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Raza A, Raina J, Sahu SK, Wadhwa P. Genetic mutations in kinases: a comprehensive review on marketed inhibitors and unexplored targets in Parkinson's disease. Neurol Sci 2025; 46:1509-1524. [PMID: 39760821 DOI: 10.1007/s10072-024-07970-2] [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: 10/15/2024] [Accepted: 12/18/2024] [Indexed: 01/07/2025]
Abstract
This comprehensive review navigates the landscape of genetic mutations in kinases, offering a thorough examination of both marketed inhibitors and unexplored targets in the context of Parkinson's Disease (PD). Although existing treatments for PD primarily center on symptom management, progress in comprehending the molecular foundations of the disease has opened avenues for targeted therapeutic approaches. This review encompasses an in-depth analysis of four key kinases-PINK1, LRRK2, GAK, and PRKRA-revealing that LRRK2 has garnered the most attention with a plethora of marketed inhibitors. However, the study underscores notable gaps in the exploration of inhibitors for PINK1, GAK, and a complete absence for PRKRA. The observed scarcity of inhibitors for these kinases emphasizes a significant area of untapped potential in PD therapeutics. By drawing attention to these unexplored targets, the review highlights the urgent need for focused research and drug development efforts to diversify the therapeutic landscape, potentially providing novel interventions for halting or slowing the progression of PD.
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Affiliation(s)
- Amir Raza
- School of Pharmaceutical Sciences, Lovely Professional University, Jalandhar- Grand Trunk Rd, Phagwara, Punjab, India
| | - Jeevika Raina
- School of Pharmaceutical Sciences, Lovely Professional University, Jalandhar- Grand Trunk Rd, Phagwara, Punjab, India
| | - Sanjeev Kumar Sahu
- School of Pharmaceutical Sciences, Lovely Professional University, Jalandhar- Grand Trunk Rd, Phagwara, Punjab, India
| | - Pankaj Wadhwa
- School of Pharmaceutical Sciences, Lovely Professional University, Jalandhar- Grand Trunk Rd, Phagwara, Punjab, India.
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Huang YT, Calvi BR. Activation of a Src-JNK pathway in unscheduled endocycling cells of the Drosophila wing disc induces a chronic wounding response. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.03.12.642788. [PMID: 40161657 PMCID: PMC11952448 DOI: 10.1101/2025.03.12.642788] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 04/02/2025]
Abstract
The endocycle is a specialized cell cycle during which cells undergo repeated G / S phases to replicate DNA without division, leading to large polyploid cells. The transition from a mitotic cycle to an endocycle can be triggered by various stresses, which results in unscheduled, or induced endocycling cells (iECs). While iECs can be beneficial for wound healing, they can also be detrimental by impairing tissue growth or promoting cancer. However, the regulation of endocycling and its role in tissue growth remain poorly understood. Using the Drosophila wing disc as a model, we previously demonstrated that iEC growth is arrested through a Jun N-Terminal Kinase (JNK)-dependent, reversible senescence-like response. However, it remains unclear how JNK is activated in iECs and how iECs impact overall tissue structure. In this study, we performed a genetic screen and identified the Src42A-Shark-Slpr pathway as an upstream regulator of JNK in iECs, leading to their senescence-like arrest. We found that tissues recognize iECs as wounds, releasing wound-related signals that induce a JNK-dependent developmental delay. Similar to wound closure, this response triggers Src-JNK-mediated actomyosin remodeling, yet iECs persist rather than being eliminated. Our findings suggest that the tissue response to iECs shares key signaling and cytoskeletal regulatory mechanisms with wound healing and dorsal closure, a developmental process during Drosophila embryogenesis. However, because iECs are retained within the tissue, they create a unique system that may serve as a model for studying chronic wounds and tumor progression. Article summary The effects of unscheduled endocycles on tissue growth remain unclear. To investigate this, we used Drosophila to induce a switch from the mitotic cycle to the endocycle and analyzed tissue responses at both the signaling and tissue structure levels. Surprisingly, tissues recognized endocycling cells as wounds, activating regeneration signals and remodeling tissue structure. However, because these cells resist apoptosis, they persist within the tissue without being cleared. This persistence disrupts normal healing, revealing the similarities between unscheduled endocycling cells and chronic wounds. Our system has the potential to serve as a novel model for studying chronic wound responses or tumorigenesis.
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Worcester M, Nejad S, O’Donnell D, Arian S, Mishra P, Naeini AE, Li S, Yang K, Anbir A, Guevara M, Yuan NY, O’Leary S, Kaul M, Zandi R, Kuhlman TE. Human Stress Response Specificity through Bioresonance Selectivity. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.03.05.641735. [PMID: 40161696 PMCID: PMC11952327 DOI: 10.1101/2025.03.05.641735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 04/02/2025]
Abstract
In all eukaryotes, the mitogen activated protein kinase (MAPK) cascade, a multilayered interconnected network of enzymes, connects external stimuli to gene regulation, dictating cellular fate. However, mechanisms for encoding information in this complex, fluctuating network to activate specific responses remain elusive. Here, we demonstrate that the central human stress regulator protein p38 MAPK encodes information regarding experienced stresses as different frequency oscillations of its activation state. These oscillations are used to drive specific responses through frequency-dependent resonance of oscillating biochemical phosphorylation reactions between p38 and downstream targets. These interactions closely mirror those of electronic alternating current (AC) circuits and their components, providing a unique framework through which to understand signal transduction in the MAPK cascade. Finally, we demonstrate how this understanding of bioresonance allows us to induce specific genetic responses simply by exposing cells to sugar to force activation state oscillations of p38 at predetermined frequencies.
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Affiliation(s)
- Michael Worcester
- Department of Physics and Astronomy, University of California, Riverside; Riverside, CA, 92521, USA
| | - Shayan Nejad
- Department of Physics and Astronomy, University of California, Riverside; Riverside, CA, 92521, USA
| | - Devin O’Donnell
- Biophysics Program, University of California, Riverside; Riverside, CA, 92521, USA
| | - Surya Arian
- Microbiology Program, University of California, Riverside; Riverside, CA, 92521, USA
| | - Pratyasha Mishra
- Biophysics Program, University of California, Riverside; Riverside, CA, 92521, USA
| | - Arya Eimagh Naeini
- Department of Physics and Astronomy, University of California, Riverside; Riverside, CA, 92521, USA
| | - Siyu Li
- Department of Physics and Astronomy, California State Polytechnic University, Pomona; Pomona, CA, 91768, USA
| | - Kevin Yang
- Department of Physics and Astronomy, University of California, Riverside; Riverside, CA, 92521, USA
| | - Aisa Anbir
- Biophysics Program, University of California, Riverside; Riverside, CA, 92521, USA
| | - Matthew Guevara
- Department of Biochemistry, University of California, Riverside; Riverside, CA, 92521, USA
| | - Nina Y. Yuan
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside; Riverside, CA, 92521, USA
| | - Seán O’Leary
- Department of Biochemistry, University of California, Riverside; Riverside, CA, 92521, USA
| | - Marcus Kaul
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside; Riverside, CA, 92521, USA
| | - Roya Zandi
- Department of Physics and Astronomy, University of California, Riverside; Riverside, CA, 92521, USA
- Biophysics Program, University of California, Riverside; Riverside, CA, 92521, USA
| | - Thomas E. Kuhlman
- Department of Physics and Astronomy, University of California, Riverside; Riverside, CA, 92521, USA
- Biophysics Program, University of California, Riverside; Riverside, CA, 92521, USA
- Microbiology Program, University of California, Riverside; Riverside, CA, 92521, USA
- Department of Biochemistry, University of California, Riverside; Riverside, CA, 92521, USA
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Zhang Z, Zou Y, Song C, Cao K, Cai K, Chen S, Wu Y, Geng D, Sun G, Zhang N, Zhang X, Zhang Y, Sun Y, Zhang Y. Advances in the study of exosomes in cardiovascular diseases. J Adv Res 2024; 66:133-153. [PMID: 38123019 PMCID: PMC11674797 DOI: 10.1016/j.jare.2023.12.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 12/15/2023] [Accepted: 12/16/2023] [Indexed: 12/23/2023] Open
Abstract
BACKGROUND Cardiovascular disease (CVD) has been the leading cause of death worldwide for many years. In recent years, exosomes have gained extensive attention in the cardiovascular system due to their excellent biocompatibility. Studies have extensively researched miRNAs in exosomes and found that they play critical roles in various physiological and pathological processes in the cardiovascular system. These processes include promoting or inhibiting inflammatory responses, promoting angiogenesis, participating in cell proliferation and migration, and promoting pathological progression such as fibrosis. AIM OF REVIEW This systematic review examines the role of exosomes in various cardiovascular diseases such as atherosclerosis, myocardial infarction, ischemia-reperfusion injury, heart failure and cardiomyopathy. It also presents the latest treatment and prevention methods utilizing exosomes. The study aims to provide new insights and approaches for preventing and treating cardiovascular diseases by exploring the relationship between exosomes and these conditions. Furthermore, the review emphasizes the potential clinical use of exosomes as biomarkers for diagnosing cardiovascular diseases. KEY SCIENTIFIC CONCEPTS OF REVIEW Exosomes are nanoscale vesicles surrounded by lipid bilayers that are secreted by most cells in the body. They are heterogeneous, varying in size and composition, with a diameter typically ranging from 40 to 160 nm. Exosomes serve as a means of information communication between cells, carrying various biologically active substances, including lipids, proteins, and small RNAs such as miRNAs and lncRNAs. As a result, they participate in both physiological and pathological processes within the body.
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Affiliation(s)
- Zhaobo Zhang
- Department of Cardiology, The First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China
| | - Yuanming Zou
- Department of Cardiology, The First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China
| | - Chunyu Song
- Department of Cardiology, The First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China
| | - Kexin Cao
- Department of Cardiology, The First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China
| | - Kexin Cai
- Department of Cardiology, The First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China
| | - Shuxian Chen
- Department of Cardiology, The First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China
| | - Yanjiao Wu
- Department of Cardiology, The First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China
| | - Danxi Geng
- Department of Cardiology, The First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China
| | - Guozhe Sun
- Department of Cardiology, The First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China.
| | - Naijin Zhang
- Department of Cardiology, The First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China; Institute of Health Sciences, China Medical University, 77 Puhe Road, Shenbei New District, Shenyang, 110122, Liaoning Province, People's Republic of China; Key Laboratory of Reproductive and Genetic Medicine, China Medical University, National Health Commission, 77 Puhe Road, Shenbei New District, Shenyang, 110122, Liaoning Province, People's Republic of China.
| | - Xingang Zhang
- Department of Cardiology, The First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China.
| | - Yixiao Zhang
- Department of Urology Surgery, Shengjing Hospital of China Medical University, 36 Sanhao Street, Heping District, Shenyang, 110004, Liaoning Province, People's Republic of China.
| | - Yingxian Sun
- Department of Cardiology, The First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China; Institute of Health Sciences, China Medical University, 77 Puhe Road, Shenbei New District, Shenyang, 110122, Liaoning Province, People's Republic of China.
| | - Ying Zhang
- Department of Cardiology, The First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China; Institute of Health Sciences, China Medical University, 77 Puhe Road, Shenbei New District, Shenyang, 110122, Liaoning Province, People's Republic of China.
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Młynarska E, Badura K, Kurciński S, Sinkowska J, Jakubowska P, Rysz J, Franczyk B. The Role of MicroRNA in the Pathophysiology and Diagnosis of Viral Myocarditis. Int J Mol Sci 2024; 25:10933. [PMID: 39456716 PMCID: PMC11507602 DOI: 10.3390/ijms252010933] [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: 07/23/2024] [Revised: 10/03/2024] [Accepted: 10/08/2024] [Indexed: 10/28/2024] Open
Abstract
Myocarditis is a non-ischemic condition with a heterogeneous etiology, clinical course and prognosis. The most common etiology of myocarditis are viral infections, whereas the most severe complications are acute and chronic heart failure and sudden cardiac death. The heterogeneous clinical course of the disease, as well as the availability and costs of diagnostic tools such as cardiac magnetic resonance and endomyocardial biopsy, hinder the diagnosis of myocarditis and its underlying cause. Non-coding RNAs such as micro-RNAs (miRNAs; miR) have been shown to be involved in the disease's pathophysiology; however, their potential in disease diagnosis and treatment should also be considered. Non-coding RNAs are RNAs that are not translated into proteins, and they have the ability to regulate several intracellular pathways. MiRNAs regulate gene expression by binding with their targets and inhibiting protein synthesis by interfering with the translation of coding genes or causing the degradation of messenger RNA. Several miRNAs, such as miR-1, -133, -21, -15, -98, -126, -155, -148, -203, -208, -221, -222, -203 and -590, have been shown to be involved in the pathophysiology of viral myocarditis (VMC), and some of them have been shown to have diagnostic abilities. This article summarizes the available data on miRNAs and their associations with VMC.
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Affiliation(s)
- Ewelina Młynarska
- Department of Nephrocardiology, Medical University of Lodz, Ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Krzysztof Badura
- Department of Nephrocardiology, Medical University of Lodz, Ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Szymon Kurciński
- Department of Nephrocardiology, Medical University of Lodz, Ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Julia Sinkowska
- Department of Nephrocardiology, Medical University of Lodz, Ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Paulina Jakubowska
- Department of Nephrocardiology, Medical University of Lodz, Ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Jacek Rysz
- Department of Nephrology, Hypertension and Family Medicine, Medical University of Lodz, Ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Beata Franczyk
- Department of Nephrocardiology, Medical University of Lodz, Ul. Zeromskiego 113, 90-549 Lodz, Poland
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Khamrui E, Banerjee S, Mukherjee DD, Biswas K. Emerging role of MAPK signaling in glycosphingolipid-associated tumorigenesis. Glycoconj J 2024; 41:343-360. [PMID: 39368037 DOI: 10.1007/s10719-024-10168-5] [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: 08/16/2024] [Revised: 09/25/2024] [Accepted: 09/27/2024] [Indexed: 10/07/2024]
Abstract
Glycosphingolipids (GSLs) are a type of amphipathic lipid molecules consisting of hydrophobic ceramide backbone bound to carbohydrate moiety clustered in the cell surface microdomains named 'lipid rafts' and are known to participate in cell-cell communication as well as intra-cellular signaling, thereby facilitating critical normal cellular processes and functions. Over the past several decades, various GSLs have been reported to be aberrantly expressed in different cancers, many of which have been associated with their prognosis. The wide implication of MAPK signaling in controlling tumor growth, progression, and metastasis through activation of an upstream signaling cascade, often originating in the cell membrane, justifies the rationale for its plausible influence on MAPK signaling. This review highlights the role of GSLs and their metabolites in regulating different signaling pathways towards modulation of tumor cell growth, migration, and adhesion by interacting with various receptors [epidermal growth factor receptor (EGFR), and platelet derived growth factor receptor (PDGFR), and other receptor tyrosine kinases (RTKs)] leading to activation of the MAPK pathway. Furthermore, GSLs can influence the activity and localization of downstream signaling components in the MAPK pathway by regulating the activation state of kinases, which in turn, regulate the activity of MAPKs. Additionally, this review further consolidates the GSL-mediated modulation of MAPK pathway components through the regulation of gene expression. Finally, recent findings on GSL-MAPK crosstalk will be explored in this article for the identification of potential anti-cancer therapeutic targets.
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Affiliation(s)
- Elora Khamrui
- Department of Biological Sciences, Bose Institute, EN-80, Bidhan Nagar, Salt Lake, Sector-V, Kolkata, West Bengal, 700091, India
| | - Sounak Banerjee
- Department of Biological Sciences, Bose Institute, EN-80, Bidhan Nagar, Salt Lake, Sector-V, Kolkata, West Bengal, 700091, India
| | - Dipanwita Das Mukherjee
- Department of Biological Sciences, Bose Institute, EN-80, Bidhan Nagar, Salt Lake, Sector-V, Kolkata, West Bengal, 700091, India
| | - Kaushik Biswas
- Department of Biological Sciences, Bose Institute, EN-80, Bidhan Nagar, Salt Lake, Sector-V, Kolkata, West Bengal, 700091, India.
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Gupta PK, Orlovskiy S, Arias-Mendoza F, Nelson DS, Nath K. 1H and 31P Magnetic Resonance Spectroscopic Metabolomic Imaging: Assessing Mitogen-Activated Protein Kinase Inhibition in Melanoma. Cells 2024; 13:1220. [PMID: 39056801 PMCID: PMC11274771 DOI: 10.3390/cells13141220] [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: 06/18/2024] [Revised: 07/12/2024] [Accepted: 07/16/2024] [Indexed: 07/28/2024] Open
Abstract
The MAPK signaling pathway with BRAF mutations has been shown to drive the pathogenesis of 40-60% of melanomas. Inhibitors of this pathway's BRAF and MEK components are currently used to treat these malignancies. However, responses to these treatments are not always successful. Therefore, identifying noninvasive biomarkers to predict treatment responses is essential for personalized medicine in melanoma. Using noninvasive 1H magnetic resonance spectroscopy (1H MRS), we previously showed that BRAF inhibition reduces lactate and alanine tumor levels in the early stages of effective therapy and could be considered as metabolic imaging biomarkers for drug response. The present work demonstrates that these metabolic changes observed by 1H MRS and those assessed by 31P MRS are also found in preclinical human melanoma models treated with MEK inhibitors. Apart from 1H and 31P MRS, additional supporting in vitro biochemical analyses are described. Our results indicate significant early metabolic correlations with response levels to MEK inhibition in the melanoma models and are consistent with our previous study of BRAF inhibition. Given these results, our study supports the potential clinical utility of noninvasive MRS to objectively image metabolic biomarkers for the early prediction of melanoma's response to MEK inhibition.
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Affiliation(s)
- Pradeep Kumar Gupta
- Molecular Imaging Laboratory, Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA; (S.O.); (F.A.-M.); (D.S.N.)
| | - Stepan Orlovskiy
- Molecular Imaging Laboratory, Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA; (S.O.); (F.A.-M.); (D.S.N.)
| | - Fernando Arias-Mendoza
- Molecular Imaging Laboratory, Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA; (S.O.); (F.A.-M.); (D.S.N.)
- Advanced Imaging Research, Inc., Cleveland, OH 44114, USA
| | - David S. Nelson
- Molecular Imaging Laboratory, Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA; (S.O.); (F.A.-M.); (D.S.N.)
| | - Kavindra Nath
- Molecular Imaging Laboratory, Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA; (S.O.); (F.A.-M.); (D.S.N.)
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Adegbola PI, Adetutu A. Genetic and epigenetic modulations in toxicity: The two-sided roles of heavy metals and polycyclic aromatic hydrocarbons from the environment. Toxicol Rep 2024; 12:502-519. [PMID: 38774476 PMCID: PMC11106787 DOI: 10.1016/j.toxrep.2024.04.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Revised: 04/27/2024] [Accepted: 04/27/2024] [Indexed: 05/24/2024] Open
Abstract
This study emphasizes the importance of considering the metabolic and toxicity mechanisms of environmental concern chemicals in real-life exposure scenarios. Furthermore, environmental chemicals may require metabolic activation to become toxic, and competition for binding sites on receptors can affect the severity of toxicity. The multicomplex process of chemical toxicity is reflected in the activation of multiple pathways during toxicity of which AhR activation is major. Real-life exposure to a mixture of concern chemicals is common, and the composition of these chemicals determines the severity of toxicity. Nutritional essential elements can mitigate the toxicity of toxic heavy metals, while the types and ratio of composition of PAH can either increase or decrease toxicity. The epigenetic mechanisms of heavy metals and PAH toxicity involves either down-regulation or up-regulation of some non-coding RNAs (ncRNAs) whereas specific small RNAs (sRNAs) may have dual role depending on the tissue and circumstance of expression. Similarly, decrease DNA methylation and histone modification are major players in heavy metals and PAH mediated toxicity and FLT1 hypermethylation is a major process in PAH induced carcinogenesis. Overall, this review provides the understanding of the metabolism of environmental concern chemicals, emphasizing the importance of considering mixed compositions and real-life exposure scenarios in assessing their potential effects on human health and diseases development as well as the dual mechanism of toxicity via genetic or epigenetic axis.
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Affiliation(s)
- Peter Ifeoluwa Adegbola
- Department of Biochemistry and Forensic Science, First Technical University, Ibadan, Nigeria
| | - Adewale Adetutu
- Department of Biochemistry, Faculty of Basic Medical Sciences, Ladoke Akintola University of Technology, Ogbomoso, Nigeria
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Bommaraju S, Dhokne MD, Arun EV, Srinivasan K, Sharma SS, Datusalia AK. An insight into crosstalk among multiple signalling pathways contributing to the pathophysiology of PTSD and depressive disorders. Prog Neuropsychopharmacol Biol Psychiatry 2024; 131:110943. [PMID: 38228244 DOI: 10.1016/j.pnpbp.2024.110943] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2023] [Revised: 01/08/2024] [Accepted: 01/10/2024] [Indexed: 01/18/2024]
Abstract
Post-traumatic stress disorder (PTSD) and depressive disorders represent two significant mental health challenges with substantial global prevalence. These are debilitating conditions characterized by persistent, often comorbid, symptoms that severely impact an individual's quality of life. Both PTSD and depressive disorders are often precipitated by exposure to traumatic events or chronic stress. The profound impact of PTSD and depressive disorders on individuals and society necessitates a comprehensive exploration of their shared and distinct pathophysiological features. Although the activation of the stress system is essential for maintaining homeostasis, the ability to recover from it after diminishing the threat stimulus is also equally important. However, little is known about the main reasons for individuals' differential susceptibility to external stressful stimuli. The solution to this question can be found by delving into the interplay of stress with the cognitive and emotional processing of traumatic incidents at the molecular level. Evidence suggests that dysregulation in these signalling cascades may contribute to the persistence and severity of PTSD and depressive symptoms. The treatment strategies available for this disorder are antidepressants, which have shown good efficiency in normalizing symptom severity; however, their efficacy is limited in most individuals. This calls for the exploration and development of innovative medications to address the treatment of PTSD. This review delves into the intricate crosstalk among multiple signalling pathways implicated in the development and manifestation of these mental health conditions. By unravelling the complexities of crosstalk among multiple signalling pathways, this review aims to contribute to the broader knowledge base, providing insights that could inform the development of targeted interventions for individuals grappling with the challenges of PTSD and depressive disorders.
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Affiliation(s)
- Sumadhura Bommaraju
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Raebareli, Uttar Pradesh (UP) 226002, India
| | - Mrunali D Dhokne
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Raebareli, Uttar Pradesh (UP) 226002, India
| | - E V Arun
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Raebareli, Uttar Pradesh (UP) 226002, India
| | - Krishnamoorthy Srinivasan
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), SAS Nagar, Punjab 160062, India
| | - Shyam Sunder Sharma
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), SAS Nagar, Punjab 160062, India
| | - Ashok Kumar Datusalia
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Raebareli, Uttar Pradesh (UP) 226002, India; Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER) Raebareli, Uttar Pradesh (UP) 226002, India.
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10
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Engin A. Protein Kinases in Obesity, and the Kinase-Targeted Therapy. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1460:199-229. [PMID: 39287853 DOI: 10.1007/978-3-031-63657-8_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/19/2024]
Abstract
The action of protein kinases and protein phosphatases is essential for multiple physiological responses. Each protein kinase displays its own unique substrate specificity and a regulatory mechanism that may be modulated by association with other proteins. Protein kinases are classified as dual-specificity kinases and dual-specificity phosphatases. Dual-specificity phosphatases are important signal transduction enzymes that regulate various cellular processes in coordination with protein kinases and play an important role in obesity. Impairment of insulin signaling in obesity is largely mediated by the activation of the inhibitor of kappa B-kinase beta and the c-Jun N-terminal kinase (JNK). Oxidative stress and endoplasmic reticulum (ER) stress activate the JNK pathway which suppresses insulin biosynthesis. Adenosine monophosphate (AMP)-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) are important for proper regulation of glucose metabolism in mammals at both the hormonal and cellular levels. Additionally, obesity-activated calcium/calmodulin dependent-protein kinase II/p38 suppresses insulin-induced protein kinase B phosphorylation by activating the ER stress effector, activating transcription factor-4. To alleviate lipotoxicity and insulin resistance, promising targets are pharmacologically inhibited. Nifedipine, calcium channel blocker, stimulates lipogenesis and adipogenesis by downregulating AMPK and upregulating mTOR, which thereby enhances lipid storage. Contrary to the nifedipine, metformin activates AMPK, increases fatty acid oxidation, suppresses fatty acid synthesis and deposition, and thus alleviates lipotoxicity. Obese adults with vascular endothelial dysfunction have greater endothelial cells activation of unfolded protein response stress sensors, RNA-dependent protein kinase-like ER eukaryotic initiation factor-2 alpha kinase (PERK), and activating transcription factor-6. The transcriptional regulation of adipogenesis in obesity is influenced by AGC (protein kinase A (PKA), PKG, PKC) family signaling kinases. Obesity may induce systemic oxidative stress and increase reactive oxygen species in adipocytes. An increase in intracellular oxidative stress can promote PKC-β activation. Activated PKC-β induces growth factor adapter Shc phosphorylation. Shc-generated peroxides reduce mitochondrial oxygen consumption and enhance triglyceride accumulation and lipotoxicity. Liraglutide attenuates mitochondrial dysfunction and reactive oxygen species generation. Co-treatment of antiobesity and antidiabetic herbal compound, berberine with antipsychotic drug olanzapine decreases the accumulation of triglyceride. While low-dose rapamycin, metformin, amlexanox, thiazolidinediones, and saroglitazar protect against insulin resistance, glucagon-like peptide-1 analog liraglutide inhibits palmitate-induced inflammation by suppressing mTOR complex 1 (mTORC1) activity and protects against lipotoxicity.
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Affiliation(s)
- Atilla Engin
- Faculty of Medicine, Department of General Surgery, Gazi University, Besevler, Ankara, Turkey.
- Mustafa Kemal Mah. 2137. Sok. 8/14, 06520, Cankaya, Ankara, Turkey.
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Gladkikh BP, Danilov DV, D’yachenko VS, Butov GM. 1,3-Dichloroadamantyl-Containing Ureas as Potential Triple Inhibitors of Soluble Epoxide Hydrolase, p38 MAPK and c-Raf. Int J Mol Sci 2023; 25:338. [PMID: 38203510 PMCID: PMC10779153 DOI: 10.3390/ijms25010338] [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: 11/24/2023] [Revised: 12/21/2023] [Accepted: 12/21/2023] [Indexed: 01/12/2024] Open
Abstract
Soluble epoxide hydrolase (sEH) is an enzyme involved in the metabolism of bioactive lipid signaling molecules. sEH converts epoxyeicosatrienoic acids (EET) to virtually inactive dihydroxyeicosatrienoic acids (DHET). The first acids are "medicinal" molecules, the second increase the inflammatory infiltration of cells. Mitogen-activated protein kinases (p38 MAPKs) are key protein kinases involved in the production of inflammatory mediators, including tumor necrosis factor-α (TNF-α) and cyclooxygenase-2 (COX-2). p38 MAPK signaling plays an important role in the regulation of cellular processes, especially inflammation. The proto-oncogenic serine/threonine protein kinase Raf (c-Raf) is a major component of the mitogen-activated protein kinase (MAPK) pathway: ERK1/2 signaling. Normal cellular Raf genes can also mutate and become oncogenes, overloading the activity of MEK1/2 and ERK1/2. The development of multitarget inhibitors is a promising strategy for the treatment of socially dangerous diseases. We synthesized 1,3-disubstituted ureas and diureas containing a dichloroadamantyl moiety. The results of computational methods show that soluble epoxide hydrolase inhibitors can act on two more targets in different signaling pathways of mitogen-activated protein kinases p38 MAPK and c-Raf. The two chlorine atoms in the adamantyl moiety may provide additional Cl-π interactions in the active site of human sEH. Molecular dynamics studies have shown that the stability of ligand-protein complexes largely depends on the "spacer effect." The compound containing a bridge between the chloroadamantyl fragment and the ureide group forms more stable ligand-protein complexes with sEH and p38 MAPK, which indicates a better conformational ability of the molecule in the active sites of these targets. In turn, a compound containing two chlorine atoms forms a more stable complex with c-Raf, probably due to the presence of additional halogen bonds of chlorine atoms with amino acid residues.
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Affiliation(s)
- Boris P. Gladkikh
- Department of Technology of Organic and Petrochemical Synthesis, Volgograd State Technical University, Volgograd 400005, Russia; (B.P.G.); (D.V.D.); (G.M.B.)
| | - Dmitry V. Danilov
- Department of Technology of Organic and Petrochemical Synthesis, Volgograd State Technical University, Volgograd 400005, Russia; (B.P.G.); (D.V.D.); (G.M.B.)
| | - Vladimir S. D’yachenko
- Department of Technology of Organic and Petrochemical Synthesis, Volgograd State Technical University, Volgograd 400005, Russia; (B.P.G.); (D.V.D.); (G.M.B.)
- Department of Chemistry, Technology and Equipment of Chemical Industry, Volzhsky Polytechnic Institute (Branch), Volgograd State Technical University (VSTU), Volzhsky 404121, Russia
| | - Gennady M. Butov
- Department of Technology of Organic and Petrochemical Synthesis, Volgograd State Technical University, Volgograd 400005, Russia; (B.P.G.); (D.V.D.); (G.M.B.)
- Department of Chemistry, Technology and Equipment of Chemical Industry, Volzhsky Polytechnic Institute (Branch), Volgograd State Technical University (VSTU), Volzhsky 404121, Russia
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12
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Murata T, Ishiwa S, Lin X, Nakazawa Y, Tago K, Funakoshi-Tago M. The citrus flavonoid, nobiletin inhibits neuronal inflammation by preventing the activation of NF-κB. Neurochem Int 2023; 171:105613. [PMID: 37774798 DOI: 10.1016/j.neuint.2023.105613] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 07/21/2023] [Accepted: 09/11/2023] [Indexed: 10/01/2023]
Abstract
Nobiletin (5,6,7,8,3',4'-hexamethoxyflavone) is one of the flavonoids found in shikuwasa, a popular citrus fruit in Okinawa, Japan. It exerts various pharmacological effects, such as anti-tumor, antioxidant, and anti-inflammatory activities. We herein investigated whether nobiletin attenuated lipopolysaccharide (LPS)-induced inflammatory responses in the murine microglial cell line BV-2 and neuroinflammation in mice induced by an intracerebral injection of LPS. In BV-2 cells, nobiletin significantly inhibited the LPS-induced production of nitric oxide (NO) and prostaglandin E2 (PGE2) by preventing the mRNA expression of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2), respectively. Nobiletin also inhibited the LPS-induced mRNA expression of CCL2, CXCL1, IL-6, and TNFα. Nobiletin markedly attenuated the transcriptional activity of the NF-κB p65 subunit without affecting the degradation of IκBα or the nuclear localization of the NF-κB p65 subunit. Nobiletin also inhibited the LPS-induced activation of JNK, but not ERK or p38, in BV-2 cells. Furthermore, the administration of nobiletin significantly suppressed the accumulation of microglia and induction of the mRNA expression of CCL2, CXCL1, IL-6, and TNFα in the murine brain induced by injecting LPS into the striatum. Collectively, these results suggest the potential of nobiletin as a candidate anti-inflammatory drug for the prevention of neuroinflammation.
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Affiliation(s)
- Taisuke Murata
- Division of Hygienic Chemistry, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan
| | - Sho Ishiwa
- Division of Hygienic Chemistry, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan
| | - Xin Lin
- Division of Hygienic Chemistry, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan
| | - Yosuke Nakazawa
- Division of Hygienic Chemistry, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan
| | - Kenji Tago
- Department of Laboratory Sciences, Gunma University Graduate School of Health Sciences, 3-39-22 Showa-Machi, Maebashi, Gunma, 371-8514, Japan.
| | - Megumi Funakoshi-Tago
- Division of Hygienic Chemistry, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan.
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13
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Lin CY, Zhang YM, Li BZ, Shu MA, Xu WB. Identification and characterization of mitogen-activated protein kinase kinase 4 (MKK4) from the mud crab Scylla paramamosain in response to Vibrio alginolyticus and White Spot Syndrome Virus (WSSV). DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2023; 147:104755. [PMID: 37295629 DOI: 10.1016/j.dci.2023.104755] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 06/03/2023] [Accepted: 06/07/2023] [Indexed: 06/12/2023]
Abstract
Mitogen-activated protein kinase kinase 4 (MKK4), serves as a critical component of the mitogen-activated protein kinase signaling pathway, facilitating the direct phosphorylation and activation of the c-Jun N-terminal kinase (JNK) and p38 families of MAP kinases in response to environmental stresses. In the current research, we identified two MKK4 subtypes, namely SpMKK4-1 and SpMKK4-2, from Scylla paramamosain, followed by the analysis of their molecular characteristics and tissue distributions. The expression of SpMKK4s was induced upon WSSV and Vibrio alginolyticus challenges, and the bacteria clearance capacity and antimicrobial peptide (AMP) genes' expression upon bacterial infection were significantly decreased after knocking down SpMKK4s. Additionally, the overexpression of both SpMKK4s remarkably activated NF-κB reporter plasmid in HEK293T cells, suggesting the activation of the NF-κB signaling pathway. These results indicated the participation of SpMKK4s in the innate immunity of crabs, which shed light on a better understanding of the mechanisms through which MKK4s regulate innate immunity.
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Affiliation(s)
- Chen-Yang Lin
- College of Animal Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Yan-Mei Zhang
- College of Animal Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Bang-Ze Li
- College of Animal Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Miao-An Shu
- College of Animal Sciences, Zhejiang University, Hangzhou, 310058, China.
| | - Wen-Bin Xu
- College of Animal Sciences, Zhejiang University, Hangzhou, 310058, China.
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14
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Yaghoobi A, Seyedmirzaei H, Ala M. Genome- and Exome-Wide Association Studies Revealed Candidate Genes Associated with DaTscan Imaging Features. PARKINSON'S DISEASE 2023; 2023:2893662. [PMID: 37664790 PMCID: PMC10468272 DOI: 10.1155/2023/2893662] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 07/02/2023] [Accepted: 08/16/2023] [Indexed: 09/05/2023]
Abstract
Introduction Despite remarkable progress in identifying Parkinson's disease (PD) genetic risk loci, the genetic basis of PD remains largely unknown. With the help of the endophenotype approach and using data from dopamine transporter single-photon emission computerized tomography (DaTscan), we identified potentially involved genes in PD. Method We conducted an imaging genetic study by performing exome-wide association study (EWAS) and genome-wide association study (GWAS) on the specific binding ratio (SBR) of six DaTscan anatomical areas between 489 and 559 subjects of Parkinson's progression markers initiative (PPMI) cohort and 83,623 and 36,845 single-nucleotide polymorphisms (SNPs)/insertion-deletion mutations (INDELs). We also investigated the association of cerebrospinal fluid (CSF) protein concentration of our significant genes with PD progression using PPMI CSF proteome data. Results Among 83,623 SNPs/INDELs in EWAS, one SNP (rs201465075) on 1 q32.1 locus was significantly (P value = 4.03 × 10-7) associated with left caudate DaTscan SBR, and 33 SNPs were suggestive. Among 36,845 SNPs in GWAS, one SNP (rs12450112) on 17 p.12 locus was significantly (P value = 1.34 × 10-6) associated with right anterior putamen DaTscan SBR, and 39 SNPs were suggestive among which 8 SNPs were intergenic. We found that rs201465075 and rs12450112 are most likely related to IGFN1 and MAP2K4 genes. The protein level of MAP2K4 in the CSF was significantly associated with PD progression in the PPMI cohort; however, proteomic data were not available for the IGFN1 gene. Conclusion We have shown that particular variants of IGFN1 and MAP2K4 genes may be associated with PD. Since DaTscan imaging could be positive in other Parkinsonian syndromes, caution should be taken when interpreting our results. Future experimental studies are also needed to verify these findings.
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Affiliation(s)
- Arash Yaghoobi
- Institute for Research in Fundamental Sciences (IPM), School of Biological Sciences, Tehran, Iran
| | - Homa Seyedmirzaei
- Interdisciplinary Neuroscience Research Program (INRP), Tehran University of Medical Sciences, Tehran, Iran
- Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Moein Ala
- Experimental Research Center, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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Katzengruber L, Sander P, Laufer S. MKK4 Inhibitors-Recent Development Status and Therapeutic Potential. Int J Mol Sci 2023; 24:ijms24087495. [PMID: 37108658 PMCID: PMC10144091 DOI: 10.3390/ijms24087495] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 04/12/2023] [Accepted: 04/18/2023] [Indexed: 04/29/2023] Open
Abstract
MKK4 (mitogen-activated protein kinase kinase 4; also referred to as MEK4) is a dual-specificity protein kinase that phosphorylates and regulates both JNK (c-Jun N-terminal kinase) and p38 MAPK (p38 mitogen-activated protein kinase) signaling pathways and therefore has a great impact on cell proliferation, differentiation and apoptosis. Overexpression of MKK4 has been associated with aggressive cancer types, including metastatic prostate and ovarian cancer and triple-negative breast cancer. In addition, MKK4 has been identified as a key regulator in liver regeneration. Therefore, MKK4 is a promising target both for cancer therapeutics and for the treatment of liver-associated diseases, offering an alternative to liver transplantation. The recent reports on new inhibitors, as well as the formation of a startup company investigating an inhibitor in clinical trials, show the importance and interest of MKK4 in drug discovery. In this review, we highlight the significance of MKK4 in cancer development and other diseases, as well as its unique role in liver regeneration. Furthermore, we present the most recent progress in MKK4 drug discovery and future challenges in the development of MKK4-targeting drugs.
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Affiliation(s)
- Leon Katzengruber
- Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmaceutical Sciences, Faculty of Sciences, University of Tuebingen, 72076 Tübingen, Germany
| | - Pascal Sander
- Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmaceutical Sciences, Faculty of Sciences, University of Tuebingen, 72076 Tübingen, Germany
| | - Stefan Laufer
- Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmaceutical Sciences, Faculty of Sciences, University of Tuebingen, 72076 Tübingen, Germany
- Cluster of Excellence iFIT (EXC 2180) 'Image-Guided & Functionally Instructed Tumor Therapies', Eberhard Karls Universität Tübingen, 72076 Tübingen, Germany
- Tübingen Center for Academic Drug Discovery, Auf der Morgenstelle 8, 72076 Tübingen, Germany
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16
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Wang L, Mi D, Hu J, Liu W, Zhang Y, Wang C, Chen Y, Chen C. A novel methuosis inducer DZ-514 possesses antitumor activity via activation of ROS-MKK4-p38 axis in triple negative breast cancer. Cancer Lett 2023; 555:216049. [PMID: 36608865 DOI: 10.1016/j.canlet.2022.216049] [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: 11/10/2022] [Revised: 12/25/2022] [Accepted: 12/27/2022] [Indexed: 01/09/2023]
Abstract
Triple-negative breast cancer (TNBC) is one of the most malignant tumors with poor prognosis. Methuosis is a new type of nonapoptotic cell death characterized by the accumulation of cytoplasmic vacuoles. In this study, we synthesized and screened a series of N-phenyl-4-pyrimidinediamine derivatives in TNBC cells, finding that DZ-514 was the best compound with high toxicity independent of the inhibition of BCL6. DZ-514 decreased cell viability, inhibited cell cycle progression, and induced caspase-independent cell death in TNBC cells. Interestingly, DZ-514 induced cytoplasm vacuolation, which could be blocked by Baf A1, the V-ATPase inhibitor. Furthermore, we found that DZ-514-induced vacuoles were derived from macropinosomes rather than autophagosomes. Most importantly, methuosis induced by DZ-514 was partially mediated by activating the ROS-MKK4-p38 axis. Finally, we demonstrated that DZ-514 significantly inhibited tumor growth in an HCC1806 xenograft mouse model. These findings revealed that the novel methuosis inducer DZ-514 could be developed for TNBC treatment.
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Affiliation(s)
- Luzhen Wang
- School of Life Science, University of Science & Technology of China, Hefei, 230027, Anhui, China; Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, China
| | - Dazhao Mi
- Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Jinhui Hu
- The First Hospital of Hunan University of Chinese Medicine, Changsha, 410007, Hunan, China
| | - Wenjing Liu
- The Third Affiliated Hospital, Kunming Medical University, Kunming, 650118, China
| | - Yi Zhang
- Department of Breast and Thyroid Surgery, Southwest Hospital, The First Affiliated Hospital of the Army Military Medical University, Chongqing, 400038, China
| | - Chunyan Wang
- Department of the Pathology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, 650032, China.
| | - Yihua Chen
- Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China.
| | - Ceshi Chen
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, China; The Third Affiliated Hospital, Kunming Medical University, Kunming, 650118, China; Academy of Biomedical Engineering, Kunming Medical University, Kunming, 650500, China.
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Gümüş M, Koca İ, Sert Y, Dişli A, Yenilmez Tunoğlu EN, Tutar L, Tutar Y. Triad pyrazole-thiazole-coumarin heterocyclic core effectively inhibit HSP and drive cancer cells to apoptosis. J Biomol Struct Dyn 2023; 41:14382-14397. [PMID: 36826447 DOI: 10.1080/07391102.2023.2181643] [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: 01/10/2023] [Accepted: 02/11/2023] [Indexed: 02/25/2023]
Abstract
Intensive studies on hepatocellular carcinoma (HCC), which is spreading rapidly around the world and has a high mortality rate, is due to the lack of adequate preventive or curative treatment methods. Treating patients with HCC has become very challenging because of the heterogeneity in the patient population lead activation of different signaling pathways, and pathway crosstalk for patients. Therefore, understanding these molecular mechanisms and combining drugs with molecular therapies to overcome these drawbacks has become an area of utmost importance. In this study, the biological activities of the designed and characterized triad Pyrazole-Thiazol-Coumarin (PTC) compounds were determined by performing cell viability, qPCR array, apoptosis and cell cycle assays. One of the compounds (PTC10) implicitly suppresses multiple pathways (RAS/MAP kinase and PI3K-AKT) simultaneously. This action is provided by (i) arresting cancer cells at G2 phase, (ii) driving cancer cells to apoptosis and (iii) inhibiting HSP network. Remarkably, HSP is an apoptotic factor and help cancer cell to survive. HSP90 also coordinates with Cdk4/Cdc37, therefore inhibiting HSP both drives cells to arrest and apoptosis. ATP hydrolysis and aggregation assay further displayed specific HSP inhibition. Therefore, PTC provides a unique drug template for HCC treatment.
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Affiliation(s)
- Mehmet Gümüş
- Akdağmadeni Health College, Yozgat Bozok University, Yozgat, Türkiye
| | - İrfan Koca
- Department of Chemistry, Faculty of Arts and Science, Yozgat Bozok University, Yozgat, Türkiye
| | - Yusuf Sert
- Sorgun Vocational School, Yozgat Bozok University, Yozgat, Türkiye
| | - Ali Dişli
- Department of Chemistry, Faculty of Sciences, Gazi University, Ankara, Türkiye
| | | | - Lütfi Tutar
- Department of Molecular Biology and Genetics, Faculty of Arts and Sciences, Ahi Evran University, Kırşehir, Türkiye
| | - Yusuf Tutar
- Division of Biochemistry, Faculty of Pharmacy, University of Health Sciences, Istanbul, Türkiye
- Molecular Oncology Division, Health Sciences Institutes, Istanbul, Türkiye
- Personalized and Immunotherapy Applied Research Center, University of Health Sciences, Istanbul, Türkiye
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García-Flores N, Jiménez-Suárez J, Garnés-García C, Fernández-Aroca DM, Sabater S, Andrés I, Fernández-Aramburo A, Ruiz-Hidalgo MJ, Belandia B, Sanchez-Prieto R, Cimas FJ. P38 MAPK and Radiotherapy: Foes or Friends? Cancers (Basel) 2023; 15:861. [PMID: 36765819 PMCID: PMC9913882 DOI: 10.3390/cancers15030861] [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: 12/03/2022] [Revised: 01/16/2023] [Accepted: 01/24/2023] [Indexed: 01/31/2023] Open
Abstract
Over the last 30 years, the study of the cellular response to ionizing radiation (IR) has increased exponentially. Among the various signaling pathways affected by IR, p38 MAPK has been shown to be activated both in vitro and in vivo, with involvement in key processes triggered by IR-mediated genotoxic insult, such as the cell cycle, apoptosis or senescence. However, we do not yet have a definitive clue about the role of p38 MAPK in terms of radioresistance/sensitivity and its potential use to improve current radiotherapy. In this review, we summarize the current knowledge on this family of MAPKs in response to IR as well as in different aspects related to radiotherapy, such as their role in the control of REDOX, fibrosis, and in the radiosensitizing effect of several compounds.
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Affiliation(s)
- Natalia García-Flores
- Laboratorio de Oncología Molecular, Unidad de Medicina Molecular, Centro Regional de Investigaciones Biomédicas, Unidad Asociada de Biomedicina UCLM, Unidad Asociada al CSIC, Universidad de Castilla-La Mancha, 02008 Albacete, Spain
| | - Jaime Jiménez-Suárez
- Laboratorio de Oncología Molecular, Unidad de Medicina Molecular, Centro Regional de Investigaciones Biomédicas, Unidad Asociada de Biomedicina UCLM, Unidad Asociada al CSIC, Universidad de Castilla-La Mancha, 02008 Albacete, Spain
| | - Cristina Garnés-García
- Laboratorio de Oncología Molecular, Unidad de Medicina Molecular, Centro Regional de Investigaciones Biomédicas, Unidad Asociada de Biomedicina UCLM, Unidad Asociada al CSIC, Universidad de Castilla-La Mancha, 02008 Albacete, Spain
| | - Diego M. Fernández-Aroca
- Laboratorio de Oncología Molecular, Unidad de Medicina Molecular, Centro Regional de Investigaciones Biomédicas, Unidad Asociada de Biomedicina UCLM, Unidad Asociada al CSIC, Universidad de Castilla-La Mancha, 02008 Albacete, Spain
| | - Sebastia Sabater
- Laboratorio de Oncología Molecular, Unidad de Medicina Molecular, Centro Regional de Investigaciones Biomédicas, Unidad Asociada de Biomedicina UCLM, Unidad Asociada al CSIC, Universidad de Castilla-La Mancha, 02008 Albacete, Spain
- Servicio de Oncología Radioterápica, Complejo Hospitalario Universitario de Albacete, 02006 Albacete, Spain
| | - Ignacio Andrés
- Laboratorio de Oncología Molecular, Unidad de Medicina Molecular, Centro Regional de Investigaciones Biomédicas, Unidad Asociada de Biomedicina UCLM, Unidad Asociada al CSIC, Universidad de Castilla-La Mancha, 02008 Albacete, Spain
- Servicio de Oncología Radioterápica, Complejo Hospitalario Universitario de Albacete, 02006 Albacete, Spain
| | - Antonio Fernández-Aramburo
- Laboratorio de Oncología Molecular, Unidad de Medicina Molecular, Centro Regional de Investigaciones Biomédicas, Unidad Asociada de Biomedicina UCLM, Unidad Asociada al CSIC, Universidad de Castilla-La Mancha, 02008 Albacete, Spain
- Servicio de Oncología Médica, Complejo Hospitalario Universitario de Albacete, 02006 Albacete, Spain
| | - María José Ruiz-Hidalgo
- Laboratorio de Oncología Molecular, Unidad de Medicina Molecular, Centro Regional de Investigaciones Biomédicas, Unidad Asociada de Biomedicina UCLM, Unidad Asociada al CSIC, Universidad de Castilla-La Mancha, 02008 Albacete, Spain
- Departamento de Química Inorgánica, Orgánica y Bioquímica, Área de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Castilla-La Mancha, 02008 Albacete, Spain
| | - Borja Belandia
- Departamento de Biología del Cáncer, Instituto de Investigaciones Biomédicas ‘Alberto Sols’ (CSIC-UAM), Unidad Asociada de Biomedicina UCLM, Unidad Asociada al CSIC, 28029 Madrid, Spain
| | - Ricardo Sanchez-Prieto
- Laboratorio de Oncología Molecular, Unidad de Medicina Molecular, Centro Regional de Investigaciones Biomédicas, Unidad Asociada de Biomedicina UCLM, Unidad Asociada al CSIC, Universidad de Castilla-La Mancha, 02008 Albacete, Spain
- Departamento de Biología del Cáncer, Instituto de Investigaciones Biomédicas ‘Alberto Sols’ (CSIC-UAM), Unidad Asociada de Biomedicina UCLM, Unidad Asociada al CSIC, 28029 Madrid, Spain
- Departamento de Ciencias Médicas, Facultad de Medicina, Universidad de Castilla-La Mancha, 02008 Albacete, Spain
| | - Francisco J. Cimas
- Laboratorio de Oncología Molecular, Unidad de Medicina Molecular, Centro Regional de Investigaciones Biomédicas, Unidad Asociada de Biomedicina UCLM, Unidad Asociada al CSIC, Universidad de Castilla-La Mancha, 02008 Albacete, Spain
- Departamento de Química Inorgánica, Orgánica y Bioquímica, Área de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Castilla-La Mancha, 02008 Albacete, Spain
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Yeo JH, Roh DH. The mTOR inhibitor rapamycin suppresses trigeminal neuropathic pain and p-MKK4/p-p38 mitogen-activated protein kinase-mediated microglial activation in the trigeminal nucleus caudalis of mice with infraorbital nerve injury. Front Mol Neurosci 2023; 16:1172366. [PMID: 37122619 PMCID: PMC10140572 DOI: 10.3389/fnmol.2023.1172366] [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: 02/23/2023] [Accepted: 03/27/2023] [Indexed: 05/02/2023] Open
Abstract
Neuropathic pain caused by trigeminal nerve injury is a typical refractory orofacial chronic pain accompanied by the development of hyperalgesia and allodynia. We previously demonstrated that the mammalian target of rapamycin (mTOR) inhibitor rapamycin suppressed orofacial formalin injection-induced nociception; however, the underlying mechanism is unclear, and it is unknown whether it can reduce trigeminal neuropathic pain. In mice, left infraorbital nerve and partial nerve ligation (ION-pNL) was performed using a silk suture (8-0). Fourteen days after surgery, neuropathic pain behavior was examined on a whisker pad and rapamycin (0.1, 0.3, and 1.0 mg/kg) was administered intraperitoneally. Mechanical and cold sensitivities in the orofacial region were quantified using von Frey filaments and acetone solution, respectively. Changes in mTOR and related proteins, such as p-MKK3/6, p-MKK4, p-JNK, p-ERK, p-p38 MAPK, GFAP, and Iba-1, in the trigeminal nucleus caudalis (TNC) or the trigeminal ganglia (TG) tissues were examined via western blot analysis or immunohistochemistry. Mice demonstrated significant mechanical and cold allodynia 2 weeks following ION-pNL injury, both of which were significantly reduced 1 h after the administration of high-dose rapamycin (1.0 mg/kg). In the TG tissue, ION-pNL surgery or rapamycin treatment did not change p-mTOR and p-4EBP1, but rapamycin reduced the increase of p-S6 and S6 induced by ION-pNL. In the TNC tissue, neither ION-pNL surgery nor rapamycin treatment altered p-mTOR, p-S6, and p-4EBP1 expressions, whereas rapamycin significantly decreased the ION-pNL-induced increase in Iba-1 expression. In addition, rapamycin suppressed the increase in p-p38 MAPK and p-MKK4 expressions but not p-MKK3/6 expression. Moreover, p-p38 MAPK-positive cells were colocalized with increased Iba-1 in the TNC. Our findings indicate that rapamycin treatment reduces both mechanical and cold orofacial allodynia in mice with trigeminal neuropathic pain, which is closely associated with the modulation of p-MKK4/p-p38 MAPK-mediated microglial activation in the TNC.
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Kerneur C, Cano CE, Olive D. Major pathways involved in macrophage polarization in cancer. Front Immunol 2022; 13:1026954. [PMID: 36325334 PMCID: PMC9618889 DOI: 10.3389/fimmu.2022.1026954] [Citation(s) in RCA: 111] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Accepted: 09/23/2022] [Indexed: 11/16/2022] Open
Abstract
Macrophages play an important role in tissue homeostasis, tissue remodeling, immune response, and progression of cancer. Consequently, macrophages exhibit significant plasticity and change their transcriptional profile and function in response to environmental, tissue, and inflammatory stimuli resulting in pro- and anti-tumor effects. Furthermore, the categorization of tissue macrophages in inflammatory situations remains difficult; however, there is an agreement that macrophages are predominantly polarized into two different subtypes with pro- and anti-inflammatory properties, the so-called M1-like and M2-like macrophages, respectively. These two macrophage classes can be considered as the extreme borders of a continuum of many intermediate subsets. On one end, M1 are pro-inflammatory macrophages that initiate an immunological response, damage tissue integrity, and dampen tumor progression by fostering robust T and natural killer (NK) cell anti-tumoral responses. On the other end, M2 are anti-inflammatory macrophages involved in tissue remodeling and tumor growth, that promote cancer cell proliferation, invasion, tumor metastasis, angiogenesis and that participate to immune suppression. These decisive roles in tumor progression occur through the secretion of cytokines, chemokines, growth factors, and matrix metalloproteases, as well as by the expression of immune checkpoint receptors in the case of M2 macrophages. Moreover, macrophage plasticity is supported by stimuli from the Tumor Microenvironment (TME) that are relayed to the nucleus through membrane receptors and signaling pathways that result in gene expression reprogramming in macrophages, thus giving rise to different macrophage polarization outcomes. In this review, we will focus on the main signaling pathways involved in macrophage polarization that are activated upon ligand-receptor recognition and in the presence of other immunomodulatory molecules in cancer.
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Affiliation(s)
- Clément Kerneur
- ImCheck Therapeutics, Marseille, France
- Team Immunity and Cancer, Centre de Recherche en Cancérologie de Marseille (CRCM), Inserm U1068, CNRS UMR7258, Institut Paoli Calmettes, Marseille, France
- *Correspondence: Clément Kerneur, ; Carla E. Cano, ; Daniel Olive,
| | - Carla E. Cano
- ImCheck Therapeutics, Marseille, France
- *Correspondence: Clément Kerneur, ; Carla E. Cano, ; Daniel Olive,
| | - Daniel Olive
- Team Immunity and Cancer, Centre de Recherche en Cancérologie de Marseille (CRCM), Inserm U1068, CNRS UMR7258, Institut Paoli Calmettes, Marseille, France
- *Correspondence: Clément Kerneur, ; Carla E. Cano, ; Daniel Olive,
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21
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Oldach L. A Bona Fide MAP Kinase. J Biol Chem 2022; 298:102432. [PMID: 36037971 PMCID: PMC9513259 DOI: 10.1016/j.jbc.2022.102432] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/25/2022] [Indexed: 11/21/2022] Open
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22
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Liu Z, Demian W, Persaud A, Jiang C, Subramanaya AR, Rotin D. Regulation of the p38-MAPK pathway by hyperosmolarity and by WNK kinases. Sci Rep 2022; 12:14480. [PMID: 36008477 PMCID: PMC9411163 DOI: 10.1038/s41598-022-18630-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Accepted: 08/16/2022] [Indexed: 12/01/2022] Open
Abstract
p38-MAPK is a stress-response kinase activated by hyperosmolarity. Here we interrogated the pathways involved. We show that p38-MAPK signaling is activated by hyperosmotic stimulation in various solutions, cell types and colonic organoids. Hyperosmolarity sensing is detected at the level of the upstream activators of p38-MAPK: TRAF2/ASK1 (but not Rac1) and MKK3/6/4. While WNK kinases are known osmo-sensors, we found, unexpectedly, that short (2 h) inhibition of WNKs (with WNK463) led to elevated p38-MAPK activity under hyperosmolarity, which was mediated by WNK463-dependent stimulation of TAK1 or TRAF2/ASK1, the upstream activators of MKK3/6/4. However, this effect was temporary and was reversed by long-term (2 days) incubation with WNK463. Accordingly, 2 days (but not 2 h) inhibition of p38-MAPK or its upstream activators ASK1 or TAK1, or WNKs, diminished regulatory volume increase (RVI) following cell shrinkage under hyperosmolarity. We also show that RVI mediated by the ion transporter NKCC1 is dependent on p38-MAPK. Since WNKs are known activators of NKCC1, we propose a WNK- > NKCC1- > p38-MAPK pathway that controls RVI. This pathway is augmented by NHE1. Additionally, hyperosmolarity inhibited mTORC1 activation and cell proliferation. Thus, activation of p38-MAPK and WNKs is important for RVI and for cell proliferation.
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Affiliation(s)
- Zetao Liu
- Cell Biology Program, The Hospital for Sick Children, PGCRL 19-9715, 686 Bay St., Toronto, ON, M5G 0A4, Canada
- Biochemistry Department, University of Toronto, Toronto, ON, Canada
| | - Wael Demian
- Cell Biology Program, The Hospital for Sick Children, PGCRL 19-9715, 686 Bay St., Toronto, ON, M5G 0A4, Canada
- Biochemistry Department, University of Toronto, Toronto, ON, Canada
| | - Avinash Persaud
- Cell Biology Program, The Hospital for Sick Children, PGCRL 19-9715, 686 Bay St., Toronto, ON, M5G 0A4, Canada
| | - Chong Jiang
- Cell Biology Program, The Hospital for Sick Children, PGCRL 19-9715, 686 Bay St., Toronto, ON, M5G 0A4, Canada
| | - Arohan R Subramanaya
- Department of Medicine and Cell Biology, University of Pittsburgh, Pittsburgh, USA
| | - Daniela Rotin
- Cell Biology Program, The Hospital for Sick Children, PGCRL 19-9715, 686 Bay St., Toronto, ON, M5G 0A4, Canada.
- Biochemistry Department, University of Toronto, Toronto, ON, Canada.
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23
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Romero-Becerra R, Mora A, Manieri E, Nikolic I, Santamans AM, Montalvo-Romeral V, Cruz FM, Rodríguez E, León M, Leiva-Vega L, Sanz L, Bondía V, Filgueiras-Rama D, Jiménez-Borreguero LJ, Jalife J, Gonzalez-Teran B, Sabio G. MKK6 deficiency promotes cardiac dysfunction through MKK3-p38γ/δ-mTOR hyperactivation. eLife 2022; 11:e75250. [PMID: 35971771 PMCID: PMC9381040 DOI: 10.7554/elife.75250] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Accepted: 07/08/2022] [Indexed: 11/13/2022] Open
Abstract
Stress-activated p38 kinases control a plethora of functions, and their dysregulation has been linked to the development of steatosis, obesity, immune disorders, and cancer. Therefore, they have been identified as potential targets for novel therapeutic strategies. There are four p38 family members (p38α, p38β, p38γ, and p38δ) that are activated by MKK3 and MKK6. Here, we demonstrate that lack of MKK6 reduces the lifespan in mice. Longitudinal study of cardiac function in MKK6 KO mice showed that young mice develop cardiac hypertrophy which progresses to cardiac dilatation and fibrosis with age. Mechanistically, lack of MKK6 blunts p38α activation while causing MKK3-p38γ/δ hyperphosphorylation and increased mammalian target of rapamycin (mTOR) signaling, resulting in cardiac hypertrophy. Cardiac hypertrophy in MKK6 KO mice is reverted by knocking out either p38γ or p38δ or by inhibiting the mTOR pathway with rapamycin. In conclusion, we have identified a key role for the MKK3/6-p38γ/δ pathway in the development of cardiac hypertrophy, which has important implications for the clinical use of p38α inhibitors in the long-term treatment since they might result in cardiotoxicity.
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Affiliation(s)
| | - Alfonso Mora
- Centro Nacional de Investigaciones CardiovascularesMadridSpain
| | - Elisa Manieri
- Centro Nacional de Investigaciones CardiovascularesMadridSpain
| | - Ivana Nikolic
- Centro Nacional de Investigaciones CardiovascularesMadridSpain
| | | | | | | | - Elena Rodríguez
- Centro Nacional de Investigaciones CardiovascularesMadridSpain
| | - Marta León
- Centro Nacional de Investigaciones CardiovascularesMadridSpain
| | - Luis Leiva-Vega
- Centro Nacional de Investigaciones CardiovascularesMadridSpain
| | - Laura Sanz
- Centro Nacional de Investigaciones CardiovascularesMadridSpain
| | - Víctor Bondía
- Centro Nacional de Investigaciones CardiovascularesMadridSpain
| | - David Filgueiras-Rama
- Centro Nacional de Investigaciones CardiovascularesMadridSpain
- CIBER de Enfermedades CardiovascularesMadridSpain
- Hospital Clínico Universitario San CarlosMadridSpain
| | | | - José Jalife
- Centro Nacional de Investigaciones CardiovascularesMadridSpain
- CIBER de Enfermedades CardiovascularesMadridSpain
- Center for Arrhythmia Research, Department of Internal Medicine, University of Michigan, Ann ArborAnn ArborUnited States
| | - Barbara Gonzalez-Teran
- Centro Nacional de Investigaciones CardiovascularesMadridSpain
- Gladstone InstitutesSan FranciscoUnited States
| | - Guadalupe Sabio
- Centro Nacional de Investigaciones CardiovascularesMadridSpain
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24
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Lee WJ, Kim MJ, Choi HW, Lee JJ, Jung SK. Effect of Methyl Gallate on 1-Nitropyrene-Induced Keratinocyte Toxicity in a Human and Canine Skin Model. J Microbiol Biotechnol 2022; 32:869-876. [PMID: 35880479 PMCID: PMC9628917 DOI: 10.4014/jmb.2206.06004] [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: 06/07/2022] [Revised: 06/22/2022] [Accepted: 06/27/2022] [Indexed: 12/15/2022]
Abstract
The skin, which is the largest organ of the human body, is in direct contact with pollutants in the surrounding atmosphere. Meanwhile, 1-nitropyrene (1-NP), the most abundant nitro-polycyclic aromatic hydrocarbon found in particulate matter, is known to have carcinogenic effects; however, studies on its toxicity in human and canine skin are still needed. In this study, we investigated 1-NP-induced apoptosis and inflammatory pathways in HaCaT cells. In addition, we also measured the cytoprotective effect of methyl gallate (MG), which is widely distributed in medicinal and edible plants and is well known for its anti-inflammatory and antioxidant properties. MG inhibited 1-NP-induced cell death and apoptosis pathways, including the cleavage of PARP and activation of caspase-3, -7, and -9. MG also suppressed 1-NP-induced COX-2 expression and phosphorylation of mitogen-activated protein kinases (MAPKs) and MAPK kinases (MAPKKs). Our findings suggest that 1-NP induces skin toxicity in human and canine through apoptosis and inflammatory responses, and moreover, that this can be prevented by treatment with MG.
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Affiliation(s)
- Woo Jin Lee
- School of Food Science and Biotechnology, Kyungpook National University, Daegu 41566, Republic of Korea
| | - Min Jeong Kim
- School of Food Science and Biotechnology, Kyungpook National University, Daegu 41566, Republic of Korea
| | - Hyun-Wook Choi
- Department of Functional Food and Biotechnology, Jeonju University, Jeonju 55069, Republic of Korea
| | - Jeong Jae Lee
- Institute of Agricultural Science and Technology, Kyungpook National University, Daegu 41566, Republic of Korea,Corresponding authors J.J. Lee Phone: +82-53-950-6654 E-mail:
| | - Sung Keun Jung
- School of Food Science and Biotechnology, Kyungpook National University, Daegu 41566, Republic of Korea,Tailored Food Technology, Kyungpook National University, Daegu 41566, Republic of Korea,
S.K. Jung Phone: +82-53-950-7764 Fax: +82-53-950-7762 E-mail:
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25
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Wang Y, Zhang Y, Mi J, Jiang C, Wang Q, Li X, Zhao M, Geng Z, Song X, Li J, Zuo L, Ge S, Zhang Z, Wen H, Wang Z, Su F. ANKFN1 plays both protumorigenic and metastatic roles in hepatocellular carcinoma. Oncogene 2022; 41:3680-3693. [PMID: 35725908 PMCID: PMC9287179 DOI: 10.1038/s41388-022-02380-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 05/19/2022] [Accepted: 06/07/2022] [Indexed: 11/30/2022]
Abstract
Ankyrin repeat and fibronectin type III domain containing 1 (ANKFN1) is reported to be involved in human height and developmental abnormalities, but the expression profile and molecular function of ANKFN1 in hepatocellular carcinoma (HCC) remain unknown. This study aimed to evaluate the clinical significance and biological function of ANKFN1 in HCC and investigate whether ANKFN1 can be used for differential diagnosis in HCC. Here, we showed that ANKFN1 was upregulated in 126 tumor tissues compared with adjacent nontumorous tissues in HCC patients. The upregulation of ANKFN1 in HCC was associated with cirrhosis, alpha-fetoprotein (AFP) levels and poor prognosis. Moreover, silencing ANKFN1 expression suppressed HCC cell proliferation, migration, invasion, and metastasis in vitro and subcutaneous tumorigenesis in vivo. However, ANKFN1 overexpression promoted HCC proliferation and metastasis in an orthotopic liver transplantation model and attenuated the above biological effects in HCC cells. ANKFN1 significantly affected HCC cell proliferation by inducing G1/S transition and cell apoptosis. Mechanistically, we demonstrated that ANKFN1 promoted cell proliferation, migration, and invasion via activation of the cyclin D1/Cdk4/Cdk6 pathway by stimulating the MEK1/2-ERK1/2 pathway. Moreover, ANKFN1-induced cell proliferation, migration, and invasion were partially reversed by ERK1/2 inhibitors. Taken together, our results indicate that ANKFN1 promotes HCC cell proliferation and metastasis by activating the MEK1/2-ERK1/2 signaling pathway. Our work also suggests that ANKFN1 is a potential therapeutic target for HCC.
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Affiliation(s)
- Yanyan Wang
- The First Affiliated Hospital of Bengbu Medical College, Bengbu, 233004, Anhui, PR China
| | - Yue Zhang
- The First Affiliated Hospital of Bengbu Medical College, Bengbu, 233004, Anhui, PR China
| | - Jiaqi Mi
- The First Affiliated Hospital of Bengbu Medical College, Bengbu, 233004, Anhui, PR China
| | - Chenchen Jiang
- Cancer Neurobiology Group, School of Biomedical Sciences & Pharmacy, The University of Newcastle, Callaghan, NSW, 2308, Australia.,School of Medicine & Public Health, The University of Newcastle, Callaghan, NSW, 2308, Australia
| | - Qiang Wang
- Bengbu Medical College, Bengbu, 233004, Anhui, PR China
| | - Xinwei Li
- The First Affiliated Hospital of Bengbu Medical College, Bengbu, 233004, Anhui, PR China
| | - Menglin Zhao
- The First Affiliated Hospital of Bengbu Medical College, Bengbu, 233004, Anhui, PR China
| | - Zhijun Geng
- The First Affiliated Hospital of Bengbu Medical College, Bengbu, 233004, Anhui, PR China
| | - Xue Song
- The First Affiliated Hospital of Bengbu Medical College, Bengbu, 233004, Anhui, PR China
| | - Jing Li
- The First Affiliated Hospital of Bengbu Medical College, Bengbu, 233004, Anhui, PR China
| | - Lugen Zuo
- The First Affiliated Hospital of Bengbu Medical College, Bengbu, 233004, Anhui, PR China
| | - Sitang Ge
- The First Affiliated Hospital of Bengbu Medical College, Bengbu, 233004, Anhui, PR China
| | - Zining Zhang
- The First Affiliated Hospital of Bengbu Medical College, Bengbu, 233004, Anhui, PR China
| | - Hexin Wen
- The First Affiliated Hospital of Bengbu Medical College, Bengbu, 233004, Anhui, PR China
| | - Zishu Wang
- The First Affiliated Hospital of Bengbu Medical College, Bengbu, 233004, Anhui, PR China.
| | - Fang Su
- The First Affiliated Hospital of Bengbu Medical College, Bengbu, 233004, Anhui, PR China.
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26
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Zhou H, Yang D, Cheng HS, McCoy MG, Pérez-Cremades D, Haemmig S, Wong D, Chen L, Feinberg MW. miR-181b regulates vascular endothelial aging by modulating an MAP3K3 signaling pathway. FASEB J 2022; 36:e22353. [PMID: 35593587 PMCID: PMC9167053 DOI: 10.1096/fj.202200046r] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Revised: 04/26/2022] [Accepted: 05/05/2022] [Indexed: 01/10/2023]
Abstract
Endothelial cell (EC) aging plays a vital role in the pathogenesis of cardiovascular disease (CVD). MicroRNAs have emerged as crucial regulators of target gene expression by inhibiting mRNA translation and/or promoting mRNA degradation. We identify an aging-related and oxidative stress-responsive microRNA, miR-181b, that inhibits endothelial cell apoptosis and senescence. In gain- or loss-of-function studies, miR-181b regulated the expression of key apoptosis markers (Bcl2, Bax, cleaved-Caspase3) and senescence markers (p16, p21, γH2AX) and the ratio of apoptotic cells (TUNEL-positive) and senescent cells (SA-βgal-positive) in H2 O2 -induced ECs. Mechanistically, miR-181b targets MAP3K3 and modulates a MAP3K3/MKK/MAPK signaling pathway. MAP3K3 knockdown recapitulated the phenotype of miR-181b overexpression and miR-181b was dependent on MAP3K3 for regulating EC apoptosis and senescence. In vivo, miR-181b expression showed a negative correlation with increasing age in the mouse aorta. Endothelial-specific deficiency of miR-181a2b2 increased the target MAP3K3, markers of vascular senescence (p16, p21), and DNA double-strand breaks (γH2AX) in the aorta of aged mice. Collectively, this study unveils an important role of miR-181b in regulating vascular endothelial aging via an MAP3K3-MAPK signaling pathway, providing new potential therapeutic targets for antiaging therapy in CVD.
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Affiliation(s)
- Haoyang Zhou
- Department of Medicine, Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
- Department of Cardiology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Dafeng Yang
- Department of Medicine, Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
- Department of Cardiology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Henry S. Cheng
- Department of Medicine, Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Michael G McCoy
- Department of Medicine, Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Daniel Pérez-Cremades
- Department of Medicine, Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Stefan Haemmig
- Department of Medicine, Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Danny Wong
- Department of Medicine, Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Lei Chen
- Department of Cardiology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Mark W. Feinberg
- Department of Medicine, Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
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27
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Dai F, Guo M, Shao Y, Li C. Vibrio splendidus flagellin C binds tropomodulin to induce p38 MAPK-mediated p53-dependent coelomocyte apoptosis in Echinodermata. J Biol Chem 2022; 298:102091. [PMID: 35654141 PMCID: PMC9249833 DOI: 10.1016/j.jbc.2022.102091] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 05/09/2022] [Accepted: 05/13/2022] [Indexed: 12/27/2022] Open
Abstract
As a typical pathogen-associated molecular pattern, bacterial flagellin can bind Toll-like receptor 5 and the intracellular NAIP5 receptor component of the NLRC4 inflammasome to induce immune responses in mammals. However, these flagellin receptors are generally poorly understood in lower animal species. In this study, we found that the isolated flagellum of Vibrio splendidus AJ01 destroyed the integrity of the tissue structure of coelomocytes and promoted apoptosis in the sea cucumber Apostichopus japonicus. To further investigate the molecular mechanism, the novel intracellular LRR domain-containing protein tropomodulin (AjTmod) was identified as a protein that interacts with flagellin C (FliC) with a dissociation constant (Kd) of 0.0086 ± 0.33 μM by microscale thermophoresis assay. We show that knockdown of AjTmod also depressed FliC-induced apoptosis of coelomocytes. Further functional analysis with different inhibitor treatments revealed that the interaction between AjTmod and FliC could specifically activate p38 MAPK, but not JNK or ERK MAP kinases. We demonstrate that the transcription factor p38 is then translocated into the nucleus, where it mediates the expression of p53 to induce coelomocyte apoptosis. Our findings provide the first evidence that intracellular AjTmod serves as a novel receptor of FliC and mediates p53-dependent coelomocyte apoptosis by activating the p38 MAPK signaling pathway in Echinodermata.
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Affiliation(s)
- Fa Dai
- State Key Laboratory for Quality and Safety of Agro-products, Ningbo University, Ningbo, China; State-Province Joint Laboratory of Marine Biotechnology and Engineering, Ningbo University, Ningbo, China
| | - Ming Guo
- State Key Laboratory for Quality and Safety of Agro-products, Ningbo University, Ningbo, China; State-Province Joint Laboratory of Marine Biotechnology and Engineering, Ningbo University, Ningbo, China
| | - Yina Shao
- State Key Laboratory for Quality and Safety of Agro-products, Ningbo University, Ningbo, China; State-Province Joint Laboratory of Marine Biotechnology and Engineering, Ningbo University, Ningbo, China
| | - Chenghua Li
- State Key Laboratory for Quality and Safety of Agro-products, Ningbo University, Ningbo, China; State-Province Joint Laboratory of Marine Biotechnology and Engineering, Ningbo University, Ningbo, China; Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Qingdao, PR China.
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28
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Nikou SA, Zhou C, Griffiths JS, Kotowicz NK, Coleman BM, Green MJ, Moyes DL, Gaffen SL, Naglik JR, Parker PJ. The Candida albicans toxin candidalysin mediates distinct epithelial inflammatory responses through p38 and EGFR-ERK pathways. Sci Signal 2022; 15:eabj6915. [PMID: 35380879 PMCID: PMC7612652 DOI: 10.1126/scisignal.abj6915] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The fungal pathogen Candida albicans secretes the peptide toxin candidalysin, which damages epithelial cells and drives an innate inflammatory response mediated by the epidermal growth factor receptor (EGFR) and mitogen-activated protein kinase (MAPK) pathways and the transcription factor c-Fos. In cultured oral epithelial cells, candidalysin activated the MAPK p38, which resulted in heat shock protein 27 (Hsp27) activation, IL-6 release, and EGFR phosphorylation without affecting the induction of c-Fos. p38 activation was not triggered by EGFR but by two nonredundant pathways involving MAPK kinases (MKKs) and the kinase Src, which differentially controlled p38 signaling outputs. Whereas MKKs mainly promoted p38-dependent release of IL-6, Src promoted p38-mediated phosphorylation of EGFR in a ligand-independent fashion. In parallel, candidalysin also activated the EGFR-ERK pathway in a ligand-dependent manner, resulting in c-Fos activation and release of the neutrophil-activating chemokines G-CSF and GM-CSF. In mice, early clearance events of oral C. albicans infection required p38 but not c-Fos. These findings delineate how candidalysin activates the pathways downstream of the MAPKs p38 and ERK that differentially contribute to immune activation during C. albicans infection.
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Affiliation(s)
- Spyridoula-Angeliki Nikou
- Protein Phosphorylation Lab, The Francis Crick Institute; London, UK
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King’s College London; London, UK
| | - Chunsheng Zhou
- Division of Rheumatology and Clinical Immunology, University of Pittsburgh; Pittsburgh, USA
| | - James S. Griffiths
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King’s College London; London, UK
| | - Natalia K. Kotowicz
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King’s College London; London, UK
| | - Bianca M. Coleman
- Division of Rheumatology and Clinical Immunology, University of Pittsburgh; Pittsburgh, USA
| | - Mary J. Green
- Experimental Histopathology Lab, The Francis Crick Institute; London, UK
| | - David L. Moyes
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King’s College London; London, UK
| | - Sarah L. Gaffen
- Division of Rheumatology and Clinical Immunology, University of Pittsburgh; Pittsburgh, USA
| | - Julian R. Naglik
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King’s College London; London, UK
| | - Peter J. Parker
- Protein Phosphorylation Lab, The Francis Crick Institute; London, UK
- School of Cancer and Pharmaceutical Sciences, New Hunt’s House, King’s College London; London, UK
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29
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Pannkuk EL, Laiakis EC, Angdisen J, Jayatilake MM, Ake P, Lin LYT, Li HH, Fornace AJ. Small Molecule Signatures of Mice Lacking T-cell p38 Alternate Activation, a Model for Immunosuppression Conditions, after Total-Body Irradiation. Radiat Res 2022; 197:613-625. [PMID: 35245386 DOI: 10.1667/rade-21-00199.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 01/24/2022] [Indexed: 11/03/2022]
Abstract
Several diagnostic biodosimetry tools have been in development that may aid in radiological/nuclear emergency responses. Of these, correlating changes in non-invasive biofluid small-molecule signatures to tissue damage from ionizing radiation exposure show promise for inclusion in predictive biodosimetry models. Integral to dose reconstruction has been determining how genotypic variation in the general population will affect model performance. Here, we used a mouse model that lacks the T-cell receptor specific alternative p38 pathway [p38αβY323F, double knock-in (DKI) mice] to determine how attenuated autoimmune and inflammatory responses may affect dose reconstruction. We exposed adult male DKI mice (8-10 weeks old) to 2 and 7 Gy in parallel with wild-type mice and assessed perturbations in urine (days 1, 3, 7) and serum (day 1) using a global metabolomics approach. A multidimensional scaling plot showed excellent separation of radiation-exposed groups in wild-type mice with slightly dampened responses in DKI mice. Validated metabolite panels were developed for urine [N6,N6,N6-trimethyllysine (TML), N1-acetylspermidine, spermidine, carnitine, acylcarnitine C21H35NO5, 4-aminohippuric acid] and serum [phenylalanine, glutamine, propionylcarnitine, lysophosphatidylcholine (LysoPC 14:0), LysoPC (22:5)] to determine the area under the receiver operating characteristic curve (AUROC). For both urine and serum, excellent sensitivity and specificity (AUROC > 0.90) was observed for 0 Gy vs. 7 Gy groups irrespective of genotype using identical metabolite panels. Similarly, excellent to fair classification (AUROC > 0.75) was observed for ≤2 Gy vs. 7 Gy mice for both genotypes, however, model performance declined (AUROC < 0.75) between genotypes after irradiation. Overall, these results suggest immunosuppression should not compromise small molecule multiplex panels used in dose reconstruction for biodosimetry.
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Affiliation(s)
- Evan L Pannkuk
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC.,Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, Washington, DC
| | - Evagelia C Laiakis
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC.,Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, Washington, DC
| | - Jerry Angdisen
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC
| | - Meth M Jayatilake
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, Washington, DC
| | - Pelagie Ake
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC
| | - Lorreta Yun-Tien Lin
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC
| | - Heng-Hong Li
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC.,Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, Washington, DC
| | - Albert J Fornace
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC.,Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, Washington, DC
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Wang S, Mi R, Cai Z, Wang Z, Zeng C, Xie Z, Li J, Ma M, Liu W, Su H, Cen S, Wu Y, Shen H. DAPK1 Interacts with the p38 isoform MAPK14, Preventing its Nuclear Translocation and Stimulation of Bone Marrow Adipogenesis. Stem Cells 2022; 40:508-522. [PMID: 35403694 DOI: 10.1093/stmcls/sxac013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Accepted: 02/04/2022] [Indexed: 11/12/2022]
Abstract
Abstract
Bone marrow (BM) adipose tissue (BMAT), a unique adipose depot, plays an important role in diseases such as osteoporosis and bone metastasis. Precise control of mesenchymal stem cell (MSC) differentiation is critical for BMAT formation and regeneration. Here, we show that death associated protein kinase 1 (DAPK1) negatively regulates BM adipogenesis in vitro and in vivo. Prx1 creDapk1 loxp/loxp mice showed more adipocytes in the femur than Dapk1 loxp/loxp mice. Further mechanistic analyses revealed that DAPK1 inhibits p38 mitogen-activated protein kinase (MAPK) signaling in the nucleus by binding the p38 isoform MAPK14, decreasing p38 nuclear activity, which subsequently inhibits BM adipogenesis. The inhibitory effect of DAPK1 against MAPK14 was independent of its kinase activity. In addition, the decreased DAPK1 was observed in the BM-MSCs of ageing mice. Our results reveal a previously undescribed function for DAPK1 in the regulation of adipogenesis, and may also reveal the underlying mechanism of BMAT formation in ageing.
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Affiliation(s)
- Shan Wang
- Center for Biotherapy, Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen 518033, P.R. China
| | - Rujia Mi
- Center for Biotherapy, Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen 518033, P.R. China
| | - Zhaopeng Cai
- Department of Orthopedics, Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen 518033, P.R. China
| | - Ziming Wang
- Department of Orthopedics, Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen 518033, P.R. China
| | - Chenying Zeng
- Center for Biotherapy, Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen 518033, P.R. China
| | - Zhongyu Xie
- Department of Orthopedics, Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen 518033, P.R. China
| | - Jinteng Li
- Department of Orthopedics, Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen 518033, P.R. China
| | - Mengjun Ma
- Department of Orthopedics, Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen 518033, P.R. China
| | - Wenjie Liu
- Department of Orthopedics, Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen 518033, P.R. China
| | - Hongjun Su
- Center for Biotherapy, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou 510120, P.R. China
| | - Shuizhong Cen
- Department of Orthopedics, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou 510120, P.R. China
| | - Yanfeng Wu
- Center for Biotherapy, Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen 518033, P.R. China
| | - Huiyong Shen
- Department of Orthopedics, Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen 518033, P.R. China
- Department of Orthopedics, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou 510120, P.R. China
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31
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de Klerk DJ, de Keijzer MJ, Dias LM, Heemskerk J, de Haan LR, Kleijn TG, Franchi LP, Heger M. Strategies for Improving Photodynamic Therapy Through Pharmacological Modulation of the Immediate Early Stress Response. Methods Mol Biol 2022; 2451:405-480. [PMID: 35505025 DOI: 10.1007/978-1-0716-2099-1_20] [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] [Indexed: 06/14/2023]
Abstract
Photodynamic therapy (PDT) is a minimally to noninvasive treatment modality that has emerged as a promising alternative to conventional cancer treatments. PDT induces hyperoxidative stress and disrupts cellular homeostasis in photosensitized cancer cells, resulting in cell death and ultimately removal of the tumor. However, various survival pathways can be activated in sublethally afflicted cancer cells following PDT. The acute stress response is one of the known survival pathways in PDT, which is activated by reactive oxygen species and signals via ASK-1 (directly) or via TNFR (indirectly). The acute stress response can activate various other survival pathways that may entail antioxidant, pro-inflammatory, angiogenic, and proteotoxic stress responses that culminate in the cancer cell's ability to cope with redox stress and oxidative damage. This review provides an overview of the immediate early stress response in the context of PDT, mechanisms of activation by PDT, and molecular intervention strategies aimed at inhibiting survival signaling and improving PDT outcome.
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Affiliation(s)
- Daniel J de Klerk
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, Zhejiang, People's Republic of China
- Laboratory of Experimental Oncology, Department of Pathology, Erasmus MC, Rotterdam, The Netherlands
| | - Mark J de Keijzer
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, Zhejiang, People's Republic of China
- Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
| | - Lionel M Dias
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, Zhejiang, People's Republic of China
- Faculdade de Ciências da Saúde (FCS-UBI), Universidade da Beira Interior, Covilhã, Portugal
| | - Jordi Heemskerk
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, Zhejiang, People's Republic of China
| | - Lianne R de Haan
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, Zhejiang, People's Republic of China
- Laboratory of Experimental Oncology, Department of Pathology, Erasmus MC, Rotterdam, The Netherlands
| | - Tony G Kleijn
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, Zhejiang, People's Republic of China
- Laboratory of Experimental Oncology, Department of Pathology, Erasmus MC, Rotterdam, The Netherlands
| | - Leonardo P Franchi
- Departamento de Bioquímica e Biologia Molecular, Instituto de Ciências Biológicas (ICB) 2, Universidade Federal de Goiás (UFG), Goiânia, GO, Brazil
- Faculty of Philosophy, Department of Chemistry, Center of Nanotechnology and Tissue Engineering-Photobiology and Photomedicine Research Group, Sciences, and Letters of Ribeirão Preto, University of São Paulo, São Paulo, Brazil
| | - Michal Heger
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, Zhejiang, People's Republic of China.
- Laboratory of Experimental Oncology, Department of Pathology, Erasmus MC, Rotterdam, The Netherlands.
- Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
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Caliz AD, Vertii A, Fisch V, Yoon S, Yoo HJ, Keaney JF, Kant S. Mitogen-activated protein kinase kinase 7 in inflammatory, cancer, and neurological diseases. Front Cell Dev Biol 2022; 10:979673. [PMID: 36340039 PMCID: PMC9630596 DOI: 10.3389/fcell.2022.979673] [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: 06/27/2022] [Accepted: 10/10/2022] [Indexed: 11/13/2022] Open
Abstract
Stress-activated mitogen-activated protein kinase kinase 7 (MKK7) is a member of the dual-specificity mitogen-activated protein kinase family. In the human body, MKK7 controls essential physiological processes, including but not limited to proliferation and differentiation in multiple tissues and organs. MKK7, along with the MKK4 pathway, has been implicated in stress-activated activities and biological events that are mediated by c-Jun N-terminal kinase (JNK) signaling. Although numerous studies have been performed to identify the role of JNK in multiple biological processes, there are limited publications that focus on dissecting the independent role of MKK7. Recent research findings have spurred testing via in vivo genetically deficient models, uncovering previously undocumented JNK-independent functions of MKK7. Here we discuss both JNK-dependent and-independent functions of MKK7 in vivo. This review summarizes the role of MKK7 in inflammation, cytokine production, cancer, and neurological diseases.
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Affiliation(s)
- Amada D Caliz
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
| | - Anastassiia Vertii
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, United States
| | - Vijay Fisch
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
| | - Soonsang Yoon
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
| | - Hyung-Jin Yoo
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
| | - John F Keaney
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
| | - Shashi Kant
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
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Wang Y, Shen Y. Exosomal miR-455-3p from BMMSCs prevents cardiac ischemia-reperfusion injury. Hum Exp Toxicol 2022; 41:9603271221102508. [PMID: 35577544 DOI: 10.1177/09603271221102508] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
OBJECTIVE Bone marrow mesenchymal stem cells (BMMSCs) exert protective effects against myocardial infarction (MI). Here, we focused on the function and mechanism of miR-455-3p from BMMSCs-derived exosomes (BMMSCs-Exo) in myocardial infarction. MATERIALS AND METHODS BMMSCs were isolated from rat bone marrow, and the exosomes from the culture medium of BMMSCs were separated, and administered to H9C2 cells under hypoxia-reperfusion (H/R) stimulation. MTT and TUNEL staining analyzed cell viability and apoptosis, respectively. RT-qPCR determined miR-455-3p expression. Apoptosis-related proteins, autophagy-associated proteins, and the MEKK1-MKK4-JNK signaling pathway were detected. The interaction between miR-455-3p and MEKK1 was confirmed through dual luciferase activity and RIP assay. An in vivo ischemia reperfusion (I/R) model was established in rats. 2, 3, 5 triphenyltetrazolium chloride (TTC) staining, hematoxylin-eosin (H&E) staining, Masson staining, and TUNEL staining evaluated the infarct volume and histopathological changes. RESULTS miR-455-3p's expression was down-regulated in BMMSCs-derived exosomes, I/R myocardial tissues, and H/R myocardial cells. miR-455-3p enriched by BMMSC exosomes reduced H/R-mediated cardiomyocyte damage and death-related autophagy. miR-455-3p upregulation suppressed MEKK1-MKK4-JNK. MEKK1 overexpression notably mitigated cell apoptosis, cramped cell viability, suppressed autophagy expansion, and attenuated Exo-miR-455-3p's protection on H/R myocardial cells. In-vivo trials reflected that BMMSC exosomes enriched with miR-455-3p repressed ischemia reperfusion-induced myocardial damage and myocardial cell function. CONCLUSION miR-455-3p, shuttled by exosomes from MSCs, targets the MEKK1-MKK4-JNK signaling pathway to guard against myocardial ischemia-reperfusion damage.
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Affiliation(s)
- Yue Wang
- Department of Cardiology, Sinopharm Dongfeng General Hospital, Hubei University of Medicine, Shiyan, China
| | - Yusi Shen
- Second Department of Orthopedic Rehabilitation, Taihe Hospital, Hubei University of Medicine, Shiyan, China
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Kim GD. Ursolic Acid Decreases the Proliferation of MCF-7 Cell-Derived Breast Cancer Stem-Like Cells by Modulating the ERK and PI3K/AKT Signaling Pathways. Prev Nutr Food Sci 2021; 26:434-444. [PMID: 35047440 PMCID: PMC8747966 DOI: 10.3746/pnf.2021.26.4.434] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Cancer stem cells are strong drivers of metastasis and cancer relapse, which makes them important therapeutic targets. Ursolic acid (UA), a pentacyclic triterpenoid, has anticancer effects in various types of cancer; however, little is known about its effect on the growth of MCF-7 cell-derived breast cancer stem (BCS)-like cells in estrogen receptor positive breast cancer. In this study, the anticancer activity of UA in MCF-7 cell-derived BCS-like cells and its mechanism of action were evaluated. Furthermore, its inhibitory effects on the proliferation of MCF-7 cell-derived BCS-like cells were compared with that on MCF-7 cells. In MCF-7 cells, UA increased p53 and p21 expression but decreased cyclin D, cyclin E, CDK4, and CDK2 expression to induce cell cycle arrest in the G0/G1 phase. Moreover, UA significantly suppressed migration, invasion, and colony formation in MCF-7 cells, and suppressed mammosphere formation in a concentration- dependent manner. In MCF-7 cell-derived BCS-like cells, UA significantly decreased migration, suppressed p-PI3K, p-AKT, and p-ERK expression, and enhanced p-FoxO1/FoxO3a expression. Accordingly, in MCF-7 cell-derived BCS-like cells, UA suppressed proliferation in part by downregulating ERK and PI3K/AKT signaling pathways. These findings provide the first evidence for the selective effects of UA in BCSs.
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Affiliation(s)
- Gi Dae Kim
- Department of Food and Nutrition, Kyungnam University, Gyeongnam 51767, Korea
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35
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The p38 MAPK Components and Modulators as Biomarkers and Molecular Targets in Cancer. Int J Mol Sci 2021; 23:ijms23010370. [PMID: 35008796 PMCID: PMC8745478 DOI: 10.3390/ijms23010370] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 12/27/2021] [Accepted: 12/27/2021] [Indexed: 02/07/2023] Open
Abstract
The mitogen-activated protein kinase (MAPK) family is an important bridge in the transduction of extracellular and intracellular signals in different responses at the cellular level. Within this MAPK family, the p38 kinases can be found altered in various diseases, including cancer, where these kinases play a fundamental role, sometimes with antagonistic mechanisms of action, depending on several factors. In fact, this family has an immense number of functionalities, many of them yet to be discovered in terms of regulation and action in different types of cancer, being directly involved in the response to cancer therapies. To date, three main groups of MAPKs have been identified in mammals: the extracellular signal-regulated kinases (ERK), Jun N-terminal kinase (JNK), and the different isoforms of p38 (α, β, γ, δ). In this review, we highlight the mechanism of action of these kinases, taking into account their extensive regulation at the cellular level through various modifications and modulations, including a wide variety of microRNAs. We also analyze the importance of the different isoforms expressed in the different tissues and their possible role as biomarkers and molecular targets. In addition, we include the latest preclinical and clinical trials with different p38-related drugs that are ongoing with hopeful expectations in the present/future of developing precision medicine in cancer.
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36
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Maik-Rachline G, Wortzel I, Seger R. Alternative Splicing of MAPKs in the Regulation of Signaling Specificity. Cells 2021; 10:cells10123466. [PMID: 34943973 PMCID: PMC8699841 DOI: 10.3390/cells10123466] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2021] [Revised: 11/26/2021] [Accepted: 12/01/2021] [Indexed: 12/12/2022] Open
Abstract
The mitogen-activated protein kinase (MAPK) cascades transmit signals from extracellular stimuli to a variety of distinct cellular processes. The MAPKKs in each cascade specifically phosphorylate and activate their cognate MAPKs, indicating that this step funnels various signals into a seemingly linear pathway. Still, the effects of these cascades vary significantly, depending on the identity of the extracellular signals, which gives rise to proper outcomes. Therefore, it is clear that the specificity of the signals transmitted through the cascades is tightly regulated in order to secure the desired cell fate. Indeed, many regulatory components or processes that extend the specificity of the cascades have been identified. Here, we focus on a less discussed mechanism, that is, the role of distinct components in each tier of the cascade in extending the signaling specificity. We cover the role of distinct genes, and the alternatively spliced isoforms of MAPKKs and MAPKs, in the signaling specificity. The alternatively spliced MEK1b and ERK1c, which form an independent signaling route, are used as the main example. Unlike MEK1/2 and ERK1/2, this route’s functions are limited, including mainly the regulation of mitotic Golgi fragmentation. The unique roles of the alternatively spliced isoforms indicate that these components play an essential role in determining the proper cell fate in response to distinct stimulations.
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Scepanovic G, Hunter MV, Kafri R, Fernandez-Gonzalez R. p38-mediated cell growth and survival drive rapid embryonic wound repair. Cell Rep 2021; 37:109874. [PMID: 34686334 DOI: 10.1016/j.celrep.2021.109874] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 08/02/2021] [Accepted: 09/30/2021] [Indexed: 12/18/2022] Open
Abstract
Embryos repair wounds rapidly, with no inflammation or scarring, in a process that involves polarization of the actomyosin cytoskeleton. Actomyosin polarization results in the assembly of a contractile cable around the wound that drives wound closure. Here, we demonstrate that a contractile actomyosin cable is not sufficient for rapid wound repair in Drosophila embryos. We show that wounding causes activation of the serine/threonine kinase p38 mitogen-activated protein kinase (MAPK) in the cells adjacent to the wound. p38 activation reduces the levels of wound-induced reactive oxygen species in the cells around the wound, limiting wound size. In addition, p38 promotes an increase in volume in the cells around the wound, thus facilitating the collective cell movements that drive rapid wound healing. Our data indicate that p38 regulates cell volumes through the sodium-potassium-chloride cotransporter NKCC1. Our work reveals cell growth and cell survival as cell behaviors critical for embryonic wound repair.
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Affiliation(s)
- Gordana Scepanovic
- Department of Cell and Systems Biology, University of Toronto, Toronto, ON M5S 3G5, Canada; Ted Rogers Centre for Heart Research, University of Toronto, Toronto, ON M5G 1M1, Canada
| | - Miranda Victoria Hunter
- Department of Cell and Systems Biology, University of Toronto, Toronto, ON M5S 3G5, Canada; Ted Rogers Centre for Heart Research, University of Toronto, Toronto, ON M5G 1M1, Canada
| | - Ran Kafri
- Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Rodrigo Fernandez-Gonzalez
- Department of Cell and Systems Biology, University of Toronto, Toronto, ON M5S 3G5, Canada; Ted Rogers Centre for Heart Research, University of Toronto, Toronto, ON M5G 1M1, Canada; Institute of Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada; Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
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Blanton HL, Pietrzak A, McHann MC, Guindon J. Sex and dose-dependent antinociceptive effects of the JNK (c-Jun N-terminal kinase) inhibitor SU 3327 are mediated by CB 2 receptors in female, and CB 1/CB 2 receptors in male mice in an inflammatory pain model. Brain Res Bull 2021; 177:39-52. [PMID: 34530070 DOI: 10.1016/j.brainresbull.2021.09.004] [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: 05/07/2021] [Revised: 08/31/2021] [Accepted: 09/07/2021] [Indexed: 11/30/2022]
Abstract
Activation of c-Jun N-terminal kinases (JNKs) has been implicated in the development and persistence of inflammatory and neuropathic pain in animal models. Moreover, JNKs have been involved in the maintenance of chronic pain, as well as development of tolerance to antinociceptive agents in the opioid and cannabinoid class of compounds. In this study, we evaluated the antinociceptive effects of the JNK inhibitor SU 3327 (0.3-30 mg/kg) in the formalin pain model with an emphasis on the sex-specific actions of this compound. In wild-type C57BL6J mice, SU 3327 produced strong antinociceptive effects in the formalin pain model which were mediated by CB2 receptors in females, and both CB1 and CB2 receptors in males. SU 3327 at a dose of 10 mg/kg produced antinociception, hypothermia, motor impairment, and hypolocomotion to a similar extent in both males and females. The antinociceptive effects of SU 3327 were more potent in males at lower doses (1 and 3 mg/kg), while females were more sensitive to the hypothermic, and motor-suppression effects at lower (3 mg/kg) doses versus males. Analysis of spinal cords, using qPCR following SU 3327 administration in the formalin test, revealed changes in cannabinoid, tolerance and inflammatory markers in females only, and only in the high (10-30 mg/kg) dose conditions. Indeed, females showed an increase in mRNA levels of cannabinoid (CB2), but a decrease in tolerance (β-arrestin 1) and inflammatory (TNF-α, IL-1β, IL-6)-associated markers. The differences between males and females, in this study, support sex as an important factor in nociception and antinociceptive responses mediated by JNK and the endocannabinoid system.
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Affiliation(s)
- Henry L Blanton
- Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, 3601 4th Street STOP 6592, Lubbock, TX 79430, USA
| | - Agata Pietrzak
- Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, 3601 4th Street STOP 6592, Lubbock, TX 79430, USA
| | - Melissa C McHann
- Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, 3601 4th Street STOP 6592, Lubbock, TX 79430, USA
| | - Josée Guindon
- Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, 3601 4th Street STOP 6592, Lubbock, TX 79430, USA; Center of Excellence for Translational Neuroscience and Therapeutics, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
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Rasmussen NR, Reiner DJ. Nuclear translocation of the tagged endogenous MAPK MPK-1 denotes a subset of activation events in C. elegans development. J Cell Sci 2021; 134:272044. [PMID: 34341823 PMCID: PMC8445601 DOI: 10.1242/jcs.258456] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Accepted: 07/14/2021] [Indexed: 11/20/2022] Open
Abstract
The extracellular signal-regulated kinases (ERKs) are mitogen-activated protein kinases (MAPKs) that are utilized downstream of Ras to Raf to MEK signaling to control activation of a wide array of targets. Activation of ERKs is elevated in Ras-driven tumors and RASopathies, and thus is a target for pharmacological inhibition. Regulatory mechanisms of ERK activation have been studied extensively in vitro and in cultured cells, but little in living animals. In this study, we tagged the Caenorhabditis elegans ERK-encoding gene, mpk-1. MPK-1 is ubiquitously expressed with elevated expression in certain contexts. We detected cytosol-to-nuclear translocation of MPK-1 in maturing oocytes and hence validated nuclear translocation as a reporter of some activation events. During patterning of vulval precursor cells (VPCs), MPK-1 is necessary and sufficient for the central cell, P6.p, to assume the primary fate. Yet MPK-1 translocates to the nuclei of all six VPCs in a temporal and concentration gradient centered on P6.p. This observation contrasts with previous results using the ERK nuclear kinase translocation reporter of substrate activation, raising questions about mechanisms and indicators of MPK-1 activation. This system and reagent promise to provide critical insights into the regulation of MPK-1 activation within a complex intercellular signaling network. Summary: Tagged endogenous C. elegans MPK-1 shows activation-dependent cytosol-to-nuclear translocation. This tool provides novel insights into MPK-1 localization compared with other markers of in vivo ERK activation.
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Affiliation(s)
- Neal R Rasmussen
- Institute of Biosciences and Technology, College of Medicine, Texas A&M Health Science Center, Texas A&M University, Houston, 77030, USA
| | - David J Reiner
- Institute of Biosciences and Technology, College of Medicine, Texas A&M Health Science Center, Texas A&M University, Houston, 77030, USA
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Traub B, Roth A, Kornmann M, Knippschild U, Bischof J. Stress-activated kinases as therapeutic targets in pancreatic cancer. World J Gastroenterol 2021; 27:4963-4984. [PMID: 34497429 PMCID: PMC8384741 DOI: 10.3748/wjg.v27.i30.4963] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 05/17/2021] [Accepted: 07/20/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is a dismal disease with high incidence and poor survival rates. With the aim to improve overall survival of pancreatic cancer patients, new therapeutic approaches are urgently needed. Protein kinases are key regulatory players in basically all stages of development, maintaining physiologic functions but also being involved in pathogenic processes. c-Jun N-terminal kinases (JNK) and p38 kinases, representatives of the mitogen-activated protein kinases, as well as the casein kinase 1 (CK1) family of protein kinases are important mediators of adequate response to cellular stress following inflammatory and metabolic stressors, DNA damage, and others. In their physiologic roles, they are responsible for the regulation of cell cycle progression, cell proliferation and differentiation, and apoptosis. Dysregulation of the underlying pathways consequently has been identified in various cancer types, including pancreatic cancer. Pharmacological targeting of those pathways has been the field of interest for several years. While success in earlier studies was limited due to lacking specificity and off-target effects, more recent improvements in small molecule inhibitor design against stress-activated protein kinases and their use in combination therapies have shown promising in vitro results. Consequently, targeting of JNK, p38, and CK1 protein kinase family members may actually be of particular interest in the field of precision medicine in patients with highly deregulated kinase pathways related to these kinases. However, further studies are warranted, especially involving in vivo investigation and clinical trials, in order to advance inhibition of stress-activated kinases to the field of translational medicine.
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Affiliation(s)
- Benno Traub
- Department of General and Visceral Surgery, Ulm University Hospital, Ulm 89081, Germany
| | - Aileen Roth
- Department of General and Visceral Surgery, Ulm University Hospital, Ulm 89081, Germany
| | - Marko Kornmann
- Department of General and Visceral Surgery, Ulm University Hospital, Ulm 89081, Germany
| | - Uwe Knippschild
- Department of General and Visceral Surgery, Ulm University Hospital, Ulm 89081, Germany
| | - Joachim Bischof
- Department of General and Visceral Surgery, Ulm University Hospital, Ulm 89081, Germany
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Enthalpy-Entropy Compensation in the Promiscuous Interaction of an Intrinsically Disordered Protein with Homologous Protein Partners. Biomolecules 2021; 11:biom11081204. [PMID: 34439869 PMCID: PMC8391806 DOI: 10.3390/biom11081204] [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: 07/13/2021] [Revised: 08/01/2021] [Accepted: 08/09/2021] [Indexed: 01/07/2023] Open
Abstract
Intrinsically disordered proteins (IDPs) can engage in promiscuous interactions with their protein targets; however, it is not clear how this feature is encoded in the primary sequence of the IDPs and to what extent the surface properties and the shape of the binding cavity dictate the binding mode and the final bound conformation. Here we show, using a combination of nuclear magnetic resonance (NMR) spectroscopy and isothermal titration calorimetry (ITC), that the promiscuous interaction of the intrinsically disordered regulatory domain of the mitogen-activated protein kinase kinase MKK4 with p38α and JNK1 is facilitated by folding-upon-binding into two different conformations, despite the high sequence conservation and structural homology between p38α and JNK1. Our results support a model whereby the specific surface properties of JNK1 and p38α dictate the bound conformation of MKK4 and that enthalpy–entropy compensation plays a major role in maintaining comparable binding affinities for MKK4 towards the two kinases.
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Yang Z, Sun H, Ma W, Wu K, Peng G, Ou T, Wu S. Down-regulation of Polo-like kinase 4 (PLK4) induces G1 arrest via activation of the p38/p53/p21 signalling pathway in bladder cancer. FEBS Open Bio 2021; 11:2631-2646. [PMID: 34342940 PMCID: PMC8409300 DOI: 10.1002/2211-5463.13262] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 06/22/2021] [Accepted: 08/02/2021] [Indexed: 12/24/2022] Open
Abstract
Polo-like kinase 4 (PLK4) has been reported to contribute to tumor growth, invasion, and metastasis. However, the role of PLK4 in human bladder cancer (BC) remains unclear. Here, we demonstrate the regulatory function of PLK4 in human BC progression. PLK4 is overexpressed in BC cell lines and tissues, and its overexpression correlated with poor prognosis. Our transcriptome analysis combined with subsequent functional assays indicated that PLK4 inhibition can suppress BC cell growth and induce cell cycle arrest at G1 phase via activation of the p38/p53/p21 pathway in vitro and in vivo. Overall, our data suggest that PLK4 is a critical regulator of BC cell proliferation, and thus it may have potential as a novel molecular target for BC treatment.
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Affiliation(s)
- Ziyi Yang
- Shenzhen University Health Science Center, Shenzhen, Guangdong province, China.,Institute of Urology, The Third Affiliated Hospital of Shenzhen University (Luohu Hospital Group), Shenzhen, 518000, Guangdong province, China
| | - Haiyan Sun
- Institute of Urology, The Third Affiliated Hospital of Shenzhen University (Luohu Hospital Group), Shenzhen, 518000, Guangdong province, China
| | - Wenlong Ma
- Institute of Urology, The Third Affiliated Hospital of Shenzhen University (Luohu Hospital Group), Shenzhen, 518000, Guangdong province, China
| | - Kai Wu
- Institute of Urology, The Third Affiliated Hospital of Shenzhen University (Luohu Hospital Group), Shenzhen, 518000, Guangdong province, China
| | - Guoyu Peng
- Institute of Urology, The Third Affiliated Hospital of Shenzhen University (Luohu Hospital Group), Shenzhen, 518000, Guangdong province, China
| | - Tong Ou
- Institute of Urology, The Third Affiliated Hospital of Shenzhen University (Luohu Hospital Group), Shenzhen, 518000, Guangdong province, China
| | - Song Wu
- Shenzhen University Health Science Center, Shenzhen, Guangdong province, China.,Institute of Urology, The Third Affiliated Hospital of Shenzhen University (Luohu Hospital Group), Shenzhen, 518000, Guangdong province, China
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43
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Su YL, Jiang YF, Chen HJ, Ye S, Zhou WH, Liu HP, Dong JD, Wei JG, Qin QW, Sun H. Molecular characterization, expression and function analysis of Epinephelus coioides MKK4 response to SGIV and Vibrio alginolyticus infection. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2021; 119:104020. [PMID: 33476669 DOI: 10.1016/j.dci.2021.104020] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/03/2020] [Revised: 01/13/2021] [Accepted: 01/13/2021] [Indexed: 06/12/2023]
Abstract
Mitogen-activated protein kinase 4 (MKK4), a member of the MAP kinase family, play important roles in response to many environmental and cellular stresses in mammals. In this study, three MKK4 subtypes, EcMKK4-1, EcMKK4-2 and EcMKK4-3, were obtained from grouper Epinephelus coioides. The open reading frame (ORF) of EcMKK4s are obtained and the EcMKK4s proteins contain highly conserved domains: a S_TKc domain, a canonical diphosphorylation group and two conserved MKKK ATP binding motifs, Asp-Phe-Gly (DFG) and Ala-Pro-Glu (APE). EcMKK4s could be found both in the cytoplasmic and nuclear. The EcMKK4s mRNA were detected in all E. coioides tissues examined with the different expression levels, and the expression were up-regulated during SGIV (Singapore grouper iridescent virus) or Vibrio alginolyticus infection. EcMKK4 could significantly reduce the activation of AP-1 reporter gene. The results suggested that EcMKK4s might play important roles in pathogen-caused inflammation.
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Affiliation(s)
- Yu-Ling Su
- Joint Laboratory of Guangdong Province and Hong Kong Regions on Marine Bioresource Conservation and Exploitation, College of Marine Sciences, South China Agricultural University, Guangzhou 510642, Guangdong Province, PR China
| | - Yu-Feng Jiang
- Department of Laboratory, Jining No.1 People's Hospital; Postdoctoral Mobile Station of Shandong University of Traditional Chinese Medicine, Shandong, 272111, PR China
| | - He-Jia Chen
- Joint Laboratory of Guangdong Province and Hong Kong Regions on Marine Bioresource Conservation and Exploitation, College of Marine Sciences, South China Agricultural University, Guangzhou 510642, Guangdong Province, PR China
| | - Shi Ye
- Joint Laboratory of Guangdong Province and Hong Kong Regions on Marine Bioresource Conservation and Exploitation, College of Marine Sciences, South China Agricultural University, Guangzhou 510642, Guangdong Province, PR China
| | - Wei-Hua Zhou
- Hainan Key Laboratory of Tropical Marine Biotechnology, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou 510301, PR China
| | - Hong-Ping Liu
- Joint Laboratory of Guangdong Province and Hong Kong Regions on Marine Bioresource Conservation and Exploitation, College of Marine Sciences, South China Agricultural University, Guangzhou 510642, Guangdong Province, PR China
| | - Jun-De Dong
- Hainan Key Laboratory of Tropical Marine Biotechnology, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou 510301, PR China
| | - Jing-Guang Wei
- Joint Laboratory of Guangdong Province and Hong Kong Regions on Marine Bioresource Conservation and Exploitation, College of Marine Sciences, South China Agricultural University, Guangzhou 510642, Guangdong Province, PR China
| | - Qi-Wei Qin
- Joint Laboratory of Guangdong Province and Hong Kong Regions on Marine Bioresource Conservation and Exploitation, College of Marine Sciences, South China Agricultural University, Guangzhou 510642, Guangdong Province, PR China.
| | - Hongyan Sun
- Joint Laboratory of Guangdong Province and Hong Kong Regions on Marine Bioresource Conservation and Exploitation, College of Marine Sciences, South China Agricultural University, Guangzhou 510642, Guangdong Province, PR China.
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44
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Sawada Y, Nakatsuji T, Dokoshi T, Kulkarni NN, Liggins MC, Sen G, Gallo RL. Cutaneous innate immune tolerance is mediated by epigenetic control of MAP2K3 by HDAC8/9. Sci Immunol 2021; 6:eabe1935. [PMID: 34021025 PMCID: PMC8363943 DOI: 10.1126/sciimmunol.abe1935] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Accepted: 04/22/2021] [Indexed: 01/07/2023]
Abstract
The skin typically tolerates exposure to various microbes and chemicals in the environment. Here, we investigated how the epidermis maintains this innate immune tolerance to stimuli that are recognized by Toll-like receptors (TLRs). Loss of tolerance to TLR ligands occurred after silencing of the histone deacetylases (HDACs) HDAC8 and HDAC9 in keratinocytes. Transcriptional analysis identified MAP2K3 as suppressed by HDAC8/9 activity and a potential key intermediary for establishing this tolerance. HDAC8/9 influenced acetylation at H3K9 and H3K27 marks in the MAP2K3 promoter. Proteomic analysis further identified SSRP1 and SUPT16H as associated with HDAC8/9 and responsible for transcriptional elongation of MAP2K3. Silencing of MAP2K3 blocked the capacity of HDAC8/9 to influence cytokine responses. Relevance in vivo was supported by observations of increased MAP2K3 in human inflammatory skin conditions and the capacity of keratinocyte HDAC8/9 to influence dendritic cell maturation and T cell proliferation. Keratinocyte-specific deletion of HDAC8/9 also increased inflammation in mice after exposure to ultraviolet radiation, imiquimod, or Staphylococcus aureus These findings define a mechanism for the epidermis to regulate inflammation in the presence of ubiquitous TLR ligands.
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Affiliation(s)
- Yu Sawada
- Department of Dermatology, University of California, San Diego, San Diego, CA, USA
| | - Teruaki Nakatsuji
- Department of Dermatology, University of California, San Diego, San Diego, CA, USA
| | - Tatsuya Dokoshi
- Department of Dermatology, University of California, San Diego, San Diego, CA, USA
| | | | - Marc C Liggins
- Department of Dermatology, University of California, San Diego, San Diego, CA, USA
| | - George Sen
- Department of Dermatology, University of California, San Diego, San Diego, CA, USA
| | - Richard L Gallo
- Department of Dermatology, University of California, San Diego, San Diego, CA, USA.
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Sałaciak K, Pytka K. Biased agonism in drug discovery: Is there a future for biased 5-HT 1A receptor agonists in the treatment of neuropsychiatric diseases? Pharmacol Ther 2021; 227:107872. [PMID: 33905796 DOI: 10.1016/j.pharmthera.2021.107872] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 04/17/2021] [Accepted: 04/19/2021] [Indexed: 12/11/2022]
Abstract
Serotonin (5-HT) is one of the fundamental neurotransmitters that contribute to the information essential for an organism's normal, physiological function. Serotonin acts centrally and systemically. The 5-HT1A receptor is the most widespread serotonin receptor, and participates in many brain-related disorders, including anxiety, depression, and cognitive impairments. The 5-HT1A receptor can activate several different biochemical pathways and signals through both G protein-dependent and G protein-independent pathways. Preclinical experiments indicate that distinct signaling pathways in specific brain regions may be crucial for antidepressant-like, anxiolytic-like, and procognitive responses. Therefore, the development of new ligands that selectively target a particular signaling pathway(s) could open new possibilities for more effective and safer pharmacotherapy. This review discusses the current state of preclinical studies focusing on the concept of functional selectivity (biased agonism) regarding the 5-HT1A receptor and its role in antidepressant-like, anxiolytic-like, and procognitive regulation. Such work highlights not only the differential effects of targeted autoreceptors, vs. heteroreceptors, but also the importance of targeting specific downstream intracellular signaling processes, thereby enhancing favorable over unfavorable signaling activation.
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Affiliation(s)
- Kinga Sałaciak
- Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland
| | - Karolina Pytka
- Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland.
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Atypical p38 Signaling, Activation, and Implications for Disease. Int J Mol Sci 2021; 22:ijms22084183. [PMID: 33920735 PMCID: PMC8073329 DOI: 10.3390/ijms22084183] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 03/29/2021] [Accepted: 04/13/2021] [Indexed: 02/07/2023] Open
Abstract
The mitogen-activated protein kinase (MAPK) p38 is an essential family of kinases, regulating responses to environmental stress and inflammation. There is an ever-increasing plethora of physiological and pathophysiological conditions attributed to p38 activity, ranging from cell division and embryonic development to the control of a multitude of diseases including retinal, cardiovascular, and neurodegenerative diseases, diabetes, and cancer. Despite the decades of intense investigation, a viable therapeutic approach to disrupt p38 signaling remains elusive. A growing body of evidence supports the pathological significance of an understudied atypical p38 signaling pathway. Atypical p38 signaling is driven by a direct interaction between the adaptor protein TAB1 and p38α, driving p38 autophosphorylation independent from the classical MKK3 and MKK6 pathways. Unlike the classical MKK3/6 signaling pathway, atypical signaling is selective for just p38α, and at present has only been characterized during pathophysiological stimulation. Recent studies have linked atypical signaling to dermal and vascular inflammation, myocardial ischemia, cancer metastasis, diabetes, complications during pregnancy, and bacterial and viral infections. Additional studies are required to fully understand how, when, where, and why atypical p38 signaling is induced. Furthermore, the development of selective TAB1-p38 inhibitors represents an exciting new opportunity to selectively inhibit pathological p38 signaling in a wide array of diseases.
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D'Orazi G, Cordani M, Cirone M. Oncogenic pathways activated by pro-inflammatory cytokines promote mutant p53 stability: clue for novel anticancer therapies. Cell Mol Life Sci 2021; 78:1853-1860. [PMID: 33070220 PMCID: PMC11072129 DOI: 10.1007/s00018-020-03677-7] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Revised: 09/03/2020] [Accepted: 10/06/2020] [Indexed: 12/14/2022]
Abstract
Inflammation and cancerogenesis are strongly interconnected processes, not only because inflammation promotes DNA instability, but also because both processes are driven by pathways such as NF-kB, STAT3, mTOR and MAPKs. Interestingly, these pathways regulate the release of pro-inflammatory cytokines such as IL-6, TNF-α and IL-1β that in turn control their activation and play a crucial role in shaping immune response. The transcription factor p53 is the major tumor suppressor that is often mutated in cancer, contributing to tumor progression. In this overview, we highlight how the interplay between pro-inflammatory cytokines and pro-inflammatory/pro-oncogenic pathways, regulating and being regulated by UPR signaling and autophagy, affects the stability of mutp53 that in turn is able to control autophagy, UPR signaling, cytokine release and the activation of the same oncogenic pathways to preserve its own stability and promote tumorigenesis. Interrupting these positive feedback loops may represent a promising strategy in anticancer therapy, particularly against cancers carrying mutp53.
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Affiliation(s)
- Gabriella D'Orazi
- Department of Research and Advanced Technologies, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Marco Cordani
- IMDEA Nanociencia, C/Faraday 9, Ciudad Universitaria de Cantoblanco, Madrid, Spain
| | - Mara Cirone
- Department of Experimental Medicine, Laboratory Affiliated to Pasteur Institute Italy Foundation Cenci Bolognetti, Sapienza University of Rome, Rome, Italy.
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48
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Kumar GS, Page R, Peti W. The interaction of p38 with its upstream kinase MKK6. Protein Sci 2021; 30:908-913. [PMID: 33554397 DOI: 10.1002/pro.4039] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 01/29/2021] [Accepted: 02/02/2021] [Indexed: 02/06/2023]
Abstract
Mitogen-activated protein kinase (MAPK; p38, ERK, and JNK) cascades are evolutionarily conserved signaling pathways that regulate the cellular response to a variety of extracellular stimuli, such as growth factors and interleukins. The MAPK p38 is activated by its specific upstream MAPK kinases, MKK6 and MKK3. However, a comprehensive molecular understanding of how these cognate upstream kinases bind and activate p38 is still missing. Here, we combine NMR spectroscopy and isothermal titration calorimetry to define the binding interface between full-length MKK6 and p38. It was shown that p38 engages MKK6 not only via its hydrophobic docking groove, but also influences helix αF, a secondary structural element that plays a key role in organizing the kinase core. It was also shown that, unlike MAPK phosphatases, the p38 conserved docking (CD) site is much less affected by MKK6 binding. Finally, it was demonstrated that these interactions with p38 are conserved independent of the MKK6 activation state. Together, the results revealed differences between specificity markers of p38 regulation by upstream kinases, which do not effectively engage the CD site, and downstream phosphatases, which require the CD site for productive binding.
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Affiliation(s)
- Ganesan Senthil Kumar
- Department of Molecular Biology and Biophysics, University of Connecticut Health Center, Farmington, Connecticut, USA
| | - Rebecca Page
- Department of Cell Biology, University of Connecticut Health Center, Farmington, Connecticut, USA
| | - Wolfgang Peti
- Department of Molecular Biology and Biophysics, University of Connecticut Health Center, Farmington, Connecticut, USA
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49
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Huang T, Hosseinibarkooie S, Borne AL, Granade ME, Brulet JW, Harris TE, Ferris HA, Hsu KL. Chemoproteomic profiling of kinases in live cells using electrophilic sulfonyl triazole probes. Chem Sci 2021; 12:3295-3307. [PMID: 34164099 PMCID: PMC8179411 DOI: 10.1039/d0sc06623k] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Accepted: 01/08/2021] [Indexed: 12/23/2022] Open
Abstract
Sulfonyl-triazoles are a new class of electrophiles that mediate covalent reaction with tyrosine residues on proteins through sulfur-triazole exchange (SuTEx) chemistry. Recent studies demonstrate the broad utility and tunability of SuTEx chemistry for chemical proteomics and protein ligand discovery. Here, we present a strategy for mapping protein interaction networks of structurally complex binding elements using functionalized SuTEx probes. We show that the triazole leaving group (LG) can serve as a releasable linker for embedding hydrophobic fragments to direct molecular recognition while permitting efficient proteome-wide identification of binding sites in live cells. We synthesized a series of SuTEx probes functionalized with a lipid kinase fragment binder for discovery of ligandable tyrosines residing in catalytic and regulatory domains of protein and metabolic kinases in live cells. We performed competition studies with kinase inhibitors and substrates to demonstrate that probe binding is occurring in an activity-dependent manner. Our functional studies led to discovery of probe-modified sites within the C2 domain that were important for downregulation of protein kinase C-alpha in response to phorbol ester activation. Our proof of concept studies highlight the triazole LG of SuTEx probes as a traceless linker for locating protein binding sites targeted by complex recognition elements in live cells.
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Affiliation(s)
- Tao Huang
- Department of Chemistry, University of Virginia McCormick Road, P.O. Box 400319 Charlottesville Virginia 22904 USA +1-434-297-4864
| | | | - Adam L Borne
- Department of Pharmacology, University of Virginia School of Medicine Charlottesville Virginia 22908 USA
| | - Mitchell E Granade
- Department of Pharmacology, University of Virginia School of Medicine Charlottesville Virginia 22908 USA
| | - Jeffrey W Brulet
- Department of Chemistry, University of Virginia McCormick Road, P.O. Box 400319 Charlottesville Virginia 22904 USA +1-434-297-4864
| | - Thurl E Harris
- Department of Pharmacology, University of Virginia School of Medicine Charlottesville Virginia 22908 USA
| | - Heather A Ferris
- Department of Medicine, University of Virginia School of Medicine Charlottesville Virginia 22903 USA
| | - Ku-Lung Hsu
- Department of Chemistry, University of Virginia McCormick Road, P.O. Box 400319 Charlottesville Virginia 22904 USA +1-434-297-4864
- Department of Pharmacology, University of Virginia School of Medicine Charlottesville Virginia 22908 USA
- University of Virginia Cancer Center, University of Virginia Charlottesville VA 22903 USA
- Department of Molecular Physiology and Biological Physics, University of Virginia Charlottesville Virginia 22908 USA
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50
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Role of Transportome in the Gills of Chinese Mitten Crabs in Response to Salinity Change: A Meta-Analysis of RNA-Seq Datasets. BIOLOGY 2021; 10:biology10010039. [PMID: 33430106 PMCID: PMC7827906 DOI: 10.3390/biology10010039] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 12/26/2020] [Accepted: 01/06/2021] [Indexed: 12/13/2022]
Abstract
Chinese mitten crab (CMC) or Eriocheir sinensis is a strong osmoregulator that can keep rigorous cellular homeostasis. CMC can flourish in freshwater, as well as seawater, habitats and represents the most important species for freshwater aquaculture. Salt stress can have direct effects on several stages (e.g., reproduction, molting, growth, etc.) of the CMC life cycle. To get a better overview of the genes involved in the gills of CMC under different salinity conditions, we conducted an RNA-Seq meta-analysis on the transcriptomes of four publicly available datasets. The meta-analysis identified 405 differentially expressed transcripts (DETs), of which 40% were classified into various transporter classes, including accessory factors and primary active transporters as the major transport classes. A network analysis of the DETs revealed that adaptation to salinity is a highly regulated mechanism in which different functional modules play essential roles. To the best of our knowledge, this study is the first to conduct a transcriptome meta-analysis of gills from crab RNA-Seq datasets under salinity. Additionally, this study is also the first to focus on the differential expression of diverse transporters and channels (transportome) in CMC. Our meta-analysis opens new avenues for a better understanding of the osmoregulation mechanism and the selection of potential transporters associated with salinity change.
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