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Tiwari S, Phoolmala, Goyal S, Yadav RK, Chaturvedi RK. Bisphenol-F and Bisphenol-S (BPF and BPS) Impair the Stemness of Neural Stem Cells and Neuronal Fate Decision in the Hippocampus Leading to Cognitive Dysfunctions. Mol Neurobiol 2024; 61:9347-9368. [PMID: 38635025 DOI: 10.1007/s12035-024-04160-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Accepted: 04/01/2024] [Indexed: 04/19/2024]
Abstract
Neurogenesis occurs throughout life in the hippocampus of the brain, and many environmental toxicants inhibit neural stem cell (NSC) function and neuronal generation. Bisphenol-A (BPA), an endocrine disrupter used for surface coating of plastic products causes injury in the developing and adult brain; thus, many countries have banned its usage in plastic consumer products. BPA analogs/alternatives such as bisphenol-F (BPF) and bisphenol-S (BPS) may also cause neurotoxicity; however, their effects on neurogenesis are still not known. We studied the effects of BPF and BPS exposure from gestational day 6 to postnatal day 21 on neurogenesis. We found that exposure to non-cytotoxic concentrations of BPF and BPS significantly decreased the number/size of neurospheres, BrdU+ (proliferating NSC marker) and MAP-2+ (neuronal marker) cells and GFAP+ astrocytes in the hippocampus NSC culture, suggesting reduced NSC stemness and self-renewal and neuronal differentiation and increased gliogenesis. These analogs also reduced the number of BrdU/Sox-2+, BrdU/Dcx+, and BrdU/NeuN+ co-labeled cells in the hippocampus of the rat brain, suggesting decreased NSC proliferation and impaired maturation of newborn neurons. BPF and BPS treatment increases BrdU/cleaved caspase-3+ cells and Bax-2 and cleaved caspase protein levels, leading to increased apoptosis in hippocampal NSCs. Transmission electron microscopy studies suggest that BPF and BPS also caused degeneration of neuronal myelin sheath, altered mitochondrial morphology, and reduced number of synapses in the hippocampus leading to altered cognitive functions. These results suggest that BPF and BPS exposure decreased the NSC pool, inhibited neurogenesis, induced apoptosis of NSCs, caused myelin degeneration/synapse degeneration, and impaired learning and memory in rats.
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Affiliation(s)
- Saurabh Tiwari
- Molecular Neurotoxicology and Cell Integrity Laboratory, Systems Toxicology and Health Risk Assessment Group, FEST Division, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow, 226001, Uttar Pradesh (U.P.), India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Phoolmala
- Molecular Neurotoxicology and Cell Integrity Laboratory, Systems Toxicology and Health Risk Assessment Group, FEST Division, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow, 226001, Uttar Pradesh (U.P.), India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Shweta Goyal
- Molecular Neurotoxicology and Cell Integrity Laboratory, Systems Toxicology and Health Risk Assessment Group, FEST Division, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow, 226001, Uttar Pradesh (U.P.), India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Ranjeet Kumar Yadav
- Molecular Neurotoxicology and Cell Integrity Laboratory, Systems Toxicology and Health Risk Assessment Group, FEST Division, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow, 226001, Uttar Pradesh (U.P.), India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Rajnish Kumar Chaturvedi
- Molecular Neurotoxicology and Cell Integrity Laboratory, Systems Toxicology and Health Risk Assessment Group, FEST Division, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow, 226001, Uttar Pradesh (U.P.), India.
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
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Lin X, Liu W, Hu X, Liu Z, Wang F, Wang J. The role of polyphenols in modulating mitophagy: Implications for therapeutic interventions. Pharmacol Res 2024; 207:107324. [PMID: 39059613 DOI: 10.1016/j.phrs.2024.107324] [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: 04/29/2024] [Revised: 07/18/2024] [Accepted: 07/22/2024] [Indexed: 07/28/2024]
Abstract
This review rigorously assesses the burgeoning research into the role of polyphenols in modulating mitophagy, an essential cellular mechanism for the targeted removal of impaired mitochondria. These natural compounds, known for their low toxicity, are underscored for their potential in therapeutic strategies against a diverse array of diseases, such as neurodegenerative, cardiovascular, and musculoskeletal disorders. The analysis penetrates deeply into the molecular mechanisms whereby polyphenols promote mitophagy, particularly by influencing crucial signaling pathways and transcriptional regulators, including the phosphatase and tensin homolog (PTEN) induced putative kinase 1 (PINK1)/parkin and forkhead box O3 (FOXO3a) pathways. Noteworthy discoveries include the neuroprotective properties of resveratrol and curcumin, which affect both autophagic pathways and mitochondrial dynamics, and the pioneering integration of polyphenols with other natural substances to amplify therapeutic effectiveness. Furthermore, the review confronts the issue of polyphenol bioavailability and emphasizes the imperative for clinical trials to corroborate their therapeutic viability. By delivering an exhaustive synthesis of contemporary insights and recent advancements in polyphenol and mitophagy research, this review endeavors to catalyze additional research and foster the creation of innovative therapeutic modalities that exploit the distinctive attributes of polyphenols to manage and prevent disease.
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Affiliation(s)
- Xinyu Lin
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Wenkai Liu
- Deyang Sixth People's Hospital, Deyang 618000, China
| | - Xizhuo Hu
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Zhiqiang Liu
- Deyang Sixth People's Hospital, Deyang 618000, China
| | - Fang Wang
- Chengdu First People's Hospital, Sichuan, China
| | - Jinlian Wang
- Traditional Chinese Medicine Hospital of Meishan, Meishan 620010, China.
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Li S, Yang F, Cheng F, Zhu L, Yan Y. Lipotoxic hepatocyte derived LIMA1 enriched small extracellular vesicles promote hepatic stellate cells activation via inhibiting mitophagy. Cell Mol Biol Lett 2024; 29:82. [PMID: 38822260 PMCID: PMC11140962 DOI: 10.1186/s11658-024-00596-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Accepted: 05/10/2024] [Indexed: 06/02/2024] Open
Abstract
BACKGROUND Hepatic stellate cells (HSCs) play a crucial role in the development of fibrosis in non-alcoholic fatty liver disease (NAFLD). Small extracellular vesicles (sEV) act as mediators for intercellular information transfer, delivering various fibrotic factors that impact the function of HSCs in liver fibrosis. In this study, we investigated the role of lipotoxic hepatocyte derived sEV (LTH-sEV) in HSCs activation and its intrinsic mechanisms. METHODS High-fat diet (HFD) mice model was constructed to confirm the expression of LIMA1. The relationship between LIMA1-enriched LTH-sEV and LX2 activation was evaluated by measurement of fibrotic markers and related genes. Levels of mitophagy were detected using mt-keima lentivirus. The interaction between LIMA1 and PINK1 was discovered through database prediction and molecular docking. Finally, sEV was injected to investigate whether LIMA1 can accelerate HFD induced liver fibrosis in mice. RESULTS LIMA1 expression was upregulated in lipotoxic hepatocytes and was found to be positively associated with the expression of the HSCs activation marker α-SMA. Lipotoxicity induced by OPA led to an increase in both the level of LIMA1 protein in LTH-sEV and the release of LTH-sEV. When HSCs were treated with LTH-sEV, LIMA1 was observed to hinder LX2 mitophagy while facilitating LX2 activation. Further investigation revealed that LIMA1 derived from LTH-sEV may inhibit PINK1-Parkin-mediated mitophagy, consequently promoting HSCs activation. Knocking down LIMA1 significantly attenuates the inhibitory effects of LTH-sEV on mitophagy and the promotion of HSCs activation. CONCLUSIONS Lipotoxic hepatocyte-derived LIMA1-enriched sEVs play a crucial role in promoting HSCs activation in NAFLD-related liver fibrosis by negatively regulating PINK1 mediated mitophagy. These findings provide new insights into the pathological mechanisms involved in the development of fibrosis in NAFLD.
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Affiliation(s)
- Shihui Li
- Department of Laboratory Medicine, Wujin Hospital Affiliated With Jiangsu University, Changzhou, 213017, China
- Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, China
| | - Fuji Yang
- Department of Laboratory Medicine, Wujin Hospital Affiliated With Jiangsu University, Changzhou, 213017, China
- Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, China
| | - Fang Cheng
- Department of Laboratory Medicine, Wujin Hospital Affiliated With Jiangsu University, Changzhou, 213017, China
- Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, China
| | - Ling Zhu
- Changzhou Key Laboratory of Molecular Diagnostics and Precision Cancer Medicine, Wujin Hospital Affiliated With Jiangsu University (Wujin Clinical College of Xuzhou Medical University), Changzhou, 213017, China
| | - Yongmin Yan
- Department of Laboratory Medicine, Wujin Hospital Affiliated With Jiangsu University, Changzhou, 213017, China.
- Changzhou Key Laboratory of Molecular Diagnostics and Precision Cancer Medicine, Wujin Hospital Affiliated With Jiangsu University (Wujin Clinical College of Xuzhou Medical University), Changzhou, 213017, China.
- Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine, Jiangsu University, Changzhou, 213017, China.
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Ouyang H, Miao H, Li Z, Wu D, Gao SC, Dai YY, Gao XD, Chai HS, Hu WY, Zhu JF. Yinhuang granule alleviates carbon tetrachloride-induced liver fibrosis in mice and its mechanism. World J Hepatol 2024; 16:264-278. [PMID: 38495271 PMCID: PMC10941736 DOI: 10.4254/wjh.v16.i2.264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Revised: 01/09/2024] [Accepted: 02/01/2024] [Indexed: 02/27/2024] Open
Abstract
BACKGROUND Liver fibrosis is a formidable global medical challenge, with no effective clinical treatment currently available. Yinhuang granule (YHG) is a proprietary Chinese medicine comprising Scutellariae Radix and Lonicerae Japonicae Flos. It is frequently used for upper respiratory tract infections, pharyngitis, as well as acute and chronic tonsillitis. AIM To investigate the potential of YHG in alleviating carbon tetrachloride (CCl4)-induced liver fibrosis in mice. METHODS To induce a hepatic fibrosis model in mice, this study involved intraperitoneal injections of 2 mL/kg of CCl4 twice a week for 4 wk. Meanwhile, liver fibrosis mice in the low dose of YHG (0.4 g/kg) and high dose of YHG (0.8 g/kg) groups were orally administered YHG once a day for 4 wk. Serum alanine/aspartate aminotransferase (ALT/AST) activity and liver hydroxyproline content were detected. Sirius red and Masson's trichrome staining assay were conducted. Real-time polymerase chain reaction, western-blot and enzyme-linked immunosorbent assay were conducted. Liver glutathione content, superoxide dismutase activity level, reactive oxygen species and protein carbonylation amount were detected. RESULTS The administration of YHG ameliorated hepatocellular injury in CCl4-treated mice, as reflected by decreased serum ALT/AST activity and improved liver histological evaluation. YHG also attenuated liver fibrosis, evident through reduced liver hydroxyproline content, improvements in Sirius red and Masson's trichrome staining, and lowered serum hyaluronic acid levels. Furthermore, YHG hindered the activation of hepatic stellate cells (HSCs) and ameliorated oxidative stress injury and inflammation in liver from CCl4-treated mice. YHG prompted the nuclear accumulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and upregulated the expression of Nrf2-dependent downstream antioxidant genes. In addition, YHG promoted mitochondrial biogenesis in liver from CCl4-treated mice, as demonstrated by increased liver adenosine triphosphate content, mitochondrial DNA levels, and the expression of peroxisome proliferator-activated receptor gamma coactivator 1 alpha and nuclear respiratory factor 1. CONCLUSION YHG effectively attenuates CCl4-induced liver fibrosis in mice by inhibiting the activation of HSCs, reducing inflammation, alleviating liver oxidative stress damage through Nrf2 activation, and promoting liver mitochondrial biogenesis.
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Affiliation(s)
- Hao Ouyang
- Department of Liver, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Hui Miao
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 201203, China
| | - Zhen Li
- Department of Liver, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Duan Wu
- Department of Liver, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Si-Cheng Gao
- Department of Liver, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yao-Yao Dai
- Department of Liver, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Xiao-Di Gao
- Department of Liver, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Hai-Sheng Chai
- Department of Liver, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Wei-Ye Hu
- Department of Liver, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Jun-Feng Zhu
- Department of Liver, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
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Zhao Y, Zhou Y, Wang D, Huang Z, Xiao X, Zheng Q, Li S, Long D, Feng L. Mitochondrial Dysfunction in Metabolic Dysfunction Fatty Liver Disease (MAFLD). Int J Mol Sci 2023; 24:17514. [PMID: 38139341 PMCID: PMC10743953 DOI: 10.3390/ijms242417514] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Revised: 12/06/2023] [Accepted: 12/08/2023] [Indexed: 12/24/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) has become an increasingly common disease in Western countries and has become the major cause of liver cirrhosis or hepatocellular carcinoma (HCC) in addition to viral hepatitis in recent decades. Furthermore, studies have shown that NAFLD is inextricably linked to the development of extrahepatic diseases. However, there is currently no effective treatment to cure NAFLD. In addition, in 2020, NAFLD was renamed metabolic dysfunction fatty liver disease (MAFLD) to show that its pathogenesis is closely related to metabolic disorders. Recent studies have reported that the development of MAFLD is inextricably associated with mitochondrial dysfunction in hepatocytes and hepatic stellate cells (HSCs). Simultaneously, mitochondrial stress caused by structural and functional disorders stimulates the occurrence and accumulation of fat and lipo-toxicity in hepatocytes and HSCs. In addition, the interaction between mitochondrial dysfunction and the liver-gut axis has also become a new point during the development of MAFLD. In this review, we summarize the effects of several potential treatment strategies for MAFLD, including antioxidants, reagents, and intestinal microorganisms and metabolites.
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Affiliation(s)
- Ying Zhao
- Division of Liver Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu 610041, China; (Y.Z.); (Y.Z.); (D.W.); (Z.H.); (X.X.); (Q.Z.); (S.L.); (D.L.)
- Regeneration Medicine Research Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yanni Zhou
- Division of Liver Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu 610041, China; (Y.Z.); (Y.Z.); (D.W.); (Z.H.); (X.X.); (Q.Z.); (S.L.); (D.L.)
- Regeneration Medicine Research Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Dan Wang
- Division of Liver Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu 610041, China; (Y.Z.); (Y.Z.); (D.W.); (Z.H.); (X.X.); (Q.Z.); (S.L.); (D.L.)
- Regeneration Medicine Research Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Ziwei Huang
- Division of Liver Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu 610041, China; (Y.Z.); (Y.Z.); (D.W.); (Z.H.); (X.X.); (Q.Z.); (S.L.); (D.L.)
- Regeneration Medicine Research Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xiong Xiao
- Division of Liver Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu 610041, China; (Y.Z.); (Y.Z.); (D.W.); (Z.H.); (X.X.); (Q.Z.); (S.L.); (D.L.)
- Regeneration Medicine Research Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Qing Zheng
- Division of Liver Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu 610041, China; (Y.Z.); (Y.Z.); (D.W.); (Z.H.); (X.X.); (Q.Z.); (S.L.); (D.L.)
- Regeneration Medicine Research Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Shengfu Li
- Division of Liver Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu 610041, China; (Y.Z.); (Y.Z.); (D.W.); (Z.H.); (X.X.); (Q.Z.); (S.L.); (D.L.)
- NHC Key Laboratory of Transplant Engineering and Immunology, West China Hospital Sichuan University, Chengdu 610041, China
| | - Dan Long
- Division of Liver Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu 610041, China; (Y.Z.); (Y.Z.); (D.W.); (Z.H.); (X.X.); (Q.Z.); (S.L.); (D.L.)
- NHC Key Laboratory of Transplant Engineering and Immunology, West China Hospital Sichuan University, Chengdu 610041, China
| | - Li Feng
- Division of Liver Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu 610041, China; (Y.Z.); (Y.Z.); (D.W.); (Z.H.); (X.X.); (Q.Z.); (S.L.); (D.L.)
- Regeneration Medicine Research Center, West China Hospital, Sichuan University, Chengdu 610041, China
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Yao Y, Chen D, Yue Z. The regulatory role and mechanism of exosomes in hepatic fibrosis. Front Pharmacol 2023; 14:1284742. [PMID: 38108065 PMCID: PMC10722150 DOI: 10.3389/fphar.2023.1284742] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 11/20/2023] [Indexed: 12/19/2023] Open
Abstract
Globally, the prevalence and fatality rates of liver disorders are on the rise. Among chronic liver conditions, hepatic fibrosis stands out as a central pathological process. Despite this, approved treatments for hepatic fibrosis are currently lacking. Exosomes, small extracellular vesicles secreted by various cell types, play a significant role in intercellular communication and have emerged as essential mediators in liver fibrosis. In this regard, this review compiles the mechanisms through which exosomes regulate hepatic fibrosis, encompassing diverse targets and signaling pathways. Furthermore, it delves into the regulatory impact of exosomes modulated by natural plant-derived, endogenous, and synthetic compounds as potential therapeutic strategies for addressing hepatic fibrosis.
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Affiliation(s)
- Youli Yao
- College of Electronics and Information Engineering, Shandong University of Science and Technology, Qingdao, China
| | - Da Chen
- College of Electronics and Information Engineering, Shandong University of Science and Technology, Qingdao, China
| | - Zengchang Yue
- Department of Neurology, Mindong Hospital Affiliated to Fujian Medical University, Ningde, China
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Al-Toukhy GM, Suef RA, Hassan S, Farag MMS, El-Tayeb TA, Mansour MTM. Photobiological modulation of hepatoma cell lines and hepatitis B subviral particles secretion in response to 650 nm low level laser treatment. J Egypt Natl Canc Inst 2023; 35:33. [PMID: 37870653 DOI: 10.1186/s43046-023-00190-3] [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: 04/25/2022] [Accepted: 09/06/2023] [Indexed: 10/24/2023] Open
Abstract
BACKGROUND Chronic hepatitis B virus (HBV) infection is a serious global health concern, with an increased incidence and risk of developing cirrhosis and hepatocellular carcinoma (HCC). Patients chronically infected with HBV are likely to experience chronic oxidative stress, leading to mitochondrial dysfunction. Photobiomodulation is induced by the absorption of low-level laser therapy (LLLT) with a red or infrared laser by cytochrome C oxidase enzyme, resulting in mitochondrial photoactivation. Although it is widely used in clinical practice, the use of LLL as adjuvant therapy for persistent HBV infection is uncommon. This study aimed to investigate the effect of LLLT dosage from 2 J/cm2 to 10 J/cm2 of red diode laser (650 nm) on both hepatoma cell lines (HepG2.2.15 [integrated HBV genome stable cell model] and non-integrated HepG2), with a subsequent impact on HBVsvp production. METHODS The present study evaluated the effects of different fluences of low-level laser therapy (LLLT) irradiation on various aspects of hepatoma cell behavior, including morphology, viability, ultrastructure, and its impact on HBVsvp synthesis. RESULTS In response to LLLT irradiation, we observed a considerable reduction in viability, proliferation, and HBVsvp production in both hepatoma cell lines HepG2.2.15 and HepG2. Ultrastructural modification of mitochondria and nuclear membranes: This effect was dose, cell type, and time-dependent. CONCLUSIONS The use of LLLT may be a promising therapy for HCC and HBV patients by reducing cell proliferation, HBVsvp production, and altering mitochondrial and nuclear structure involved in cellular death inducers. Further research is required to explore its clinical application.
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Affiliation(s)
- Ghada M Al-Toukhy
- Department of Virology and Immunology, Children's Cancer Hospital, Cairo, 57357, Egypt.
| | - Reda A Suef
- Department of Botany and Microbiology, Faculty of Science, Al-Azhar University, Cairo, 11884, Egypt
| | - Sarah Hassan
- Pathology and Electron Microscopy, Theodor Bilharz Research Institute, Giza, Egypt
| | - Mohamed M S Farag
- Department of Botany and Microbiology, Faculty of Science, Al-Azhar University, Cairo, 11884, Egypt
- Biomedical Research Department, Armed Forces College of Medicine, Cairo, Egypt
| | - Tarek A El-Tayeb
- National Institute of Laser Enhanced Science (NILES), Cairo University, Cairo, Egypt
| | - Mohamed T M Mansour
- Department of Virology and Immunology, National Cancer Institute, Cairo University, Cairo, Egypt
- Children Cancer Hospital, Cairo, 57357, Egypt
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Martinez-Gonzalez L, Martinez A. Emerging clinical investigational drugs for the treatment of amyotrophic lateral sclerosis. Expert Opin Investig Drugs 2023; 32:141-160. [PMID: 36762798 DOI: 10.1080/13543784.2023.2178416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/11/2023]
Abstract
INTRODUCTION Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder caused by motoneuron death with a median survival time of 3-5 years since disease onset. There are no effective treatments to date. However, a variety of innovative investigational drugs and biological-based therapies are under clinical development. AREAS COVERED This review provides an overview of the clinical investigational small molecules as well as a brief summary of the biological-based therapies that are currently undergoing clinical trials for the treatment of ALS. All the data were obtained from ClinicalTrials.gov (registered through November 1). EXPERT OPINION Drug discovery for ALS is an active and evolving field, where many investigational clinical drugs are in different trials. There are several mechanisms of action supporting all these new therapies, although proteostasis is gaining stage. Probably, small orally bioavailable molecules able to recover functional TDP-43 homeostasis may have solid chances to modify ALS progression.
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Affiliation(s)
- Loreto Martinez-Gonzalez
- Centro de Investigaciones Biológicas "Margarita Salas"-CSIC, Madrid, Spain.,Centro de Investigación Biomédica en Red en enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
| | - Ana Martinez
- Centro de Investigaciones Biológicas "Margarita Salas"-CSIC, Madrid, Spain.,Centro de Investigación Biomédica en Red en enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
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Ilha M, Meira Martins LA, da Silveira Moraes K, Dias CK, Thomé MP, Petry F, Rohden F, Borojevic R, Trindade VMT, Klamt F, Barbé‐Tuana F, Lenz G, Guma FCR. Caveolin-1 influences mitochondrial plasticity and function in hepatic stellate cell activation. Cell Biol Int 2022; 46:1787-1800. [PMID: 35971753 PMCID: PMC9804617 DOI: 10.1002/cbin.11876] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Revised: 03/21/2022] [Accepted: 05/26/2022] [Indexed: 01/05/2023]
Abstract
Caveolin-1 (Cav-1) is an integral membrane protein present in all organelles, responsible for regulating and integrating multiple signals as a platform. Mitochondria are extremely adaptable to external cues in chronic liver diseases, and expression of Cav-1 may affect mitochondrial flexibility in hepatic stellate cells (HSCs) activation. We previously demonstrated that exogenous expression of Cav-1 was sufficient to increase some classical markers of activation in HSCs. Here, we aimed to evaluate the influence of exogenous expression and knockdown of Cav-1 on regulating the mitochondrial plasticity, metabolism, endoplasmic reticulum (ER)-mitochondria distance, and lysosomal activity in HSCs. To characterize the mitochondrial, lysosomal morphology, and ER-mitochondria distance, we perform transmission electron microscope analysis. We accessed mitochondria and lysosomal networks and functions through a confocal microscope and flow cytometry. The expression of mitochondrial machinery fusion/fission genes was examined by real-time polymerase chain reaction. Total and mitochondrial cholesterol content was measured using Amplex Red. To define energy metabolism, we used the Oroboros system in the cells. We report that GRX cells with exogenous expression or knockdown of Cav-1 changed mitochondrial morphometric parameters, OXPHOS metabolism, ER-mitochondria distance, lysosomal activity, and may change the activation state of HSC. This study highlights that Cav-1 may modulate mitochondrial function and structural reorganization in HSC activation, being a potential candidate marker for chronic liver diseases and a molecular target for therapeutic intervention.
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Affiliation(s)
- Mariana Ilha
- Programa de Pós‐Graduação em Ciências Biológicas‐Bioquímica, Instituto de Ciências Básicas da SaúdeUniversidade Federal do Rio Grande do Sul – UFRGSPorto AlegreRio Grande do SulBrasil,Department of Clinical Nutrition, Institute of Public Health and Clinical NutritionUniversity of Eastern FinlandKuopioFinland
| | - Leo A. Meira Martins
- Programa de Pós‐Graduação em Ciências Biológicas‐Bioquímica, Instituto de Ciências Básicas da SaúdeUniversidade Federal do Rio Grande do Sul – UFRGSPorto AlegreRio Grande do SulBrasil,Departamento de Fisiologia, Instituto de Ciências Básicas da SaúdeUniversidade Federal do Rio Grande do Sul ‐ UFRGSPorto AlegreRio Grande do SulBrasil
| | - Ketlen da Silveira Moraes
- Departamento de Bioquímica, Instituto de Ciências Básicas da SaúdeUniversidade Federal do Rio Grande do Sul ‐ UFRGSPorto AlegreRio Grande do SulBrasil
| | - Camila K. Dias
- Programa de Pós‐Graduação em Ciências Biológicas‐Bioquímica, Instituto de Ciências Básicas da SaúdeUniversidade Federal do Rio Grande do Sul – UFRGSPorto AlegreRio Grande do SulBrasil
| | - Marcos P. Thomé
- Departamento de Biofísica e Centro de BiotecnologiaUniversidade Federal do Rio Grande do Sul ‐ UFRGSPorto AlegreRio Grande do SulBrasil
| | - Fernanda Petry
- Programa de Pós‐Graduação em Ciências Biológicas‐Bioquímica, Instituto de Ciências Básicas da SaúdeUniversidade Federal do Rio Grande do Sul – UFRGSPorto AlegreRio Grande do SulBrasil
| | - Francieli Rohden
- Programa de Pós‐Graduação em Ciências Biológicas‐Bioquímica, Instituto de Ciências Básicas da SaúdeUniversidade Federal do Rio Grande do Sul – UFRGSPorto AlegreRio Grande do SulBrasil
| | - Radovan Borojevic
- Centro de Medicina RegenerativaFaculdade Arthur Sa Earp Neto ‐ Faculdade de Medicina de PetrópolisRio de JaneiroBrasil
| | - Vera M. T. Trindade
- Departamento de Bioquímica, Instituto de Ciências Básicas da SaúdeUniversidade Federal do Rio Grande do Sul ‐ UFRGSPorto AlegreRio Grande do SulBrasil
| | - Fábio Klamt
- Departamento de Bioquímica, Instituto de Ciências Básicas da SaúdeUniversidade Federal do Rio Grande do Sul ‐ UFRGSPorto AlegreRio Grande do SulBrasil
| | - Florência Barbé‐Tuana
- Programa de Pós‐Graduação em Biologia Celular e MolecularEscola de Ciências da Pontifícia Universidade Católica do Rio Grande do Sul‐ PUCRSPorto AlegreRio Grande do SulBrasil
| | - Guido Lenz
- Departamento de Biofísica e Centro de BiotecnologiaUniversidade Federal do Rio Grande do Sul ‐ UFRGSPorto AlegreRio Grande do SulBrasil
| | - Fátima C. R. Guma
- Departamento de Bioquímica, Instituto de Ciências Básicas da SaúdeUniversidade Federal do Rio Grande do Sul ‐ UFRGSPorto AlegreRio Grande do SulBrasil,Centro de Microscopia e MicroanáliseUniversidade Federal do Rio Grande do Sul ‐ UFRGSPorto AlegreRio Grande do SulBrasil
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10
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Neves PFR, Milanesi BB, Paz LV, de Miranda Monteiro VAC, Neves LT, da Veiga LC, da Silva RB, Sulzbach JH, Knijkik GP, de Revoredo Ribeiro EC, de Souza Silva EL, Vieira MQ, Bagatini PB, Wieck A, Mestriner RG, Xavier LL. Age-related tolerance to paraquat-induced parkinsonism in Drosophila melanogaster. Toxicol Lett 2022; 361:43-53. [DOI: 10.1016/j.toxlet.2022.03.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 02/28/2022] [Accepted: 03/28/2022] [Indexed: 11/28/2022]
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11
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da Costa CC, Martins LAM, Koth AP, Ramos JMO, Guma FTCR, de Oliveira CM, Pedra NS, Fischer G, Helena ES, Gioda CR, Sanches PRS, Junior ASV, Soares MSP, Spanevello RM, Gamaro GD, de Souza ICC. Static Magnetic Stimulation Induces Changes in the Oxidative Status and Cell Viability Parameters in a Primary Culture Model of Astrocytes. Cell Biochem Biophys 2021; 79:873-885. [PMID: 34176101 DOI: 10.1007/s12013-021-01015-7] [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] [Accepted: 06/14/2021] [Indexed: 11/24/2022]
Abstract
Astrocytes play an important role in the central nervous system function and may contribute to brain plasticity response during static magnetic fields (SMF) brain therapy. However, most studies evaluate SMF stimulation in brain plasticity while few studies evaluate the consequences of SMF at the cellular level. Thus, we here evaluate the effects of SMF at 305 mT (medium-intensity) in a primary culture of healthy/normal cortical astrocytes obtained from neonatal (1 to 2-day-old) Wistar rats. After reaching confluence, cells were daily subjected to SMF stimulation for 5 min, 15 min, 30 min, and 40 min during 7 consecutive days. Oxidative stress parameters, cell cycle, cell viability, and mitochondrial function were analyzed. The antioxidant capacity was reduced in groups stimulated for 5 and 40 min. Although no difference was observed in the enzymatic activity of superoxide dismutase and catalase or the total thiol content, lipid peroxidation was increased in all stimulated groups. The cell cycle was changed after 40 min of SMF stimulation while 15, 30, and 40 min led cells to death by necrosis. Mitochondrial function was reduced after SMF stimulation, although imaging analysis did not reveal substantial changes in the mitochondrial network. Results mainly revealed that SMF compromised healthy astrocytes' oxidative status and viability. This finding reveals how important is to understand the SMF stimulation at the cellular level since this therapeutic approach has been largely used against neurological and psychiatric diseases.
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Affiliation(s)
- Caroline Crespo da Costa
- NeuroCell Laboratory, Universidade Federal de Pelotas Campus Universitário, S/N, Capão do Leão-RS, 96160-000, Brasil
| | - Léo Anderson Meira Martins
- Department of Physiology, Universidade Federal do Rio Grande do Sul, Rua Sarmento Leite, 500, Bairro Centro Histórico, Porto Alegre, Rio Grande do Sul, 90050-170, Brasil
| | - André Peres Koth
- NeuroCell Laboratory, Universidade Federal de Pelotas Campus Universitário, S/N, Capão do Leão-RS, 96160-000, Brasil
| | - Jéssica Marques Obelar Ramos
- NeuroCell Laboratory, Universidade Federal de Pelotas Campus Universitário, S/N, Capão do Leão-RS, 96160-000, Brasil
| | - Fátima Theresinha Costa Rodrigues Guma
- Department of Biochemistry, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600, Bairro Santa Cecília, Porto Alegre, Rio Grande do Sul, 90035-000, Brasil
| | - Cleverson Moraes de Oliveira
- Department of Biochemistry, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600, Bairro Santa Cecília, Porto Alegre, Rio Grande do Sul, 90035-000, Brasil
| | - Nathália Stark Pedra
- Laboratory of Neurochemistry, Inflammation and Cancer, Universidade Federal de Pelotas Campus Universitário, S/N, Capão do Leão-RS, 96160-000, Brasil
| | - Geferson Fischer
- Laboratory of Virology and Immunology, Universidade Federal de Pelotas Campus Universitário, S/N, Capão do Leão-RS, 96160-000, Brasil
| | - Eduarda Santa Helena
- Department of Physiological Sciences, Universidade Federal de Rio Grande Avenida Itália, Km 8, Bairro Carreiros, Rio Grande, Rio Grande do Sul, 96203-900, Brasil
| | - Carolina Rosa Gioda
- Department of Physiological Sciences, Universidade Federal de Rio Grande Avenida Itália, Km 8, Bairro Carreiros, Rio Grande, Rio Grande do Sul, 96203-900, Brasil
| | - Paulo Roberto Stefani Sanches
- Laboratory of the Research and Development Service in Biomedical Engineering- Hospital de Clínicas de Porto Alegre Rua Ramiro Barcelos, 2350- Bairro Santa Cecília, Porto Alegre-RS, 90035-903, Brasil
| | - Antonio Sergio Varela Junior
- Institute of Biological Science, Universidade Federal do Rio Grande Avenida Itália, Km 8, Bairro Carreiros, Rio Grande, Rio Grande do Sul, 96203-900, Brasil
| | - Mayara Sandrielly Pereira Soares
- Laboratory of Neurochemistry, Inflammation and Cancer, Universidade Federal de Pelotas Campus Universitário, S/N, Capão do Leão-RS, 96160-000, Brasil
| | - Rosélia Maria Spanevello
- Laboratory of Neurochemistry, Inflammation and Cancer, Post-Graduate Program in Biochemistry and Bioprospection, Universidade Federal de Pelotas Campus Universitário, S/N, Capão do Leão-RS, 96160-000, Brasil
| | - Giovana Duzzo Gamaro
- NeuroCell Laboratory, Universidade Federal de Pelotas Campus Universitário, S/N, Capão do Leão-RS, 96160-000, Brasil
| | - Izabel Cristina Custódio de Souza
- Coordinator of NeuroCell Laboratory, Laboratory of Histology, Department of Morphology, Post-Graduate Program in Biochemistry and Bioprospection, Universidade Federal de Pelotas Avenida Duque de Caxias, 250, 96030-000, Pelotas, Rio Grande do Sul, Brasil.
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12
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Luo X, Xu ZX, Wu JC, Luo SZ, Xu MY. Hepatocyte-derived exosomal miR-27a activates hepatic stellate cells through the inhibition of PINK1-mediated mitophagy in MAFLD. MOLECULAR THERAPY - NUCLEIC ACIDS 2021; 26:1241-1254. [PMID: 34853724 PMCID: PMC8607138 DOI: 10.1016/j.omtn.2021.10.022] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Revised: 06/26/2021] [Accepted: 10/29/2021] [Indexed: 11/22/2022]
Abstract
The role of exosome-mediated mitophagy in the crosstalk between hepatocytes (HCs) and hepatic stellate cells (HSCs) in metabolic-associated fatty liver disease (MAFLD) remains unknown. Serum exosomal miR-27a levels were markedly increased and positively correlated with liver fibrosis in MAFLD patients and mice. Exosomal miR-27a was released from lipotoxic HCs and specifically transmitted to recipient-activated HSCs. PINK1, the key target of miR-27a, primarily mediates mitophagy. Overexpression of miR-27a or knockdown of PINK1 or lipotoxic HC-exosomal miR-27a impaired mitochondria (inhibiting mitophagy, respiration, membrane potential, and transcription while promoting reactive oxygen species production) in activated HSCs and stimulated HSC-derived fibroblasts (promoting activation and proliferation while inhibiting autophagy). High exosomal miR-27a serum levels and a lack of hepatic PINK1-mediated mitophagy were directly related to liver fibrosis in MAFLD mice. Lipotoxic HC exosome transplantation aggravated the degree of PINK1-mediated mitophagy suppression, steatohepatitis, lipidosis, and fibrosis in the livers of MAFLD mice with cirrhosis. Both in vitro and in vivo, exosomes derived from miR-27a-knockdown HCs could not facilitate the abovementioned deteriorating effects. In conclusion, lipotoxic HC-exosomal miR-27a plays a pivotal role in inhibiting mitophagy and in promoting MAFLD-related liver fibrosis by negatively regulating PINK1 expression.
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13
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Dou SD, Zhang JN, Xie XL, Liu T, Hu JL, Jiang XY, Wang MM, Jiang HD. MitoQ inhibits hepatic stellate cell activation and liver fibrosis by enhancing PINK1/parkin-mediated mitophagy. Open Med (Wars) 2021; 16:1718-1727. [PMID: 34825063 PMCID: PMC8590110 DOI: 10.1515/med-2021-0394] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2021] [Revised: 10/05/2021] [Accepted: 10/22/2021] [Indexed: 12/12/2022] Open
Abstract
Mitophagy affects the activation of hepatic stellate cells (HSCs). Mitochondria-targeted ubiquinone (MitoQ) is a mitochondria-targeted antioxidant that reduces the production of intracellular reactive oxygen species (ROS). However, its relationship with mitophagy remains unclear. This study evaluated mitophagy during HSC activation and the effects of MitoQ on mitophagy in cell culture and in an animal model of the activation of HSCs. We found that MitoQ reduced the activation of HSCs and alleviated hepatic fibrosis. PINK1 (PTEN-induced putative kinase 1) is a putative serine/threonine kinase located in the mitochondria’s outer membrane. While the activation of primary HSCs or LX-2 cells was associated with reduced PINK1/parkin-mediated mitophagy, MitoQ reduced intracellular ROS levels, enhanced PINK1/parkin-mediated mitophagy, and inhibited the activation of HSCs. After knocking down the key mitophagy-related protein, PINK1, in LX-2 cells to block mitophagy, MitoQ intervention failed to inhibit HSC activation. Our results showed that MitoQ inhibited the activation of HSCs and alleviated hepatic fibrosis by enhancing PINK1/parkin-mediated mitophagy.
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Affiliation(s)
- Shi-Ding Dou
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Disease, Hebei, China.,Department of Infectious Diseases, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Jiu-Na Zhang
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Disease, Hebei, China
| | - Xiao-Li Xie
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Disease, Hebei, China
| | - Ting Liu
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Disease, Hebei, China
| | - Jun-Li Hu
- Emergency Department, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Xiao-Yu Jiang
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Disease, Hebei, China
| | - Miao-Miao Wang
- Department of Infectious Diseases, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Hui-Ding Jiang
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Disease, Hebei, China
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In situ observation of mitochondrial biogenesis as the early event of apoptosis. iScience 2021; 24:103038. [PMID: 34553131 PMCID: PMC8441175 DOI: 10.1016/j.isci.2021.103038] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 07/28/2021] [Accepted: 08/22/2021] [Indexed: 12/25/2022] Open
Abstract
Mitochondrial biogenesis is a cell response to external stimuli which is generally believed to suppress apoptosis. However, during the process of apoptosis, whether mitochondrial biogenesis occurs in the early stage of the apoptotic cells remains unclear. To address this question, we constructed the COX8-EGFP-ACTIN-mCherry HeLa cells with recombinant fluorescent proteins respectively tagged on the nucleus and mitochondria and monitored the mitochondrial changes in the living cells exposed to gamma-ray radiation. Besides in situ detection of mitochondrial fluorescence changes, we also examined the cell viability, nuclear DNA damage, reactive oxygen species (ROS), mitochondrial superoxide, citrate synthase activity, ATP, cytoplasmic and mitochondrial calcium, mitochondrial mass, mitochondrial morphology, and protein expression related to mitochondrial biogenesis, as well as the apoptosis biomarkers. As a result, we confirmed that significant mitochondrial biogenesis took place preceding the radiation-induced apoptosis, and it was closely correlated with the apoptotic cells at late stage. The involved mechanism was also discussed.
Dual fluorescence approach was used for in situ observation of living cell processes Radiation-induced effects of mitochondrial biogenesis and apoptosis were observed Relationship between mitochondrial biogenesis and apoptosis was revisited Assessing early mitochondrial biogenesis is critical for predicting later fate of cells
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15
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Park JS, Ma H, Roh YS. Ubiquitin pathways regulate the pathogenesis of chronic liver disease. Biochem Pharmacol 2021; 193:114764. [PMID: 34529948 DOI: 10.1016/j.bcp.2021.114764] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 09/05/2021] [Accepted: 09/08/2021] [Indexed: 02/07/2023]
Abstract
Chronic liver disease (CLD) is considered the leading cause of global mortality. In westernized countries, increased consumption of alcohol and overeating foods with high fat/ high glucose promote progression of CLD such as alcoholic liver disease (ALD) and non-alcoholic liver disease (NAFLD). Accumulating evidence and research suggest that ubiquitin, a 75 amino acid protein, plays crucial role in the pathogenesis of CLD through dynamic post-translational modifications (PTMs) exerting diverse cellular outcomes such as protein degradation through ubiquitin-proteasome system (UPS) and autophagy, and regulation of signal transduction. In this review, we present the function of ubiquitination and latest findings on diverse mechanism of PTMs, UPS and autophagy which significantly contribute to the pathogenesis of alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), cirrhosis, and HCC. Despite its high prevalence, morbidity, and mortality, there are only few FDA approved drugs that could be administered to CLD patients. The goal of this review is to present a variety of pathways and therapeutic targets involving ubiquitination in the pathogenesis of CLD. Further, this review summarizes collective views of pharmaceutical inhibition or activation of recent drugs targeting UPS and autophagy system to highlight potential targets and new approaches to treat CLD.
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Affiliation(s)
- Jeong-Su Park
- College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju 28160, South Korea
| | - Hwan Ma
- College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju 28160, South Korea
| | - Yoon-Seok Roh
- College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju 28160, South Korea.
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16
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Pomegranate Extract (POMx) Induces Mitochondrial Dysfunction and Apoptosis of Oral Cancer Cells. Antioxidants (Basel) 2021; 10:antiox10071117. [PMID: 34356350 PMCID: PMC8301084 DOI: 10.3390/antiox10071117] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Revised: 07/10/2021] [Accepted: 07/10/2021] [Indexed: 12/13/2022] Open
Abstract
The anticancer effect of pomegranate polyphenolic extract POMx in oral cancer cells has rarely been explored, especially where its impact on mitochondrial functioning is concerned. Here, we attempt to evaluate the proliferation modulating function and mechanism of POMx against human oral cancer (Ca9-22, HSC-3, and OC-2) cells. POMx induced ATP depletion, subG1 accumulation, and annexin V/Western blotting-detected apoptosis in these three oral cancer cell lines but showed no toxicity to normal oral cell lines (HGF-1). POMx triggered mitochondrial membrane potential (MitoMP) disruption and mitochondrial superoxide (MitoSOX) generation associated with the differential downregulation of several antioxidant gene mRNA/protein expressions in oral cancer cells. POMx downregulated mitochondrial mass, mitochondrial DNA copy number, and mitochondrial biogenesis gene mRNA/protein expression in oral cancer cells. Moreover, POMx induced both PCR-based mitochondrial DNA damage and γH2AX-detected nuclear DNA damage in oral cancer cells. In conclusion, POMx provides antiproliferation and apoptosis of oral cancer cells through mechanisms of mitochondrial impairment.
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17
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Goyal S, Tiwari S, Seth B, Tandon A, Shankar J, Sinha M, Singh SJ, Priya S, Chaturvedi RK. Bisphenol-A inhibits mitochondrial biogenesis via impairment of GFER mediated mitochondrial protein import in the rat brain hippocampus. Neurotoxicology 2021; 85:18-32. [PMID: 33878312 DOI: 10.1016/j.neuro.2021.04.001] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 04/05/2021] [Accepted: 04/06/2021] [Indexed: 12/22/2022]
Abstract
Mitochondrial biogenesis relies on different protein import machinery, as mitochondrial proteins are imported from the cytosol. The mitochondrial intermembrane space assembly (MIA) pathway consists of GFER/ALR and CHCHD4/Mia40, responsible for importing proteins and their oxidative folding inside the mitochondria. The MIA pathway plays an essential role in complex IV (COX IV) biogenesis via importing copper chaperone COX17, associated with the respiratory chain. BPA, an environmental toxicant, found in consumable plastics, causes neurotoxicity via impairment in mitochondrial dynamics, neurogenesis, and cognitive functions. We studied the levels of key regulatory proteins of mitochondrial import pathways and mitochondrial biogenesis after BPA exposure in the rat hippocampus. BPA caused a significant reduction in the levels of mitochondrial biogenesis proteins (PGC1α, and TFAM) and mitochondrial import protein (GFER). Immunohistochemical analysis showed reduced co-localization of NeuN with GFER, PGC-1α, and TFAM suggesting impaired mitochondrial biogenesis and protein import. BPA exposure resulted in damaged mitochondria with distorted cristae in neurons and caused a significant reduction in GFER localization inside IMS as depicted by immunogold electron microscopy. The reduced levels of GFER resulted in defective COX17 import. The translocation of cytochrome c into the cytosol and increased cleaved caspase-3 levels triggered apoptosis due to BPA toxicity. Overall, our study implicates GFER as a potential target for impaired mitochondrial protein machinery, biogenesis, and apoptosis against BPA neurotoxicity in the rat hippocampus.
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Affiliation(s)
- Shweta Goyal
- Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh, 226001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Saurabh Tiwari
- Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh, 226001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Brashket Seth
- Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh, 226001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Ankit Tandon
- Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh, 226001, India; Department of Biochemistry, School of Dental Sciences, Babu Banarasi Das University, BBD City, Faizabad Road, Lucknow, U.P, 226 028, India
| | - Jai Shankar
- Advanced Imaging Facility, CSIR-IITR, Lucknow, India
| | - Meetali Sinha
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India; Computational Toxicology Facility, CSIR-IITR, Lucknow, India
| | - Sangh Jyoti Singh
- Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh, 226001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Smriti Priya
- Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh, 226001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Rajnish Kumar Chaturvedi
- Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh, 226001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
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Madruga E, Maestro I, Martínez A. Mitophagy Modulation, a New Player in the Race against ALS. Int J Mol Sci 2021; 22:ijms22020740. [PMID: 33450997 PMCID: PMC7828440 DOI: 10.3390/ijms22020740] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 01/09/2021] [Accepted: 01/11/2021] [Indexed: 02/06/2023] Open
Abstract
Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease that usually results in respiratory paralysis in an interval of 2 to 4 years. ALS shows a multifactorial pathogenesis with an unknown etiology, and currently lacks an effective treatment. The vast majority of patients exhibit protein aggregation and a dysfunctional mitochondrial accumulation in their motoneurons. As a result, autophagy and mitophagy modulators may be interesting drug candidates that mitigate key pathological hallmarks of the disease. This work reviews the most relevant evidence that correlate mitophagy defects and ALS, and discusses the possibility of considering mitophagy as an interesting target in the search for an effective treatment for ALS.
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Affiliation(s)
- Enrique Madruga
- Centro de Investigaciones Biológicas-CSIC, Ramiro de Maeztu 9, 28040 Madrid, Spain; (E.M.); (I.M.)
| | - Inés Maestro
- Centro de Investigaciones Biológicas-CSIC, Ramiro de Maeztu 9, 28040 Madrid, Spain; (E.M.); (I.M.)
| | - Ana Martínez
- Centro de Investigaciones Biológicas-CSIC, Ramiro de Maeztu 9, 28040 Madrid, Spain; (E.M.); (I.M.)
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, 28031 Madrid, Spain
- Correspondence: ; Tel.: +34-918373112
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Zhang Q, Zhang C, Ge J, Lv MW, Talukder M, Guo K, Li YH, Li JL. Ameliorative effects of resveratrol against cadmium-induced nephrotoxicity via modulating nuclear xenobiotic receptor response and PINK1/Parkin-mediated Mitophagy. Food Funct 2020; 11:1856-1868. [PMID: 32068207 DOI: 10.1039/c9fo02287b] [Citation(s) in RCA: 126] [Impact Index Per Article: 25.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Cadmium (Cd) is a toxic pollutant with high nephrotoxicity in the agricultural environment. Resveratrol has been found to have a renoprotective effect but the underlying mechanisms of this have not yet been fully elucidated. The aim of this study is to illustrate the antagonism of resveratrol against Cd-induced nephrotoxicity. A total of 80 birds were divided randomly into 4 groups and treated via diet for 90 days as follows: control group (Con); 400 mg kg-1 resveratrol group (Resv); 140 mg kg-1 Cd group (Cd 140); and 140 mg kg-1 Cd + 400 mg kg-1 resveratrol group (Cd + Resv). It was observed that resveratrol treatment dramatically alleviated Cd-induced histopathological lesions of the kidney. Simultaneously, resveratrol mitigated Cd-induced oxidative stress by reducing MDA and H2O2 production, alleviating GSH depletion and restoring the activity of antioxidant enzymes (T-SOD, Cu-Zn SOD, CAT, GST and GSH-Px). Resveratrol activated NXRs (CAR/PXR/AHR/Nrf2) signaling pathways and exerted antidotal roles by enhancing the phase I and II detoxification systems to relieve oxidative damage. Moreover, resveratrol ameliorated Cd-induced ultrastructural abnormality and mitochondria dysfunction by recovering mitochondrial function-related factors VDAC1, Cyt C and Sirt3 upregulation and Sirt1, PGC-1α, Nrf1 and TFAM transcription restrictions. Resveratrol attenuated Cd-induced excessive mitochondrial fission and promoted mitochondrial fusion, which reversed PINK1/Parkin-mediated mitophagy initiation. Collectively, our findings explicate the potential protection against Cd-induced nephrotoxicity and mitochondria damage.
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Affiliation(s)
- Qi Zhang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, P. R. China.
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A Comprehensive Review of Natural Products against Liver Fibrosis: Flavonoids, Quinones, Lignans, Phenols, and Acids. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2020; 2020:7171498. [PMID: 33082829 PMCID: PMC7556091 DOI: 10.1155/2020/7171498] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 07/23/2020] [Accepted: 07/25/2020] [Indexed: 12/18/2022]
Abstract
Liver fibrosis resulting from continuous long-term hepatic damage represents a heavy burden worldwide. Liver fibrosis is recognized as a complicated pathogenic mechanism with extracellular matrix (ECM) accumulation and hepatic stellate cell (HSC) activation. A series of drugs demonstrate significant antifibrotic activity in vitro and in vivo. No specific agents with ideally clinical efficacy for liver fibrosis treatment have been developed. In this review, we summarized the antifibrotic effects and molecular mechanisms of 29 kinds of common natural products. The mechanism of these compounds is correlated with anti-inflammatory, antiapoptotic, and antifibrotic activities. Moreover, parenchymal hepatic cell survival, HSC deactivation, and ECM degradation by interfering with multiple targets and signaling pathways are also involved in the antifibrotic effects of these compounds. However, there remain two bottlenecks for clinical breakthroughs. The low bioavailability of natural products should be improved, and the combined application of two or more compounds should be investigated for more prominent pharmacological effects. In summary, exploration on natural products against liver fibrosis is becoming increasingly extensive. Therefore, natural products are potential resources for the development of agents to treat liver fibrosis.
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de Oliveira CM, Martins LAM, de Sousa AC, Moraes KDS, Costa BP, Vieira MQ, Coelho BP, Borojevic R, de Oliveira JR, Guma FCR. Resveratrol increases the activation markers and changes the release of inflammatory cytokines of hepatic stellate cells. Mol Cell Biochem 2020; 476:649-661. [PMID: 33073314 DOI: 10.1007/s11010-020-03933-1] [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: 06/26/2020] [Accepted: 10/07/2020] [Indexed: 02/07/2023]
Abstract
The phytoalexin Resveratrol (3,5,4'-trihydroxystilbene; RSV) has been related to numerous beneficial effects on health by its cytoprotection and chemoprevention activities. Liver fibrosis is characterized by the extracellular matrix accumulation after hepatic injury and can lead to cirrhosis. Hepatic stellate cells (HSC) play a crucial role during fibrogenesis and liver wound healing by changing their quiescent phenotype to an activated phenotype for protecting healthy areas from damaged areas. Strategies on promoting the activated HSC death, the quiescence return or the cellular activation stimuli decrease play an important role on reducing liver fibrosis. Here, we evaluated the RSV effects on some markers of activation in GRX, an HSC model. We further evaluated the RSV influence in the ability of GRX on releasing inflammatory mediators. RSV at 1 and 10 µM did not alter the protein content of α-SMA, collagen I and GFAP; but 50 µM increased the content of these activation-related proteins. Also, RSV did not change the myofibroblast-like morphology of GRX. Interestingly, RSV at 10 and 50 µM decreased the GRX migration and collagen-I gel contraction. Finally, we showed that RSV triggered the increase in the TNF-α and IL-10 content in culture media of GRX while the opposite occurred for the IL-6 content. Altogether, these results suggested that RSV did not decrease the activation state of GRX and oppositely, triggered a pro-activation effect at the 50 µM concentration. However, despite the increase of TNF- α in culture media, these results on IL-6 and IL-10 secretion were in accordance with the anti-inflammatory role of RSV in our model.
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Affiliation(s)
- Cleverson Moraes de Oliveira
- Departmento de Bioquímica, ICBS, Universidade Federal Do Rio Grande Do Sul (UFRGS), Rua Ramiro Barcelos, 2600-Anexo I, Porto Alegre, RS, CEP, 90035-003, Brazil.
| | - Leo Anderson Meira Martins
- Departmento de Bioquímica, ICBS, Universidade Federal Do Rio Grande Do Sul (UFRGS), Rua Ramiro Barcelos, 2600-Anexo I, Porto Alegre, RS, CEP, 90035-003, Brazil.,Departamento de Fisiologia, ICBS, Universidade Federal Do Rio Grande Do Sul, Rua Sarmento Leite, Porto Alegre, RS, CEP, 500, Brazil
| | - Arieli Cruz de Sousa
- Departmento de Bioquímica, ICBS, Universidade Federal Do Rio Grande Do Sul (UFRGS), Rua Ramiro Barcelos, 2600-Anexo I, Porto Alegre, RS, CEP, 90035-003, Brazil
| | - Ketlen da Silveira Moraes
- Departmento de Bioquímica, ICBS, Universidade Federal Do Rio Grande Do Sul (UFRGS), Rua Ramiro Barcelos, 2600-Anexo I, Porto Alegre, RS, CEP, 90035-003, Brazil
| | - Bruna Pasqualotto Costa
- Laboratório de Pesquisa Em Biofísica Celular E Inflamação, Pontifícia Universidade Católica Do Rio Grande Do Sul (PUCRS), Porto Alegre, RS, Brazil
| | - Moema Queiroz Vieira
- Departmento de Bioquímica, ICBS, Universidade Federal Do Rio Grande Do Sul (UFRGS), Rua Ramiro Barcelos, 2600-Anexo I, Porto Alegre, RS, CEP, 90035-003, Brazil
| | - Bárbara Paranhos Coelho
- Departmento de Bioquímica, ICBS, Universidade Federal Do Rio Grande Do Sul (UFRGS), Rua Ramiro Barcelos, 2600-Anexo I, Porto Alegre, RS, CEP, 90035-003, Brazil
| | - Radovan Borojevic
- Centro de Medicina Regenerativa, Faculdade de Medicina de Petrópolis, Petrópolis, RJ, Brazil
| | - Jarbas Rodrigues de Oliveira
- Laboratório de Pesquisa Em Biofísica Celular E Inflamação, Pontifícia Universidade Católica Do Rio Grande Do Sul (PUCRS), Porto Alegre, RS, Brazil
| | - Fátima Costa Rodrigues Guma
- Departmento de Bioquímica, ICBS, Universidade Federal Do Rio Grande Do Sul (UFRGS), Rua Ramiro Barcelos, 2600-Anexo I, Porto Alegre, RS, CEP, 90035-003, Brazil.,Centro de Microscopia E Microanálise (CMM), Universidade Federal Do Rio Grande Do Sul, Av. Bento Gonçalves, 9500 - Prédio 43.177 - Bl 1Campus do Vale, Porto Alegre, RS, CEP, 91501-970, Brazil
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22
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De R, Mazumder S, Bandyopadhyay U. Mediators of mitophagy that regulate mitochondrial quality control play crucial role in diverse pathophysiology. Cell Biol Toxicol 2020; 37:333-366. [PMID: 33067701 DOI: 10.1007/s10565-020-09561-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Accepted: 10/05/2020] [Indexed: 02/06/2023]
Abstract
Mitochondria are double membrane-bound cellular work-horses constantly functioning to regulate vital aspects of cellular metabolism, bioenergetics, proliferation and death. Biogenesis, homeostasis and regulated turnover of mitochondria are stringently regulated to meet the bioenergetic requirements. Diverse external and internal stimuli including oxidative stress, diseases, xenobiotics and even age profoundly affect mitochondrial integrity. Damaged mitochondria need immediate segregation and selective culling to maintain physiological homeostasis. Mitophagy is a specialised form of macroautophagy that constantly checks mitochondrial quality followed by elimination of rogue mitochondria by lysosomal targeting through multiple pathways tightly regulated and activated in context-specific manners. Mitophagy is implicated in diverse oxidative stress-associated metabolic, proliferating and degenerative disorders owing to the centrality of mitopathology in diseases as well as the common mandate to eliminate damaged mitochondria for restoring physiological homeostasis. With improved health care and growing demand for precision medicine, specifically targeting the keystone factors in pathogenesis, more exploratory studies are focused on mitochondrial quality control as underlying guardian of cellular pathophysiology. In this context, mitophagy emerged as a promising area to focus biomedical research for identifying novel therapeutic targets against diseases linked with physiological redox perturbation. The present review provides a comprehensive account of the recent developments on mitophagy along with precise discussion on its impact on major diseases and possibilities of therapeutic modulation.
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Affiliation(s)
- Rudranil De
- Amity Institute of Biotechnology, Amity University, Kolkata, Plot No: 36, 37 & 38, Major Arterial Road, Action Area II, Kadampukur Village, Newtown, Kolkata, West Bengal, 700135, India
| | - Somnath Mazumder
- Division of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Kolkata, West Bengal, 700032, India
- Department of Zoology, Raja Peary Mohan College, 1 Acharya Dhruba Pal Road, Uttarpara, West Bengal, 712258, India
| | - Uday Bandyopadhyay
- Division of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Kolkata, West Bengal, 700032, India.
- Division of Molecular Medicine, Bose Institute, P-1/12, CIT Rd, Scheme VIIM, Kankurgachi, Kolkata, West Bengal, 700054, India.
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23
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Kochi C, Pokkunuri I, Salvi A, Asghar M, Salim S. Simulated vehicle exhaust exposure (SVEE) in rats impairs renal mitochondrial function. Clin Exp Hypertens 2020; 42:571-579. [DOI: 10.1080/10641963.2020.1766059] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Affiliation(s)
- Camila Kochi
- Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX, USA
| | - Indira Pokkunuri
- Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX, USA
- Heart and Kidney Institute, University of Houston, Houston, TX, USA
| | - Ankita Salvi
- The Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Mohammad Asghar
- Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX, USA
- Heart and Kidney Institute, University of Houston, Houston, TX, USA
| | - Samina Salim
- Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX, USA
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24
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Mantovanelli GC, Mito MS, Ricardo LL, Menezes PVMDC, Carvalho Contesoto ID, Nascimento CRAD, Wagner Zampieri AL, Stulp GF, Constantin RP, Ishii-Iwamoto EL. Differential Effects of Exogenous Resveratrol on the Growth and Energy Metabolism of Zea mays and the Weed Ipomoea grandifolia. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2020; 68:3006-3016. [PMID: 31986035 DOI: 10.1021/acs.jafc.9b06304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
An increase in crop competitiveness relative to weed interference has the potential to reduce crop yield losses. In this study, the effects of phytoalexin resveratrol were examined in Zea mays L. (corn) and in the weed species Ipomoea grandifolia (Dammer) O'Donell (morning glory). At a concentration range from 220 to 2200 μM resveratrol exerted a stimulus on Z. mays seedling growth that was more pronounced at low concentrations; in the weed species I. grandifolia, resveratrol exerted inhibitory action on seedling growth in all of the assayed concentration range. In I. grandifolia, resveratrol also inhibited the respiratory activity of the primary roots. In mitochondria isolated from Z. mays roots, resveratrol at concentrations above 440 μM inhibited the respiration coupled to ADP phosphorylation and the activities of NADH-oxidase, succinate-oxidase, and ATPsynthase. These effects were not reproduced in Z. mays grown in the presence of resveratrol as the respiratory activities of the roots were not affected. The finding that the resveratrol exerts beneficial effects on growth of Z. mays seedlings and inhibits the growth of I. grandifolia heightens the potential of resveratrol application for crop protection.
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Affiliation(s)
| | - Márcio Shigueaki Mito
- Laboratory of Biological Oxidations, Department of Biochemistry, State University of Maringa, 87020900 Maringa, Brazil
| | - Letycia Lopes Ricardo
- Department of Engineering and Exact Sciences, Federal University of Paraná, 85950000 Palotina, Brazil
| | | | - Isabela de Carvalho Contesoto
- Laboratory of Biological Oxidations, Department of Biochemistry, State University of Maringa, 87020900 Maringa, Brazil
| | | | - Ana Luiza Wagner Zampieri
- Laboratory of Biological Oxidations, Department of Biochemistry, State University of Maringa, 87020900 Maringa, Brazil
| | - Gabriel Felipe Stulp
- Laboratory of Biological Oxidations, Department of Biochemistry, State University of Maringa, 87020900 Maringa, Brazil
| | - Rodrigo Polimeni Constantin
- Laboratory of Biological Oxidations, Department of Biochemistry, State University of Maringa, 87020900 Maringa, Brazil
| | - Emy Luiza Ishii-Iwamoto
- Laboratory of Biological Oxidations, Department of Biochemistry, State University of Maringa, 87020900 Maringa, Brazil
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25
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Shakeri F, Bianconi V, Pirro M, Sahebkar A. Effects of Plant and Animal Natural Products on Mitophagy. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:6969402. [PMID: 32308807 PMCID: PMC7086453 DOI: 10.1155/2020/6969402] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/01/2019] [Revised: 02/11/2020] [Accepted: 02/22/2020] [Indexed: 01/07/2023]
Abstract
Mitophagy is a protected cellular process that is essential for autophagic removal of damaged mitochondria and for preservation of a healthy mitochondrial population. In the last years, a particular interest has been devoted in studying the effects of natural compounds on mitophagy. Different natural compounds may modulate mitochondrial oxidative phosphorylation, the production of mitochondrial reactive oxygen species, the expression of mitophagy- and autophagy-related genes, and the activities of transcription factors which regulate the expression of mitochondrial proteins, thereby controlling mitochondrial damage and mitophagy. Remarkably, since mitochondrial function has a crucial role in the pathogenesis of various diseases (e.g., cancer, atherosclerosis, Duchenne muscular dystrophy, diabetes complications, Alzheimer's disease, and hepatic steatosis), these effects might have important therapeutic implications. In this review, preclinical studies investigating the role of different natural compounds in the modulation of mitophagy will be discussed.
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Affiliation(s)
- Farzaneh Shakeri
- Natural Products and Medicinal Plants Research Center, North Khorasan University of Medical Sciences, Bojnurd, Iran
- Department of Physiology, School of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Vanessa Bianconi
- Unit of Internal Medicine, Angiology and Arteriosclerosis Diseases, Department of Medicine, University of Perugia, Perugia, Italy
| | - Matteo Pirro
- Unit of Internal Medicine, Angiology and Arteriosclerosis Diseases, Department of Medicine, University of Perugia, Perugia, Italy
| | - Amirhossein Sahebkar
- Halal Research Center of IRI, FDA, Tehran, Iran
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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26
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Links between cancer metabolism and cisplatin resistance. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2020; 354:107-164. [PMID: 32475471 DOI: 10.1016/bs.ircmb.2020.01.005] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Cisplatin is one of the most potent and widely used chemotherapeutic agent in the treatment of several solid tumors, despite the high toxicity and the frequent relapse of patients due to the onset of drug resistance. Resistance to chemotherapeutic agents, either intrinsic or acquired, is currently one of the major problems in oncology. Thus, understanding the biology of chemoresistance is fundamental in order to overcome this challenge and to improve the survival rate of patients. Studies over the last 30 decades have underlined how resistance is a multifactorial phenomenon not yet completely understood. Recently, tumor metabolism has gained a lot of interest in the context of chemoresistance; accumulating evidence suggests that the rearrangements of the principal metabolic pathways within cells, contributes to the sensitivity of tumor to the drug treatment. In this review, the principal metabolic alterations associated with cisplatin resistance are highlighted. Improving the knowledge of the influence of metabolism on cisplatin response is fundamental to identify new possible metabolic targets useful for combinatory treatments, in order to overcome cisplatin resistance.
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27
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Costanzini A, Sgarbi G, Maresca A, Del Dotto V, Solaini G, Baracca A. Mitochondrial Mass Assessment in a Selected Cell Line under Different Metabolic Conditions. Cells 2019; 8:cells8111454. [PMID: 31752092 PMCID: PMC6912592 DOI: 10.3390/cells8111454] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Revised: 09/27/2019] [Accepted: 11/14/2019] [Indexed: 01/14/2023] Open
Abstract
Changes of quantity and/or morphology of cell mitochondria are often associated with metabolic modulation, pathology, and apoptosis. Exogenous fluorescent probes used to investigate changes in mitochondrial content and dynamics are strongly dependent, for their internalization, on the mitochondrial membrane potential and composition, thus limiting the reliability of measurements. To overcome this limitation, genetically encoded recombinant fluorescent proteins, targeted to different cellular districts, were used as reporters. Here, we explored the potential use of mitochondrially targeted red fluorescent probe (mtRFP) to quantify, by flow cytometry, mitochondrial mass changes in cells exposed to different experimental conditions. We first demonstrated that the mtRFP fluorescence intensity is stable during cell culture and it is related with the citrate synthase activity, an established marker of the mitochondrial mass. Incidentally, the expression of mtRFP inside mitochondria did not alter the oxygen consumption rate under both state 3 and 4 respiration conditions. In addition, using this method, we showed for the first time that different inducers of mitochondrial mass change, such as hypoxia exposure or resveratrol treatment of cells, could be consistently detected. We suggest that transfection and selection of stable clones expressing mtRFP is a reliable method to monitor mitochondrial mass changes, particularly when pathophysiological or experimental conditions change ΔΨm, as it occurs during mitochondrial uncoupling or hypoxia/anoxia conditions.
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Affiliation(s)
- Anna Costanzini
- Laboratory of Biochemistry and Mitochondrial Pathophysiology, Department of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, Italy; (A.C.); (G.S.)
- Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy
| | - Gianluca Sgarbi
- Laboratory of Biochemistry and Mitochondrial Pathophysiology, Department of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, Italy; (A.C.); (G.S.)
| | - Alessandra Maresca
- UOC Clinica Neurologica, IRCCS Istituto delle Scienze Neurologiche di Bologna, 40126 Bologna, Italy;
| | - Valentina Del Dotto
- Unit of Neurology, Department of Biomedical and Neuromotor Sciences, University of Bologna, 40139 Bologna, Italy;
| | - Giancarlo Solaini
- Laboratory of Biochemistry and Mitochondrial Pathophysiology, Department of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, Italy; (A.C.); (G.S.)
- Correspondence: (G.S.); (A.B.); Tel.: +39-051-2091215 (G.S.); Tel.: +39-051-2091244 (A.B.)
| | - Alessandra Baracca
- Laboratory of Biochemistry and Mitochondrial Pathophysiology, Department of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, Italy; (A.C.); (G.S.)
- Correspondence: (G.S.); (A.B.); Tel.: +39-051-2091215 (G.S.); Tel.: +39-051-2091244 (A.B.)
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Abdrakhmanov A, Kulikov AV, Luchkina EA, Zhivotovsky B, Gogvadze V. Involvement of mitophagy in cisplatin-induced cell death regulation. Biol Chem 2019; 400:161-170. [PMID: 29924729 DOI: 10.1515/hsz-2018-0210] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2018] [Accepted: 06/14/2018] [Indexed: 01/05/2023]
Abstract
Mitophagy, the selective degradation of mitochondria via the autophagic pathway, is a vital mechanism of mitochondrial quality control in cells. The removal of malfunctioning or damaged mitochondria is essential for normal cellular physiology and tissue development. Stimulation of mitochondrial permeabilization and release of proapoptotic factors from the intermembrane space is an essential step in triggering the mitochondrial pathway of cell death. In this study, we analyzed the extent to which mitophagy interferes with cell death, attenuating the efficiency of cancer therapy. We show that stimulation of mitophagy suppressed cisplatin-induced apoptosis, while mitophagy inhibition stimulates apoptosis and autophagy. Suppression of mitophagy involved production of reactive oxygen species, and the fate of cell was dependent on the interplay between endoplasmic reticulum stress and autophagy.
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Affiliation(s)
| | | | | | - Boris Zhivotovsky
- MV Lomonosov Moscow State University, 119991 Moscow, Russia.,Institute of Environmental Medicine, Division of Toxicology, Karolinska Institutet, Box 210, SE-171 77 Stockholm, Sweden
| | - Vladimir Gogvadze
- MV Lomonosov Moscow State University, 119991 Moscow, Russia.,Institute of Environmental Medicine, Division of Toxicology, Karolinska Institutet, Box 210, SE-171 77 Stockholm, Sweden
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29
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Cocetta V, Ragazzi E, Montopoli M. Mitochondrial Involvement in Cisplatin Resistance. Int J Mol Sci 2019; 20:ijms20143384. [PMID: 31295873 PMCID: PMC6678541 DOI: 10.3390/ijms20143384] [Citation(s) in RCA: 91] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Revised: 07/03/2019] [Accepted: 07/08/2019] [Indexed: 12/25/2022] Open
Abstract
Cisplatin is one of the worldwide anticancer drugs and, despite its toxicity and frequent recurrence of resistance phenomena, it still remains the only therapeutic option for several tumors. Circumventing cisplatin resistance remains, therefore, a major goal for clinical therapy and represents a challenge for scientific research. Recent studies have brought to light the fundamental role of mitochondria in onset, progression, and metastasis of cancer, as well as its importance in the resistance to chemotherapy. The aim of this review is to give an overview of the current knowledge about the implication of mitochondria in cisplatin resistance and on the recent development in this research field. Recent studies have highlighted the role of mitochondrial DNA alterations in onset of resistance phenomena, being related both to redox balance alterations and to signal crosstalk with the nucleus, allowing a rewiring of cell metabolism. Moreover, an important role of the mitochondrial dynamics in the adaptation mechanism of cancer cells to challenging environment has been revealed. Giving bioenergetic plasticity to tumor cells, mitochondria allow cells to evade death pathways in stressful conditions, including chemotherapy. So far, even if the central role of mitochondria is recognized, little is known about the specific mechanisms implicated in the resistance. Nevertheless, mitochondria appear to be promising pharmacological targets for overcoming cisplatin resistance, but further studies are necessary.
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Affiliation(s)
- Veronica Cocetta
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Largo Egidio Meneghetti 2, 35131 Padua, Italy
| | - Eugenio Ragazzi
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Largo Egidio Meneghetti 2, 35131 Padua, Italy
| | - Monica Montopoli
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Largo Egidio Meneghetti 2, 35131 Padua, Italy.
- Venetian Institute of Molecular Medicine (VIMM), Via Orus 2, 35129 Padua, Italy.
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Wang N, Luo Z, Jin M, Sheng W, Wang HT, Long X, Wu Y, Hu P, Xu H, Zhang X. Exploration of age-related mitochondrial dysfunction and the anti-aging effects of resveratrol in zebrafish retina. Aging (Albany NY) 2019; 11:3117-3137. [PMID: 31105084 PMCID: PMC6555466 DOI: 10.18632/aging.101966] [Citation(s) in RCA: 76] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Accepted: 05/07/2019] [Indexed: 02/07/2023]
Abstract
It is currently believed that aging is closely linked with mitochondrial dysfunction, and that resveratrol exhibits anti-aging and neuroprotective effects by improving mitochondrial function, even though the mechanisms are not well defined. This study explored mitochondrial quality (mitochondrial DNA integrity and copy number), mitochondrial function (fusion/fission, mitophagy/autophagy), antioxidant system and activity of the Akt/mTOR and Ampk/Sirt1/Pgc1α pathways, and inflammation in aging zebrafish retinas to identify the probable mechanisms of resveratrol's anti-aging and neuroprotective effects. mtDNA integrity, mtDNA copy number, mitochondrial fusion regulators, mitophagy, and antioxidant-related genes were all decreased whereas Akt/mTOR activity and inflammation was increased upon aging in zebrafish retinas. Resveratrol was shown to not only increase mitochondrial quality and function, but also to suppress Akt/mTOR activity in zebrafish retinas. These results support the notion that mitochondrial dysfunction and increased Akt/mTOR activity are major players in age-related retinal neuropathy in zebrafish, and demonstrate a trend towards mitochondrial fragmentation in the aging retina. Importantly, resveratrol promoted mitochondrial function, up-regulating Ampk/Sirt1/Pgc1α, and down-regulated Akt/mTOR pathway activity in zebrafish retinas, suggesting that it may be able to prevent age-related oculopathy.
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Affiliation(s)
- Ning Wang
- Affiliated Eye Hospital of Nanchang University, Jiangxi Research Institute of Ophthalmology and Visual Science, Nanchang, China
- Queen Mary School of Nanchang University, Nanchang, China
- Equal contribution
| | - Zhiwen Luo
- Affiliated Eye Hospital of Nanchang University, Jiangxi Research Institute of Ophthalmology and Visual Science, Nanchang, China
- Queen Mary School of Nanchang University, Nanchang, China
- Equal contribution
| | - Ming Jin
- Affiliated Eye Hospital of Nanchang University, Jiangxi Research Institute of Ophthalmology and Visual Science, Nanchang, China
- Equal contribution
| | - Weiwei Sheng
- Affiliated Eye Hospital of Nanchang University, Jiangxi Research Institute of Ophthalmology and Visual Science, Nanchang, China
- Queen Mary School of Nanchang University, Nanchang, China
| | - Han-Tsing Wang
- Institute of Life Science of Nanchang University, Nanchang, China
- School of Life Sciences of Nanchang University, Nanchang, China
- Jiangxi Provincial Collaborative Innovation Center for Cardiovascular, Digestive and Neuropsychiatric Diseases, Nanchang, China
| | - Xinyi Long
- Affiliated Eye Hospital of Nanchang University, Jiangxi Research Institute of Ophthalmology and Visual Science, Nanchang, China
- Queen Mary School of Nanchang University, Nanchang, China
| | - Yue Wu
- Affiliated Eye Hospital of Nanchang University, Jiangxi Research Institute of Ophthalmology and Visual Science, Nanchang, China
- Queen Mary School of Nanchang University, Nanchang, China
| | - Piaopiao Hu
- Affiliated Eye Hospital of Nanchang University, Jiangxi Research Institute of Ophthalmology and Visual Science, Nanchang, China
- Jiangxi Provincial Collaborative Innovation Center for Cardiovascular, Digestive and Neuropsychiatric Diseases, Nanchang, China
| | - Hong Xu
- Institute of Life Science of Nanchang University, Nanchang, China
- School of Life Sciences of Nanchang University, Nanchang, China
- Jiangxi Provincial Collaborative Innovation Center for Cardiovascular, Digestive and Neuropsychiatric Diseases, Nanchang, China
| | - Xu Zhang
- Affiliated Eye Hospital of Nanchang University, Jiangxi Research Institute of Ophthalmology and Visual Science, Nanchang, China
- Jiangxi Provincial Collaborative Innovation Center for Cardiovascular, Digestive and Neuropsychiatric Diseases, Nanchang, China
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Bobermin LD, Roppa RHA, Quincozes-Santos A. Adenosine receptors as a new target for resveratrol-mediated glioprotection. Biochim Biophys Acta Mol Basis Dis 2019; 1865:634-647. [PMID: 30611861 DOI: 10.1016/j.bbadis.2019.01.004] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Revised: 12/16/2018] [Accepted: 01/02/2019] [Indexed: 12/11/2022]
Abstract
Resveratrol, a natural polyphenolic compound, has been studied as a neuroprotective molecule. Our group has demonstrated that such effect is closely associated with modulation of glial functionality, but the underlying mechanisms are not fully understood. Because astrocytes actively participate in the brain inflammatory response, and activation of adenosine receptors can attenuate inflammatory processes, the aim of this study was to investigate the role of adenosine receptors as a mechanism for resveratrol glioprotection, particularly regarding to neuroinflammation. Therefore, primary astrocyte cultures were co-incubated with resveratrol and selective antagonists of A1, A2A, and A3 adenosine receptors, as well as with caffeine (a non-selective adenosine receptor antagonist), and then challenged with bacterial inflammogen lipopolysaccharide (LPS). Caffeine and selective adenosine receptor antagonists abolished the anti-inflammatory effect of resveratrol. In accordance with these effects, resveratrol prevented LPS-induced decrease in mRNA levels of adenosine receptors. Resveratrol could also prevent the activation of pro-inflammatory signaling pathways, such as nuclear factor κB (NFκB) and p38 mitogen-activated protein kinase (p38 MAPK) in a mechanism dependent on adenosine receptors. Conversely, trophic factors and protective signaling pathways, including sirtuin 1 (SIRT1), nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and phosphoinositide 3-kinase (PI3K)/Akt were positively modulated by resveratrol in both LPS-stimulated and unstimulated astrocytes, but adenosine receptor antagonism did not abrogate all effects of resveratrol. To our knowledge, our data provide the first evidence that adenosine receptors are involved in the anti-inflammatory activity of resveratrol in astrocytes, thus exerting an important role for resveratrol-mediated glioprotection.
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Affiliation(s)
- Larissa Daniele Bobermin
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
| | - Ricardo Haack Amaral Roppa
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - André Quincozes-Santos
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil; Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
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Ding Q, Xie XL, Wang MM, Yin J, Tian JM, Jiang XY, Zhang D, Han J, Bai Y, Cui ZJ, Jiang HQ. The role of the apoptosis-related protein BCL-B in the regulation of mitophagy in hepatic stellate cells during the regression of liver fibrosis. Exp Mol Med 2019; 51:1-13. [PMID: 30635551 PMCID: PMC6329697 DOI: 10.1038/s12276-018-0199-6] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2018] [Revised: 09/28/2018] [Accepted: 10/08/2018] [Indexed: 12/13/2022] Open
Abstract
The clearance of activated hepatic stellate cells (HSCs) by apoptosis is critical for the reversibility of hepatic fibrosis. Mitochondrial homeostasis is regulated by mitophagy, which is an efficient way of clearing injured mitochondria that plays an important role in apoptosis. However, the role of mitophagy in apoptosis in HSCs and hepatic fibrosis is still unclear. Here, we show that mitophagy is enhanced in parallel with increased apoptosis in hepatic stellate cells during the reversal of hepatic fibrosis. The inhibition of mitophagy suppressed apoptosis in HSCs and aggravated hepatic fibrosis in mice. In contrast, the activation of mitophagy induced apoptosis in HSCs. Furthermore, we confirmed that BCL-B, which is a member of the BCL-2 family, is a regulator mediating mitophagy-related apoptosis. The knockdown of BCL-B resulted in increased apoptosis and mitophagy in HSCs, while the overexpression of BCL-B caused the opposite effects. BCL-B inhibited the phosphorylation of Parkin (a key regulator of mitophagy) and directly bound phospho-Parkin. Altogether, enhanced mitophagy promotes apoptosis in HSCs during the reversal of hepatic fibrosis. BCL-B suppresses mitophagy in HSCs by binding and suppressing phospho-Parkin, thereby inhibiting apoptosis. BCL-B-dependent mitophagy is a new pathway for the regulation of apoptosis in HSCs during the regression of hepatic fibrosis. Clearing away defective mitochondria helps destroy cells in the liver that contribute to tissue scarring; the signaling pathway involved offers a new therapeutic target. Hui-Qing Jiang and colleagues from the Hebei Institute of Gastroenterology in Shijiazhuang, China, induced liver fibrosis in mice and showed that as the animals recovered and the damage to their liver tissue was reversed, injured mitochondria were cleared from fibrosis-causing cells in tandem with the cells’ controlled destruction. Experimentally inhibiting the process of mitochondrial clearance also inhibited cell death and aggravated fibrotic scarring in the mice. The researchers identified a signaling pathway that regulates mitochondrial cleanup and, in turn, also controlled cell death. Targeting this pathway offer a potential new therapeutic strategy for reversing liver fibrosis in patients.
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Affiliation(s)
- Qian Ding
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Shijiazhuang, Hebei, China
| | - Xiao-Li Xie
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Shijiazhuang, Hebei, China
| | - Miao-Miao Wang
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Shijiazhuang, Hebei, China
| | - Jie Yin
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Shijiazhuang, Hebei, China
| | - Jin-Mei Tian
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Shijiazhuang, Hebei, China
| | - Xiao-Yu Jiang
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Shijiazhuang, Hebei, China
| | - Di Zhang
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Shijiazhuang, Hebei, China
| | - Jing Han
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Shijiazhuang, Hebei, China
| | - Yun Bai
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Shijiazhuang, Hebei, China
| | - Zi-Jin Cui
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Shijiazhuang, Hebei, China
| | - Hui-Qing Jiang
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Shijiazhuang, Hebei, China.
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Marcondes NA, Terra SR, Lasta CS, Hlavac NRC, Dalmolin ML, Lacerda LDA, Faulhaber GAM, González FHD. Comparison of JC‐1 and MitoTracker probes for mitochondrial viability assessment in stored canine platelet concentrates: A flow cytometry study. Cytometry A 2018; 95:214-218. [DOI: 10.1002/cyto.a.23567] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Revised: 06/18/2018] [Accepted: 06/27/2018] [Indexed: 11/09/2022]
Affiliation(s)
| | - Silvia Resende Terra
- Clinical Pathology Laboratory, Veterinary Medicine FacultyUniversidade do Sul de Santa Catarina Tubarão Brazil
| | - Camila Serina Lasta
- Department of Veterinary Clinical PathologyUniversidade Federal do Rio Grande do Sul Porto Alegre Brazil
- Department of HealthCentro Universitário Ritter dos Reis – UniRitter Porto Alegre Brazil
| | - Nicole Regina Capacchi Hlavac
- Clinical Pathology Laboratory, Veterinary Medicine FacultyUniversidade do Sul de Santa Catarina Tubarão Brazil
- Department of Veterinary Clinical PathologyUniversidade Federal do Rio Grande do Sul Porto Alegre Brazil
| | | | | | - Gustavo Adolpho Moreira Faulhaber
- Laboratório Zanol Porto Alegre Brazil
- Department of Internal MedicineUniversidade Federal do Rio Grande do Sul Porto Alegre Brazil
- Post‐Graduation Program in Medicine: Medical SciencesUniversidade Federal do Rio Grande do Sul Porto Alegre Brazil
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Octyl gallate reduces ATP levels and Ki67 expression leading HepG2 cells to cell cycle arrest and mitochondria-mediated apoptosis. Toxicol In Vitro 2017; 48:11-25. [PMID: 29288082 DOI: 10.1016/j.tiv.2017.12.017] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2017] [Revised: 12/09/2017] [Accepted: 12/22/2017] [Indexed: 12/17/2022]
Abstract
Octyl gallate (OG) is an antioxidant that has shown anti-tumor, anti-diabetic and anti-amyloidogenic activities. Mitochondria play an important role in hepatocellular carcinoma, mainly by maintaining accelerated cellular proliferation through the production of ATP. Thus, the mitochondria may be a target for antitumor therapies. Here, we investigated the effects of OG in the hepatocarcinoma cell line (HepG2) and the mechanisms involved. We report, for the first time, that treatment with OG for 24h inhibited HepG2 cell growth by decreasing mitochondrial activity and mass, which led to the reduction of ATP levels. This reduction in the energy supply triggered a decrease in Ki67 protein expression, leading cells to cycle arrest. In addition, treatment with two doses of OG for 48h induced loss of mitochondrial functionality, mitochondrial swelling and apoptosis. Finally, we report that HepG2 cells had no resistance to treatment after multiple doses. Collectively, our findings indicate that metabolic dysregulation and Ki67 protein reduction are key events in the initial anti-proliferative action of OG, whereas mitochondrial swelling and apoptosis induction are involved in the action mechanism of OG after prolonged exposure. This suggests that OG targets mitochondria, thus representing a candidate for further research on therapies for hepatocarcinoma.
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Bae M, Park YK, Lee JY. Food components with antifibrotic activity and implications in prevention of liver disease. J Nutr Biochem 2017; 55:1-11. [PMID: 29268106 DOI: 10.1016/j.jnutbio.2017.11.003] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Revised: 09/18/2017] [Accepted: 11/11/2017] [Indexed: 12/26/2022]
Abstract
Increasing prevalence of nonalcoholic fatty liver disease (NAFLD) in parallel with the obesity epidemic has been a major public health concern. NAFLD is the most common chronic liver disease in the United States, ranging from fatty liver to steatohepatitis, fibrosis and cirrhosis in the liver. In response to chronic liver injury, fibrogenesis in the liver occurs as a protective response; however, prolonged and dysregulated fibrogenesis can lead to liver fibrosis, which can further progress to cirrhosis and eventually hepatocellular carcinoma. Interplay of hepatocytes, macrophages and hepatic stellate cells (HSCs) in the hepatic inflammatory and oxidative milieu is critical for the development of NAFLD. In particular, HSCs play a major role in the production of extracellular matrix proteins. Studies have demonstrated that bioactive food components and natural products, including astaxanthin, curcumin, blueberry, silymarin, coffee, vitamin C, vitamin E, vitamin D, resveratrol, quercetin and epigallocatechin-3-gallate, have antifibrotic effects in the liver. This review summarizes current knowledge of the mechanistic insight into the antifibrotic actions of the aforementioned bioactive food components.
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Affiliation(s)
- Minkyung Bae
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT 06269, USA
| | - Young-Ki Park
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT 06269, USA
| | - Ji-Young Lee
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT 06269, USA; Department of Food and Nutrition, Kyung Hee University, Seoul, South Korea.
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Hlavac N, Lasta CS, Dalmolin ML, Lacerda LA, de Korte D, Marcondes NA, Terra SR, Fernandes FB, González FHD. In vitro properties of concentrated canine platelets stored in two additive solutions: a comparative study. BMC Vet Res 2017; 13:334. [PMID: 29141627 PMCID: PMC5688706 DOI: 10.1186/s12917-017-1236-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2017] [Accepted: 10/30/2017] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND Platelet transfusion therapy poses many challenges in veterinary clinical practice. Lack of readily available blood donors, short shelf-life, and inability to administer a sufficient number of platelets to meet a dog's transfusion need are the major difficulties encountered. Platelet additive solutions are already in use at American and European human blood banks, showing to be a realistic alternative. This study compares the in vitro platelet function in plasma, Composol, or SSP+ during storage for 13 days. Platelet rich plasma-platelet concentrate with 35% plasma and 65% platelet additive solutions (Composol or SSP+) and a control group (100% plasma) were prepared. Swirling, platelet count, blood gases, metabolic variables, platelet activation markers, and apoptosis markers were analyzed on days 1, 5, 9 and 13. RESULTS Swirling was well preserved and pH was acceptable (> 6.2) during storage for all platelet additive solutions units until day 9. SSP + units showed more stable pH and metabolic variables until day 13. Platelets in plasma showed higher glucose consumption than in Composol or in SSP+. The platelet additive solutions units showed better platelet metabolism maintenance, reduced glucose consumption and lactate production. The apoptotic markers were still low for 9 days in platelet concentrates with platelet additive solutions, suggesting the possibility to extend the shelf life with the use of SSP+ or Composol. CONCLUSIONS Our findings suggest that the uses of Composol and SSP+ in canine platelet concentrates are potential alternatives in veterinary blood banks.
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Affiliation(s)
- N. Hlavac
- Clinical Pathology Laboratory, Veterinary Medicine Faculty, Universidade do Sul de Santa Catarina, Tubarão, Brazil
| | - C. S. Lasta
- Veterinary Medicine Faculty, Centro Universitário Ritter dos Reis – Laureatte International Universities, Porto Alegre, Brazil
| | - M. L. Dalmolin
- Blut’s Diagnosis Center and Veterinary Services, Porto Alegre, Brazil
| | - L. A. Lacerda
- Blut’s Diagnosis Center and Veterinary Services, Porto Alegre, Brazil
| | - D. de Korte
- Sanquin Blood Bank and Sanquin Research, Sanquin, Amsterdam, the Netherlands
| | - N. A. Marcondes
- Post-Graduation Program in Medicine: Medical Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - S. R. Terra
- Clinical Pathology Laboratory, Veterinary Medicine Faculty, Universidade do Sul de Santa Catarina, Tubarão, Brazil
| | | | - F. H. D. González
- Department of Veterinary Clinical Pathology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
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Madreiter-Sokolowski CT, Sokolowski AA, Graier WF. Dosis Facit Sanitatem-Concentration-Dependent Effects of Resveratrol on Mitochondria. Nutrients 2017; 9:nu9101117. [PMID: 29027961 PMCID: PMC5691733 DOI: 10.3390/nu9101117] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2017] [Revised: 09/20/2017] [Accepted: 10/07/2017] [Indexed: 01/04/2023] Open
Abstract
The naturally occurring polyphenol, resveratrol (RSV), is known for a broad range of actions. These include a positive impact on lifespan and health, but also pro-apoptotic anti-cancer properties. Interestingly, cell culture experiments have revealed a strong impact of RSV on mitochondrial function. The compound was demonstrated to affect mitochondrial respiration, structure and mass of mitochondria as well as mitochondrial membrane potential and, ultimately, mitochondria-associated cell death pathways. Notably, the mitochondrial effects of RSV show a very strict and remarkable concentration dependency: At low concentrations, RSV (<50 μM) fosters cellular antioxidant defense mechanisms, activates AMP-activated protein kinase (AMPK)- and sirtuin 1 (SIRT1)-linked pathways and enhances mitochondrial network formation. These mechanisms crucially contribute to the cytoprotective effects of RSV against toxins and disease-related damage, in vitro and in vivo. However, at higher concentrations, RSV (>50 μM) triggers changes in (sub-)cellular Ca2+ homeostasis, disruption of mitochondrial membrane potential and activation of caspases selectively yielding apoptotic cancer cell death, in vitro and in vivo. In this review, we discuss the promising therapeutic potential of RSV, which is most probably related to the compound’s concentration-dependent manipulation of mitochondrial function and structure.
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Affiliation(s)
- Corina T Madreiter-Sokolowski
- Institute of Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstraße 6/6, 8010 Graz, Austria.
| | - Armin A Sokolowski
- Department of Dentistry and Maxillofacial Surgery, Medical University of Graz, Billrothgasse 4, 8010 Graz, Austria.
| | - Wolfgang F Graier
- Institute of Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstraße 6/6, 8010 Graz, Austria.
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The Temporal Pattern, Flux, and Function of Autophagy in Spinal Cord Injury. Int J Mol Sci 2017; 18:ijms18020466. [PMID: 28230791 PMCID: PMC5343998 DOI: 10.3390/ijms18020466] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2016] [Revised: 02/16/2017] [Accepted: 02/17/2017] [Indexed: 12/15/2022] Open
Abstract
Previous studies have indicated that autophagy plays a critical role in spinal cord injury (SCI), including traumatic spinal cord injury (TSCI) and ischemia-reperfusion spinal cord injury (IRSCI). However, while the understanding of mechanisms underlying autophagy in SCI has progressed, there remain several controversial points: (1) temporal pattern results of autophagic activation after SCI are not consistent across studies; (2) effect of accumulation of autophagosomes due to the blockade or enhancement of autophagic flux is uncertain; (3) overall effect of enhanced autophagy remains undefined, with both beneficial and detrimental outcomes reported in SCI literature. In this review, the temporal pattern of autophagic activation, autophagic flux, autophagic cell death, relationship between autophagy and apoptosis, and pharmacological intervention of autophagy in TSCI (contusion injury, compression injury and hemisection injury) and IRSCI are discussed. Types of SCI and severity appear to contribute to differences in outcomes regarding temporal pattern, flux, and function of autophagy. With future development of specific strategies on autophagy intervention, autophagy may play an important role in improving functional recovery in patients with SCI.
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Autophagy protects against cholesterol-induced apoptosis in pancreatic β-cells. Biochem Biophys Res Commun 2017; 482:678-685. [DOI: 10.1016/j.bbrc.2016.11.093] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2016] [Accepted: 11/15/2016] [Indexed: 01/04/2023]
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Denardin CC, Martins LAM, Parisi MM, Vieira MQ, Terra SR, Barbé-Tuana FM, Borojevic R, Vizzotto M, Emanuelli T, Guma FCR. Autophagy induced by purple pitanga (Eugenia uniflora L.) extract triggered a cooperative effect on inducing the hepatic stellate cell death. Cell Biol Toxicol 2016; 33:197-206. [PMID: 27744523 DOI: 10.1007/s10565-016-9366-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2016] [Accepted: 10/07/2016] [Indexed: 12/18/2022]
Abstract
Activated hepatic stellate cells (HSC) are the major source of collagen I in liver fibrosis. Eugenia uniflora L. is a tree species that is widely distributed in South America. E. uniflora L. fruit-popularly known as pitanga-has been shown to exert beneficial properties. Autophagy contributes to the maintenance of cellular homeostasis and survival under stress situation, but it has also been suggested to be an alternative cell death pathway. Mitochondria play a pivotal role on signaling cell death. Mitophagy of damaged mitochondria is an important cell defense mechanism against organelle-mediated cell death signaling. We previously found that purple pitanga extract induced mitochondrial dysfunction, cell cycle arrest, and death by apoptosis and necrosis in GRX cells, a well-established activated HSC line. We evaluated the effects of 72-h treatment with crescent concentrations of purple pitanga extract (5 to 100 μg/mL) on triggering autophagy in GRX cells, as this is an important mechanism to cells under cytotoxic conditions. We found that all treated cells presented an increase in the mRNA expression of autophagy-related protein 7 (ATG7). Concomitantly, flow cytometry and ultrastructural analysis of treated cells revealed an increase of autophagosomes/autolysosomes that consequentially led to an increased mitophagy. As purple pitanga extract was previously found to be broadly cytotoxic to GRX cells, we postulated that autophagy contributes to this scenario, where cell death seems to be an inevitable fate. Altogether, the effectiveness on inducing activated HSC death can make purple pitanga extract a good candidate on treating liver fibrosis.
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Affiliation(s)
- Cristiane C Denardin
- Programa de Pós-Graduação em Ciências Biológicas-Bioquímica, ICBS, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil
- Curso de Farmácia, Universidade Federal do Pampa (UNIPAMPA), Campus Uruguaiana, Uruguaiana, RS, Brasil
| | - Leo A M Martins
- Programa de Pós-Graduação em Ciências Biológicas-Bioquímica, ICBS, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil
| | - Mariana M Parisi
- Programa de Pós-Graduação em Ciências Biológicas-Bioquímica, ICBS, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil
| | - Moema Queiroz Vieira
- Programa de Pós-Graduação em Ciências Biológicas-Bioquímica, ICBS, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil
| | - Silvia R Terra
- Programa de Pós-Graduação em Ciências Biológicas-Bioquímica, ICBS, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil
| | - Florencia M Barbé-Tuana
- Programa de Pós-Graduação em Ciências Biológicas-Bioquímica, ICBS, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil
| | - Radovan Borojevic
- Departamento de Histologia e Embriologia, ICB, UFRJ, Rio de Janeiro, RJ, Brasil
| | - Márcia Vizzotto
- Empresa Brasileira de Pesquisa Agropecuária de Clima Temperado, Pelotas, RS, Brasil
| | - Tatiana Emanuelli
- Núcleo Integrado de Desenvolvimento em Análises Laboratoriais (NIDAL), Departamento de Tecnologia e Ciência de Alimentos, Universidade Federal de Santa Maria, Santa Maria, RS, Brasil
| | - Fátima Costa Rodrigues Guma
- Programa de Pós-Graduação em Ciências Biológicas-Bioquímica, ICBS, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil.
- Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos 2600-Anexo, Lab 21, CEP: 90035-003, Porto Alegre, RS, Brasil.
- Centro de Microscopia e Microanálise, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil.
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Kang JW, Hong JM, Lee SM. Melatonin enhances mitophagy and mitochondrial biogenesis in rats with carbon tetrachloride-induced liver fibrosis. J Pineal Res 2016; 60:383-93. [PMID: 26882442 DOI: 10.1111/jpi.12319] [Citation(s) in RCA: 177] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2016] [Accepted: 02/09/2016] [Indexed: 12/14/2022]
Abstract
Liver fibrosis leads to liver cirrhosis and failure, and no effective treatment is currently available. Growing evidence supports a link between mitochondrial dysfunction and liver fibrogenesis and mitochondrial quality control-based therapy has emerged as a new therapeutic target. We investigated the protective mechanisms of melatonin against mitochondrial dysfunction-involved liver fibrosis, focusing on mitophagy and mitochondrial biogenesis. Rats were treated with carbon tetrachloride (CCl4) dissolved in olive oil (0.5 mL/kg, twice a week, i.p.) for 8 wk. Melatonin was administered orally at 2.5, 5, and 10 mg/kg once a day. Chronic CCl4 exposure induced collagen deposition, hepatocellular damage, and oxidative stress, and melatonin attenuated these increases. Increases in mRNA and protein expression levels of transforming growth factor β1 and α-smooth muscle actin in response to CCl4 were attenuated by melatonin. Melatonin attenuated hallmarks of mitochondrial dysfunction, such as mitochondrial swelling and glutamate dehydrogenase release. Chronic CCl4 exposure impaired mitophagy and mitochondrial biogenesis, and melatonin attenuated this impairment, as indicated by increases in mitochondrial DNA and in protein levels of PTEN-induced putative kinase 1 (PINK1); Parkin; peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α); nuclear respiratory factor 1 (NRF1); and transcription factor A, mitochondrial (TFAM). CCl4-mediated decreases in mitochondrial fission- and fusion-related proteins, such as dynamin-related protein 1 (DRP1) and mitofusin 2, were also attenuated by melatonin. Moreover, melatonin induced AMP-activated protein kinase (AMPK) phosphorylation. These results suggest that melatonin protects against liver fibrosis via upregulation of mitophagy and mitochondrial biogenesis, and may be useful as an anti-fibrotic treatment.
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Affiliation(s)
- Jung-Woo Kang
- School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do, Korea
| | - Jeong-Min Hong
- School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do, Korea
| | - Sun-Mee Lee
- School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do, Korea
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de Oliveira MR, Nabavi SF, Manayi A, Daglia M, Hajheydari Z, Nabavi SM. Resveratrol and the mitochondria: From triggering the intrinsic apoptotic pathway to inducing mitochondrial biogenesis, a mechanistic view. Biochim Biophys Acta Gen Subj 2016; 1860:727-45. [PMID: 26802309 DOI: 10.1016/j.bbagen.2016.01.017] [Citation(s) in RCA: 139] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2015] [Revised: 12/19/2015] [Accepted: 01/06/2016] [Indexed: 12/12/2022]
Abstract
BACKGROUND Mitochondria, the power plants of the cell, are known as a cross-road of different cellular signaling pathways. These cytoplasmic double-membraned organelles play a pivotal role in energy metabolism and regulate calcium flux in the cells. It is well known that mitochondrial dysfunction is associated with different diseases such as neurodegeneration and cancer. A growing body of literature has shown that polyphenolic compounds exert direct effects on mitochondrial ultra-structure and function. Resveratrol is known as one of the most common bioactive constituents of red wine, which improves mitochondrial functions under in vitro and in vivo conditions. SCOPE OF REVIEW This paper aims to review the molecular pathways underlying the beneficial effects of resveratrol on mitochondrial structure and functions. In addition, we discuss the chemistry and main sources of resveratrol. MAJOR CONCLUSIONS Resveratrol represents the promising effects on mitochondria in different experimental models. However, there are several reports on the detrimental effects elicited by resveratrol on mitochondria. GENERAL SIGNIFICANCE An understanding of the chemistry and source of resveratrol, its bioavailability and the promising effects on mitochondria brings a new hope to therapy of mitochondrial dysfunction-related diseases.
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Affiliation(s)
- Marcos Roberto de Oliveira
- Department of Chemistry, ICET, Federal University of Mato Grosso (UFMT), Av. Fernando Corrêa da Costa, 2367, CEP 78060-900 Cuiabá, MT, Brazil.
| | - Seyed Fazel Nabavi
- Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Azadeh Manayi
- Medicinal Plants Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Maria Daglia
- Department of Drug Sciences, Medicinal Chemistry and Pharmaceutical Technology Section, University of Pavia, Italy
| | - Zohreh Hajheydari
- Department of Dermatology, Boo Ali Sina (Avicenna) Hospital, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Seyed Mohammad Nabavi
- Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran.
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Weiskirchen R. Hepatoprotective and Anti-fibrotic Agents: It's Time to Take the Next Step. Front Pharmacol 2016; 6:303. [PMID: 26779021 PMCID: PMC4703795 DOI: 10.3389/fphar.2015.00303] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2015] [Accepted: 12/11/2015] [Indexed: 12/21/2022] Open
Abstract
Hepatic fibrosis and cirrhosis cause strong human suffering and necessitate a monetary burden worldwide. Therefore, there is an urgent need for the development of therapies. Pre-clinical animal models are indispensable in the drug discovery and development of new anti-fibrotic compounds and are immensely valuable for understanding and proofing the mode of their proposed action. In fibrosis research, inbreed mice and rats are by far the most used species for testing drug efficacy. During the last decades, several hundred or even a thousand different drugs that reproducibly evolve beneficial effects on liver health in respective disease models were identified. However, there are only a few compounds (e.g., GR-MD-02, GM-CT-01) that were translated from bench to bedside. In contrast, the large number of drugs successfully tested in animal studies is repeatedly tested over and over engender findings with similar or identical outcome. This circumstance undermines the 3R (Replacement, Refinement, Reduction) principle of Russell and Burch that was introduced to minimize the suffering of laboratory animals. This ethical framework, however, represents the basis of the new animal welfare regulations in the member states of the European Union. Consequently, the legal authorities in the different countries are halted to foreclose testing of drugs in animals that were successfully tested before. This review provides a synopsis on anti-fibrotic compounds that were tested in classical rodent models. Their mode of action, potential sources and the observed beneficial effects on liver health are discussed. This review attempts to provide a reference compilation for all those involved in the testing of drugs or in the design of new clinical trials targeting hepatic fibrosis.
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Affiliation(s)
- Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy, and Clinical Chemistry, RWTH University Hospital Aachen Aachen, Germany
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Natale G, Lenzi P, Lazzeri G, Falleni A, Biagioni F, Ryskalin L, Fornai F. Compartment-dependent mitochondrial alterations in experimental ALS, the effects of mitophagy and mitochondriogenesis. Front Cell Neurosci 2015; 9:434. [PMID: 26594150 PMCID: PMC4635226 DOI: 10.3389/fncel.2015.00434] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2015] [Accepted: 10/15/2015] [Indexed: 12/12/2022] Open
Abstract
Amyotrophic lateral sclerosis (ALS) is characterized by massive loss of motor neurons. Data from ALS patients and experimental models indicate that mitochondria are severely damaged within dying or spared motor neurons. Nonetheless, recent data indicate that mitochondrial preservation, although preventing motor neuron loss, fails to prolong lifespan. On the other hand, the damage to motor axons plays a pivotal role in determining both lethality and disease course. Thus, in the present article each motor neuron compartment (cell body, central, and peripheral axons) of G93A SOD-1 mice was studied concerning mitochondrial alterations as well as other intracellular structures. We could confirm the occurrence of ALS-related mitochondrial damage encompassing total swelling, matrix dilution and cristae derangement along with non-pathological variations of mitochondrial size and number. However, these alterations occur to a different extent depending on motor neuron compartment. Lithium, a well-known autophagy inducer, prevents most pathological changes. However, the efficacy of lithium varies depending on which motor neuron compartment is considered. Remarkably, some effects of lithium are also evident in wild type mice. Lithium is effective also in vitro, both in cell lines and primary cell cultures from the ventral spinal cord. In these latter cells autophagy inhibition within motor neurons in vitro reproduced ALS pathology which was reversed by lithium. Muscle and glial cells were analyzed as well. Cell pathology was mostly severe within peripheral axons and muscles of ALS mice. Remarkably, when analyzing motor axons of ALS mice a subtotal clogging of axoplasm was described for the first time, which was modified under the effects of lithium. The effects induced by lithium depend on several mechanisms such as direct mitochondrial protection, induction of mitophagy and mitochondriogenesis. In this study, mitochondriogenesis induced by lithium was confirmed in situ by a novel approach using [2-3H]-adenosine.
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Affiliation(s)
- Gianfranco Natale
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa Italy
| | - Paola Lenzi
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa Italy
| | - Gloria Lazzeri
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa Italy
| | - Alessandra Falleni
- Department of Clinical and Experimental Medicine, University of Pisa Italy
| | | | - Larisa Ryskalin
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa Italy
| | - Francesco Fornai
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa Italy ; I.R.C.C.S., Neuromed Pozzilli, Italy
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Ruffoli R, Bartalucci A, Frati A, Fornai F. Ultrastructural studies of ALS mitochondria connect altered function and permeability with defects of mitophagy and mitochondriogenesis. Front Cell Neurosci 2015; 9:341. [PMID: 26388731 PMCID: PMC4555074 DOI: 10.3389/fncel.2015.00341] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2015] [Accepted: 08/17/2015] [Indexed: 12/11/2022] Open
Abstract
The key role of mitochondria in patients affected by amyotrophic lateral sclerosis (ALS) is well documented by electron microscopy studies of motor neurons within spinal cord and brainstem. Nonetheless, recent studies challenged the role of mitochondria placed within the cell body of motor neuron. In fact, it was demonstrated that, despite preservation of mitochondria placed within this compartment, there is no increase in the lifespan of transgenic mouse models of ALS. Thus, the present mini-review comments on morphological findings of mitochondrial alterations in ALS patients in connection with novel findings about mitochondrial dynamics within various compartments of motor neurons. The latter issue was recently investigated in relationship with altered calcium homeostasis and autophagy, which affect mitochondria in ALS. In fact, it was recently indicated that a pathological mitophagy, mitochondriogenesis and calcium homeostasis produce different ultrastructural effects within specific regions of motor neurons. This might explain why specific compartments of motor neurons possess different thresholds to mitochondrial damage. In particular, it appears that motor axons represent the most sensitive compartment which undergoes the earliest and most severe alterations in the course of ALS. It is now evident that altered calcium buffering is compartment-dependent, as well as mitophagy and mitochondriogenesis. On the other hand, mitochondrial homeostasis strongly relies on calcium handling, the removal of altered mitochondria through the autophagy flux (mitophagy) and the biogenesis of novel mitochondria (mitochondriogenesis). Thus, recent findings related to altered calcium storage and impaired autophagy flux in ALS may help to understand the occurrence of mitochondrial alterations as a hallmark in ALS patients. At the same time, the compartmentalization of such dysfunctions may be explained considering the compartments of calcium dynamics and autophagy flux within motor neurons.
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Affiliation(s)
- Riccardo Ruffoli
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa Pisa, Italy
| | - Alessia Bartalucci
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa Pisa, Italy
| | | | - Francesco Fornai
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa Pisa, Italy ; I.R.C.C.S., Neuromed Pozzilli, Italy
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Abnormal Glucose Metabolism in Alzheimer's Disease: Relation to Autophagy/Mitophagy and Therapeutic Approaches. Neurochem Res 2015; 40:2557-69. [PMID: 26077923 DOI: 10.1007/s11064-015-1631-0] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2015] [Revised: 05/09/2015] [Accepted: 05/29/2015] [Indexed: 12/19/2022]
Abstract
Diminished glucose metabolism accompanies many neurodegenerative diseases including Alzheimer's disease. An understanding of the relation of these metabolic changes to the disease will enable development of novel therapeutic strategies. Following a metabolic challenge, cells generally conserve energy to preserve viability. This requires activation of many cellular repair/regenerative processes such as mitophagy/autophagy and fusion/fission. These responses may diminish cell function in the long term. Prolonged fission induces mitophagy/autophagy which promotes repair but if prolonged progresses to mitochondrial degradation. Abnormal glucose metabolism alters protein signaling including the release of proteins from the mitochondria or migration of proteins from the cytosol to the mitochondria or nucleus. This overview provides an insight into the different mechanisms of autophagy/mitophagy and mitochondrial dynamics in response to the diminished metabolism that occurs with diseases, especially neurodegenerative diseases such as Alzheimer's disease. The review discusses multiple aspects of mitochondrial responses including different signaling proteins and pathways of mitophagy and mitochondrial biogenesis. Improving cellular bioenergetics and mitochondrial dynamics will alter protein signaling and improve cellular/mitochondrial repair and regeneration. An understanding of these changes will suggest new therapeutic strategies.
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