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Baldensperger T, Preissler M, Becker CFW. Non-enzymatic posttranslational protein modifications in protein aggregation and neurodegenerative diseases. RSC Chem Biol 2025; 6:129-149. [PMID: 39722676 PMCID: PMC11667106 DOI: 10.1039/d4cb00221k] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Accepted: 12/18/2024] [Indexed: 12/28/2024] Open
Abstract
Highly reactive metabolic intermediates and other small molecules frequently react with amino acid side chains, leading to non-enzymatic posttranslational modifications (nPTMs) of proteins. The abundance of these modifications increases under high metabolic activity or stress conditions and can dramatically impact protein structure and function. Although protein quality control mechanisms typically mitigate the effects of these impaired proteins, in long-lived and degradation-resistant proteins, nPTMs accumulate. In some cases, such as cataract development and diabetes, clear links between nPTMs, aging, and disease progression have been established. In neurodegenerative diseases such as Alzheimer's and Parkinson's disease, a key question is whether accumulation of nPTMs is a cause or consequence of protein aggregation. This review focuses on major nPTMs found on proteins with central roles in neurodegenerative diseases such as α-synuclein, β-amyloid, and tau. We summarize current knowledge on the formation of these modifications and discuss their potential impact on disease onset and progression. Additionally, we examine what is known to date about how nPTMs impair cellular detoxification, repair, and degradation systems. Finally, we critically discuss the available methodologies to systematically investigate nPTMs at the molecular level and outline suitable approaches to study their effects on protein aggregation. We aim to foster more research into the role of nPTMs in neurodegeneration by adapting methodologies that have proven successful in studying enzymatic posttranslational modifications. Specifically, we advocate for site-specific incorporation of these modifications into target proteins using advanced chemical and molecular biology techniques.
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Affiliation(s)
- Tim Baldensperger
- University of Vienna, Faculty of Chemistry, Institute of Biological Chemistry Währinger Str. 38 1090 Vienna Austria
| | - Miriam Preissler
- University of Vienna, Faculty of Chemistry, Institute of Biological Chemistry Währinger Str. 38 1090 Vienna Austria
- University of Vienna, Vienna Doctoral School in Chemistry (DoSChem) Währinger Str. 42 1090 Vienna Austria
| | - Christian F W Becker
- University of Vienna, Faculty of Chemistry, Institute of Biological Chemistry Währinger Str. 38 1090 Vienna Austria
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de Araujo NF, Nobrega NRC, Dos Reis Costa DEF, Simplicio JA, de Assis Rabelo Ribeiro N, Tirapelli CR, Bonaventura D. Sodium nitrite induces tolerance in the mouse aorta: Involvement of the renin-angiotensin system, nitric oxide synthase, and reactive oxygen species. Eur J Pharmacol 2024; 985:177056. [PMID: 39427861 DOI: 10.1016/j.ejphar.2024.177056] [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: 06/15/2024] [Revised: 10/09/2024] [Accepted: 10/10/2024] [Indexed: 10/22/2024]
Abstract
Nitrites have emerged as promising therapeutic agents for cardiovascular diseases, alongside nitrates. While chronic use of organic nitrates is well recognized to lead to vascular tolerance, the tolerance associated with nitrite therapy remains incompletely understood. The aim of the present study was to investigate vascular tolerance to sodium nitrite and the underlying molecular mechanisms. Endothelium-denuded aortic rings isolated from male Balb/C mice were incubated with either the EC50 (10-4 mol/L) or EC100 (10-2 mol/L) concentration of sodium nitrite for 15 min to induce tolerance. The EC100 concentration of sodium nitrite induced vascular tolerance. Pre-incubation with captopril and losartan effectively reversed sodium nitrite-induced tolerance. Similarly, pre-incubation with L-NAME and L-arginine prevented sodium nitrite-induced tolerance. Increased levels of reactive oxidative species (ROS) and reduced bioavailability of nitric oxide (NO) were observed in tolerant aortas. Increased superoxide dismutase (SOD) activity and decreased catalase activity were also verified in tolerant aortas. Both captopril and L-NAME prevented the increased levels of ROS observed in tolerant aortas. Furthermore, pre-incubation with catalase effectively prevented sodium nitrite-induced tolerance. Our findings suggest that sodium nitrite induces vascular tolerance through a signaling pathway involving the renin-angiotensin system, nitric oxide synthase, and ROS. This study contributes to the understanding of the interaction between nitrites and vascular tolerance and highlights potential targets to overcome or prevent this phenomenon.
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Affiliation(s)
- Natalia Ferreira de Araujo
- Laboratory of Vascular Pharmacology, Department of Pharmacology, Biological Sciences Institute, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Natalia Ribeiro Cabacinha Nobrega
- Laboratory of Vascular Pharmacology, Department of Pharmacology, Biological Sciences Institute, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Daniela Esteves Ferreira Dos Reis Costa
- Laboratory of Vascular Pharmacology, Department of Pharmacology, Biological Sciences Institute, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Janaina Aparecida Simplicio
- Laboratory of Pharmacology, Department of Psychiatric Nursing and Human Sciences, Nursing School, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Naiara de Assis Rabelo Ribeiro
- Laboratory of Vascular Pharmacology, Department of Pharmacology, Biological Sciences Institute, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Carlos Renato Tirapelli
- Laboratory of Pharmacology, Department of Psychiatric Nursing and Human Sciences, Nursing School, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Daniella Bonaventura
- Laboratory of Vascular Pharmacology, Department of Pharmacology, Biological Sciences Institute, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
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Aldridge JL, Alexander ED, Franklin AA, Frasier CR. Decreased ability to manage increases in reactive oxygen species may underlie susceptibility to arrhythmias in mice lacking Scn1b. Am J Physiol Heart Circ Physiol 2024; 327:H723-H732. [PMID: 39120465 PMCID: PMC11482272 DOI: 10.1152/ajpheart.00265.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Revised: 07/31/2024] [Accepted: 08/05/2024] [Indexed: 08/10/2024]
Abstract
Scn1b plays essential roles in the heart, where it encodes β1-subunits that serve as modifiers of gene expression, cell surface channel activity, and cardiac conductivity. Reduced β1 function is linked to electrical instability in various diseases with cardiac manifestations and increased susceptibility to arrhythmias. Recently, we demonstrated that loss of Scn1b in mice leads to compromised mitochondria energetics and reactive oxygen species (ROS) production. In this study, we examined the link between increased ROS and arrhythmia susceptibility in Scn1b-/- mice. In addition, ROS-scavenging capacity can be overwhelmed during prolonged oxidative stress, increasing arrhythmia susceptibility. Therefore, we isolated whole hearts and cardiomyocytes from Scn1b-/- and Scn1b+/+ mice and subjected them to an oxidative challenge with diamide, a glutathione oxidant. Next, we analyzed gene expression and activity of antioxidant enzymes in Scn1b-/- hearts. Cells isolated from Scn1b-/- hearts died faster and displayed higher rates of ROS accumulation preceding cell death compared with those from Scn1b+/+. Furthermore, Scn1b-/- hearts showed higher arrhythmia scores and spent less time free of arrhythmia. Lastly, we found that protein expression and enzymatic activity of glutathione peroxidase is increased in Scn1b-/- hearts compared with wild type. Our results indicate that Scn1b-/- mice have decreased capability to manage ROS during prolonged oxidative stress. ROS accumulation is elevated and appears to overwhelm ROS scavenging through the glutathione system. This imbalance creates the potential for altered cell energetics that may underlie increased susceptibility to arrhythmias or other adverse cardiac outcomes.NEW & NOTEWORTHY Using an oxidative challenge, we demonstrated that isolated cells from Scn1b-/- mice are more susceptible to cell death and surges in reactive oxygen species accumulation. At the whole organ level, they were also more susceptible to the formation of cardiac arrhythmias. This may in part be due to changes to the glutathione antioxidant system.
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Affiliation(s)
- Jessa L Aldridge
- Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, United States
| | - Emily Davis Alexander
- Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, United States
| | - Allison A Franklin
- Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, United States
| | - Chad R Frasier
- Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, United States
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Duță C, Muscurel C, Dogaru CB, Stoian I. Ferroptosis-A Shared Mechanism for Parkinson's Disease and Type 2 Diabetes. Int J Mol Sci 2024; 25:8838. [PMID: 39201524 PMCID: PMC11354749 DOI: 10.3390/ijms25168838] [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: 06/30/2024] [Revised: 07/31/2024] [Accepted: 08/06/2024] [Indexed: 09/02/2024] Open
Abstract
Type 2 diabetes (T2D) and Parkinson's disease (PD) are the two most frequent age-related chronic diseases. There are many similarities between the two diseases: both are chronic diseases; both are the result of a decrease in a specific substance-insulin in T2D and dopamine in PD; and both are caused by the destruction of specific cells-beta pancreatic cells in T2D and dopaminergic neurons in PD. Recent epidemiological and experimental studies have found that there are common underlying mechanisms in the pathophysiology of T2D and PD: chronic inflammation, mitochondrial dysfunction, impaired protein handling and ferroptosis. Epidemiological research has indicated that there is a higher risk of PD in individuals with T2D. Moreover, clinical studies have observed that the symptoms of Parkinson's disease worsen significantly after the onset of T2D. This article provides an up-to-date review on the intricate interplay between oxidative stress, reactive oxygen species (ROS) and ferroptosis in PD and T2D. By understanding the shared molecular pathways and how they can be modulated, we can develop more effective therapies, or we can repurpose existing drugs to improve patient outcomes in both disorders.
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Haikal A, Ali AR. Chemical composition and toxicity studies on Lantana camara L. flower essential oil and its in silico binding and pharmacokinetics to superoxide dismutase 1 for amyotrophic lateral sclerosis (ALS) therapy. RSC Adv 2024; 14:24250-24264. [PMID: 39104562 PMCID: PMC11299056 DOI: 10.1039/d4ra04281f] [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: 06/11/2024] [Accepted: 07/28/2024] [Indexed: 08/07/2024] Open
Abstract
Using the gas chromatography mass spectrometry method, the chemical components of essential oil from flowers of Lantana camara growing in Egypt are analyzed. Through this investigation, 22 chemicals from floral oil were identified. Most of the oil is made up of sesquiterpene caryophyllene (15.51%) and monoterpene sabinene (14.90%). When the oil's composition was compared to oils extracted from the same plant on several continents, we observed that the essential components were largely the same with some difference in proportions and some compounds due to geographical differences. A molecular docking study of essential oil components was conducted with human superoxide dismutase 1, a target involved in the pathophysiology of amyotrophic lateral sclerosis (ALS). Isospathulenol showed a comparable docking score to the reference ligand bound to the dismutase enzyme. Isospathulenol showed a reasonable drug score with some safety concerns. In addition, isospathulenol is predicted to have high GI absorption, good permeability through the blood-brain barrier and reasonable bioavailability score with ease access to synthetic modifications. In addition, the same compound is devoid from any violation to Lipinski rules or any PAINS alerts. This may establish the promising characteristics of such a compound to be optimized into potential drug candidates for treatment of ALS.
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Affiliation(s)
- Abdullah Haikal
- Department of Pharmacognosy, Faculty of Pharmacy, Mansoura University Mansoura 35516 Egypt +201129608369
| | - Ahmed R Ali
- Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University Mansoura 35516 Egypt
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, New Mansoura University New Mansoura 7723730 Egypt +20-10-9838-4072
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Bai Y, Dong Y, Zheng L, Zeng H, Wei Y, Shi H. Cassava phosphatase PP2C1 modulates thermotolerance via fine-tuning dephosphorylation of antioxidant enzymes. PLANT PHYSIOLOGY 2024; 194:2724-2738. [PMID: 38198213 DOI: 10.1093/plphys/kiae009] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 11/13/2023] [Accepted: 11/15/2023] [Indexed: 01/12/2024]
Abstract
Global warming is an adverse environmental factor that threatens crop yields and food security. 2C-type protein phosphatases (PP2Cs), as core protein phosphatase components, play important roles in plant hormone signaling to cope with various environmental stresses. However, the function and underlying mechanism of PP2Cs in the heat stress response remain elusive in tropical crops. Here, we report that MePP2C1 negatively regulated thermotolerance in cassava (Manihot esculenta Crantz), accompanied by the modulation of reactive oxygen species (ROS) accumulation and the underlying antioxidant enzyme activities of catalase (CAT) and ascorbate peroxidase (APX). Further investigation found that MePP2C1 directly interacted with and dephosphorylated MeCAT1 and MeAPX2 at serine (S) 112 and S160 residues, respectively. Moreover, in vitro and in vivo assays showed that protein phosphorylation of MeCAT1S112 and MeAPX2S160 was essential for their enzyme activities, and MePP2C1 negatively regulated thermotolerance and redox homeostasis by dephosphorylating MeCAT1S112 and MeAPX2S160. Taken together, this study illustrates the direct relationship between MePP2C1-mediated protein dephosphorylation of MeCAT1 and MeAPX2 and ROS accumulation in thermotolerance to provide insights for adapting to global warming via fine-tuning thermotolerance of the tropical crop cassava.
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Affiliation(s)
- Yujing Bai
- National Key Laboratory for Tropical Crop Breeding, School of Breeding and Multiplication (Sanya Institute of Breeding and Multiplication), Key Laboratory of Biotechnology of Salt Tolerant Crops of Hainan Province, School of Tropical Agriculture and Forestry, Hainan University, Sanya, Hainan Province 572025, China
- Hainan Yazhou Bay Seed Laboratory, Sanya, Hainan Province 572025, China
| | - Yabin Dong
- National Key Laboratory for Tropical Crop Breeding, School of Breeding and Multiplication (Sanya Institute of Breeding and Multiplication), Key Laboratory of Biotechnology of Salt Tolerant Crops of Hainan Province, School of Tropical Agriculture and Forestry, Hainan University, Sanya, Hainan Province 572025, China
- Hainan Yazhou Bay Seed Laboratory, Sanya, Hainan Province 572025, China
| | - Liyan Zheng
- National Key Laboratory for Tropical Crop Breeding, School of Breeding and Multiplication (Sanya Institute of Breeding and Multiplication), Key Laboratory of Biotechnology of Salt Tolerant Crops of Hainan Province, School of Tropical Agriculture and Forestry, Hainan University, Sanya, Hainan Province 572025, China
- Hainan Yazhou Bay Seed Laboratory, Sanya, Hainan Province 572025, China
| | - Hongqiu Zeng
- National Key Laboratory for Tropical Crop Breeding, School of Breeding and Multiplication (Sanya Institute of Breeding and Multiplication), Key Laboratory of Biotechnology of Salt Tolerant Crops of Hainan Province, School of Tropical Agriculture and Forestry, Hainan University, Sanya, Hainan Province 572025, China
- Hainan Yazhou Bay Seed Laboratory, Sanya, Hainan Province 572025, China
| | - Yunxie Wei
- National Key Laboratory for Tropical Crop Breeding, School of Breeding and Multiplication (Sanya Institute of Breeding and Multiplication), Key Laboratory of Biotechnology of Salt Tolerant Crops of Hainan Province, School of Tropical Agriculture and Forestry, Hainan University, Sanya, Hainan Province 572025, China
- Hainan Yazhou Bay Seed Laboratory, Sanya, Hainan Province 572025, China
| | - Haitao Shi
- National Key Laboratory for Tropical Crop Breeding, School of Breeding and Multiplication (Sanya Institute of Breeding and Multiplication), Key Laboratory of Biotechnology of Salt Tolerant Crops of Hainan Province, School of Tropical Agriculture and Forestry, Hainan University, Sanya, Hainan Province 572025, China
- Hainan Yazhou Bay Seed Laboratory, Sanya, Hainan Province 572025, China
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Li Q, Huang Z, Zhong Z, Bian F, Zhang X. Integrated Genomics and Transcriptomics Provide Insights into Salt Stress Response in Bacillus subtilis ACP81 from Moso Bamboo Shoot ( Phyllostachys praecox) Processing Waste. Microorganisms 2024; 12:285. [PMID: 38399690 PMCID: PMC10893186 DOI: 10.3390/microorganisms12020285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Revised: 01/26/2024] [Accepted: 01/26/2024] [Indexed: 02/25/2024] Open
Abstract
Salt stress is detrimental to the survival of microorganisms, and only a few bacterial species produce hydrolytic enzymes. In this study, we investigated the expression of salt stress-related genes in the salt-tolerant bacterial strain Bacillus subtilis ACP81, isolated from bamboo shoot processing waste, at the transcription level. The results indicate that the strain could grow in 20% NaCl, and the sub-lethal concentration was 6% NaCl. Less neutral protease and higher cellulase and β-amylase activities were observed for B. subtilis ACP81 under sub-lethal concentrations than under the control concentration (0% NaCl). Transcriptome analysis showed that the strain adapted to high-salt conditions by upregulating the expression of genes involved in cellular processes (membrane synthesis) and defense systems (flagellar assembly, compatible solute transport, glucose metabolism, and the phosphotransferase system). Interestingly, genes encoding cellulase and β-amylase-related (malL, celB, and celC) were significantly upregulated and were involved in starch and sucrose metabolic pathways, and the accumulated glucose was effective in mitigating salt stress. RT-qPCR was performed to confirm the sequencing data. This study emphasizes that, under salt stress conditions, ACP81 exhibits enhanced cellulase and β-amylase activities, providing an important germplasm resource for saline soil reclamation and enzyme development.
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Affiliation(s)
- Qiaoling Li
- China National Bamboo Research Center, Key Laboratory of State Forestry and Grassland Administration on Bamboo Forest Ecology and Resource Utilization, Hangzhou 310012, China; (Q.L.); (Z.H.); (Z.Z.); (F.B.)
- National Long-Term Observation and Research Station for Forest Ecosystem in Hangzhou-Jiaxing-Huzhou Plain, Hangzhou 310012, China
| | - Zhiyuan Huang
- China National Bamboo Research Center, Key Laboratory of State Forestry and Grassland Administration on Bamboo Forest Ecology and Resource Utilization, Hangzhou 310012, China; (Q.L.); (Z.H.); (Z.Z.); (F.B.)
- National Long-Term Observation and Research Station for Forest Ecosystem in Hangzhou-Jiaxing-Huzhou Plain, Hangzhou 310012, China
| | - Zheke Zhong
- China National Bamboo Research Center, Key Laboratory of State Forestry and Grassland Administration on Bamboo Forest Ecology and Resource Utilization, Hangzhou 310012, China; (Q.L.); (Z.H.); (Z.Z.); (F.B.)
- National Long-Term Observation and Research Station for Forest Ecosystem in Hangzhou-Jiaxing-Huzhou Plain, Hangzhou 310012, China
| | - Fangyuan Bian
- China National Bamboo Research Center, Key Laboratory of State Forestry and Grassland Administration on Bamboo Forest Ecology and Resource Utilization, Hangzhou 310012, China; (Q.L.); (Z.H.); (Z.Z.); (F.B.)
- National Long-Term Observation and Research Station for Forest Ecosystem in Hangzhou-Jiaxing-Huzhou Plain, Hangzhou 310012, China
| | - Xiaoping Zhang
- China National Bamboo Research Center, Key Laboratory of State Forestry and Grassland Administration on Bamboo Forest Ecology and Resource Utilization, Hangzhou 310012, China; (Q.L.); (Z.H.); (Z.Z.); (F.B.)
- National Long-Term Observation and Research Station for Forest Ecosystem in Hangzhou-Jiaxing-Huzhou Plain, Hangzhou 310012, China
- Engineering Research Center of Biochar of Zhejiang Province, Hangzhou 310012, China
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Kobayashi H, Matsubara S, Yoshimoto C, Shigetomi H, Imanaka S. The role of mitochondrial dynamics in the pathophysiology of endometriosis. J Obstet Gynaecol Res 2023; 49:2783-2791. [PMID: 37681703 DOI: 10.1111/jog.15791] [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: 08/03/2023] [Accepted: 08/31/2023] [Indexed: 09/09/2023]
Abstract
AIM Endometriosis is a chronic disease of reproductive age, associated with pelvic pain and infertility. Endometriotic cells adapt to changing environments such as oxidative stress and hypoxia in order to survive. However, the underlying mechanisms remain to be fully elucidated. In this review, we summarize our current understanding of the pathogenesis of endometriosis, focusing primarily on the molecular basis of energy metabolism, redox homeostasis, and mitochondrial function, and discuss perspectives on future research directions. METHODS Papers published up to March 31, 2023 in the PubMed and Google Scholar databases were included in this narrative literature review. RESULTS Mitochondria serve as a central hub sensing a multitude of physiological processes, including energy production and cellular redox homeostasis. Under hypoxia, endometriotic cells favor glycolysis and actively produce pyruvate, nicotinamide adenine dinucleotide phosphate (NADPH), and other metabolites for cell proliferation. Mitochondrial fission and fusion dynamics may regulate the phenotypic plasticity of cellular energy metabolism, that is, aerobic glycolysis or OXPHOS. Endometriotic cells have been reported to have reduced mitochondrial numbers, increased lamellar cristae, improved energy efficiency, and enhanced cell proliferation and survival. Increased mitochondrial fission and fusion turnover by hypoxic and normoxic conditions suggests an activation of mitochondrial quality control mechanisms. Recently, candidate molecules that influence mitochondrial dynamics have begun to be identified. CONCLUSION This review suggests that unique energy metabolism and redox homeostasis driven by mitochondrial dynamics may be linked to the pathophysiology of endometriosis. However, further studies are needed to elucidate the regulatory mechanisms of mitochondrial dynamics in endometriosis.
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Affiliation(s)
- Hiroshi Kobayashi
- Department of Gynecology and Reproductive Medicine, Ms.Clinic MayOne, Kashihara, Japan
- Department of Obstetrics and Gynecology, Nara Medical University, Kashihara, Japan
| | - Sho Matsubara
- Department of Obstetrics and Gynecology, Nara Medical University, Kashihara, Japan
- Department of Medicine, Kei Oushin Clinic, Nishinomiya, Japan
| | - Chiharu Yoshimoto
- Department of Obstetrics and Gynecology, Nara Medical University, Kashihara, Japan
- Department of Obstetrics and Gynecology, Nara Prefecture General Medical Center, Nara, Japan
| | - Hiroshi Shigetomi
- Department of Obstetrics and Gynecology, Nara Medical University, Kashihara, Japan
- Department of Gynecology and Reproductive Medicine, Aska Ladies Clinic, Nara, Japan
| | - Shogo Imanaka
- Department of Gynecology and Reproductive Medicine, Ms.Clinic MayOne, Kashihara, Japan
- Department of Obstetrics and Gynecology, Nara Medical University, Kashihara, Japan
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Batiha GES, Lukman HY, Shaheen HM, Wasef L, Hafiz AA, Conte-Junior CA, Al-Farga A, Chamba MVM, Lawal B. A Systematic Review of Phytochemistry, Nutritional Composition, and Pharmacologic Application of Species of the Genus Viola in Noncommunicable Diseases (NCDs). EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2023; 2023:5406039. [PMID: 37941895 PMCID: PMC10630019 DOI: 10.1155/2023/5406039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 06/03/2023] [Accepted: 10/11/2023] [Indexed: 11/10/2023]
Abstract
Viola L. is the largest genus of the Violaceae family with more than 500 species across the globe. The present extensive literature survey revealed Viola species to be a group of important nutritional and medicinal plants used for the ethnomedicinal treatment of noncommunicable diseases (NCDs) such as diabetes, asthma, lung diseases, and fatigue. Many plant species of this genus have also received scientific validation of their pharmacological activities including neuroprotective, immunomodulatory, anticancer, antihypertensive, antidyslipidemic, analgesic, antipyretic, diuretic, anti-inflammatory, anthelmintic, and antioxidant. Viola is highly rich in different natural products some of which have been isolated and identified in the past few decades; these include flavonoids terpenoids and phenylpropanoids of different pharmacological activities. The pharmacokinetics and clinical studies on this genus are lacking, and the present review is aimed at summarizing the current understanding of the ethnopharmacology, phytochemistry, nutritional composition, and pharmacological profile of medicinal plants from the Viola genus to reveal its therapeutic potentials, gaps, and subsequently open a new window for future pharmacological research.
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Affiliation(s)
- Gaber El-Saber Batiha
- Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour 22511, AlBeheira, Egypt
| | - Halimat Yusuf Lukman
- Department of Chemical Sciences, Biochemistry Unit, College of Natural and Applied Sciences, Summit University Offa, Offa PMB 4412, Nigeria
| | - Hazem M. Shaheen
- Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour 22511, AlBeheira, Egypt
| | - Lamiaa Wasef
- Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour 22511, AlBeheira, Egypt
| | - Amin A. Hafiz
- Department of Clinical Nutrition, Faculty of Applied Medical Sciences, Umm Al-Qura University, Mecca, Saudi Arabia
| | - Carlos Adam Conte-Junior
- Laboratory of Advanced Analysis in Biochemistry and Molecular Biology (LAABBM), Department of Biochemistry, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro RJ 21941-909, Brazil
| | - Ammar Al-Farga
- Biochemistry Department, Faculty of Science, University of Jeddah, Jeddah 21577, Saudi Arabia
| | - Moses V. M. Chamba
- Department of Physics and Biochemical Sciences, Malawi University of Business and Applied Sciences, Private Bag 303, Chichiri, Blantyre 3, Malawi
| | - Bashir Lawal
- Faculty of Medical Science, New Gate University, Minna, Nigeria
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Jahankhani K, Taghipour N, Mashhadi Rafiee M, Nikoonezhad M, Mehdizadeh M, Mosaffa N. Therapeutic effect of trace elements on multiple myeloma and mechanisms of cancer process. Food Chem Toxicol 2023; 179:113983. [PMID: 37567355 DOI: 10.1016/j.fct.2023.113983] [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: 05/29/2023] [Revised: 07/09/2023] [Accepted: 08/07/2023] [Indexed: 08/13/2023]
Abstract
In the human body, trace elements and other micronutrients play a vital role in growth, health and immune system function. The trace elements are Iron, Manganese, Copper, Iodine, Zinc, Cobalt, Fluoride, and Selenium. Estimating the serum levels of trace elements in hematologic malignancy patients can determine the severity of the tumor. Multiple myeloma (MM) is a hematopoietic malignancy and is characterized by plasma cell clonal expansion in bone marrow. Despite the advances in treatment methods, myeloma remains largely incurable. In addition to conventional medicine, treatment is moving toward less expensive noninvasive alternatives. One of the alternative treatments is the use of dietary supplements. In this review, we focused on the effect of three trace elements including iron, zinc and selenium on important mechanisms such as the immune system, oxidative and antioxidant factors and cell cycle. Using some trace minerals in combination with approved drugs can increase patients' recovery speed. Trace elements can be used as not only a preventive but also a therapeutic tool, especially in reducing inflammation in hematological cancers such as multiple myeloma. We hope that the prospect of the correct use of trace element supplements in the future could be promising for the treatment of diseases.
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Affiliation(s)
- Kasra Jahankhani
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Niloofar Taghipour
- Medical Nanotechnology and Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Maryam Nikoonezhad
- Department of Immunology, School of Medicine, Tarbiat Modarres University, Tehran, Iran
| | - Mahshid Mehdizadeh
- Hematopoietic Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nariman Mosaffa
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Singh N, Sherin GR, Mugesh G. Antioxidant and Prooxidant Nanozymes: From Cellular Redox Regulation to Next-Generation Therapeutics. Angew Chem Int Ed Engl 2023; 62:e202301232. [PMID: 37083312 DOI: 10.1002/anie.202301232] [Citation(s) in RCA: 41] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Revised: 04/20/2023] [Accepted: 04/21/2023] [Indexed: 04/22/2023]
Abstract
Nanozymes, nanomaterials with enzyme-mimicking activity, have attracted tremendous interest in recent years owing to their ability to replace natural enzymes in various biomedical applications, such as biosensing, therapeutics, drug delivery, and bioimaging. In particular, the nanozymes capable of regulating the cellular redox status by mimicking the antioxidant enzymes in mammalian cells are of great therapeutic significance in oxidative-stress-mediated disorders. As the distinction of physiological oxidative stress (oxidative eustress) and pathological oxidative stress (oxidative distress) occurs at a fine borderline, it is a great challenge to design nanozymes that can differentially sense the two extremes in cells, tissues and organs and mediate appropriate redox chemical reactions. In this Review, we summarize the advances in the development of redox-active nanozymes and their biomedical applications. We primarily highlight the therapeutic significance of the antioxidant and prooxidant nanozymes in various disease model systems, such as cancer, neurodegeneration, and cardiovascular diseases. The future perspectives of this emerging area of research and the challenges associated with the biomedical applications of nanozymes are described.
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Affiliation(s)
- Namrata Singh
- Department of Inorganic and Physical Chemistry, Indian Institute of Science, Bangalore, 560012, India
- Current address: Department of Medical Biochemistry and Biophysics, Karolinska Institute, Biomedicum, Solnavägen 9, 171 65, Solna, Sweden
| | - G R Sherin
- Department of Inorganic and Physical Chemistry, Indian Institute of Science, Bangalore, 560012, India
| | - Govindasamy Mugesh
- Department of Inorganic and Physical Chemistry, Indian Institute of Science, Bangalore, 560012, India
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12
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Fiorilla I, Martinotti S, Todesco AM, Bonsignore G, Cavaletto M, Patrone M, Ranzato E, Audrito V. Chronic Inflammation, Oxidative Stress and Metabolic Plasticity: Three Players Driving the Pro-Tumorigenic Microenvironment in Malignant Mesothelioma. Cells 2023; 12:2048. [PMID: 37626858 PMCID: PMC10453755 DOI: 10.3390/cells12162048] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Revised: 07/30/2023] [Accepted: 08/10/2023] [Indexed: 08/27/2023] Open
Abstract
Malignant pleural mesothelioma (MPM) is a lethal and rare cancer, even if its incidence has continuously increased all over the world. Asbestos exposure leads to the development of mesothelioma through multiple mechanisms, including chronic inflammation, oxidative stress with reactive oxygen species (ROS) generation, and persistent aberrant signaling. Together, these processes, over the years, force normal mesothelial cells' transformation. Chronic inflammation supported by "frustrated" macrophages exposed to asbestos fibers is also boosted by the release of pro-inflammatory cytokines, chemokines, growth factors, damage-associated molecular proteins (DAMPs), and the generation of ROS. In addition, the hypoxic microenvironment influences MPM and immune cells' features, leading to a significant rewiring of metabolism and phenotypic plasticity, thereby supporting tumor aggressiveness and modulating infiltrating immune cell responses. This review provides an overview of the complex tumor-host interactions within the MPM tumor microenvironment at different levels, i.e., soluble factors, metabolic crosstalk, and oxidative stress, and explains how these players supporting tumor transformation and progression may become potential and novel therapeutic targets in MPM.
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Affiliation(s)
- Irene Fiorilla
- Department of Science and Technological Innovation (DISIT), University of Eastern Piedmont, 15121 Alessandria, Italy; (I.F.); (S.M.); (A.M.T.); (G.B.); (M.P.); (E.R.)
- Department of Integrated Activities Research and Innovation (DAIRI), Public Hospital Azienda Ospedaliera “SS. Antonio e Biagio e Cesare Arrigo”, 15121 Alessandria, Italy
| | - Simona Martinotti
- Department of Science and Technological Innovation (DISIT), University of Eastern Piedmont, 15121 Alessandria, Italy; (I.F.); (S.M.); (A.M.T.); (G.B.); (M.P.); (E.R.)
- Department of Integrated Activities Research and Innovation (DAIRI), Public Hospital Azienda Ospedaliera “SS. Antonio e Biagio e Cesare Arrigo”, 15121 Alessandria, Italy
| | - Alberto Maria Todesco
- Department of Science and Technological Innovation (DISIT), University of Eastern Piedmont, 15121 Alessandria, Italy; (I.F.); (S.M.); (A.M.T.); (G.B.); (M.P.); (E.R.)
- Department of Integrated Activities Research and Innovation (DAIRI), Public Hospital Azienda Ospedaliera “SS. Antonio e Biagio e Cesare Arrigo”, 15121 Alessandria, Italy
| | - Gregorio Bonsignore
- Department of Science and Technological Innovation (DISIT), University of Eastern Piedmont, 15121 Alessandria, Italy; (I.F.); (S.M.); (A.M.T.); (G.B.); (M.P.); (E.R.)
- Department of Integrated Activities Research and Innovation (DAIRI), Public Hospital Azienda Ospedaliera “SS. Antonio e Biagio e Cesare Arrigo”, 15121 Alessandria, Italy
| | - Maria Cavaletto
- Department for Sustainable Development and Ecological Transition (DISSTE), University of Eastern Piedmont, 13100 Vercelli, Italy;
| | - Mauro Patrone
- Department of Science and Technological Innovation (DISIT), University of Eastern Piedmont, 15121 Alessandria, Italy; (I.F.); (S.M.); (A.M.T.); (G.B.); (M.P.); (E.R.)
- Department of Integrated Activities Research and Innovation (DAIRI), Public Hospital Azienda Ospedaliera “SS. Antonio e Biagio e Cesare Arrigo”, 15121 Alessandria, Italy
| | - Elia Ranzato
- Department of Science and Technological Innovation (DISIT), University of Eastern Piedmont, 15121 Alessandria, Italy; (I.F.); (S.M.); (A.M.T.); (G.B.); (M.P.); (E.R.)
- Department of Integrated Activities Research and Innovation (DAIRI), Public Hospital Azienda Ospedaliera “SS. Antonio e Biagio e Cesare Arrigo”, 15121 Alessandria, Italy
| | - Valentina Audrito
- Department of Science and Technological Innovation (DISIT), University of Eastern Piedmont, 15121 Alessandria, Italy; (I.F.); (S.M.); (A.M.T.); (G.B.); (M.P.); (E.R.)
- Department of Integrated Activities Research and Innovation (DAIRI), Public Hospital Azienda Ospedaliera “SS. Antonio e Biagio e Cesare Arrigo”, 15121 Alessandria, Italy
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13
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Gao G, You L, Zhang J, Chang YZ, Yu P. Brain Iron Metabolism, Redox Balance and Neurological Diseases. Antioxidants (Basel) 2023; 12:1289. [PMID: 37372019 DOI: 10.3390/antiox12061289] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Revised: 06/10/2023] [Accepted: 06/13/2023] [Indexed: 06/29/2023] Open
Abstract
The incidence of neurological diseases, such as Parkinson's disease, Alzheimer's disease and stroke, is increasing. An increasing number of studies have correlated these diseases with brain iron overload and the resulting oxidative damage. Brain iron deficiency has also been closely linked to neurodevelopment. These neurological disorders seriously affect the physical and mental health of patients and bring heavy economic burdens to families and society. Therefore, it is important to maintain brain iron homeostasis and to understand the mechanism of brain iron disorders affecting reactive oxygen species (ROS) balance, resulting in neural damage, cell death and, ultimately, leading to the development of disease. Evidence has shown that many therapies targeting brain iron and ROS imbalances have good preventive and therapeutic effects on neurological diseases. This review highlights the molecular mechanisms, pathogenesis and treatment strategies of brain iron metabolism disorders in neurological diseases.
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Affiliation(s)
- Guofen Gao
- Ministry of Education Key Laboratory of Molecular and Cellular Biology, The Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Sciences, Hebei Normal University, No. 20 Nan'erhuan Eastern Road, Shijiazhuang 050024, China
| | - Linhao You
- Ministry of Education Key Laboratory of Molecular and Cellular Biology, The Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Sciences, Hebei Normal University, No. 20 Nan'erhuan Eastern Road, Shijiazhuang 050024, China
| | - Jianhua Zhang
- Ministry of Education Key Laboratory of Molecular and Cellular Biology, The Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Sciences, Hebei Normal University, No. 20 Nan'erhuan Eastern Road, Shijiazhuang 050024, China
| | - Yan-Zhong Chang
- Ministry of Education Key Laboratory of Molecular and Cellular Biology, The Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Sciences, Hebei Normal University, No. 20 Nan'erhuan Eastern Road, Shijiazhuang 050024, China
| | - Peng Yu
- Ministry of Education Key Laboratory of Molecular and Cellular Biology, The Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Sciences, Hebei Normal University, No. 20 Nan'erhuan Eastern Road, Shijiazhuang 050024, China
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14
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Rupert C, Aversana CD, Mosca L, Montanaro V, Arcaniolo D, De Sio M, Bilancio A, Altucci L, Palinski W, Pili R, de Nigris F. Therapeutic targeting of P2X4 receptor and mitochondrial metabolism in clear cell renal carcinoma models. J Exp Clin Cancer Res 2023; 42:134. [PMID: 37231503 DOI: 10.1186/s13046-023-02713-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Accepted: 05/17/2023] [Indexed: 05/27/2023] Open
Abstract
BACKGROUND Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cancer. Large-scale metabolomic data have associated metabolic alterations with the pathogenesis and progression of renal carcinoma and have correlated mitochondrial activity with poor survival in a subset of patients. The aim of this study was to determine whether targeting mitochondria-lysosome interaction could be a novel therapeutic approach using patient-derived organoids as avatar for drug response. METHODS RNAseq data analysis and immunohistochemistry were used to show overexpression of Purinergic receptor 4 (P2XR4) in clear cell carcinomas. Seahorse experiments, immunofluorescence and fluorescence cell sorting were used to demonstrate that P2XR4 regulates mitochondrial activity and the balance of radical oxygen species. Pharmacological inhibitors and genetic silencing promoted lysosomal damage, calcium overload in mitochondria and cell death via both necrosis and apoptosis. Finally, we established patient-derived organoids and murine xenograft models to investigate the antitumor effect of P2XR4 inhibition using imaging drug screening, viability assay and immunohistochemistry. RESULTS Our data suggest that oxo-phosphorylation is the main source of tumor-derived ATP in a subset of ccRCC cells expressing P2XR4, which exerts a critical impact on tumor energy metabolism and mitochondrial activity. Prolonged mitochondrial failure induced by pharmacological inhibition or P2XR4 silencing was associated with increased oxygen radical species, changes in mitochondrial permeability (i.e., opening of the transition pore complex, dissipation of membrane potential, and calcium overload). Interestingly, higher mitochondrial activity in patient derived organoids was associated with greater sensitivity to P2XR4 inhibition and tumor reduction in a xenograft model. CONCLUSION Overall, our results suggest that the perturbed balance between lysosomal integrity and mitochondrial activity induced by P2XR4 inhibition may represent a new therapeutic strategy for a subset of patients with renal carcinoma and that individualized organoids may be help to predict drug efficacy.
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Affiliation(s)
- Christofer Rupert
- Division of Hematology and Oncology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA
| | - Carmela Dell' Aversana
- Institute of Experimental Endocrinology and Oncology, Gaetano Salvatore (IEOS)-CNR, Naples, Italy
- Department of Precision Medicine, University of Campania L. Vanvitelli, Naples, Italy
| | - Laura Mosca
- Department of Precision Medicine, University of Campania L. Vanvitelli, Naples, Italy
| | | | - Davide Arcaniolo
- Department of Women, Child, and General and Specialistic Surgery, University of Campania L. Vanvitelli, Naples, Italy
| | - Marco De Sio
- Department of Women, Child, and General and Specialistic Surgery, University of Campania L. Vanvitelli, Naples, Italy
| | - Antonio Bilancio
- Department of Precision Medicine, University of Campania L. Vanvitelli, Naples, Italy
| | - Lucia Altucci
- Institute of Experimental Endocrinology and Oncology, Gaetano Salvatore (IEOS)-CNR, Naples, Italy
- Department of Precision Medicine, University of Campania L. Vanvitelli, Naples, Italy
- BIOGEM, Ariano Irpino, Avellino, Italy
| | - Wulf Palinski
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Roberto Pili
- Division of Hematology and Oncology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA.
| | - Filomena de Nigris
- Department of Precision Medicine, University of Campania L. Vanvitelli, Naples, Italy.
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15
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Xu W, Yang Y, Tian J, Du X, Ye Y, Liu Z, Li Y, Zhao Y. Integrated physiological and transcriptome analysis reveals potential toxicity mechanism of haloxyfop-P-methyl to Chiromantes dehaani. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2023:121879. [PMID: 37230172 DOI: 10.1016/j.envpol.2023.121879] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 05/21/2023] [Accepted: 05/23/2023] [Indexed: 05/27/2023]
Abstract
Haloxyfop-P-methyl is widely used in controlling gramineous weeds, including the invasive plant Spartina alterniflora. However, the mechanism of its toxicity to crustaceans is unclear. In this study, we adopted transcriptome analysis combined with physiologic changes to investigate the response of estuarine crab (Chiromantes dehaani) to haloxyfop-P-methyl. The results showed that the median lethal concentration (LC50) of C. dehaani to haloxyfop-P-methyl at 96 h was 12.886 mg/L. Antioxidant system analysis indicated that MDA, CAT, GR, T-GSH, and GSSG might be sensitive biomarkers that characterize the oxidative defense response of the crab. In total, 782 differentially expressed genes were identified, including 489 up-regulated and 293 down-regulated genes. Glutathione metabolism, detoxification response and energy metabolism were significantly enriched, revealing the potential toxic mechanism of haloxyfop-P-methyl to C. dehaani. These results provide a theoretical foundation for further research on haloxyfop-P-methyl toxicity to crustaceans.
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Affiliation(s)
- Wenyue Xu
- School of Life Science, East China Normal University, Shanghai, 200241, China
| | - Ying Yang
- School of Life Science, East China Normal University, Shanghai, 200241, China
| | - Jiangtao Tian
- School of Life Science, East China Normal University, Shanghai, 200241, China
| | - Xinglin Du
- School of Life Science, East China Normal University, Shanghai, 200241, China
| | - Yucong Ye
- School of Life Science, East China Normal University, Shanghai, 200241, China
| | - Zhiquan Liu
- School of Life and Environmental Sciences, Hangzhou Normal University, 311121, Hangzhou, Zhejiang, China
| | - Yiming Li
- Fishery Machinery and Instrument, Research Institute, Chinese Academy of Fisheries Sciences, Shanghai, 200092, China
| | - Yunlong Zhao
- School of Life Science, East China Normal University, Shanghai, 200241, China.
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16
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Oberacker T, Kraft L, Schanz M, Latus J, Schricker S. The Importance of Thioredoxin-1 in Health and Disease. Antioxidants (Basel) 2023; 12:antiox12051078. [PMID: 37237944 DOI: 10.3390/antiox12051078] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2023] [Revised: 05/06/2023] [Accepted: 05/09/2023] [Indexed: 05/28/2023] Open
Abstract
Thioredoxin-1 (Trx-1) is a multifunctional protein ubiquitously found in the human body. Trx-1 plays an important role in various cellular functions such as maintenance of redox homeostasis, proliferation, and DNA synthesis, but also modulation of transcription factors and control of cell death. Thus, Trx-1 is one of the most important proteins for proper cell and organ function. Therefore, modulation of Trx gene expression or modulation of Trx activity by various mechanisms, including post-translational modifications or protein-protein interactions, could cause a transition from the physiological state of cells and organs to various pathologies such as cancer, and neurodegenerative and cardiovascular diseases. In this review, we not only discuss the current knowledge of Trx in health and disease, but also highlight its potential function as a biomarker.
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Affiliation(s)
- Tina Oberacker
- Dr. Margarete Fischer-Bosch Institute for Clinical Pharmacology, 70376 Stuttgart, Germany
| | - Leonie Kraft
- Department of Internal Medicine and Nephrology, Robert-Bosch-Hospital Stuttgart, 70376 Stuttgart, Germany
| | - Moritz Schanz
- Department of Internal Medicine and Nephrology, Robert-Bosch-Hospital Stuttgart, 70376 Stuttgart, Germany
| | - Jörg Latus
- Department of Internal Medicine and Nephrology, Robert-Bosch-Hospital Stuttgart, 70376 Stuttgart, Germany
| | - Severin Schricker
- Department of Internal Medicine and Nephrology, Robert-Bosch-Hospital Stuttgart, 70376 Stuttgart, Germany
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17
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Chu Z, Yang J, Zheng W, Sun J, Wang W, Qian H. Recent advances on modulation of H2O2 in tumor microenvironment for enhanced cancer therapeutic efficacy. Coord Chem Rev 2023. [DOI: 10.1016/j.ccr.2023.215049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/11/2023]
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18
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Selenium Deficiency-Induced Oxidative Stress Causes Myocardial Injury in Calves by Activating Inflammation, Apoptosis, and Necroptosis. Antioxidants (Basel) 2023; 12:antiox12020229. [PMID: 36829789 PMCID: PMC9951920 DOI: 10.3390/antiox12020229] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 01/07/2023] [Accepted: 01/10/2023] [Indexed: 01/21/2023] Open
Abstract
Selenium (Se) is essential for human and animal health, but there have been few studies on the mechanisms of injury in dairy cows with Se deficiency. This study aimed to evaluate the effects of Se deficiency on myocardial injury in weaned calves. The Se-D group had significantly lower myocardial Se concentrations than the Se-C group. Histological analysis indicated that Se deficiency induced a large area of necrosis in the myocardium, accompanied by inflammatory changes. Se deficiency significantly decreased the expression of 10 of the 21 selenoprotein genes and increased the expression of SEPHS2. Furthermore, we found that oxidative stress occurred in the Se-D group by detection of redox-related indicators. Additionally, TUNEL staining showed that Se deficiency causes severe apoptosis in the myocardium, which was characterized by activating the exogenous apoptotic pathway and the mitochondrial apoptotic pathway. Se deficiency also induced necroptosis in the myocardium by upregulating MLKL, RIPK1, and RIPK3. Moreover, Se-deficient calves have severe inflammation in the myocardium. Se deficiency significantly reduced anti-inflammatory factor levels while increasing pro-inflammatory factor levels. We also found that the NF-κB pathway and MAPK pathway were activated in Se-deficient conditions. Our findings suggest that Se deficiency causes myocardial injury in weaned calves by regulating oxidative stress, inflammation, apoptosis, and necroptosis.
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19
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Pastori M, Stella K, Allan W, Siida R, Mpumbya JR, Solomon AM, Okumu D, Swase DT, Kimanje KR, Eliah K, Erick Nyakundi O, Boaz N. Mechanistic role of epigallocatechin-3-gallate in regulation of the antioxidant markers in ethanol induced liver damage in mice. ALEXANDRIA JOURNAL OF MEDICINE 2022. [DOI: 10.1080/20905068.2022.2132604] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/24/2022] Open
Affiliation(s)
- Mujinya Pastori
- Department of Biochemistry, Faculty of Biomedical Sciences, Kampala International University-Western Campus, Busheny, Uganda
| | - Kembambazi Stella
- Department of Biochemistry, Faculty of Biomedical Sciences, Kampala International University-Western Campus, Busheny, Uganda
| | - Wandera Allan
- Department of Biochemistry, Faculty of Biomedical Sciences, Kampala International University-Western Campus, Busheny, Uganda
| | - Robert Siida
- Department of Biochemistry, Faculty of Biomedical Sciences, Kampala International University-Western Campus, Busheny, Uganda
| | - Jackie Rachael Mpumbya
- Department of Biochemistry, Faculty of Biomedical Sciences, Kampala International University-Western Campus, Busheny, Uganda
| | - Adomi Mbina Solomon
- Department of Biochemistry, Faculty of Biomedical Sciences, Kampala International University-Western Campus, Busheny, Uganda
| | - Daniel Okumu
- Department of Biochemistry, Faculty of Biomedical Sciences, Kampala International University-Western Campus, Busheny, Uganda
| | - Dominic Terkimbi Swase
- Department of Biochemistry, Faculty of Biomedical Sciences, Kampala International University-Western Campus, Busheny, Uganda
| | - Kyobe Ronald Kimanje
- Department of Biochemistry, Faculty of Biomedical Sciences, Kampala International University-Western Campus, Busheny, Uganda
| | - Kwizera Eliah
- Department of Biochemistry, Faculty of Biomedical Sciences, Kampala International University-Western Campus, Busheny, Uganda
| | - Ondari Erick Nyakundi
- Department of Biochemistry, Faculty of Biomedical Sciences, Kampala International University-Western Campus, Busheny, Uganda
- Department of Biological Sciences, School of Pure and Applied Sciences, Kisii University, Kisii, Kenya
| | - Niwamanya Boaz
- Department of Biochemistry, Faculty of Biomedical Sciences, Kampala International University-Western Campus, Busheny, Uganda
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Mantelou AG, Barbouti A, Goussia A, Zacharioudaki A, Papoudou-Bai A, Vlachou C, Kokkoris S, Papalois A, Galaris D, Glantzounis GK. Combined administration of membrane-permeable and impermeable iron-chelating drugs attenuates ischemia/reperfusion-induced hepatic injury. Free Radic Biol Med 2022; 193:227-237. [PMID: 36243210 DOI: 10.1016/j.freeradbiomed.2022.10.266] [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: 06/22/2022] [Revised: 10/07/2022] [Accepted: 10/07/2022] [Indexed: 12/31/2022]
Abstract
BACKGROUND The underlying pathophysiological mechanisms of hepatic ischemia-reperfusion (I/R) injury have not been completely elucidated. However, it is well known that oxidative stress, caused by a burst of reactive oxygen species (ROS) production during the reperfusion phase, plays a crucial role. A growing body of evidence indicates that the intracellular availability of free iron represents a requirement for ROS-induced adverse effects, as iron catalyzes the generation of highly reactive free radicals. The aim of this study was to examine whether a combination of iron chelators with varying lipophilicity could offer enhanced protection against I/R by diminishing the conversion of weak oxidants, like H2O2, to extremely reactive ones such as hydroxyl radicals (HO.). METHODS HepG2 cells (hepatocellular carcinoma cell line) were exposed to oxidative stress conditions after pre-treatment with the iron chelators desferrioxamine (DFO) and deferiprone (DFP) alone or in combination. Labile iron pool was estimated using the calcein-acetoxymethyl ester (calcein-AM) method and DNA damage with the comet assay. We subsequently used a rabbit model (male New Zealand white rabbits) of hepatic I/R-induced injury to investigate, by measuring biochemical (ALT, ALT, ALP, γGT) and histological parameters, whether this may be true for in vivo conditions. RESULTS The combination of a membrane-permeable iron chelator (DFP) with a strong membrane-impermeable one (DFO) raises the level of protection in both hepatic cell lines exposed to oxidative stress conditions and hepatic I/R rabbit model. CONCLUSIONS Our results show that combinations of iron chelators with selected lipophilicity and iron-binding properties may represent a valuable strategy to protect against tissue damage during reperfusion after a period of ischemia.
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Affiliation(s)
- Athina G Mantelou
- HPB Unit, Department of Surgery, University Hospital of Ioannina and Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, 45110, Greece
| | - Alexandra Barbouti
- Department of Anatomy-Histology-Embryology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, 45110, Greece
| | - Anna Goussia
- Department of Pathology, University Hospital of Ioannina and Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, 45110, Greece
| | | | - Alexandra Papoudou-Bai
- Department of Pathology, University Hospital of Ioannina and Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, 45110, Greece
| | - Chara Vlachou
- Laboratory of Biological Chemistry, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, 45110, Greece
| | - Stelios Kokkoris
- First Department of Critical Care, School of Medicine, National and Kapodistrian University of Athens, Athens, 10676, Greece
| | - Apostolos Papalois
- Experimental, Educational and Research Center ELPEN, Athens, 19009, Greece; European University of Cyprus, School of Medicine, Nicosia, 2404, Cyprus
| | - Dimitrios Galaris
- Laboratory of Biological Chemistry, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, 45110, Greece
| | - Georgios K Glantzounis
- HPB Unit, Department of Surgery, University Hospital of Ioannina and Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, 45110, Greece.
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21
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Soares RB, Manguinhas R, Costa JG, Saraiva N, Gil N, Rosell R, Camões SP, Batinic-Haberle I, Spasojevic I, Castro M, Miranda JP, Amaro F, Pinto J, Fernandes AS, Guedes de Pinho P, Oliveira NG. MnTnHex-2-PyP 5+ Displays Anticancer Properties and Enhances Cisplatin Effects in Non-Small Cell Lung Cancer Cells. Antioxidants (Basel) 2022; 11:2198. [PMID: 36358570 PMCID: PMC9686800 DOI: 10.3390/antiox11112198] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 10/27/2022] [Accepted: 10/29/2022] [Indexed: 08/13/2023] Open
Abstract
The manganese(III) porphyrin MnTnHex-2-PyP5+ (MnTnHex) is a potent superoxide dismutase mimic and modulator of redox-based transcriptional activity that has been studied in the context of different human disease models, including cancer. Nevertheless, for lung cancer, hardly any information is available. Thus, the present work aims to fill this gap and reports the effects of MnTnHex in non-small cell lung cancer (NSCLC) cells, more specifically, A549 and H1975 cells, in vitro. Both cell lines were initially characterized in terms of innate levels of catalase, glutathione peroxidase 1, and peroxiredoxins 1 and 2. To assess the effect of MnTnHex in NSCLC, alone or in combination with cisplatin, endpoints related to the cell viability, cell cycle distribution, cell motility, and characterization of the volatile carbonyl compounds (VCCs) generated in the extracellular medium (i.e., exometabolome) were addressed. The results show that MnTnHex as a single drug markedly reduced the viability of both NSCLC cell lines, with some IC50 values reaching sub-micromolar levels. This redox-active drug also altered the cell cycle distribution, induced cell death, and increased the cytotoxicity pattern of cisplatin. MnTnHex also reduced collective cell migration. Finally, the metabolomics study revealed an increase in the levels of a few VCCs associated with oxidative stress in MnTnHex-treated cells. Altogether these results suggest the therapeutic potential of MnTnHex to be further explored, either alone or in combination therapy with cisplatin, in NSCLC.
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Affiliation(s)
- Rita B. Soares
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Professor Gama Pinto, 1649-003 Lisboa, Portugal
| | - Rita Manguinhas
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Professor Gama Pinto, 1649-003 Lisboa, Portugal
| | - João G. Costa
- Universidade Lusófona’s Research Center for Biosciences & Health Technologies (CBIOS), Campo Grande 376, 1749-024 Lisboa, Portugal
| | - Nuno Saraiva
- Universidade Lusófona’s Research Center for Biosciences & Health Technologies (CBIOS), Campo Grande 376, 1749-024 Lisboa, Portugal
| | - Nuno Gil
- Lung Unit, Champalimaud Clinical Centre, Champalimaud Foundation, Av. Brasília, 1400-038 Lisbon, Portugal
| | - Rafael Rosell
- Laboratory of Cellular and Molecular Biology, Institute for Health Science Research Germans Trias i Pujol (IGTP), Campus Can Ruti, Ctra de Can Ruti, Camí de les Escoles, s/n, 08916 Badalona, Barcelona, Spain
| | - Sérgio P. Camões
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Professor Gama Pinto, 1649-003 Lisboa, Portugal
| | - Ines Batinic-Haberle
- Department of Radiation Oncology, Duke University School of Medicine, Durham, NC 27710, USA
| | - Ivan Spasojevic
- Department of Medicine, Duke University School of Medicine and PK/PD Core Laboratory, Duke Cancer Institute, Duke University School of Medicine, Durham, NC 27710, USA
| | - Matilde Castro
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Professor Gama Pinto, 1649-003 Lisboa, Portugal
| | - Joana P. Miranda
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Professor Gama Pinto, 1649-003 Lisboa, Portugal
| | - Filipa Amaro
- Associate Laboratory i4HB-Institute for Health and Bioeconomy, Department of Biological Sciences, Laboratory of Toxicology, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
- UCIBIO, REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
| | - Joana Pinto
- Associate Laboratory i4HB-Institute for Health and Bioeconomy, Department of Biological Sciences, Laboratory of Toxicology, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
- UCIBIO, REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
| | - Ana S. Fernandes
- Universidade Lusófona’s Research Center for Biosciences & Health Technologies (CBIOS), Campo Grande 376, 1749-024 Lisboa, Portugal
| | - Paula Guedes de Pinho
- Associate Laboratory i4HB-Institute for Health and Bioeconomy, Department of Biological Sciences, Laboratory of Toxicology, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
- UCIBIO, REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
| | - Nuno G. Oliveira
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Professor Gama Pinto, 1649-003 Lisboa, Portugal
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22
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Stable Dried Catalase Particles Prepared by Electrospraying. NANOMATERIALS 2022; 12:nano12142484. [PMID: 35889708 PMCID: PMC9322511 DOI: 10.3390/nano12142484] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 07/07/2022] [Accepted: 07/14/2022] [Indexed: 11/17/2022]
Abstract
Therapeutic proteins and peptides are clinically important, offering potency while reducing the potential for off-target effects. Research interest in developing therapeutic polypeptides has grown significantly during the last four decades. However, despite the growing research effort, maintaining the stability of polypeptides throughout their life cycle remains a challenge. Electrohydrodynamic (EHD) techniques have been widely explored for encapsulation and delivery of many biopharmaceuticals. In this work, we explored monoaxial electrospraying for encapsulation of bovine liver catalase, investigating the effects of the different components of the electrospraying solution on the integrity and bioactivity of the enzyme. The catalase was successfully encapsulated within polymeric particles made of polyvinylpyrrolidone (PVP), dextran, and polysucrose. The polysorbate 20 content within the electrospraying solution (50 mM citrate buffer, pH 5.4) affected the catalase loading—increasing the polysorbate 20 concentration to 500 μg/mL resulted in full protein encapsulation but did not prevent loss in activity. The addition of ethanol (20% v/v) to a fully aqueous solution improves the electrospraying process by reducing surface tension, without loss of catalase activity. The polymer type was shown to have the greatest impact on preserving catalase activity within the electrosprayed particles. When PVP was the carrier there was no loss in activity compared with fresh aqueous solutions of catalase. The optimum particles were obtained from a 20% w/v PVP or 30% w/v PVP-trehalose (1:1 w/w) solution. The addition of trehalose confers stability advantages to the catalase particles. When trehalose-PVP particles were stored at 5 °C, enzymatic activity was maintained over 3 months, whereas for the PVP-only analogue a 50% reduction in activity was seen. This demonstrates that processing catalase by monoaxial electrospraying can, under optimised conditions, result in stable polymeric particles with no loss of activity.
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23
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Chaitanya NSN, Tammineni P, Nagaraju GP, Reddy ABM. Pleiotropic roles of evolutionarily conserved signaling intermediate in toll pathway (ECSIT) in pathophysiology. J Cell Physiol 2022; 237:3496-3504. [DOI: 10.1002/jcp.30832] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 06/23/2022] [Accepted: 07/04/2022] [Indexed: 11/10/2022]
Affiliation(s)
- Nyshadham S. N. Chaitanya
- Department of Animal Biology, School of Life Sciences University of Hyderabad Hyderabad Telangana India
| | - Prasad Tammineni
- Department of Animal Biology, School of Life Sciences University of Hyderabad Hyderabad Telangana India
| | | | - Aramati BM Reddy
- Department of Animal Biology, School of Life Sciences University of Hyderabad Hyderabad Telangana India
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24
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Walker KA, Basisty N, Wilson DM, Ferrucci L. Connecting aging biology and inflammation in the omics era. J Clin Invest 2022; 132:e158448. [PMID: 35838044 PMCID: PMC9282936 DOI: 10.1172/jci158448] [Citation(s) in RCA: 83] [Impact Index Per Article: 27.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Aging is characterized by the accumulation of damage to macromolecules and cell architecture that triggers a proinflammatory state in blood and solid tissues, termed inflammaging. Inflammaging has been implicated in the pathogenesis of many age-associated chronic diseases as well as loss of physical and cognitive function. The search for mechanisms that underlie inflammaging focused initially on the hallmarks of aging, but it is rapidly expanding in multiple directions. Here, we discuss the threads connecting cellular senescence and mitochondrial dysfunction to impaired mitophagy and DNA damage, which may act as a hub for inflammaging. We explore the emerging multi-omics efforts that aspire to define the complexity of inflammaging - and identify molecular signatures and novel targets for interventions aimed at counteracting excessive inflammation and its deleterious consequences while preserving the physiological immune response. Finally, we review the emerging evidence that inflammation is involved in brain aging and neurodegenerative diseases. Our goal is to broaden the research agenda for inflammaging with an eye on new therapeutic opportunities.
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Affiliation(s)
- Keenan A. Walker
- Intramural Research Program of the National Institute on Aging, NIH, Baltimore, Maryland, USA
| | - Nathan Basisty
- Intramural Research Program of the National Institute on Aging, NIH, Baltimore, Maryland, USA
| | - David M. Wilson
- Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, Diepenbeek, Belgium
| | - Luigi Ferrucci
- Intramural Research Program of the National Institute on Aging, NIH, Baltimore, Maryland, USA
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25
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Flohé L, Toppo S, Orian L. The glutathione peroxidase family: Discoveries and mechanism. Free Radic Biol Med 2022; 187:113-122. [PMID: 35580774 DOI: 10.1016/j.freeradbiomed.2022.05.003] [Citation(s) in RCA: 107] [Impact Index Per Article: 35.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2022] [Revised: 04/18/2022] [Accepted: 05/04/2022] [Indexed: 12/15/2022]
Abstract
The discoveries leading to our present understanding of the glutathione peroxidases (GPxs) are recalled. The cytosolic GPx, now GPx1, was first described by Mills in 1957 and claimed to depend on selenium by Rotruck et al., in 1972. With the determination of a stoichiometry of one selenium per subunit, GPx1 was established as the first selenoenzyme of vertebrates. In the meantime, the GPxs have grown up to a huge family of enzymes that prevent free radical formation from hydroperoxides and, thus, are antioxidant enzymes, but they are also involved in regulatory processes or synthetic functions. The kinetic mechanism of the selenium-containing GPxs is unusual in neither showing a defined KM nor any substrate saturation. More recently, the reaction mechanism has been investigated by the density functional theory and nuclear magnetic resonance of model compounds mimicking the reaction cycle. The resulting concept sees a selenolate oxidized to a selenenic acid. This very fast reaction results from a concerted dual attack on the hydroperoxide bond, a nucleophilic one by the selenolate and an electrophilic one by a proton that is unstably bound in the reaction center. Postulated intermediates have been identified either in the native enzymes or in model compounds.
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Affiliation(s)
- Leopold Flohé
- Department of Molecular Medicine, University of Padova, Italy; Departamento de Bioquímica, Universidad de la República, Montevideo, Uruguay.
| | - Stefano Toppo
- Department of Molecular Medicine, University of Padova, Italy
| | - Laura Orian
- Department of Chemical Sciences, University of Padova, Italy
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26
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Kirola L, Mukherjee A, Mutsuddi M. Recent Updates on the Genetics of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Mol Neurobiol 2022; 59:5673-5694. [PMID: 35768750 DOI: 10.1007/s12035-022-02934-z] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Accepted: 06/16/2022] [Indexed: 10/17/2022]
Abstract
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) primarily affect the motor and frontotemporal areas of the brain, respectively. These disorders share clinical, genetic, and pathological similarities, and approximately 10-15% of ALS-FTD cases are considered to be multisystemic. ALS-FTD overlaps have been linked to families carrying an expansion in the intron of C9orf72 along with inclusions of TDP-43 in the brain. Other overlapping genes (VCP, FUS, SQSTM1, TBK1, CHCHD10) are also involved in similar functions that include RNA processing, autophagy, proteasome response, protein aggregation, and intracellular trafficking. Recent advances in genome sequencing have identified new genes that are involved in these disorders (TBK1, CCNF, GLT8D1, KIF5A, NEK1, C21orf2, TBP, CTSF, MFSD8, DNAJC7). Additional risk factors and modifiers have been also identified in genome-wide association studies and array-based studies. However, the newly identified genes show higher disease frequencies in combination with known genes that are implicated in pathogenesis, thus indicating probable digenetic/polygenic inheritance models, along with epistatic interactions. Studies suggest that these genes play a pleiotropic effect on ALS-FTD and other diseases such as Alzheimer's disease, Ataxia, and Parkinsonism. Besides, there have been numerous improvements in the genotype-phenotype correlations as well as clinical trials on stem cell and gene-based therapies. This review discusses the possible genetic models of ALS and FTD, the latest therapeutics, and signaling pathways involved in ALS-FTD.
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Affiliation(s)
- Laxmi Kirola
- Department of Molecular and Human Genetics, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh, India
| | - Ashim Mukherjee
- Department of Molecular and Human Genetics, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh, India
| | - Mousumi Mutsuddi
- Department of Molecular and Human Genetics, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh, India.
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27
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Stieg DC, Wang Y, Liu LZ, Jiang BH. ROS and miRNA Dysregulation in Ovarian Cancer Development, Angiogenesis and Therapeutic Resistance. Int J Mol Sci 2022; 23:ijms23126702. [PMID: 35743145 PMCID: PMC9223852 DOI: 10.3390/ijms23126702] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 06/05/2022] [Accepted: 06/14/2022] [Indexed: 12/11/2022] Open
Abstract
The diverse repertoires of cellular mechanisms that progress certain cancer types are being uncovered by recent research and leading to more effective treatment options. Ovarian cancer (OC) is among the most difficult cancers to treat. OC has limited treatment options, especially for patients diagnosed with late-stage OC. The dysregulation of miRNAs in OC plays a significant role in tumorigenesis through the alteration of a multitude of molecular processes. The development of OC can also be due to the utilization of endogenously derived reactive oxygen species (ROS) by activating signaling pathways such as PI3K/AKT and MAPK. Both miRNAs and ROS are involved in regulating OC angiogenesis through mediating multiple angiogenic factors such as hypoxia-induced factor (HIF-1) and vascular endothelial growth factor (VEGF). The NAPDH oxidase subunit NOX4 plays an important role in inducing endogenous ROS production in OC. This review will discuss several important miRNAs, NOX4, and ROS, which contribute to therapeutic resistance in OC, highlighting the effective therapeutic potential of OC through these mechanisms.
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Affiliation(s)
- David C. Stieg
- Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA; (D.C.S.); (L.-Z.L.)
| | - Yifang Wang
- Department of Pathology, Anatomy & Cell Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA;
| | - Ling-Zhi Liu
- Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA; (D.C.S.); (L.-Z.L.)
| | - Bing-Hua Jiang
- Department of Pathology, Anatomy & Cell Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA;
- Correspondence:
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28
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Martins AWS, Silveira TLR, Remião MH, Domingues WB, Dellagostin EN, Junior ASV, Corcini CD, Costa PG, Bianchini A, Somoza GM, Robaldo RB, Campos VF. Acute exposition to Roundup Transorb® induces systemic oxidative stress and alterations in the expression of newly sequenced genes in silverside fish (Odontesthes humensis). ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2021; 28:65127-65139. [PMID: 34228309 DOI: 10.1007/s11356-021-15239-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 06/25/2021] [Indexed: 06/13/2023]
Abstract
Roundup Transorb® (RDT) is a glyphosate-based herbicide commonly used in agricultural practices worldwide. This herbicide exerts negative effects on the aquatic ecosystem and affects bioenergetic and detoxification pathways, oxidative stress, and cell damage in marine organisms. These effects might also occur at the transcriptional level; however, the expression of genes associated with oxidative stress has not been studied well. Odontesthes humensis is a native Brazilian aquatic species naturally distributed in the habitats affected by pesticides, including Roundup Transorb® (RDT). This study evaluated the toxic effects of short-term exposure to RDT on O. humensis. Moreover, the genes related to oxidative stress were sequenced and characterized, and their expressions in the gills, hepatopancreas, kidneys, and brain of the fish were quantified by quantitative reverse transcription-polymerase chain reaction. The animals were exposed to two environmentally relevant concentrations of RDT (2.07 and 3.68 mg L-1) for 24 h. Lipid peroxidation, reactive oxygen species (ROS), DNA damage, and apoptosis in erythrocytes were quantified by flow cytometry. The expression of the target genes was modulated in most tissues in the presence of the highest tested concentration of RDT. In erythrocytes, the levels of lipid peroxidation, ROS, and DNA damage were increased in the presence of both the concentrations of RDT, whereas cell apoptosis was increased in the group exposed to 3.68 mg L-1 RDT. In conclusion, acute exposure to RDT caused oxidative stress in the fish, induced negative effects on cells, and modulated the expression of genes related to the enzymatic antioxidant system in O. humensis.
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Affiliation(s)
- Amanda Weege S Martins
- Laboratório de Genômica Estrutural, Programa de Pós-Graduação em Biotecnologia, Centro de Desenvolvimento Tecnológico, Universidade Federal de Pelotas, Pelotas, RS, Brasil
| | - Tony L R Silveira
- Laboratório de Genômica Estrutural, Programa de Pós-Graduação em Biotecnologia, Centro de Desenvolvimento Tecnológico, Universidade Federal de Pelotas, Pelotas, RS, Brasil
- Instituto de Ciências Biológicas, Universidade Federal do Rio Grande, Rio Grande, RS, Brasil
| | - Mariana H Remião
- Laboratório de Genômica Estrutural, Programa de Pós-Graduação em Biotecnologia, Centro de Desenvolvimento Tecnológico, Universidade Federal de Pelotas, Pelotas, RS, Brasil
| | - William Borges Domingues
- Laboratório de Genômica Estrutural, Programa de Pós-Graduação em Biotecnologia, Centro de Desenvolvimento Tecnológico, Universidade Federal de Pelotas, Pelotas, RS, Brasil
| | - Eduardo N Dellagostin
- Laboratório de Genômica Estrutural, Programa de Pós-Graduação em Biotecnologia, Centro de Desenvolvimento Tecnológico, Universidade Federal de Pelotas, Pelotas, RS, Brasil
| | - Antônio Sergio Varela Junior
- Laboratório de Reprodução Animal, Programa de Pós-Graduação em Biologia de Ambientes Aquáticos Continentais, Instituto de Ciências Biológicas, Universidade Federal do Rio Grande, Rio Grande, RS, Brasil
- ReproPel, Programa de Pós-Graduação em Veterinária, Faculdade de Veterinária, Universidade Federal de Pelotas, Pelotas, RS, Brasil
| | - Carine D Corcini
- ReproPel, Programa de Pós-Graduação em Veterinária, Faculdade de Veterinária, Universidade Federal de Pelotas, Pelotas, RS, Brasil
| | - Patrícia G Costa
- Instituto de Ciências Biológicas, Universidade Federal do Rio Grande, Rio Grande, RS, Brasil
| | - Adalto Bianchini
- Instituto de Ciências Biológicas, Universidade Federal do Rio Grande, Rio Grande, RS, Brasil
| | - Gustavo M Somoza
- Instituto Tecnológico de Chascomús (Consejo Nacional de Investigaciones Científicas y Técnicas-Universidad Nacional de San Martin), 7130, Chascomús, Argentina
| | - Ricardo B Robaldo
- Laboratório de Fisiologia de Animais Aquáticos, Instituto de Biologia, Universidade Federal de Pelotas, Pelotas, RS, Brasil
| | - Vinicius Farias Campos
- Laboratório de Genômica Estrutural, Programa de Pós-Graduação em Biotecnologia, Centro de Desenvolvimento Tecnológico, Universidade Federal de Pelotas, Pelotas, RS, Brasil.
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29
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Xiong W, Wang Y, Zhou X. Low-dose aspirin might alleviate the symptoms of preeclampsia by increasing the expression of antioxidative enzymes. Exp Ther Med 2021; 22:1418. [PMID: 34707700 PMCID: PMC8543183 DOI: 10.3892/etm.2021.10853] [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: 12/14/2019] [Accepted: 06/22/2021] [Indexed: 02/05/2023] Open
Abstract
Preeclampsia (PE) is a pregnancy-related syndrome that is characterized by new onset of hypertension combined with proteinuria or end-organ dysfunction occurring after 20 weeks of pregnancy. Endothelial dysfunction is also commonly observed in patients with PE. PE remains a leading cause of maternal morbidity and mortality, resulting in ~76,000 maternal and 500,000 fetus and newborn deaths worldwide annually. The present study aimed to investigate the protective effect of aspirin in patients with PE. A PE model was established in C57/BL mice, followed by the detection of expression levels of antioxidative enzymes, including superoxide dismutase 1, catalase, periaxin and thioredoxin and AKT/mTOR signaling pathway-related proteins by performing western blotting. The concentration of these enzymes in serum samples from PE model mice was also assessed. Compared with the negative control group, the expression of these antioxidative enzymes was decreased in PE model mice (P<0.05). High-dose aspirin treatment enhanced PE-induced effects, whereas low-dose aspirin treatment partially reversed PE-induced effects (P<0.05). Moreover, the results indicated that the effects of aspirin treatment on PE might be mediated via the AKT/mTOR signaling pathway. Therefore, low-dose aspirin administration may serve as a therapeutic strategy for PE.
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Affiliation(s)
- Wen Xiong
- Department of Obstetrics, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610000, P.R. China
| | - Yanjun Wang
- Department of Geriatrics, West China Hospital of Sichuan University, Chengdu, Sichuan 610000, P.R. China
| | - Xine Zhou
- Department of Obstetrics, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610000, P.R. China
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30
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Halcrow PW, Lynch ML, Geiger JD, Ohm JE. Role of endolysosome function in iron metabolism and brain carcinogenesis. Semin Cancer Biol 2021; 76:74-85. [PMID: 34139350 PMCID: PMC8627927 DOI: 10.1016/j.semcancer.2021.06.013] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 06/10/2021] [Accepted: 06/11/2021] [Indexed: 02/07/2023]
Abstract
Iron, the most abundant metal in human brain, is an essential microelement that regulates numerous cellular mechanisms. Some key physiological roles of iron include oxidative phosphorylation and ATP production, embryonic neuronal development, formation of iron-sulfur clusters, and the regulation of enzymes involved in DNA synthesis and repair. Because of its physiological and pathological importance, iron homeostasis must be tightly regulated by balancing its uptake, transport, and storage. Endosomes and lysosomes (endolysosomes) are acidic organelles known to contain readily releasable stores of various cations including iron and other metals. Increased levels of ferrous (Fe2+) iron can generate reactive oxygen species (ROS) via Fenton chemistry reactions and these increases can damage mitochondria and genomic DNA as well as promote carcinogenesis. Accumulation of iron in the brain has been linked with aging, diet, disease, and cerebral hemorrhage. Further, deregulation of brain iron metabolism has been implicated in carcinogenesis and may be a contributing factor to the increased incidence of brain tumors around the world. Here, we provide insight into mechanisms by which iron accumulation in endolysosomes is altered by pH and lysosome membrane permeabilization. Such events generate excess ROS resulting in mitochondrial DNA damage, fission, and dysfunction, as well as DNA oxidative damage in the nucleus; all of which promote carcinogenesis. A better understanding of the roles that endolysosome iron plays in carcinogenesis may help better inform the development of strategic therapeutic options for cancer treatment and prevention.
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Affiliation(s)
- Peter W Halcrow
- Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, United States
| | - Miranda L Lynch
- Hauptman-Woodward Medical Research Institute, Buffalo, NY, United States
| | - Jonathan D Geiger
- Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, United States
| | - Joyce E Ohm
- Department of Cancer Genetics and Genomics, Roswell Park Cancer Institute, Buffalo, NY, United States.
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31
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Wan XL, Li N, Chen YJ, Chen XS, Yang Z, Xu L, Yang HM, Wang ZY. Protective effects of lycopene on mitochondrial oxidative injury and dysfunction in the liver of aflatoxin B 1-exposed broilers. Poult Sci 2021; 100:101441. [PMID: 34547623 PMCID: PMC8456063 DOI: 10.1016/j.psj.2021.101441] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Revised: 08/10/2021] [Accepted: 08/15/2021] [Indexed: 11/23/2022] Open
Abstract
This study was conducted to investigate the effects of lycopene (LYC) on mitochondrial oxidative injury and dysfunction in the liver of aflatoxin B1 (AFB1)-exposed broilers. A total of 192 healthy 1-day-old male broilers were randomly divided into 3 groups with 8 replicates of 8 birds each. Birds in the 3 groups were fed basal diet (control), basal diet with 100 µg/kg AFB1, and basal diet with 100 µg/kg AFB1 and 200 mg/kg LYC, respectively. The experiment lasted 42 d. The results showed that AFB1 decreased average daily body weight gain (ADG), average daily feed intake, and gain to feed ratio (G :F) compared to the control group, the LYC supplementation increased ADG and G/F compared to AFB1 group (P < 0.05). Broilers in the AFB1 group had lower mitochondrial glutathione (mGSH) concentration and glutathione peroxidase (GSH-Px), manganese superoxide dismutase (MnSOD), and thioredoxin reductase activities, and higher hydrogen peroxide (H2O2) and reactive oxygen species (ROS) concentrations than the control group (P < 0.05). The LYC increased mGSH concentration and GSH-Px and MnSOD activities, and decreased H2O2 and ROS concentrations compared to AFB1 group (P < 0.05). Broilers fed the AFB1 diet showed increased mitochondrial swelling and decreased adenosine triphosphate concentration than the control group, and LYC had opposite effects (P < 0.05). The AFB1 decreased the activities of mitochondrial electron transfer chain (ETC) complexes I, II, III, and V, downregulated the mRNA expression levels of hepatic MnSOD, thioredoxin 2, thioredoxin reductase, peroxiredoxin-3, peroxisome proliferator-activated receptor γ coactivator 1α, nuclear respiratory factor 1, and mitochondrial transcription factor A compared with the control group (P < 0.05), and LYC increased activities of mitochondrial ETC complexes III and V, and upregulated mRNA expression levels of these genes in comparison to AFB1 group (P < 0.05). In conclusion, the LYC protected broilers from AFB1-induced liver mitochondrial oxidative injury and dysfunction by stimulating mitochondrial antioxidant capacity and maintaining mitochondrial biogenesis.
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Affiliation(s)
- X L Wan
- College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu Province, 225009, P. R. China
| | - N Li
- College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu Province, 225009, P. R. China
| | - Y J Chen
- College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu Province, 225009, P. R. China
| | - X S Chen
- College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu Province, 225009, P. R. China
| | - Z Yang
- Joint International Research Laboratory of Agriculture and Agri-Product Safety of Ministry of Education of China, Yangzhou University, Yangzhou, Jiangsu Province, 225009, P. R. China
| | - L Xu
- College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu Province, 225009, P. R. China
| | - H M Yang
- College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu Province, 225009, P. R. China
| | - Z Y Wang
- College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu Province, 225009, P. R. China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of Ministry of Education of China, Yangzhou University, Yangzhou, Jiangsu Province, 225009, P. R. China.
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32
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Ruiz LM, Libedinsky A, Elorza AA. Role of Copper on Mitochondrial Function and Metabolism. Front Mol Biosci 2021; 8:711227. [PMID: 34504870 PMCID: PMC8421569 DOI: 10.3389/fmolb.2021.711227] [Citation(s) in RCA: 256] [Impact Index Per Article: 64.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 07/05/2021] [Indexed: 12/21/2022] Open
Abstract
Copper is essential for life processes like energy metabolism, reactive oxygen species detoxification, iron uptake, and signaling in eukaryotic organisms. Mitochondria gather copper for the assembly of cuproenzymes such as the respiratory complex IV, cytochrome c oxidase, and the antioxidant enzyme superoxide dismutase 1. In this regard, copper plays a role in mitochondrial function and signaling involving bioenergetics, dynamics, and mitophagy, which affect cell fate by means of metabolic reprogramming. In mammals, copper homeostasis is tightly regulated by the liver. However, cellular copper levels are tissue specific. Copper imbalances, either overload or deficiency, have been associated with many diseases, including anemia, neutropenia, and thrombocytopenia, as well as tumor development and cancer aggressivity. Consistently, new pharmacological developments have been addressed to reduce or exacerbate copper levels as potential cancer therapies. This review goes over the copper source, distribution, cellular uptake, and its role in mitochondrial function, metabolic reprograming, and cancer biology, linking copper metabolism with the field of regenerative medicine and cancer.
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Affiliation(s)
- Lina M Ruiz
- Institute of Biomedical Sciences, Faculty of Health Sciences, Universidad Autónoma de Chile, Santiago, Chile
| | - Allan Libedinsky
- Institute of Biomedical Sciences, Faculty of Medicine and Faculty of Life Sciences, Universidad Andres Bello, Santiago, Chile.,Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
| | - Alvaro A Elorza
- Institute of Biomedical Sciences, Faculty of Medicine and Faculty of Life Sciences, Universidad Andres Bello, Santiago, Chile.,Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
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Redox Signaling and Sarcopenia: Searching for the Primary Suspect. Int J Mol Sci 2021; 22:ijms22169045. [PMID: 34445751 PMCID: PMC8396474 DOI: 10.3390/ijms22169045] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 08/17/2021] [Accepted: 08/19/2021] [Indexed: 12/16/2022] Open
Abstract
Sarcopenia, the age-related decline in muscle mass and function, derives from multiple etiological mechanisms. Accumulative research suggests that reactive oxygen species (ROS) generation plays a critical role in the development of this pathophysiological disorder. In this communication, we review the various signaling pathways that control muscle metabolic and functional integrity such as protein turnover, cell death and regeneration, inflammation, organismic damage, and metabolic functions. Although no single pathway can be identified as the most crucial factor that causes sarcopenia, age-associated dysregulation of redox signaling appears to underlie many deteriorations at physiological, subcellular, and molecular levels. Furthermore, discord of mitochondrial homeostasis with aging affects most observed problems and requires our attention. The search for the primary suspect of the fundamental mechanism for sarcopenia will likely take more intense research for the secret of this health hazard to the elderly to be unlocked.
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Ma Y, Yang X, Wang H, Qin Z, Yi C, Shi C, Luo M, Chen G, Yan J, Liu X, Liu Z. CBS-derived H2S facilitates host colonization of Vibrio cholerae by promoting the iron-dependent catalase activity of KatB. PLoS Pathog 2021; 17:e1009763. [PMID: 34283874 PMCID: PMC8324212 DOI: 10.1371/journal.ppat.1009763] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 07/30/2021] [Accepted: 06/28/2021] [Indexed: 12/04/2022] Open
Abstract
Sensing and resisting oxidative stress is critical for Vibrio cholerae to survive in either the aquatic environment or the gastrointestinal tract. Previous studies mainly focused on the mechanisms of oxidative stress response regulation that rely on enzymatic antioxidant systems, while functions of non-enzymatic antioxidants are rarely discussed in V. cholerae. For the first time, we investigated the role of hydrogen sulfide (H2S), the simplest thiol compound, in protecting V. cholerae against oxidative stress. We found that degradation of L-cysteine by putative cystathionine β-synthase (CBS) is the major source of endogenous H2S in V. cholerae. Our results indicate that intracellular H2S level has a positive correlation with cbs expression, while the enhanced H2S production can render V. cholerae cells less susceptible to H2O2 in vitro. Using proteome analysis and real-time qPCR assay, we found that cbs expression could stimulate the expression of several enzymatic antioxidants, including reactive oxygen species (ROS) detoxifying enzymes SodB, KatG and AhpC, the DNA protective protein DPS and the protein redox regulator Trx1. Assays of ROS detoxification capacities revealed that CBS-derived H2S could promote catalase activity at the post-translational level, especially for KatB, which serves as an important way that endogenous H2S participates in H2O2 detoxification. The enhancement of catalase activity by H2S is achieved through facilitating the uptake of iron. Adult mice experiments showed that cbs mutant has colonization defect, while either complementation of cbs or exogenous supplement of N-Acetyl-L-Cysteine restores its fitness in the host environment. Herein, we proposed that V. cholerae regulates CBS-dependent H2S production for better survival and proliferation under ROS stress.
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Affiliation(s)
- Yao Ma
- Department of Biotechnology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoman Yang
- Department of Biotechnology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Hongou Wang
- Department of Microbiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Zixin Qin
- Department of Biotechnology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Chunrong Yi
- Department of Biotechnology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Changping Shi
- Department of Biotechnology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Mei Luo
- Department of Biotechnology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Guozhong Chen
- Department of Biotechnology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Jin Yan
- Department of Biotechnology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoyun Liu
- Department of Microbiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Zhi Liu
- Department of Biotechnology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
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Trstenjak Prebanda M, Matjan-Štefin P, Turk B, Kopitar-Jerala N. Altered Expression of Peroxiredoxins in Mouse Model of Progressive Myoclonus Epilepsy upon LPS-Induced Neuroinflammation. Antioxidants (Basel) 2021; 10:antiox10030357. [PMID: 33673502 PMCID: PMC7997206 DOI: 10.3390/antiox10030357] [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: 01/08/2021] [Revised: 02/17/2021] [Accepted: 02/23/2021] [Indexed: 11/16/2022] Open
Abstract
Stefin B (cystatin B) is an inhibitor of endo-lysosomal cysteine cathepsin, and the loss-of-function mutations in the stefin B gene were reported in patients with Unverricht–Lundborg disease (EPM1), a form of progressive myoclonus epilepsy. Stefin B-deficient mice, a mouse model of the disease, display key features of EPM1, including myoclonic seizures. Although the underlying mechanism is not yet completely clear, it was reported that the impaired redox homeostasis and inflammation in the brain contribute to the progression of the disease. In the present study, we investigated if lipopolysaccharide (LPS)-triggered neuroinflammation affected the protein levels of redox-sensitive proteins: thioredoxin (Trx1), thioredoxin reductase (TrxR), peroxiredoxins (Prxs) in brain and cerebella of stefin B-deficient mice. LPS challenge was found to result in a marked elevation of Trx1 and TrxR in the brain and cerebella of stefin B deficient mice, while Prx1 was upregulated only in cerebella after LPS challenge. Mitochondrial peroxiredoxin 3 (Prx3), was upregulated also in the cerebellar tissue lysates prepared from unchallenged stefin B deficient mice, while after LPS challenge Prx3 was upregulated in stefin B deficient brain and cerebella. Our results imply the role of oxidative stress in the progression of the disease.
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Affiliation(s)
- Mojca Trstenjak Prebanda
- Department of Biochemistry, Molecular and Structural Biology, Jožef Stefan Institute, SI-1000 Ljubljana, Slovenia; (M.T.P.); (P.M.-Š.); (B.T.)
| | - Petra Matjan-Štefin
- Department of Biochemistry, Molecular and Structural Biology, Jožef Stefan Institute, SI-1000 Ljubljana, Slovenia; (M.T.P.); (P.M.-Š.); (B.T.)
- International Postgraduate School Jožef Stefan, Jamova 39, SI-1000 Ljubljana, Slovenia
| | - Boris Turk
- Department of Biochemistry, Molecular and Structural Biology, Jožef Stefan Institute, SI-1000 Ljubljana, Slovenia; (M.T.P.); (P.M.-Š.); (B.T.)
- Faculty of Chemistry and Chemical Technology, University of Ljubljana, Večna pot 113, SI-1000 Ljubljana, Slovenia
- Institute of Regenerative Medicine, I.M. Sechenov First Moscow State Medical University, Bol’shaya Pirogovskaya Ulitsa, 19c1, 119146 Moscow, Russia
| | - Nataša Kopitar-Jerala
- Department of Biochemistry, Molecular and Structural Biology, Jožef Stefan Institute, SI-1000 Ljubljana, Slovenia; (M.T.P.); (P.M.-Š.); (B.T.)
- Correspondence: ; Tel.: +386-1-4773-510
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Interactions of zinc- and redox-signaling pathways. Redox Biol 2021; 41:101916. [PMID: 33662875 PMCID: PMC7937829 DOI: 10.1016/j.redox.2021.101916] [Citation(s) in RCA: 80] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Accepted: 02/19/2021] [Indexed: 02/07/2023] Open
Abstract
Zinc and cellular oxidants such as reactive oxygen species (ROS) each participate in a multitude of physiological functions. There is considerable overlap between the affected events, including signal transduction. While there is no obvious direct connection between zinc and ROS, mainly because the bivalent cation zinc does not change its oxidation state in biological systems, these are linked by their interaction with sulfur, forming the remarkable triad of zinc, ROS, and protein thiols. First, zinc binds to reduced thiols and can be released upon oxidation. Thereby, redox signals are translated into changes in the free zinc concentration, which can act as zinc signals. Second, zinc affects oxidation of thiols in several ways, directly as well as indirectly. A protein incorporating many of these interactions is metallothionein (MT), which is rich in cysteine and capable of binding up to seven zinc ions in its fully reduced state. Zinc binding is diminished after (partial) oxidation, while thiols show increased reactivity in the absence of bound metal ions. Adding still more complexity, the MT promoter is controlled by zinc (via metal regulatory transcription factor 1 (MTF-1)) as well as redox (via nuclear factor erythroid 2-related factor 2 (NRF2)). Many signaling cascades that are important for cell proliferation or apoptosis contain protein thiols, acting as centers for crosstalk between zinc- and redox-signaling. A prominent example for shared molecular targets for zinc and ROS are active site cysteine thiols in protein tyrosine phosphatases (PTP), their activity being downregulated by oxidation as well as zinc binding. Because zinc binding also protects PTP thiols form irreversible oxidation, there is a multi-faceted reciprocal interaction, illustrating that zinc- and redox-signaling are intricately linked on multiple levels.
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Hu A, Chen X, Luo S, Zou Q, Xie J, He D, Li X, Cheng G. Rhizobium leguminosarum Glutathione Peroxidase Is Essential for Oxidative Stress Resistance and Efficient Nodulation. Front Microbiol 2021; 12:627562. [PMID: 33633710 PMCID: PMC7900000 DOI: 10.3389/fmicb.2021.627562] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 01/04/2021] [Indexed: 11/30/2022] Open
Abstract
Glutathione (GSH) plays a key role in regulating the cellular Redox Homeostasis, and appears to be essential for initiation and development of root nodules. Glutathione peroxidase (Gpx) catalyzes the reduction of H2O2 and organic hydroperoxides by oxidation of GSH to oxidized GSH (GSSG), which in turn is reduced by glutathione reductase (GR). However, it has not been determined whether the Rhizobium leguminosarum Gpx or GR is required during symbiotic interactions with pea. To characterize the role of glutathione-dependent enzymes in the symbiotic process, single and double mutants were made in gpxA (encoding glutathione peroxidase) and gshR (encoding glutathione reductase) genes. All the mutations did not affect the rhizobial growth, but they increased the sensitivity of R. leguminosarum strains to H2O2. Mutant in GpxA had no effect on intracellular GSH levels, but can increase the expression of the catalase genes. The gshR mutant can induce the formation of normal nodules, while the gpxA single and double mutants exhibited a nodulation phenotype coupled to more than 50% reduction in the nitrogen fixation capacity, these defects in nodulation were characterized by the formation of ineffective nodules. In addition, the gpxA and gshR double mutant was severely impaired in rhizosphere colonization and competition. Quantitative proteomics using the TMT labeling method was applied to study the differential expression of proteins in bacteroids isolated from pea root nodules. A total of 27 differentially expressed proteins were identified in these root bacteroids including twenty down-regulated and seven up-regulated proteins. By sorting the down-regulated proteins, eight are transporter proteins, seven are dehydrogenase, deoxygenase, oxidase, and hydrolase. Moreover, three down-regulating proteins are directly involved in nodule process.
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Affiliation(s)
- Aiqi Hu
- Hubei Provincial Engineering and Technology Research Center for Resources and Utilization of Microbiology, College of Life Sciences, South-Central University for Nationalities, Wuhan, China
| | - Xiaohong Chen
- Hubei Provincial Engineering and Technology Research Center for Resources and Utilization of Microbiology, College of Life Sciences, South-Central University for Nationalities, Wuhan, China
| | - Sha Luo
- Hubei Provincial Engineering and Technology Research Center for Resources and Utilization of Microbiology, College of Life Sciences, South-Central University for Nationalities, Wuhan, China
| | - Qian Zou
- Hubei Provincial Engineering and Technology Research Center for Resources and Utilization of Microbiology, College of Life Sciences, South-Central University for Nationalities, Wuhan, China
| | - Jing Xie
- Hubei Provincial Engineering and Technology Research Center for Resources and Utilization of Microbiology, College of Life Sciences, South-Central University for Nationalities, Wuhan, China
| | - Donglan He
- Hubei Provincial Engineering and Technology Research Center for Resources and Utilization of Microbiology, College of Life Sciences, South-Central University for Nationalities, Wuhan, China
| | - Xiaohua Li
- Hubei Provincial Engineering and Technology Research Center for Resources and Utilization of Microbiology, College of Life Sciences, South-Central University for Nationalities, Wuhan, China
| | - Guojun Cheng
- Hubei Provincial Engineering and Technology Research Center for Resources and Utilization of Microbiology, College of Life Sciences, South-Central University for Nationalities, Wuhan, China
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Tamtaji OR, Hadinezhad T, Fallah M, Shahmirzadi AR, Taghizadeh M, Behnam M, Asemi Z. The Therapeutic Potential of Quercetin in Parkinson's Disease: Insights into its Molecular and Cellular Regulation. Curr Drug Targets 2021; 21:509-518. [PMID: 31721700 DOI: 10.2174/1389450120666191112155654] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2019] [Revised: 09/30/2019] [Accepted: 10/08/2019] [Indexed: 12/13/2022]
Abstract
Parkinson's disease (PD) is a chronic and progressive neurodegenerative disorder characterized by the progressive death of dopaminergic neurons in the substantia nigra pars compacta (SNc). PD is a multifactorial disorder, with several different factors being suggested to play a synergistic pathophysiological role, including oxidative stress, autophagy, underlying pro-inflammatory events and neurotransmitters abnormalities. Overall, PD can be viewed as the product of a complex interaction of environmental factors acting on a given genetic background. The importance of this subject has gained more attention to discover novel therapies to prevent as well as treat PD. According to previous research, drugs used to treat PD have indicated significant limitations. Therefore, the role of flavonoids has been extensively studied in PD treatment. Quercetin, a plant flavonol from the flavonoid group, has been considered as a supplemental therapy for PD. Quercetin has pharmacological functions in PD by controlling different molecular pathways. Although few studies intended to evaluate the basis for the use of quercetin in the context of PD have been conducted so far, at present, there is very little evidence available addressing the underlying mechanisms of action. Various principal aspects of these treatment procedures remain unknown. Here, currently existing knowledge supporting the use of quercetin for the clinical management of PD has been reviewed.
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Affiliation(s)
- Omid Reza Tamtaji
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
| | - Tooba Hadinezhad
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
| | - Maryam Fallah
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
| | | | - Mohsen Taghizadeh
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
| | | | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
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Matta L, Fonseca TS, Faria CC, Lima-Junior NC, De Oliveira DF, Maciel L, Boa LF, Pierucci APTR, Ferreira ACF, Nascimento JHM, Carvalho DP, Fortunato RS. The Effect of Acute Aerobic Exercise on Redox Homeostasis and Mitochondrial Function of Rat White Adipose Tissue. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:4593496. [PMID: 33603946 PMCID: PMC7868166 DOI: 10.1155/2021/4593496] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Revised: 12/01/2020] [Accepted: 01/16/2021] [Indexed: 12/21/2022]
Abstract
Physical exercise is characterized by an increase in physical and metabolic demand in face of physical stress. It is reported that a single exercise session induces physiological responses through redox signaling to increase cellular function and energy support in diverse organs. However, little is known about the effect of a single bout of exercise on the redox homeostasis and cytoprotective gene expression of white adipose tissue (WAT). Thus, we aimed at evaluating the effects of acute aerobic exercise on WAT redox homeostasis, mitochondrial metabolism, and cytoprotective genic response. Male Wistar rats were submitted to a single moderate-high running session (treadmill) and were divided into five groups: control (CTRL, without exercise), and euthanized immediately (0 h), 30 min, 1 hour, or 2 hours after the end of the exercise session. NADPH oxidase activity was higher in 0 h and 30 min groups when compared to CTRL group. Extramitochondrial ROS production was higher in 0 h group in comparison to CTRL and 2 h groups. Mitochondrial respiration in phosphorylative state increased in 0 h group when compared to CTRL, 30 min, 1, and 2 h groups. On the other hand, mitochondrial ATP production was lower in 0 h in comparison to 30 min group, increasing in 1 and 2 h groups when compared to CTRL and 0 h groups. CAT activity was lower in all exercised groups when compared to CTRL. Regarding oxidative stress biomarkers, we observed a decrease in reduced thiol content in 0 h group compared to CTRL and 2 h groups, and higher levels of protein carbonylation in 0 and 30 min groups in comparison to the other groups. The levels returned to basal condition in 2 h group. Furthermore, aerobic exercise increased NRF2, GPX2, HMOX1, SOD1, and CAT mRNA levels. Taken together, our results suggest that one session of aerobic exercise can induce a transient prooxidative state in WAT, followed by an increase in antioxidant and cytoprotective gene expression.
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Affiliation(s)
- Leonardo Matta
- Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, 21941-590, Brazil
| | - Túlio S. Fonseca
- Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, 21941-590, Brazil
| | - Caroline C. Faria
- Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, 21941-590, Brazil
| | | | - Dahienne F. De Oliveira
- Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, 21941-590, Brazil
| | - Leonardo Maciel
- Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, 21941-590, Brazil
| | - Luiz F. Boa
- Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, 21941-590, Brazil
| | | | - Andrea C. F. Ferreira
- Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, 21941-590, Brazil
- NUMPEX, Duque de Caxias Campus, Federal University of Rio de Janeiro, Brazil
| | - José H. M. Nascimento
- Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, 21941-590, Brazil
| | - Denise P. Carvalho
- Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, 21941-590, Brazil
| | - Rodrigo S. Fortunato
- Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, 21941-590, Brazil
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Papanikolaou K, Veskoukis AS, Draganidis D, Baloyiannis I, Deli CK, Poulios A, Jamurtas AZ, Fatouros IG. Redox-dependent regulation of satellite cells following aseptic muscle trauma: Implications for sports performance and nutrition. Free Radic Biol Med 2020; 161:125-138. [PMID: 33039652 DOI: 10.1016/j.freeradbiomed.2020.10.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 09/26/2020] [Accepted: 10/01/2020] [Indexed: 12/21/2022]
Abstract
Skeletal muscle satellite cells (SCs) are indispensable for tissue regeneration, remodeling and growth. Following myotrauma, SCs are activated, and assist in tissue repair. Exercise-induced muscle damage (EIMD) is characterized by a pronounced inflammatory response and the production of reactive oxygen species (ROS). Experimental evidence suggests that SCs kinetics (the propagation from a quiescent to an activated/proliferative state) following EIMD is redox-dependent and interconnected with changes in the SCs microenvironment (niche). Animal studies have shown that following aseptic myotrauma, antioxidant and/or anti-inflammatory supplementation leads to an improved recovery and skeletal muscle regeneration through enhanced SCs kinetics, suggesting a redox-dependent molecular mechanism. Although evidence suggests that antioxidant/anti-inflammatory compounds may prevent performance deterioration and enhance recovery, there is lack of information regarding the redox-dependent regulation of SCs responses following EIMD in humans. In this review, SCs kinetics following aseptic myotrauma, as well as the intrinsic redox-sensitive molecular mechanisms responsible for SCs responses are discussed. The role of redox status on SCs function should be further investigated in the future with human clinical trials in an attempt to elucidate the molecular pathways responsible for muscle recovery and provide information for potential nutritional strategies aiming at performance recovery.
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Affiliation(s)
- Konstantinos Papanikolaou
- Department of Physical Education and Sport Science, University of Thessaly, Karies, Trikala, 42132, Greece
| | - Aristidis S Veskoukis
- Department of Nutrition and Dietetics, University of Thessaly, Argonafton 1, 42132, Trikala, Greece; Department of Biochemistry and Biotechnology, University of Thessaly, Viopolis, Mezourlo, 41500, Larissa, Greece
| | - Dimitrios Draganidis
- Department of Physical Education and Sport Science, University of Thessaly, Karies, Trikala, 42132, Greece
| | - Ioannis Baloyiannis
- Department of Surgery, University Hospital of Larissa, Mezourlo, 41110, Larissa, Greece
| | - Chariklia K Deli
- Department of Physical Education and Sport Science, University of Thessaly, Karies, Trikala, 42132, Greece
| | - Athanasios Poulios
- Department of Physical Education and Sport Science, University of Thessaly, Karies, Trikala, 42132, Greece
| | - Athanasios Z Jamurtas
- Department of Physical Education and Sport Science, University of Thessaly, Karies, Trikala, 42132, Greece
| | - Ioannis G Fatouros
- Department of Physical Education and Sport Science, University of Thessaly, Karies, Trikala, 42132, Greece.
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A precise and simple method for measuring catalase activity in biological samples. CHEMICAL PAPERS 2020. [DOI: 10.1007/s11696-020-01401-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
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The Function of LmPrx6 in Diapause Regulation in Locusta migratoria Through the Insulin Signaling Pathway. INSECTS 2020; 11:insects11110763. [PMID: 33167530 PMCID: PMC7694527 DOI: 10.3390/insects11110763] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 11/02/2020] [Accepted: 11/03/2020] [Indexed: 11/16/2022]
Abstract
Simple Summary LmPrx6 of the insulin signaling pathway is significantly associated with diapause induction in Locusta migratoria L. as per our pervious transcriptome data. In the current study, we first cloned and sequenced the gene and demonstrated its similarity to other Prxs using phylogenetic analyses. Later on, we knocked down Prx6 using RNAi and showed that phosphorylation of proteins associated with the insulin signaling pathway and responses to oxidative stress were altered. Knockdown of Prx6 also resulted in a reduced ability to enter diapause, and hence, we are of the opinion that this gene could serve as an effective target for RNAi-based control of L. migratoria L. The study has provided some helpful insights into the diversified roles of Prx6 in locusts and will be of interest to other insect pests for examining the relatively unexplored group of proteins as well. Abstract Peroxiredoxins (Prxs), which scavenge reactive oxygen species (ROS), are cysteine-dependent peroxide reductases that group into six structurally discernable classes: AhpC-Prx1, BCP-PrxQ, Prx5, Prx6, Tpx, and AhpE. A previous study showed that forkhead box protein O (FOXO) in the insulin signaling pathway (ISP) plays a vital role in regulating locust diapause by phosphorylation, which can be promoted by the high level of ROS. Furthermore, the analysis of transcriptome between diapause and non-diapause phenotypes showed that one of the Prxs, LmPrx6, which belongs to the Prx6 class, was involved. We presumed that LmPrx6 might play a critical role in diapause induction of Locusta migratoria and LmPrx6 may therefore provide a useful target of control methods based on RNA interference (RNAi). To verify our hypothesis, LmPrx6 was initially cloned from L. migratoria to make dsLmPrx6 and four important targets were tested, including protein-tyrosine phosphorylase 1B (LmPTP1B), insulin receptor (LmIR), RAC serine/threonine-protein kinase (LmAKT), and LmFOXO in ISP. When LmPrx6 was knocked down, the diapause rate was significantly reduced. The phosphorylation level of LmPTP1B significantly decreased while the phosphorylation levels of LmIR, LmAKT, and LmFOXO were significantly increased. Moreover, we identified the effect on two categories of genes downstream of LmFOXO, including stress tolerance and storage of energy reserves. Results showed that the mRNA levels of catalase and Mn superoxide dismutase (Mn-SOD), which enhanced stress tolerance, were significantly downregulated after silencing of LmPrx6. The mRNA levels of glycogen synthase and phosphoenolpyruvate carboxy kinase (PEPCK) that influence energy storage were also downregulated after knocking down of LmPrx6. The silencing of LmPrx6 indicates that this regulatory protein may probably be an ideal target for RNAi-based diapause control of L. migratoria.
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Kirtonia A, Sethi G, Garg M. The multifaceted role of reactive oxygen species in tumorigenesis. Cell Mol Life Sci 2020; 77:4459-4483. [PMID: 32358622 PMCID: PMC11105050 DOI: 10.1007/s00018-020-03536-5] [Citation(s) in RCA: 277] [Impact Index Per Article: 55.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2019] [Revised: 03/29/2020] [Accepted: 04/20/2020] [Indexed: 02/06/2023]
Abstract
Redox homeostasis is an essential requirement of the biological systems for performing various normal cellular functions including cellular growth, differentiation, senescence, survival and aging in humans. The changes in the basal levels of reactive oxygen species (ROS) are detrimental to cells and often lead to several disease conditions including cardiovascular, neurological, diabetes and cancer. During the last two decades, substantial research has been done which clearly suggests that ROS are essential for the initiation, progression, angiogenesis as well as metastasis of cancer in several ways. During the last two decades, the potential of dysregulated ROS to enhance tumor formation through the activation of various oncogenic signaling pathways, DNA mutations, immune escape, tumor microenvironment, metastasis, angiogenesis and extension of telomere has been discovered. At present, surgery followed by chemotherapy and/or radiotherapy is the major therapeutic modality for treating patients with either early or advanced stages of cancer. However, the majority of patients relapse or did not respond to initial treatment. One of the reasons for recurrence/relapse is the altered levels of ROS in tumor cells as well as in cancer-initiating stem cells. One of the critical issues is targeting the intracellular/extracellular ROS for significant antitumor response and relapse-free survival. Indeed, a large number of FDA-approved anticancer drugs are efficient to eliminate cancer cells and drug resistance by increasing ROS production. Thus, the modulation of oxidative stress response might represent a potential approach to eradicate cancer in combination with FDA-approved chemotherapies, radiotherapies as well as immunotherapies.
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Affiliation(s)
- Anuradha Kirtonia
- Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR), Amity University Campus, Sector-125, Noida, Uttar Pradesh, 201313, India
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore.
| | - Manoj Garg
- Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR), Amity University Campus, Sector-125, Noida, Uttar Pradesh, 201313, India.
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Roles of Reactive Oxygen Species in Cardiac Differentiation, Reprogramming, and Regenerative Therapies. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:2102841. [PMID: 32908625 PMCID: PMC7475763 DOI: 10.1155/2020/2102841] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Accepted: 07/22/2020] [Indexed: 12/11/2022]
Abstract
Reactive oxygen species (ROS) have been implicated in mechanisms of heart development and regenerative therapies such as the use of pluripotent stem cells. The roles of ROS mediating cell fate are dependent on the intensity of stimuli, cellular context, and metabolic status. ROS mainly act through several targets (such as kinases and transcription factors) and have diverse roles in different stages of cardiac differentiation, proliferation, and maturation. Therefore, further detailed investigation and characterization of redox signaling will help the understanding of the molecular mechanisms of ROS during different cellular processes and enable the design of targeted strategies to foster cardiac regeneration and functional recovery. In this review, we focus on the roles of ROS in cardiac differentiation as well as transdifferentiation (direct reprogramming). The potential mechanisms are discussed in regard to ROS generation pathways and regulation of downstream targets. Further methodological optimization is required for translational research in order to robustly enhance the generation efficiency of cardiac myocytes through metabolic modulations. Additionally, we highlight the deleterious effect of the host's ROS on graft (donor) cells in a paracrine manner during stem cell-based implantation. This knowledge is important for the development of antioxidant strategies to enhance cell survival and engraftment of tissue engineering-based technologies. Thus, proper timing and level of ROS generation after a myocardial injury need to be tailored to ensure the maximal efficacy of regenerative therapies and avoid undesired damage.
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45
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Michalska P, León R. When It Comes to an End: Oxidative Stress Crosstalk with Protein Aggregation and Neuroinflammation Induce Neurodegeneration. Antioxidants (Basel) 2020; 9:antiox9080740. [PMID: 32806679 PMCID: PMC7463521 DOI: 10.3390/antiox9080740] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 07/27/2020] [Accepted: 08/07/2020] [Indexed: 12/13/2022] Open
Abstract
Neurodegenerative diseases are characterized by a progressive loss of neurons in the brain or spinal cord that leads to a loss of function of the affected areas. The lack of effective treatments and the ever-increasing life expectancy is raising the number of individuals affected, having a tremendous social and economic impact. The brain is particularly vulnerable to oxidative damage given the high energy demand, low levels of antioxidant defenses, and high levels of metal ions. Driven by age-related changes, neurodegeneration is characterized by increased oxidative stress leading to irreversible neuronal damage, followed by cell death. Nevertheless, neurodegenerative diseases are known as complex pathologies where several mechanisms drive neuronal death. Herein we discuss the interplay among oxidative stress, proteinopathy, and neuroinflammation at the early stages of neurodegenerative diseases. Finally, we discuss the use of the Nrf2-ARE pathway as a potential therapeutic strategy based on these molecular mechanisms to develop transformative medicines.
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Affiliation(s)
- Patrycja Michalska
- Instituto Teófilo Hernando y Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, 28029 Madrid, Spain
- Instituto de Investigación Sanitaria, Servicio de Farmacología Clínica, Hospital Universitario de la Princesa, 28006 Madrid, Spain
- Correspondence: (P.M.); (R.L.); Tel.: +34-91-497-27-66 (P.M. & R.L.)
| | - Rafael León
- Instituto Teófilo Hernando y Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, 28029 Madrid, Spain
- Instituto de Investigación Sanitaria, Servicio de Farmacología Clínica, Hospital Universitario de la Princesa, 28006 Madrid, Spain
- Instituto de Química Médica, Consejo Superior de Investigaciones Científicas (IQM-CSIC), 28006 Madrid, Spain
- Correspondence: (P.M.); (R.L.); Tel.: +34-91-497-27-66 (P.M. & R.L.)
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Khoma V, Gnatyshyna L, Martinyuk V, Rarok Y, Mudra A, Stoliar O. Biochemical Responses of the Bivalve Mollusk Unio tumidus Inhabiting a Small Power Plant Reservoir on the Dniester River Basin, Ukraine. BULLETIN OF ENVIRONMENTAL CONTAMINATION AND TOXICOLOGY 2020; 105:67-75. [PMID: 32409854 DOI: 10.1007/s00128-020-02873-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 05/02/2020] [Indexed: 06/11/2023]
Abstract
Hydropower plants (HPPs) can affect the hydrological regime. However, biochemical responses of aquatic animals for the evaluation of this disturbing are not applied yet. The specimens of Unio tumidus were sampled in a reservoir (R) of a small HPP as well as downstream from the dam (DS). Biochemical indexes in the digestive gland and alkali labile phosphates (ALP) in the gonads were examined. The R-mollusks showed low cholinesterase, catalase and caspase-3 activities, and metallothionein concentration, but elevated levels of zinc and copper, oxidized glutathione and protein carbonyls. Concentrations of lactate, pyruvate and ALP, activity of superoxide dismutase and glutathione S-transferase, and lipid peroxidation level were similar in both groups. Integrated biomarker response (IBR/n) index (n = 13) was 2.17 and 0.29 in the R- and DS-groups correspondingly. We suggest that using integrative biological response based on the biochemical markers of bivalve mollusks can be a valid early warning step in assessing 'environmental flow' impact.
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Affiliation(s)
- Vira Khoma
- Ternopil Volodymyr Hnatiuk National Pedagogical University, Kryvonosa Str 2, Ternopil, 46027, Ukraine
| | - Lesya Gnatyshyna
- Ternopil Volodymyr Hnatiuk National Pedagogical University, Kryvonosa Str 2, Ternopil, 46027, Ukraine
- I. Horbachevsky Ternopil National Medical University, Ternopil, Ukraine
| | - Viktoria Martinyuk
- Ternopil Volodymyr Hnatiuk National Pedagogical University, Kryvonosa Str 2, Ternopil, 46027, Ukraine
| | - Yulya Rarok
- Ternopil Volodymyr Hnatiuk National Pedagogical University, Kryvonosa Str 2, Ternopil, 46027, Ukraine
| | - Alla Mudra
- I. Horbachevsky Ternopil National Medical University, Ternopil, Ukraine
| | - Oksana Stoliar
- Ternopil Volodymyr Hnatiuk National Pedagogical University, Kryvonosa Str 2, Ternopil, 46027, Ukraine.
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Palma JM, Mateos RM, López-Jaramillo J, Rodríguez-Ruiz M, González-Gordo S, Lechuga-Sancho AM, Corpas FJ. Plant catalases as NO and H 2S targets. Redox Biol 2020; 34:101525. [PMID: 32505768 PMCID: PMC7276441 DOI: 10.1016/j.redox.2020.101525] [Citation(s) in RCA: 108] [Impact Index Per Article: 21.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Revised: 03/24/2020] [Accepted: 03/25/2020] [Indexed: 12/20/2022] Open
Abstract
Catalase is a powerful antioxidant metalloenzyme located in peroxisomes which also plays a central role in signaling processes under physiological and adverse situations. Whereas animals contain a single catalase gene, in plants this enzyme is encoded by a multigene family providing multiple isoenzymes whose number varies depending on the species, and their expression is regulated according to their tissue/organ distribution and the environmental conditions. This enzyme can be modulated by reactive oxygen and nitrogen species (ROS/RNS) as well as by hydrogen sulfide (H2S). Catalase is the major protein undergoing Tyr-nitration [post-translational modification (PTM) promoted by RNS] during fruit ripening, but the enzyme from diverse sources is also susceptible to undergo other activity-modifying PTMs. Data on S-nitrosation and persulfidation of catalase from different plant origins are given and compared here with results from obese children where S-nitrosation of catalase occurs. The cysteine residues prone to be S-nitrosated in catalase from plants and from bovine liver have been identified. These evidences assign to peroxisomes a crucial statement in the signaling crossroads among relevant molecules (NO and H2S), since catalase is allocated in these organelles. This review depicts a scenario where the regulation of catalase through PTMs, especially S-nitrosation and persulfidation, is highlighted.
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Affiliation(s)
- José M Palma
- Group of Antioxidants, Free Radicals and Nitric Oxide in Biotechnology, Food and Agriculture, Dept. Biochemistry, Cell and Molecular Biology of Plants, Estación Experimental del Zaidín, CSIC, Granada, Spain.
| | - Rosa M Mateos
- Imflammation, Nutrition, Metabolism and Oxidative Stress Study Group (INMOX), Biomedical Research and Innovation Institute of Cádiz (INiBICA), Research Unit, Puerta del Mar University Hospital, Cádiz, Spain; Area of Biochemistry and Molecular Biology, Department of Biomedicine, Biotechnology and Public Health, University of Cádiz, Cádiz, Spain
| | | | - Marta Rodríguez-Ruiz
- Laboratório de Fisiologia do Desenvolvimiento Vegetal; Instituto de Biociências-Universidad de São Paulo; Cidade Universitária-São Paulo-SP, Brazil
| | - Salvador González-Gordo
- Group of Antioxidants, Free Radicals and Nitric Oxide in Biotechnology, Food and Agriculture, Dept. Biochemistry, Cell and Molecular Biology of Plants, Estación Experimental del Zaidín, CSIC, Granada, Spain
| | - Alfonso M Lechuga-Sancho
- Imflammation, Nutrition, Metabolism and Oxidative Stress Study Group (INMOX), Biomedical Research and Innovation Institute of Cádiz (INiBICA), Research Unit, Puerta del Mar University Hospital, Cádiz, Spain; Department of Child and Mother Health and Radiology, Medical School, University of Cádiz, Cádiz, Spain
| | - Francisco J Corpas
- Group of Antioxidants, Free Radicals and Nitric Oxide in Biotechnology, Food and Agriculture, Dept. Biochemistry, Cell and Molecular Biology of Plants, Estación Experimental del Zaidín, CSIC, Granada, Spain
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48
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Forciniti S, Greco L, Grizzi F, Malesci A, Laghi L. Iron Metabolism in Cancer Progression. Int J Mol Sci 2020; 21:E2257. [PMID: 32214052 PMCID: PMC7139548 DOI: 10.3390/ijms21062257] [Citation(s) in RCA: 68] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 03/21/2020] [Accepted: 03/22/2020] [Indexed: 12/11/2022] Open
Abstract
Iron is indispensable for cell metabolism of both normal and cancer cells. In the latter, several disruptions of its metabolism occur at the steps of tumor initiation, progression and metastasis. Noticeably, cancer cells require a large amount of iron, and exhibit a strong dependence on it for their proliferation. Numerous iron metabolism-related proteins and signaling pathways are altered by iron in malignancies, displaying the pivotal role of iron in cancer. Iron homeostasis is regulated at several levels, from absorption by enterocytes to recycling by macrophages and storage in hepatocytes. Mutations in HFE gene alter iron homeostasis leading to hereditary hemochromatosis and to an increased cancer risk because the accumulation of iron induces oxidative DNA damage and free radical activity. Additionally, the iron capability to modulate immune responses is pivotal in cancer progression. Macrophages show an iron release phenotype and potentially deliver iron to cancer cells, resulting in tumor promotion. Overall, alterations in iron metabolism are among the metabolic and immunological hallmarks of cancer, and further studies are required to dissect how perturbations of this element relate to tumor development and progression.
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Affiliation(s)
- Stefania Forciniti
- Humanitas Clinical and Research Center, IRCCS, Department of Gastroenterology—Laboratory of Molecular Gastroenterology, Rozzano, 20089 Milan, Italy; (S.F.); (L.G.)
| | - Luana Greco
- Humanitas Clinical and Research Center, IRCCS, Department of Gastroenterology—Laboratory of Molecular Gastroenterology, Rozzano, 20089 Milan, Italy; (S.F.); (L.G.)
| | - Fabio Grizzi
- Department of Immunology and Inflammation, Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano, 20089 Milan, Italy;
| | - Alberto Malesci
- Humanitas Clinical and Research Center, IRCCS, Department of Gastroenterology, Rozzano, 20089 Milan, Italy;
| | - Luigi Laghi
- Humanitas Clinical and Research Center, IRCCS, Department of Gastroenterology—Laboratory of Molecular Gastroenterology, Rozzano, 20089 Milan, Italy; (S.F.); (L.G.)
- Department of Medicine and Surgery, University of Parma, 43100 Parma, Italy
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Peroxiredoxin 5 deficiency exacerbates iron overload-induced neuronal death via ER-mediated mitochondrial fission in mouse hippocampus. Cell Death Dis 2020; 11:204. [PMID: 32205843 PMCID: PMC7090063 DOI: 10.1038/s41419-020-2402-7] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Revised: 03/02/2020] [Accepted: 03/02/2020] [Indexed: 01/01/2023]
Abstract
Iron is an essential element for cellular functions, including those of neuronal cells. However, an imbalance of iron homeostasis, such as iron overload, has been observed in several neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease. Iron overload causes neuronal toxicity through mitochondrial fission, dysregulation of Ca2+, ER-stress, and ROS production. Nevertheless, the precise mechanisms between iron-induced oxidative stress and iron toxicity related to mitochondria and endoplasmic reticulum (ER) in vivo are not fully understood. Here, we demonstrate the role of peroxiredoxin 5 (Prx5) in iron overload-induced neurotoxicity using Prx5-deficient mice. Iron concentrations and ROS levels in mice fed a high iron diet were significantly higher in Prx5−/− mice than wildtype (WT) mice. Prx5 deficiency also exacerbated ER-stress and ER-mediated mitochondrial fission via Ca2+/calcineurin-mediated dephosphorylation of Drp1 at Serine 637. Moreover, immunoreactive levels of cleaved caspase3 in the CA3 region of the hippocampus were higher in iron-loaded Prx5−/− mice than WT mice. Furthermore, treatment with N-acetyl-cysteine, a reactive oxygen species (ROS) scavenger, attenuated iron overload-induced hippocampal damage by inhibiting ROS production, ER-stress, and mitochondrial fission in iron-loaded Prx5−/− mice. Therefore, we suggest that iron overload-induced oxidative stress and ER-mediated mitochondrial fission may be essential for understanding iron-mediated neuronal cell death in the hippocampus and that Prx5 may be useful as a novel therapeutic target in the treatment of iron overload-mediated diseases and neurodegenerative diseases.
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50
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Kim JY, Kim MH, Lee HJ, Huh JW, Lee SR, Lee HS, Lee DS. Peroxiredoxin 4 inhibits insulin-induced adipogenesis through regulation of ER stress in 3T3-L1 cells. Mol Cell Biochem 2020; 468:97-109. [PMID: 32185676 DOI: 10.1007/s11010-020-03714-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Accepted: 03/06/2020] [Indexed: 02/06/2023]
Abstract
Obesity was originally considered a disease endemic to developed countries but has since emerged as a global health problem. Obesity is characterized by abnormal or excessive lipid accumulation (World Health Organization, WHO) resulting from pre-adipocyte differentiation (adipogenesis). The endoplasmic reticulum (ER) produces proteins and cholesterol and shuttles these compounds to their target sites. Many studies have implicated ER stress, indicative of ER dysfunction, in adipogenesis. Reactive oxygen species (ROS) are also known to be involved in pre-adipocyte differentiation. Prx4 specific to the ER lumen exhibits ROS scavenging activity, and we thereby focused on ER-specific Prx4 in tracking changes in adipocyte differentiation and lipid accumulation. Overexpression of Prx4 reduced ER stress and suppressed lipid accumulation by regulating adipogenic gene expression during adipogenesis. Our results demonstrate that Prx4 inhibits ER stress, lowers ROS levels, and attenuates pre-adipocyte differentiation. These findings suggested enhancing the activity of Prx4 may be helpful in the treatment of obesity; the data also support the development of new therapeutic approaches to obesity and obesity-related metabolic disorders.
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Affiliation(s)
- Jae Yeop Kim
- School of Life Sciences, BK21 Plus KNU Creative Bioresearch Group, Kyungpook National University, Daegu, Republic of Korea.,School of Life Sciences & Biotechnology, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea
| | - Mi Hye Kim
- School of Life Sciences, BK21 Plus KNU Creative Bioresearch Group, Kyungpook National University, Daegu, Republic of Korea.,School of Life Sciences & Biotechnology, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea
| | - Hong Jun Lee
- College of Medicine, Chungbuk National University, Chungbuk, Republic of Korea.,Research Institute, E-Biogen Inc, Seoul, Korea
| | - Jae-Won Huh
- National Primate Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju, Republic of Korea
| | - Sang-Rae Lee
- National Primate Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju, Republic of Korea
| | - Hyun-Shik Lee
- School of Life Sciences, BK21 Plus KNU Creative Bioresearch Group, Kyungpook National University, Daegu, Republic of Korea.,School of Life Sciences & Biotechnology, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea
| | - Dong-Seok Lee
- School of Life Sciences, BK21 Plus KNU Creative Bioresearch Group, Kyungpook National University, Daegu, Republic of Korea. .,School of Life Sciences & Biotechnology, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea.
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