina de Sevilla-Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain
| | - Rocío Ruiz
- Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla, Sevilla, Spain; Instituto de Biomedicina de Sevilla-Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain.
| | - Rocío M de Pablos
- Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla, Sevilla, Spain; Instituto de Biomedicina de Sevilla-Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain
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Montero JA, Lorda-Diez CI, Hurle JM. Confluence of Cellular Degradation Pathways During Interdigital Tissue Remodeling in Embryonic Tetrapods. Front Cell Dev Biol 2020; 8:593761. [PMID: 33195267 PMCID: PMC7644521 DOI: 10.3389/fcell.2020.593761] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Accepted: 10/07/2020] [Indexed: 12/12/2022] Open
Abstract
Digits develop in the distal part of the embryonic limb primordium as radial prechondrogenic condensations separated by undifferentiated mesoderm. In a short time interval the interdigital mesoderm undergoes massive degeneration to determine the formation of free digits. This fascinating process has often been considered as an altruistic cell suicide that is evolutionarily-regulated in species with different degrees of digit webbing. Initial descriptions of interdigit remodeling considered lysosomes as the primary cause of the degenerative process. However, the functional significance of lysosomes lost interest among researcher and was displaced to a secondary role because the introduction of the term apoptosis. Accumulating evidence in recent decades has revealed that, far from being a unique method of embryonic cell death, apoptosis is only one among several redundant dying mechanisms accounting for the elimination of tissues during embryonic development. Developmental cell senescence has emerged in the last decade as a primary factor implicated in interdigit remodeling. Our review proposes that cell senescence is the biological process identified by vital staining in embryonic models and implicates lysosomes in programmed cell death. We review major structural changes associated with interdigit remodeling that may be driven by cell senescence. Furthermore, the identification of cell senescence lacking tissue degeneration, associated with the maturation of the digit tendons at the same stages of interdigital remodeling, allowed us to distinguish between two functionally distinct types of embryonic cell senescence, “constructive” and “destructive.”
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Affiliation(s)
- Juan A Montero
- Departamento de Anatomiìa y Biologiìa Celular and Instituto de Investigación Sanitaria Valdecilla (IDIVAL), Universidad de Cantabria, Santander, Spain
| | - Carlos I Lorda-Diez
- Departamento de Anatomiìa y Biologiìa Celular and Instituto de Investigación Sanitaria Valdecilla (IDIVAL), Universidad de Cantabria, Santander, Spain
| | - Juan M Hurle
- Departamento de Anatomiìa y Biologiìa Celular and Instituto de Investigación Sanitaria Valdecilla (IDIVAL), Universidad de Cantabria, Santander, Spain
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Matsumoto Y, Yamaguchi Y, Hamachi M, Nonomura K, Muramatsu Y, Yoshida H, Miura M. Apoptosis is involved in maintaining the character of the midbrain and the diencephalon roof plate after neural tube closure. Dev Biol 2020; 468:101-109. [PMID: 32979334 DOI: 10.1016/j.ydbio.2020.09.015] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2020] [Revised: 09/19/2020] [Accepted: 09/19/2020] [Indexed: 02/02/2023]
Abstract
Apoptosis, a major form of programmed cell death, is massively observed in neural plate border and subsequently in the roof plate (RP). While deficiency of apoptosis often results in brain malformations including exencephaly and hydrocephalus, the impact of apoptosis on RP formation and maintenance remains unclear. Here we described that mouse embryos deficient in Apaf1, a gene crucial for the intrinsic apoptotic pathway, in C57BL/6 genetic background exhibited narrow and discontinuous expression of RP marker genes in the midline of the midbrain and the diencephalon. Instead, cells positive for the neuroectodermal gene SOX1 ectopically accumulated in the midline. A lineage-tracing experiment suggests that these ectopic SOX1-positive cells began to accumulate in the midline of apoptosis-deficient embryos after E9.5. These embryos further displayed malformation of the subcommissural organ, which has been discussed in the etiology of hydrocephalus. Thus, the apoptosis machinery prevents ectopic emergence of SOX1-positive cells in the midbrain and the diencephalon RP, and helps in maintaining the character of the RP in the diencephalon and midbrain, thereby ensuring proper brain development.
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Affiliation(s)
- Yudai Matsumoto
- Department of Genetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Yoshifumi Yamaguchi
- Hibernation Metabolism, Physiology, and Development Group, Institute of Low Temperature Science, Hokkaido University, Sapporo, Hokkaido, 060-0819, Japan; Global Station for Biosurfaces and Drug Discovery, Hokkaido University, Sapporo, Hokkaido, 060-0812, Japan.
| | - Misato Hamachi
- Department of Genetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Keiko Nonomura
- Division of Embryology, National Institute for Basic Biology (NIBB), Higashiyama 5-1, Myodaiji, Okazaki, 444-8787, Japan
| | - Yukiko Muramatsu
- Department of Genetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Hiroki Yoshida
- Division of Molecular and Cellular Immunoscience, Department of Biomolecular Sciences, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan
| | - Masayuki Miura
- Department of Genetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, 113-0033, Japan.
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Aeby E, Lee HG, Lee YW, Kriz A, del Rosario BC, Oh HJ, Boukhali M, Haas W, Lee JT. Decapping enzyme 1A breaks X-chromosome symmetry by controlling Tsix elongation and RNA turnover. Nat Cell Biol 2020; 22:1116-1129. [PMID: 32807903 DOI: 10.1038/s41556-020-0558-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Accepted: 07/09/2020] [Indexed: 12/27/2022]
Abstract
How allelic asymmetry is generated remains a major unsolved problem in epigenetics. Here we model the problem using X-chromosome inactivation by developing "BioRBP", an enzymatic RNA-proteomic method that enables probing of low-abundance interactions and an allelic RNA-depletion and -tagging system. We identify messenger RNA-decapping enzyme 1A (DCP1A) as a key regulator of Tsix, a noncoding RNA implicated in allelic choice through X-chromosome pairing. DCP1A controls Tsix half-life and transcription elongation. Depleting DCP1A causes accumulation of X-X pairs and perturbs the transition to monoallelic Tsix expression required for Xist upregulation. While ablating DCP1A causes hyperpairing, forcing Tsix degradation resolves pairing and enables Xist upregulation. We link pairing to allelic partitioning of CCCTC-binding factor (CTCF) and show that tethering DCP1A to one Tsix allele is sufficient to drive monoallelic Xist expression. Thus, DCP1A flips a bistable switch for the mutually exclusive determination of active and inactive Xs.
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