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Ye C, Ning Z, Hu T, Zhao X, Mu W. Melatonin modulates autophagy, mitochondria and antioxidant in the liver and brain of Perccottus glenni during recovery from freezing. Comp Biochem Physiol A Mol Integr Physiol 2025; 303:111824. [PMID: 39947457 DOI: 10.1016/j.cbpa.2025.111824] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Revised: 02/02/2025] [Accepted: 02/10/2025] [Indexed: 02/17/2025]
Abstract
The Amur sleeper (Percottus glenii), a freeze tolerant fish species, can survive being frozen in ice, survival after recovery from freezing. This study investigated the role of melatonin in the recovery of Perccottus glenni following freezing. The fish were categorized into the following groups: non-treated control (Con), pinealectomy (Px), melatonin injection (Mlt), sham control (Sham), and saline injection control (Sal). The results revealed that the melatonin levels were affected by pinealectomy and melatonin injection. The liver and brain of the Px and Mlt groups exhibited autophagy after 4 h, along with the differential expression of endoplasmic reticulum stress-related genes. Furthermore, the activities of the mitochondrial complex initially increased at 4 h and then decreased by 12 h in the Px and Mlt groups, while antioxidant enzyme activities varied across groups and time points. These findings indicated that melatonin plays a key role in the recovery of P. glenni in a time-dependent manner, affecting autophagy, mitochondrial function, and antioxidant capacity. This study is the first to demonstrate melatonin's time-dependent role in facilitating the recovery of P. glenni after freezing, highlighting its critical involvement in modulating autophagy, mitochondrial function, and antioxidant processes. These findings shed light on the physiological mechanisms underlying freeze tolerance and recovery in fish, offering valuable insights for understanding and potentially enhancing the recovery processes in other species.
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Affiliation(s)
- Cunrun Ye
- Department of Fisheries Physiology and Resources Utilization, State Key Laboratory of Life Sciences and Technologies, Harbin Normal University, Harbin 150025, PR China
| | - Zhaoyang Ning
- Department of Fisheries Physiology and Resources Utilization, State Key Laboratory of Life Sciences and Technologies, Harbin Normal University, Harbin 150025, PR China
| | - Tingting Hu
- Department of Fisheries Physiology and Resources Utilization, State Key Laboratory of Life Sciences and Technologies, Harbin Normal University, Harbin 150025, PR China
| | - Xiaoyu Zhao
- Department of Fisheries Physiology and Resources Utilization, State Key Laboratory of Life Sciences and Technologies, Harbin Normal University, Harbin 150025, PR China
| | - Weijie Mu
- Department of Fisheries Physiology and Resources Utilization, State Key Laboratory of Life Sciences and Technologies, Harbin Normal University, Harbin 150025, PR China.
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Lin J, Li F, Jiao J, Qian Y, Xu M, Wang F, Sun X, Zhou T, Wu H, Kong X. Quercetin, a natural flavonoid, protects against hepatic ischemia-reperfusion injury via inhibiting Caspase-8/ASC dependent macrophage pyroptosis. J Adv Res 2025; 70:555-569. [PMID: 38735388 PMCID: PMC11976413 DOI: 10.1016/j.jare.2024.05.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 04/20/2024] [Accepted: 05/08/2024] [Indexed: 05/14/2024] Open
Abstract
INTRODUCTION Hepatic ischemia-reperfusion injury (IRI) is an inevitable adverse event following liver surgery, leading to liver damage and potential organ failure. Despite advancements, effective interventions for hepatic IRI remain elusive, posing a significant clinical challenge. The innate immune response significantly contributes to the pathogenesis of hepatic IRI by promoting an inflammatory cytotoxic cycle. We have reported that blocking GSDMD-induced pyroptosis in innate immunity cells protected hepatic IRI from inflammatory injury. However, the search for effective pyroptosis inhibitors continues. OBJECTIVES This study aims to evaluate whether quercetin, a natural flavonoid, can inhibit GSDMD-induced pyroptosis and mitigate hepatic IRI. METHODS We established the hepatic IRI murine model and cellular pyroptosis model to evaluate the efficacy of quercetin. RESULTS Quercetin effectively alleviated hepatic IRI-induced tissue necrosis and inflammation. We found that during hepatic IRI, the cleavage of GSDMD occurred in hepatic macrophages, but not in other non-parenchymal cells. Quercetin inhibited the cleavage of GSDMD in macrophages. Moreover, we found that quercetin blocked the ASC assembly to inhibit the formation of NLRP3 inflammasomes and AIM2 inflammasomes, suppressing macrophage pyroptosis. Co-immunoprecipitation experiments confirmed that quercetin inhibited the interaction between ASC and Caspase-8, which is the mechanism of ASC complex and inflammasome formation. Overexpression of Caspase-8 abolished the anti-pyroptosis effect of quercetin in NLRP3 and AIM2 inflammasome signaling. Furthermore, we found that the hepatoprotective activity of quercetin was reduced in myelocytic GSDMD-deficient mice. CONCLUSION Our findings suggest that quercetin has beneficial effects on hepatic IRI. Quercetin could attenuate hepatic IRI and target inhibition of macrophage pyroptosis via blocking Caspase-8/ASC interaction. We recommend that quercetin might serve as a targeted approach for the prevention and personalized treatment of hepatic IRI in perioperative patients.
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Affiliation(s)
- Jiacheng Lin
- Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Fuyang Li
- Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Junzhe Jiao
- Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yihan Qian
- Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Min Xu
- Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Fang Wang
- Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xuehua Sun
- Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Tao Zhou
- Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China; Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
| | - Hailong Wu
- Shanghai Key Laboratory of Molecular Imaging, Collaborative Innovation Center for Biomedicines, Shanghai University of Medicine and Health Sciences, Shanghai, China.
| | - Xiaoni Kong
- Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.
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Li D, Wu Q, Li Z, Chen B, Sun X, Wu Q, Ding Z, Liu L, Fang J, Zeng R, Gu Y, Ding B. Exploring the Therapeutic Mechanism of Xinbao Pill in Brain Injury After Cardiopulmonary Resuscitation Based on Network Pharmacology, Metabolomics, and Experimental Verification. CNS Neurosci Ther 2025; 31:e70297. [PMID: 40035287 PMCID: PMC11877134 DOI: 10.1111/cns.70297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2024] [Revised: 01/15/2025] [Accepted: 02/13/2025] [Indexed: 03/05/2025] Open
Abstract
BACKGROUND Post-cardiopulmonary resuscitation brain injury (PBI) is essentially the cerebral ischemia reperfusion (CIR) injury, which is the main cause of death and long-term disability in patients with cardiac arrest. So far, there is no treatment for PBI; thus, it is urgent to develop new drugs or therapies for the prevention and treatment of brain injury after cardiopulmonary resuscitation. Although multiple constituent herbs or active ingredients of Xinbao Pill (XBP) have shown neuroprotective effects, whether XBP could play a therapeutic role on PBI is still unknown. This study aimed to illustrate the neuroprotective effect of XBP on PBI and probe the underlying mechanisms. METHOD We first performed the cell and animal experiments to validate the protective effect of XBP on neurological function. We next identified the potential differential metabolites via metabolomics analysis. We further conducted a comprehensive network pharmacology analysis including overlap gene analysis, protein-protein interaction network, and gene-biological process-module function network to preliminarily investigate the specific mechanism of action (MOA) of XBP against PBI. Finally, PCR, MTT, ELISA assay, as well as Western blotting experiments were made to validate our proposed molecular mechanisms. RESULT The in vitro experiment showed that XBP could increase cell viability and ameliorate cell morphological damage in PC12 cells exposed to oxygen-glucose deprivation and reoxygenation (OGD/RO) conditions. The in vivo experiment demonstrated that XBP improved the Neurologic Deficit Score (NDS), lowered the Neuron-Specific Enolase (NSE) level as well as reversed the typical neuropathological changes in PBI rats, indicating its neuroprotective effect on PBI. Further metabolomics analysis identified 94 differential metabolites after XBP treatment, and multiple metabolites were highly related to CIR. Moreover, network pharmacology results revealed that the therapeutic effect of XBP on PBI may be relevant to mitochondrial quality control (MQC). Mechanistically, XBP could not only promote the expressions of marker proteins including PGC1α, NRF1, TFAM, OPA1, MFN1 as well as MFN2 in mitochondrial biogenesis and mitochondrial fusion but also inhibit those proteins containing DRP1, MFF, FIS1, p62, PINK1, Parkin as well as LC3 in mitochondrial fission and mitophagy. Finally, AMP-activated protein kinase (AMPK) inhibitor was demonstrated to play a crucial role in regulating MQC. CONCLUSIONS Our study first determined that XBP might be an underlying anti-PBI formula, which also deciphered the potential MOAs of XBP against PBI by a network pharmacology approach combined with in vivo and in vitro experimental validation.
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Affiliation(s)
- Dongli Li
- The Second Affiliated Hospital of Guangzhou University of Chinese MedicineGuangdong Provincial Hospital of Chinese MedicineGuangzhouChina
- Guangdong Provincial Key Laboratory of Research on Emergency in TCMGuangzhouChina
| | - Qihui Wu
- Clinical Research Center, Hainan Hospital, Guangdong Provincial Hospital of Chinese MedicineHainan Medical UniversityHaikouChina
| | - Zunjiang Li
- The Second Affiliated Hospital of Guangzhou University of Chinese MedicineGuangdong Provincial Hospital of Chinese MedicineGuangzhouChina
| | - Baijian Chen
- The Second Affiliated Hospital of Guangzhou University of Chinese MedicineGuangdong Provincial Hospital of Chinese MedicineGuangzhouChina
| | - Xing Sun
- The Second Affiliated Hospital of Guangzhou University of Chinese MedicineGuangdong Provincial Hospital of Chinese MedicineGuangzhouChina
| | - Qiqi Wu
- The Second Affiliated Hospital of Guangzhou University of Chinese MedicineGuangdong Provincial Hospital of Chinese MedicineGuangzhouChina
| | - Zhenzhu Ding
- The Second Affiliated Hospital of Guangzhou University of Chinese MedicineGuangdong Provincial Hospital of Chinese MedicineGuangzhouChina
| | - Linling Liu
- The Second Affiliated Hospital of Guangzhou University of Chinese MedicineGuangdong Provincial Hospital of Chinese MedicineGuangzhouChina
| | - Jiansong Fang
- Science and Technology Innovation CenterGuangzhou University of Chinese MedicineGuangzhouChina
| | - Ruifeng Zeng
- The Second Affiliated Hospital of Guangzhou University of Chinese MedicineGuangdong Provincial Hospital of Chinese MedicineGuangzhouChina
- Guangdong Provincial Key Laboratory of Research on Emergency in TCMGuangzhouChina
| | - Yong Gu
- Clinical Research Center, Hainan Hospital, Guangdong Provincial Hospital of Chinese MedicineHainan Medical UniversityHaikouChina
| | - Banghan Ding
- The Second Affiliated Hospital of Guangzhou University of Chinese MedicineGuangdong Provincial Hospital of Chinese MedicineGuangzhouChina
- Guangdong Provincial Key Laboratory of Research on Emergency in TCMGuangzhouChina
- The Second Clinical College of Guangzhou University of Chinese MedicineGuangzhouChina
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Yaghoobi A, Rezaee M, Hedayati N, Keshavarzmotamed A, Khalilzad MA, Russel R, Asemi Z, Rajabi Moghadam H, Mafi A. Insight into the cardioprotective effects of melatonin: shining a spotlight on intercellular Sirt signaling communication. Mol Cell Biochem 2025; 480:799-823. [PMID: 38980593 DOI: 10.1007/s11010-024-05002-3] [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: 11/30/2023] [Accepted: 03/25/2024] [Indexed: 07/10/2024]
Abstract
Cardiovascular diseases (CVDs) are the leading causes of death and illness worldwide. While there have been advancements in the treatment of CVDs using medication and medical procedures, these conventional methods have limited effectiveness in halting the progression of heart diseases to complete heart failure. However, in recent years, the hormone melatonin has shown promise as a protective agent for the heart. Melatonin, which is secreted by the pineal gland and regulates our sleep-wake cycle, plays a role in various biological processes including oxidative stress, mitochondrial function, and cell death. The Sirtuin (Sirt) family of proteins has gained attention for their involvement in many cellular functions related to heart health. It has been well established that melatonin activates the Sirt signaling pathways, leading to several beneficial effects on the heart. These include preserving mitochondrial function, reducing oxidative stress, decreasing inflammation, preventing cell death, and regulating autophagy in cardiac cells. Therefore, melatonin could play crucial roles in ameliorating various cardiovascular pathologies, such as sepsis, drug toxicity-induced myocardial injury, myocardial ischemia-reperfusion injury, hypertension, heart failure, and diabetic cardiomyopathy. These effects may be partly attributed to the modulation of different Sirt family members by melatonin. This review summarizes the existing body of literature highlighting the cardioprotective effects of melatonin, specifically the ones including modulation of Sirt signaling pathways. Also, we discuss the potential use of melatonin-Sirt interactions as a forthcoming therapeutic target for managing and preventing CVDs.
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Affiliation(s)
- Alireza Yaghoobi
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Malihe Rezaee
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Neda Hedayati
- School of Medicine, Iran University of Medical Science, Tehran, Iran
| | | | | | - Reitel Russel
- Department of Cell Systems and Anatomy, UT Health. Long School of Medicine, San Antonio, TX, USA.
| | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
| | - Hasan Rajabi Moghadam
- Department of Cardiology, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Alireza Mafi
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran.
- Nutrition and Food Security Research Center, Isfahan University of Medical Sciences, Isfahan, Iran.
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Abadi RNS, Jazinaki MS, Bahari H, Rashidmayvan M, Amini MR, Aliakbarian M, Khodashahi R, Malekahmadi M. Impact of Melatonin Supplementation on Glycemic Parameters in Patients with Type 2 Diabetes: A Systematic Review and Meta-analysis. Curr Pharm Des 2025; 31:645-657. [PMID: 39428939 DOI: 10.2174/0113816128345623241004080849] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2024] [Revised: 08/30/2024] [Accepted: 09/06/2024] [Indexed: 10/22/2024]
Abstract
BACKGROUND Several previous studies indicated that melatonin supplementation may positively affect glycemic control in patients with diabetes. However, research on the influence of melatonin supplementation on glycemic parameters remains inconclusive. Therefore, this study aimed to assess the impacts of melatonin supplementation on glycemic parameters in type 2 diabetes by conducting a meta-analysis. METHODS PubMed/Medline, Scopus, and Web of Science were comprehensively searched until July 2024 to find eligible randomized clinical trials (RCTs). The overall effect sizes were estimated by using the randomeffect model and presented as weighted mean differences (WMD) with a 95% confidence interval (CI). Furthermore, the heterogeneity among the included trials was assessed by performing the Cochran Q test and interpreted based on the I² statistic. RESULTS Of the 1361 papers, eight eligible RCTs were included in this meta-analysis. Our findings indicated that melatonin supplementation significantly decreased fasting blood glucose (WMD = -12.65 mg/dl; 95% CI: -20.38, -4.92; P = 0.001), insulin (WMD = -2.30 μU/ml; 95% CI: -3.20, -1.40; P < 0.001), hemoglobin A1c (WMD = -0.79 %; 95% CI: -1.28, -0.29; P = 0.002), and HOMA-IR (WMD, -0.83; 95% CI: -1.59 to - 0.07; P = 0.03). CONCLUSION According to the results of the current meta-analysis, persons with type 2 diabetes who supplement with melatonin had improved glycemic control. It looks that supplementing with melatonin at a dose exceeding 6 mg daily for over a period of 12 weeks may be more successful than other forms of intervention. Nevertheless, further research with larger sample sizes is necessary to draw definitive conclusions.
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Affiliation(s)
- Reza Nejad Shahrokh Abadi
- Clinical Research Development Unit, Faculty of Medicine, Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Hossein Bahari
- Transplant Research Center, Clinical Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Rashidmayvan
- Department of Nutrition, Food Sciences and Clinical Biochemistry, Social Determinants of Health Research Center, School of Medicine, Gonabad University of Medical Science, Gonabad, Iran
| | - Mohammad Reza Amini
- Student Research Committee, Department of Clinical Nutrition and Dietetics, Faculty of Nutrition Sciences and Food Technology, National Nutrition & Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Nutrition and Food Security Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mohsen Aliakbarian
- Transplant Research Center, Clinical Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Rozita Khodashahi
- Transplant Research Center, Clinical Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Clinical Research Development Unit, Faculty of Medicine, Imam Reza Hospital, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Infectious Diseases and Tropical Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahsa Malekahmadi
- Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
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Hu Y, Fan Y, Li N, Xu C, Wang J. Expression of LncRNAs in anterior capsule of lens in patients with pathologic myopia complicated with cataract. Int Ophthalmol 2024; 45:10. [PMID: 39680214 DOI: 10.1007/s10792-024-03366-5] [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: 05/26/2024] [Accepted: 11/20/2024] [Indexed: 12/17/2024]
Abstract
PURPOSE To explore the expressions and functions of lncRNAs in the pathogenesis of pathologic myopia complicated with cataract (PMC). METHODS The anterior capsular tissues were collected from patients with age-related cataract (ARC) and PMC. One group of the samples was used to detected by whole-transcriptome sequencing (LC-Bio, Hangzhou, China) and investigated by GO and KEGG enrichment analysis. We selected the Metastasis Associated Lung Adenocarcinoma Transcript 1 (MALAT1), predicted the miRNAs with gene binding sites to it and the downstream mRNAs with gene binding sites to miRNAs through the Starbase and Targetscan websites. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed on the other group to further preliminarily validate the prediction. RESULTS A total of 471 lncRNAs were significantly differential expressed in PMC group compared with ARC group, in which 231 lncRNAs were up-regulated, including MALAT1, and 240 lncRNAs were down-regulated. GO and KEGG enrichment analysis showed that lncRNAs targeted differential mRNAs were involved in various biological functions, cell components, molecular functions and signaling pathways. Taking MALAT1 as an example, we predicted that it had binding sites with 113 miRNAs such as hsa-miR-20a-5p, has-miR-20b-5p, hsa-miR-26a-5p, has-miR-106-5p and hsa-miR-204-5p, which were lower in PMC group than these in ARC group. Inversely, the downstream mRNAs of the above miRNAs, such as MMP9, TNF-α, TGF-β2, NF-KB, IL6 and Smad4 were higher. CONCLUSION The differentially expressed lncRNAs, especially MALAT1, may act as ceRNA via sponging miRNAs and to regulate the targeting downstream mRNAs in development of PMC and participate in numerous biological processes through interconnected signaling pathways.
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Affiliation(s)
- Yaru Hu
- Department of Ophthalmology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, 233004, Anhui, China
- Department of Ophthalmology, Fuyang People's Hospital, Fuyang, 236000, Anhui, China
| | - Yuchen Fan
- Department of Ophthalmology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, 233004, Anhui, China
| | - Na Li
- Department of Ophthalmology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, 233004, Anhui, China
| | - Che Xu
- Department of Ophthalmology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, 233004, Anhui, China
| | - Jianfeng Wang
- Department of Ophthalmology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, 233004, Anhui, China.
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Shi X, Zhang J, Gao J, Guo D, Zhang S, Chen X, Tang H. Melatonin attenuates liver ischemia-reperfusion injury via inhibiting the PGAM5-mPTP pathway. PLoS One 2024; 19:e0312853. [PMID: 39471139 PMCID: PMC11521291 DOI: 10.1371/journal.pone.0312853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Accepted: 10/14/2024] [Indexed: 11/01/2024] Open
Abstract
Phosphoglycerate mutase/protein phosphatase (PGAM5)-mediated cell death plays an important role in multiple liver diseases. However, few studies have confirmed the regulatory mechanism of melatonin acting on PGAM5-mediated cell death in the context of liver ischemia-reperfusion (I/R) injury. The liver I/R injury model and cell hypoxia-reoxygenation model were established after melatonin pretreatment. Liver injury, cell activity, cell apoptosis, oxidative stress index, and PGAM5 protein expression were detected. To investigate the role of PGAM5 in melatonin-mediated liver protection during I/R injury, PGAM5 silencing, and overexpression were performed before melatonin pretreatment. Our results indicated that PGAM5 was significantly elevated by I/R injury, and predominantly localized in the necrosis area. However, treatment with melatonin blocked PGAM5 activation and conferred a survival advantage of hepatocytes in liver I/R injury, similar to the results achieved by silencing PGAM5. In terms of mechanism, we illustrated that activated PGAM5 promoted mitochondrial permeability transition pore (mPTP) opening, and administration of melatonin inhibited mPTP opening and interrupted hepatocytes death via blocking PGAM5. Our data indicated that the PGAM5-mPTP axis is responsible for I/R-induced liver injury. In contrast, melatonin supplementation blocked the PGAM5-mPTP axis and thus decreased cell death, providing a protective advantage to hepatocytes in I/R. These results established a new paradigm in melatonin-mediated hepatocyte protection under the burden of I/R attack.
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Affiliation(s)
- Xiaoyi Shi
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Henan Engineering Technology Research Center of Organ Transplantation, Zhengzhou, Henan, China
- ZhengZhou Engineering Laboratory of Organ Transplantation Technique and Application, Zhengzhou, Henan, China
| | - Jiakai Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Henan Engineering Technology Research Center of Organ Transplantation, Zhengzhou, Henan, China
- ZhengZhou Engineering Laboratory of Organ Transplantation Technique and Application, Zhengzhou, Henan, China
| | - Jie Gao
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Henan Engineering Technology Research Center of Organ Transplantation, Zhengzhou, Henan, China
- ZhengZhou Engineering Laboratory of Organ Transplantation Technique and Application, Zhengzhou, Henan, China
| | - Danfeng Guo
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Henan Engineering Technology Research Center of Organ Transplantation, Zhengzhou, Henan, China
- ZhengZhou Engineering Laboratory of Organ Transplantation Technique and Application, Zhengzhou, Henan, China
| | - Shuijun Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Henan Engineering Technology Research Center of Organ Transplantation, Zhengzhou, Henan, China
- ZhengZhou Engineering Laboratory of Organ Transplantation Technique and Application, Zhengzhou, Henan, China
| | - Xu Chen
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Henan Engineering Technology Research Center of Organ Transplantation, Zhengzhou, Henan, China
- ZhengZhou Engineering Laboratory of Organ Transplantation Technique and Application, Zhengzhou, Henan, China
| | - Hongwei Tang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Henan Engineering Technology Research Center of Organ Transplantation, Zhengzhou, Henan, China
- ZhengZhou Engineering Laboratory of Organ Transplantation Technique and Application, Zhengzhou, Henan, China
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Grzeszczuk M, Mrozowska M, Kmiecik A, Rusak A, Jabłońska K, Ciesielska U, Dzięgiel P, Nowińska K. The Effect of Hypoxia on Irisin Expression in HL-1 Cardiomyocytes. In Vivo 2024; 38:2126-2133. [PMID: 39187335 PMCID: PMC11363745 DOI: 10.21873/invivo.13675] [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: 05/01/2024] [Revised: 05/28/2024] [Accepted: 06/12/2024] [Indexed: 08/28/2024]
Abstract
BACKGROUND/AIM Cardiovascular diseases (CVD) are the leading cause of death worldwide. In 2019, 523 million people were diagnosed with CVD, with 18.6 million deaths. Improved treatment and diagnostics could reduce CVD's impact. Irisin (Ir) is crucial for heart function and may be a biomarker for heart attack. Ir is a glycoprotein with sugar residues attached to its protein structure. This glycosylation affects Ir stability, solubility, and receptor interactions on target cells. Its secondary structure includes a fibronectin type III domain, essential for its biological functions. Ir helps cardiomyocytes to respond to hypoxia and protects mitochondria. The aim of the study was to determine the FNDC5 gene expression level and the Ir level in HL-1 cardiomyocytes subjected to hypoxia. MATERIALS AND METHODS We examined the effect of hypoxia on the expression levels of the FNDC5 gene and those of Ir in mouse cardiomyocytes of the HL-1 cell line. Real-time PCR (RT-PCR) was used to estimate the expression levels of the FNDC5 gene. Western blot and immunofluorescence methods were used to analyze the Ir protein levels. RESULTS Analyses showed an increased Ir level in HL-1 cardiomyocytes in response to hypoxia. This is the first study to confirm the presence of Ir in HL-1 cells. CONCLUSION The observed increase in Ir expression in murine cardiomyocytes is associated with the hypoxic environment and can be potentially used to diagnose hypoxia and CVD.
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Affiliation(s)
- Maciej Grzeszczuk
- Division of Histology and Embryology, Department of Human Morphology and Embryology, Wroclaw Medical University, Wroclaw, Poland;
| | - Monika Mrozowska
- Division of Histology and Embryology, Department of Human Morphology and Embryology, Wroclaw Medical University, Wroclaw, Poland
| | - Alicja Kmiecik
- Division of Histology and Embryology, Department of Human Morphology and Embryology, Wroclaw Medical University, Wroclaw, Poland
| | - Agnieszka Rusak
- Division of Histology and Embryology, Department of Human Morphology and Embryology, Wroclaw Medical University, Wroclaw, Poland
| | - Karolina Jabłońska
- Division of Histology and Embryology, Department of Human Morphology and Embryology, Wroclaw Medical University, Wroclaw, Poland
| | - Urszula Ciesielska
- Division of Histology and Embryology, Department of Human Morphology and Embryology, Wroclaw Medical University, Wroclaw, Poland
| | - Piotr Dzięgiel
- Division of Histology and Embryology, Department of Human Morphology and Embryology, Wroclaw Medical University, Wroclaw, Poland
- Department of Physiotherapy, Wroclaw University School of Physical Education, Wroclaw, Poland
| | - Katarzyna Nowińska
- Division of Histology and Embryology, Department of Human Morphology and Embryology, Wroclaw Medical University, Wroclaw, Poland
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Wu XY, Zhao MJ, Liao W, Liu T, Liu JY, Gong JH, Lai X, Xu XS. Oridonin attenuates liver ischemia-reperfusion injury by suppressing PKM2/NLRP3-mediated macrophage pyroptosis. Cell Immunol 2024; 401-402:104838. [PMID: 38810591 DOI: 10.1016/j.cellimm.2024.104838] [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: 02/22/2024] [Revised: 05/07/2024] [Accepted: 05/22/2024] [Indexed: 05/31/2024]
Abstract
BACKGROUND The NOD-like receptor protein 3 (NLRP3) mediated pyroptosis of macrophages is closely associated with liver ischemia reperfusion injury (IRI). As a covalent inhibitor of NLRP3, Oridonin (Ori), has strong anti-inflammasome effect, but its effect and mechanisms for liver IRI are still unknown. METHODS Mice and liver macrophages were treated with Ori, respectively. Co-IP and LC-MS/MS analysis of the interaction between PKM2 and NLRP3 in macrophages. Liver damage was detected using H&E staining. Pyroptosis was detected by WB, TEM, and ELISA. RESULTS Ori ameliorated liver macrophage pyroptosis and liver IRI. Mechanistically, Ori inhibited the interaction between pyruvate kinase M2 isoform (PKM2) and NLRP3 in hypoxia/reoxygenation（H/R）-induced macrophages, while the inhibition of PKM2/NLRP3 reduced liver macrophage pyroptosis and liver IRI. CONCLUSION Ori exerted protective effects on liver IRI via suppressing PKM2/NLRP3-mediated liver macrophage pyroptosis, which might become a potential therapeutic target in the clinic.
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Affiliation(s)
- Xin-Yi Wu
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, China
| | - Min-Jie Zhao
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, China
| | - Wei Liao
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, China
| | - Tao Liu
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, China
| | - Jun-Yan Liu
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, China
| | - Jun-Hua Gong
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, China
| | - Xing Lai
- Department of Hepatobiliary Surgery, the People's Hospital of Tongnan District Chongqing City, China.
| | - Xue-Song Xu
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, China.
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10
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Zhou H, Chen N, He B, Ma Z, Liu W, Xu B. Melatonin modulates the differentiation of neural stem cells exposed to manganese via SIRT1/β-catenin signaling. Food Chem Toxicol 2024; 184:114349. [PMID: 38081531 DOI: 10.1016/j.fct.2023.114349] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Revised: 11/28/2023] [Accepted: 12/05/2023] [Indexed: 12/19/2023]
Abstract
Excessive exposure of children to manganese (Mn) in the environment has a bearing on developmental neurotoxicity. Although melatonin (Mel) can play a neuroprotective role by modulating the differentiation of neural stem cells (NSCs) in the developing brain, its specific mechanism under Mn overexposure remains to be explored. Here, we cultured primary NSCs as an available model to investigate the relevant molecular mechanism of Mel mitigation on Mn-induced disorder of NSCs differentiation through sirtuin 1 (SIRT1)/β-catenin pathway. It was found that Mel could facilitate the differentiation of Mn-treated NSCs into neurons. Further, our results uncovered that the pro-differentiation mechanism of Mel depended upon ascending the activity of SIRT1, thereby weakening β-catenin acetylation and increasing phosphorylation of β-catenin ser675 in the cytoplasm, which facilitates the nuclear translocation of β-catenin. Furthermore, the role of SIRT1 in Mel-mediated signal transduction was investigated through the pretreatment of NSCs using a highly specific SIRT1 inhibitor, EX527. After EX527 pretreatment, Mel could not maintain its protective effect. Overall, our results revealed that Mel could alleviate Mn-induced disorder of NSCs differentiation through the activation of the SIRT1/β-catenin pathway.
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Affiliation(s)
- Han Zhou
- Department of Environmental Health, School of Public Health, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China
| | - Nan Chen
- Department of Environmental Health, School of Public Health, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China
| | - Bin He
- Department of Environmental Health, School of Public Health, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China
| | - Zhuo Ma
- Key laboratory of Environmental Stress and Chronic Disease Control and Prevention (China Medical University), Ministry of Education, No.77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China; Department of Environmental Health, School of Public Health, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China
| | - Wei Liu
- Key laboratory of Environmental Stress and Chronic Disease Control and Prevention (China Medical University), Ministry of Education, No.77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China; Department of Environmental Health, School of Public Health, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China
| | - Bin Xu
- Key laboratory of Environmental Stress and Chronic Disease Control and Prevention (China Medical University), Ministry of Education, No.77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China; Department of Environmental Health, School of Public Health, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China.
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11
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Zeng Y, Fang Q, Chen J, Wang Y, Liu X, Zhang X, Shi Y, Zhan H, Zhong X, Yao M, Huang H, Wu W. Melatonin Improves Mitochondrial Dysfunction and Attenuates Neuropathic Pain by Regulating SIRT1 in Dorsal Root Ganglions. Neuroscience 2023; 534:29-40. [PMID: 37832908 DOI: 10.1016/j.neuroscience.2023.10.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 09/28/2023] [Accepted: 10/08/2023] [Indexed: 10/15/2023]
Abstract
Neuropathic pain is a debilitating chronic pain condition and is refractory to the currently available treatments. Emerging evidence suggests that melatonin exerts analgesic effects in rodent models of neuropathic pain. Nevertheless, the exact underlying mechanisms of the analgesic effects of melatonin on neuropathic pain are largely unknown. Here, we observed that spinal nerve ligation (SNL) in rats L5 and L6 induced an obvious decrease in the 50% paw withdrawal threshold (PWT) and paw withdrawal latency (PWL), indicating the induction of mechanical allodynia and the hyperalgesia, and melatonin prevented the genesis and maintenance of mechanical allodynia and the hyperalgesia. Notably, the inhibitory action of melatonin on SNL-induced mechanical allodynia and heat hypersensitivity was inhibited by a SIRT1 inhibitor (EX527). Melatonin treatment increased the expression of neuronal sirtuin1 (SIRT1) in DRGs following nerve injury. Furthermore, melatonin treatment restored the injury-dependent decrease in mitochondrial membrane potential and peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) and reduced the injury-dependent increase in hydrogen peroxide and 8-hydroxy-2-deoxyguanosine (8-OHdG), which was inhibited by EX527. In addition, we found that EX527 impeded the inhibitory effects of melatonin on the SNL-induced increased expression of cytokines tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β). In conclusion, the above data demonstrated that melatonin alleviated mechanical allodynia and hyperalgesia induced by peripheral nerve injury via SIRT1 activation. Melatonin resolved mitochondrial dysfunction-oxidative stress-dependent and neuroinflammation mechanisms that were driven by SIRT1 after nerve injury.
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Affiliation(s)
- Yanyan Zeng
- Department of Rehabilitation, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, Guangdong, China
| | - Qian Fang
- Department of Rehabilitation, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, Guangdong, China
| | - Jiali Chen
- Department of Rehabilitation, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, Guangdong, China
| | - Yaping Wang
- Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Key Laboratory of Mental Health of the Ministry of Education, Guangdong Province Key Laboratory of Psychiatric Disorders, Southern Medical University, Guangzhou 510515, Guangdong, China
| | - Xinli Liu
- Department of Rehabilitation, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, Guangdong, China
| | - Xuefei Zhang
- Department of Rehabilitation, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, Guangdong, China
| | - Yu Shi
- Department of Rehabilitation, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, Guangdong, China
| | - Hongrui Zhan
- Department of Rehabilitation, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai 519000, Guangdong Province, China
| | - Xiongxiong Zhong
- Department of Anesthesiology, Shenzhen People's Hospital, Shenzhen, China
| | - Mengyu Yao
- Department of Orthopedics, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, Guangdong, China
| | - Huai Huang
- Department of Hyperbaric Oxygen Rehabilitation (Intensive Rehabilitation Center), Southern Theater Command General Hospital of PLA, Guangzhou 510010, Guangdong, China
| | - Wen Wu
- Department of Rehabilitation, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, Guangdong, China.
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12
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Yang X, Wang J, Dai X, Ma N, Cheng H, Guo H, Chen S, Huang Y, Wu J. The mechanism and targeted intervention of the HIF-1 pathway in improving atherosclerotic heart's sensitivity to ischemic postconditioning. Free Radic Biol Med 2023; 208:494-509. [PMID: 37660838 DOI: 10.1016/j.freeradbiomed.2023.08.030] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2023] [Revised: 08/30/2023] [Accepted: 08/31/2023] [Indexed: 09/05/2023]
Abstract
BACKGROUND IPoC possesses a preventive effect against IR injury in healthy myocardium, but IPoC's protective effect on atherosclerotic myocardium is controversial. The current investigation aims to determine whether IPoC remains protective in atherosclerotic myocardium subjected to ischemia-reperfusion (IR) injury; to explore the specific mechanisms by which IPoC exerts cardioprotection; to explore whether HIF-1 upregulation combined with IPoC could further the provide cardioprotection; and to gaze at the specific mechanism whereby combined treatment expert the cardioprotection. METHODS ApoE-/- mice fed with a high-fat diet (HFD) were used to develop a model of atherosclerosis. The myocardial IR model was induced by occlusion of the left anterior descending (LAD) artery for 45 min, followed by reperfusion for 120 min. The protection of IPoC in both healthy and atherosclerotic myocardium was evaluated by measuring oxidative stress, apoptosis, infarct size, pathology, mitochondrial dysfunction and morphology of myocardium. The specific mechanism by which IPoC exerts cardioprotection in healthy and atherosclerotic myocardium was observed by measuring the expression of proteins involved in HIF-1, APMK and RISK pathways. The effect of HIF-1α overexpression on the cardioprotection by IPoC was observed by intravenous AAV9 -HIF-1α injection. RESULTS In healthy ischemic myocardium, IPoC exerted myocardial protective effects (antioxidant, anti-apoptosis, and improved mitochondrial function) through the activation of HIF-1, AMPK and RISK pathways. In atherosclerotic ischemic myocardium, IPoC exerted cardioprotection only through the activation of HIF-1 pathway; however, HIF-1 overexpression combined IPoC restored the activation of AMPK and RISK pathways, thereby further alleviating the myocardial IR injury. CONCLUSIONS In the atherosclerotic state, the HIF-1 pathway is the intrinsic mechanism by which IPoC exerts cardioprotective effects. The combination of HIF-1 upregulation and IPoC has a significant effect in reducing myocardial injury, which is worth being promoted and advocated. In addition, HIF-1-AMPK and HIF-1-RISK may be two endogenous cardioprotective signalling pathways with great value, which deserve to be thoroughly investigated in the future.
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Affiliation(s)
- Xue Yang
- Department of Anesthesiology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Jiang Wang
- Department of Anesthesiology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Xiaowen Dai
- Department of Anesthesiology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Ning Ma
- Department of Anesthesiology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Hu Cheng
- Department of Anesthesiology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Hai Guo
- Department of Anesthesiology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Siyu Chen
- Department of Anesthesiology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Yidan Huang
- Department of Anesthesiology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Jianjiang Wu
- Department of Anesthesiology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China.
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Mouratidou C, Pavlidis ET, Katsanos G, Kotoulas SC, Mouloudi E, Tsoulfas G, Galanis IN, Pavlidis TE. Hepatic ischemia-reperfusion syndrome and its effect on the cardiovascular system: The role of treprostinil, a synthetic prostacyclin analog. World J Gastrointest Surg 2023; 15:1858-1870. [PMID: 37901735 PMCID: PMC10600776 DOI: 10.4240/wjgs.v15.i9.1858] [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: 06/09/2023] [Revised: 07/20/2023] [Accepted: 07/25/2023] [Indexed: 09/21/2023] Open
Abstract
Hepatic ischemia-reperfusion syndrome has been the subject of intensive study and experimentation in recent decades since it is responsible for the outcome of several clinical entities, such as major hepatic resections and liver transplantation. In addition to the organ's post reperfusion injury, this syndrome appears to play a central role in the dysfunction of distant tissues and systems. Thus, continuous research should be directed toward finding effective therapeutic options to improve the outcome and reduce the postoperative morbidity and mortality rates. Treprostinil is a synthetic analog of prostaglandin I2, and its experimental administration has shown encouraging results. It has already been approved by the Food and Drug Administration in the United States for pulmonary arterial hypertension and has been used in liver transplantation, where preliminary encouraging results showed its safety and feasibility by using continuous intravenous administration at a dose of 5 ng/kg/min. Treprostinil improves renal and hepatic function, diminishes hepatic oxidative stress and lipid peroxidation, reduces hepatictoll-like receptor 9 and inflammation, inhibits hepatic apoptosis and restores hepatic adenosine triphosphate (ATP) levels and ATP synthases, which is necessary for functional maintenance of mitochondria. Treprostinil exhibits vasodilatory properties and antiplatelet activity and regulates proinflammatory cytokines; therefore, it can potentially minimize ischemia-reperfusion injury. Additionally, it may have beneficial effects on cardiovascular parameters, and much current research interest is concentrated on this compound.
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Affiliation(s)
| | - Efstathios T Pavlidis
- 2nd Propedeutic Department of Surgery, Hippokration General Hospital, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
| | - Georgios Katsanos
- Department of Transplantation, Hippokration General Hospital, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
| | | | - Eleni Mouloudi
- Intensive Care Unit, Hippokration General Hospital, Thessaloniki 54642, Greece
| | - Georgios Tsoulfas
- Department of Transplantation, Hippokration General Hospital, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
| | - Ioannis N Galanis
- 2nd Propedeutic Department of Surgery, Hippokration General Hospital, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
| | - Theodoros E Pavlidis
- 2nd Propedeutic Department of Surgery, Hippokration General Hospital, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
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14
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Yang YN, Zhang MQ, Yu FL, Han B, Bao MY, Yan-He, Li X, Zhang Y. Peroxisom proliferator-activated receptor-γ coactivator-1α in neurodegenerative disorders: A promising therapeutic target. Biochem Pharmacol 2023; 215:115717. [PMID: 37516277 DOI: 10.1016/j.bcp.2023.115717] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Revised: 07/26/2023] [Accepted: 07/26/2023] [Indexed: 07/31/2023]
Abstract
Neurodegenerative disorders (NDDs) are characterized by progressive loss of selectively vulnerable neuronal populations and myelin sheath, leading to behavioral and cognitive dysfunction that adversely affect the quality of life. Identifying novel therapies that attenuate the progression of NDDs would be of significance. Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), a widely expressed transcriptional regulator, modulates the expression of genes engaged in mitochondrial biosynthesis, metabolic regulation, and oxidative stress (OS). Emerging evidences point to the strong connection between PGC-1α and NDDs, suggesting its positive impaction on the progression of NDDs. Therefore, it is urgent to gain a deeper and broader understanding between PGC-1α and NDDs. To this end, this review presents a comprehensive overview of PGC-1α, including its basic characteristics, the post-translational modulations, as well as the interacting transcription factors. Secondly, the pathogenesis of PGC-1α in various NDDs, such as Alzheimer's (AD), Parkinson's (PD), and Huntington's disease (HD) is briefly discussed. Additionally, this study summarizes the underlying mechanisms that PGC-1α is neuroprotective in NDDs via regulating neuroinflammation, OS, and mitochondrial dysfunction. Finally, we briefly outline the shortcomings of current NDDs drug therapy, and summarize the functions and potential applications of currently available PGC-1α modulators (activator or inhibitors). Generally, this review updates our insight of the important role of PGC-1α on the development of NDDs, and provides a promising therapeutic target/ drug for the treatment of NDDs.
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Affiliation(s)
- Ya-Na Yang
- Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry (Shaanxi Normal University), The Ministry of Education, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi 710119, China
| | - Mao-Qing Zhang
- Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry (Shaanxi Normal University), The Ministry of Education, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi 710119, China
| | - Feng-Lin Yu
- Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry (Shaanxi Normal University), The Ministry of Education, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi 710119, China
| | - Bing Han
- Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry (Shaanxi Normal University), The Ministry of Education, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi 710119, China
| | - Ming-Yue Bao
- Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry (Shaanxi Normal University), The Ministry of Education, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi 710119, China
| | - Yan-He
- Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry (Shaanxi Normal University), The Ministry of Education, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi 710119, China
| | - Xing Li
- Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry (Shaanxi Normal University), The Ministry of Education, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi 710119, China
| | - Yuan Zhang
- Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry (Shaanxi Normal University), The Ministry of Education, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi 710119, China.
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15
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Yuan Y, Tian Y, Jiang H, Cai LY, Song J, Peng R, Zhang XM. Mechanism of PGC-1α-mediated mitochondrial biogenesis in cerebral ischemia-reperfusion injury. Front Mol Neurosci 2023; 16:1224964. [PMID: 37492523 PMCID: PMC10363604 DOI: 10.3389/fnmol.2023.1224964] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Accepted: 06/21/2023] [Indexed: 07/27/2023] Open
Abstract
Cerebral ischemia-reperfusion injury (CIRI) is a series of cascade reactions that occur after blood flow recanalization in the ischemic zone in patients with cerebral infarction, causing an imbalance in intracellular homeostasis through multiple pathologies such as increased oxygen free radicals, inflammatory response, calcium overload, and impaired energy metabolism, leading to mitochondrial dysfunction and ultimately apoptosis. Rescue of reversibly damaged neurons in the ischemic hemispheric zone is the key to saving brain infarction and reducing neurological deficits. Complex and active neurological functions are highly dependent on an adequate energy supply from mitochondria. Mitochondrial biogenesis (MB), a process that generates new functional mitochondria and restores normal mitochondrial function by replacing damaged mitochondria, is a major mechanism for maintaining intra-mitochondrial homeostasis and is involved in mitochondrial quality control to ameliorate mitochondrial dysfunction and thus protects against CIRI. The main regulator of MB is peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), which improves mitochondrial function to protect against CIRI by activating its downstream nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (TFAM) to promote mitochondrial genome replication and transcription. This paper provides a theoretical reference for the treatment of neurological impairment caused by CIRI by discussing the mechanisms of mitochondrial biogenesis during cerebral ischemia-reperfusion injury.
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Affiliation(s)
- Ying Yuan
- School of Acupuncture-Moxibustion and Orthopedics, Hubei University of Chinese Medicine, Wuhan, China
| | - Yuan Tian
- School of Acupuncture-Moxibustion and Orthopedics, Hubei University of Chinese Medicine, Wuhan, China
| | - Hui Jiang
- School of Acupuncture-Moxibustion and Orthopedics, Hubei University of Chinese Medicine, Wuhan, China
| | - Luo-yang Cai
- School of Acupuncture-Moxibustion and Orthopedics, Hubei University of Chinese Medicine, Wuhan, China
| | - Jie Song
- School of Acupuncture-Moxibustion and Orthopedics, Hubei University of Chinese Medicine, Wuhan, China
| | - Rui Peng
- School of Acupuncture-Moxibustion and Orthopedics, Hubei University of Chinese Medicine, Wuhan, China
- Sub-Health Institute Hubei University of Chinese Medicine, Wuhan, China
| | - Xiao-ming Zhang
- School of Acupuncture-Moxibustion and Orthopedics, Hubei University of Chinese Medicine, Wuhan, China
- Sub-Health Institute Hubei University of Chinese Medicine, Wuhan, China
- Hubei Provincial Collaborative Innovation Center for Preventive Treatment of Disease by Acupuncture, Wuhan, China
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16
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Esteban-Zubero E, López-Pingarrón L, Ramírez JM, Reyes-Gonzales MC, Azúa-Romeo FJ, Soria-Aznar M, Agil A, García JJ. Melatonin Preserves Fluidity in Cell and Mitochondrial Membranes against Hepatic Ischemia-Reperfusion. Biomedicines 2023; 11:1940. [PMID: 37509579 PMCID: PMC10377318 DOI: 10.3390/biomedicines11071940] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 07/03/2023] [Accepted: 07/06/2023] [Indexed: 07/30/2023] Open
Abstract
We evaluated the in vivo effects of melatonin treatment on oxidative damage in the liver in an experimental model of ischemia-reperfusion. A total of 37 male Sprague-Dawley rats were randomly divided into four groups: control, ischemia, ischemia + reperfusion, and ischemia + reperfusion + melatonin. Hepatic ischemia was maintained for 20 min, and the clamp was removed to initiate vascular reperfusion for 30 min. Melatonin (50 mg/kg body weight) was intraperitoneally administered. Fluidity was measured by polarization changes in 1-(4-trimethylammoniumphenyl)-6-phenyl-1,3,5-hexatriene-p-toluene sulfonate). After 20 min of ischemia, no significant changes were observed in cell and mitochondrial membrane fluidity levels, lipid peroxidation, and protein carbonylation. However, after 30 min of reperfusion, membrane fluidity decreased compared to controls. Increases in lipid and protein oxidation were also seen in hepatic homogenates of animals exposed to reperfusion. Melatonin injected 30 min before ischemia and reperfusion fully prevented membrane rigidity and both lipid and protein oxidation. Livers from ischemia-reperfusion showed histopathological alterations and positive labeling with antibodies to oxidized lipids and proteins. Melatonin reduced the severity of these morphological changes and protected against in vivo ischemia-reperfusion-induced toxicity in the liver. Therefore, melatonin might be a candidate for co-treatment for patients with hepatic vascular occlusion followed by reperfusion.
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Affiliation(s)
- Eduardo Esteban-Zubero
- Department of Pharmacology, Physiology and Legal and Forensic Medicine, Faculty of Medicine, University of Zaragoza, 50009 Zaragoza, Spain
| | - Laura López-Pingarrón
- Department of Pharmacology, Physiology and Legal and Forensic Medicine, Faculty of Medicine, University of Zaragoza, 50009 Zaragoza, Spain
| | | | - Marcos César Reyes-Gonzales
- Department of Pharmacology, Physiology and Legal and Forensic Medicine, Faculty of Medicine, University of Zaragoza, 50009 Zaragoza, Spain
| | - Francisco Javier Azúa-Romeo
- Department of Human Anatomy and Histology, Faculty of Medicine, University of Zaragoza, 50009 Zaragoza, Spain
| | - Marisol Soria-Aznar
- Department of Pharmacology, Physiology and Legal and Forensic Medicine, Faculty of Medicine, University of Zaragoza, 50009 Zaragoza, Spain
| | - Ahmad Agil
- Department of Pharmacology, Faculty of Medicine, University of Granada, 18071 Granada, Spain
| | - José Joaquín García
- Department of Pharmacology, Physiology and Legal and Forensic Medicine, Faculty of Medicine, University of Zaragoza, 50009 Zaragoza, Spain
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Wang L, Wang W, Han R, Liu Y, Wu B, Luo J. Protective effects of melatonin on myocardial microvascular endothelial cell injury under hypertensive state by regulating Mst1. BMC Cardiovasc Disord 2023; 23:179. [PMID: 37005605 PMCID: PMC10068162 DOI: 10.1186/s12872-023-03159-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Accepted: 03/01/2023] [Indexed: 04/04/2023] Open
Abstract
BACKGROUND This study explored the protective effects of melatonin on the hypertensive model in myocardial microvascular endothelial cells. METHODS Mouse myocardial microvascular endothelial cells were intervened with angiotensin II to establish hypertensive cell model and divided into control, hypertension (HP), hypertension + adenovirus negative control (HP + Ad-NC), hypertension + adenovirus carrying Mst1 (HP + Ad-Mst1), hypertension + melatonin (HP + MT), hypertension + adenovirus negative control + melatonin (HP + Ad-NC + MT), and hypertension + adenovirus carrying Mst1 + melatonin (HP + Ad-Mst1 + MT) groups. Autophagosomes were observed by transmission electron microscope. Mitochondrial membrane potential was detected by JC-1 staining. Apoptosis was detected by flow cytometry. Oxidative stress markers of MDA, SOD and GSH-PX were measured. The expression of LC3 and p62 was detected by immunofluorescence. Expression levels of Mst1, p-Mst1, Beclin1, LC3, and P62 were detected with Western blot. RESULTS Compared with the control group, the autophagosomes in HP, HP + Ad-Mst1, and HP + Ad-NC groups were significantly reduced. Compared with HP group, the autophagosomes in HP + Ad-Mst1 group were significantly reduced. The apoptosis of HP + MT group was significantly lower than HP group. Compared with HP + Ad-Mst1 group, the apoptosis of HP + Ad-Mst1 + MT group was significantly reduced. The ratio of JC-1 monomer in HP + MT group was significantly lower than HP group. Compared with HP + Ad-Mst1 group, the mitochondrial membrane potential of HP + Ad-Mst1 + MT group was also significantly reduced. MDA content in HP + MT group was significantly reduced, but SOD and GSH-PX activities were significantly increased. Compared with HP + Ad-Mst1 group, MDA content in HP + Ad-Mst1 + MT group was significantly reduced, whereas SOD and GSH-PX activities were increased significantly. Mst1 and p-Mst1 proteins in HP + MT group were significantly reduced. Compared with HP + Ad-Mst1 group, Mst1 and p-Mst1 in HP + Ad-Mst1 + MT group were reduced. P62 level was significantly decreased, while Beclin1 and LC3II levels were significantly increased. P62 in HP + MT group was significantly reduced, while Beclin1 and LC3II were significantly increased. Compared with HP + Ad-Mst1 group, P62 in HP + Ad-Mst1 + MT group was significantly reduced, but Beclin1 and LC3II were significantly increased. CONCLUSION Melatonin may inhibit apoptosis, increase mitochondrial membrane potential, and increase autophagy of myocardial microvascular endothelial cells under hypertensive state via inhibiting Mst1 expression, thereby exerting myocardial protective effect.
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Affiliation(s)
- Lingpeng Wang
- Department of Cardiology, the First Affiliated Hospital, Xinjiang Medical University, Urumqi, 830000, China
| | - Wei Wang
- Department of Internal Medicine, The First Affiliated Hospital, Xinjiang Medical University, No. 137, Liyushan South Road, Urumqi, Xinjiang, 830000, China
| | - Ruimei Han
- Department of Cardiology, Shanghai Xuhui Central Hospital, Shanghai, 200031, China
| | - Yang Liu
- Department of Internal Medicine, The First Affiliated Hospital, Xinjiang Medical University, No. 137, Liyushan South Road, Urumqi, Xinjiang, 830000, China
| | - Bin Wu
- Department of Geriatrics, Xinjiang Military General Hospital, 359 Youhao North Street, Urumqi, Xinjiang, 830000, China.
| | - Jian Luo
- Department of Internal Medicine, The First Affiliated Hospital, Xinjiang Medical University, No. 137, Liyushan South Road, Urumqi, Xinjiang, 830000, China.
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18
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Reiter RJ, Sharma R, Cucielo MS, Tan DX, Rosales-Corral S, Gancitano G, de Almeida Chuffa LG. Brain washing and neural health: role of age, sleep, and the cerebrospinal fluid melatonin rhythm. Cell Mol Life Sci 2023; 80:88. [PMID: 36917314 PMCID: PMC11072793 DOI: 10.1007/s00018-023-04736-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2022] [Revised: 02/02/2023] [Accepted: 02/24/2023] [Indexed: 03/16/2023]
Abstract
The brain lacks a classic lymphatic drainage system. How it is cleansed of damaged proteins, cellular debris, and molecular by-products has remained a mystery for decades. Recent discoveries have identified a hybrid system that includes cerebrospinal fluid (CSF)-filled perivascular spaces and classic lymph vessels in the dural covering of the brain and spinal cord that functionally cooperate to remove toxic and non-functional trash from the brain. These two components functioning together are referred to as the glymphatic system. We propose that the high levels of melatonin secreted by the pineal gland directly into the CSF play a role in flushing pathological molecules such as amyloid-β peptide (Aβ) from the brain via this network. Melatonin is a sleep-promoting agent, with waste clearance from the CNS being highest especially during slow wave sleep. Melatonin is also a potent and versatile antioxidant that prevents neural accumulation of oxidatively-damaged molecules which contribute to neurological decline. Due to its feedback actions on the suprachiasmatic nucleus, CSF melatonin rhythm functions to maintain optimal circadian rhythmicity, which is also critical for preserving neurocognitive health. Melatonin levels drop dramatically in the frail aged, potentially contributing to neurological failure and dementia. Melatonin supplementation in animal models of Alzheimer's disease (AD) defers Aβ accumulation, enhances its clearance from the CNS, and prolongs animal survival. In AD patients, preliminary data show that melatonin use reduces neurobehavioral signs such as sundowning. Finally, melatonin controls the mitotic activity of neural stem cells in the subventricular zone, suggesting its involvement in neuronal renewal.
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Affiliation(s)
- Russel J Reiter
- Department of Cell Systems and Anatomy, Long School of Medicine, UT Health San Antonio, San Antonio, TX, 78229, USA.
| | - Ramaswamy Sharma
- Department of Cell Systems and Anatomy, Long School of Medicine, UT Health San Antonio, San Antonio, TX, 78229, USA.
| | - Maira Smaniotto Cucielo
- Department of Structural and Functional Biology-IBB/UNESP, Institute of Biosciences of Botucatu, Universidade Estadual Paulista, Botucatu, São Paulo, 18618-689, Brazil
| | | | - Sergio Rosales-Corral
- Centro de Investigacion Biomedica de Occidente, Instituto Mexicano del Seguro Social, Guadalajara, Mexico
| | - Giuseppe Gancitano
- 1st "Tuscania" Paratrooper Regiment, Italian Ministry of Defense, 57127, Leghorn, Italy
| | - Luiz Gustavo de Almeida Chuffa
- Department of Structural and Functional Biology-IBB/UNESP, Institute of Biosciences of Botucatu, Universidade Estadual Paulista, Botucatu, São Paulo, 18618-689, Brazil
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19
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miR-9a-5p Protects Ischemic Stroke by Regulating Oxidative Stress and Mitochondrial Autophagy. DISEASE MARKERS 2023; 2023:5146305. [PMID: 36845011 PMCID: PMC9957637 DOI: 10.1155/2023/5146305] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 09/29/2022] [Accepted: 10/17/2022] [Indexed: 02/19/2023]
Abstract
Purpose Present research is aimed at exploring the effect of miR-9a-5p on mitochondrial autophagy and alleviating cellular oxidative stress injury in ischemic stroke. Methods SH-SY5Y cells were cultured with oxygen-glucose deprivation/reoxygenation (OGD/R) to simulate ischemia/reperfusion. The cells were treated in an anaerobic incubator (95% N2, 5% CO2) for 2 h and then reoxygenated in the normoxic condition for 24 h with 2 ml of normal medium. Cells were transfected with miR-9a-5p mimic/inhibitor or negative control. The RT-qPCR assay was utilized to measure the mRNA expression. Western blot was utilized to evaluate the protein expression. The CCK-8 assay was conducted to detect cell viability. Flow cytometry was applied to examine apoptosis and the cell cycle. The ELISA assay was applied to measure the contents of SOD and MDA in mitochondria. Autophagosomes were observed via electron microscopy. Results By comparison with the control group, the miR-9a-5p expression in the OGD/R group obviously declined. Mitochondrial crista breaks, vacuole-like changes, and increased autophagosome formation were observed in the OGD/R group. OGD/R injury enhanced oxidative stress damage and mitophagy. When transfected with the miR-9a-5p mimic, mitophagosome production of SH-SY5Y cells decreased and oxidative stress injury was inhibited. However, the miR-9a-5p inhibitor obviously increased mitophagosome production and enhanced oxidative stress injury. Conclusion miR-9a-5p protects against ischemic stroke by inhibiting OGD/R-induced mitochondrial autophagy and alleviating cellular oxidative stress injury.
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20
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Zhu SF, Yuan W, Du YL, Wang BL. Research progress of lncRNA and miRNA in hepatic ischemia-reperfusion injury. Hepatobiliary Pancreat Dis Int 2023; 22:45-53. [PMID: 35934611 DOI: 10.1016/j.hbpd.2022.07.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 07/18/2022] [Indexed: 02/07/2023]
Abstract
BACKGROUND Hepatic ischemia-reperfusion injury (HIRI) is a common complication of liver surgeries, such as hepatectomy and liver transplantation. In recent years, several non-coding RNAs (ncRNAs) including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) have been identified as factors involved in the pathological progression of HIRI. In this review, we summarized the latest research on lncRNAs, miRNAs and the lncRNA-miRNA regulatory networks in HIRI. DATA SOURCES The PubMed and Web of Science databases were searched for articles published up to December 2021 using the following keywords: "hepatic ischemia-reperfusion injury", "lncRNA", "long non-coding RNA", "miRNA" and "microRNA". The bibliography of the selected articles was manually screened to identify additional studies. RESULTS The mechanism of HIRI is complex, and involves multiple lncRNAs and miRNAs. The roles of lncRNAs such as AK139328, CCAT1, MALAT1, TUG1 and NEAT1 have been established in HIRI. In addition, numerous miRNAs are associated with apoptosis, autophagy, oxidative stress and cellular inflammation that accompany HIRI pathogenesis. Based on the literature, we conclude that four lncRNA-miRNA regulatory networks mediate the pathological progression of HIRI. Furthermore, the expression levels of some lncRNAs and miRNAs undergo significant changes during the progression of HIRI, and thus are potential prognostic markers and therapeutic targets. CONCLUSIONS Complex lncRNA-miRNA-mRNA networks regulate HIRI progression through mutual activation and antagonism. It is necessary to screen for more HIRI-associated lncRNAs and miRNAs in order to identify novel therapeutic targets.
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Affiliation(s)
- Shan-Fei Zhu
- Department of Hepatobiliary Surgery, Guangzhou Red Cross Hospital of Jinan University, Guangzhou 510220, China
| | - Wei Yuan
- Department of Hepatobiliary Surgery, Guangzhou Red Cross Hospital of Jinan University, Guangzhou 510220, China
| | - Yong-Liang Du
- Department of Hepatobiliary Surgery, Guangzhou Red Cross Hospital of Jinan University, Guangzhou 510220, China
| | - Bai-Lin Wang
- Department of Hepatobiliary Surgery, Guangzhou Red Cross Hospital of Jinan University, Guangzhou 510220, China.
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21
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Liu C, Liu Y, Ma B, Zhou M, Zhao X, Fu X, Kan S, Hu W, Zhu R. Mitochondrial regulatory mechanisms in spinal cord injury: A narrative review. Medicine (Baltimore) 2022; 101:e31930. [PMID: 36401438 PMCID: PMC9678589 DOI: 10.1097/md.0000000000031930] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/03/2022] Open
Abstract
Spinal cord injury is a severe central nervous system injury that results in the permanent loss of motor, sensory, and autonomic functions below the level of injury with limited recovery. The pathological process of spinal cord injury includes primary and secondary injuries, characterized by a progressive cascade. Secondary injury impairs the ability of the mitochondria to maintain homeostasis and leads to calcium overload, excitotoxicity, and oxidative stress, further exacerbating the injury. The defective mitochondrial function observed in these pathologies accelerates neuronal cell death and inhibits regeneration. Treatment of spinal cord injury by preserving mitochondrial biological function is a promising, although still underexplored, therapeutic strategy. This review aimed to explore mitochondrial-based therapeutic advances after spinal cord injury. Specifically, it briefly describes the characteristics of spinal cord injury. It then broadly discusses the drugs used to protect the mitochondria (e.g., cyclosporine A, acetyl-L-carnitine, and alpha-tocopherol), phenomena associated with mitochondrial damage processes (e.g., mitophagy, ferroptosis, and cuproptosis), mitochondrial transplantation for nerve cell regeneration, and innovative mitochondrial combined protection therapy.
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Affiliation(s)
- Chengjiang Liu
- Department of Spine Surgery, Tianjin Union Medical Center Tianjin, Tianjin, China
| | - Yidong Liu
- Department of Spine Surgery, Tianjin Union Medical Center Tianjin, Tianjin, China
| | - Boyuan Ma
- Department of Spine Surgery, Tianjin Union Medical Center Tianjin, Tianjin, China
| | - Mengmeng Zhou
- Department of Spine Surgery, Tianjin Union Medical Center Tianjin, Tianjin, China
| | - Xinyan Zhao
- Department of Spine Surgery, Tianjin Union Medical Center Tianjin, Tianjin, China
| | - Xuanhao Fu
- Department of Spine Surgery, Tianjin Union Medical Center Tianjin, Tianjin, China
| | - Shunli Kan
- Department of Spine Surgery, Tianjin Union Medical Center Tianjin, Tianjin, China
| | - Wei Hu
- Department of Spine Surgery, Tianjin Union Medical Center Tianjin, Tianjin, China
| | - Rusen Zhu
- Department of Spine Surgery, Tianjin Union Medical Center Tianjin, Tianjin, China
- *Correspondence: Rusen Zhu, Department of Spine Surgery, Tianjin Union Medical Center190jieyuan Road, Honggiao District, Tianjin 300121, China (e-mail: )
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22
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Hardeland R. Redox Biology of Melatonin: Discriminating Between Circadian and Noncircadian Functions. Antioxid Redox Signal 2022; 37:704-725. [PMID: 35018802 PMCID: PMC9587799 DOI: 10.1089/ars.2021.0275] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 12/31/2021] [Indexed: 12/15/2022]
Abstract
Melatonin has not only to be seen as a regulator of circadian clocks. In addition to its chronobiotic functions, it displays other actions, especially in cell protection. This includes antioxidant, anti-inflammatory, and mitochondria-protecting effects. Although protection is also modulated by the circadian system, the respective actions of melatonin can be distinguished and differ with regard to dose requirements in therapeutic settings. It is the aim of this article to outline these differences in terms of function, signaling, and dosage. Focus has been placed on both the nexus and the dissecting properties between circadian and noncircadian mechanisms. This has to consider details beyond the classic view of melatonin's role, such as widespread synthesis in extrapineal tissues, formation in mitochondria, effects on the mitochondrial permeability transition pore, and secondary signaling, for example, via upregulation of sirtuins and by regulating noncoding RNAs, especially microRNAs. The relevance of these findings, the differences and connections between circadian and noncircadian functions of melatonin shed light on the regulation of inflammation, including macrophage/microglia polarization, damage-associated molecular patterns, avoidance of cytokine storms, and mitochondrial functions, with numerous consequences to antioxidative protection, that is, aspects of high actuality with regard to deadly viral and bacterial diseases. Antioxid. Redox Signal. 37, 704-725.
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Affiliation(s)
- Rüdiger Hardeland
- Johann Friedrich Blumenbach Institute of Zoology and Anthropology, University of Goettingen, Goettingen, Germany
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23
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Melatonin Alleviates Acute Kidney Injury by Inhibiting NRF2/Slc7a11 Axis-Mediated Ferroptosis. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:4776243. [PMID: 35979396 PMCID: PMC9377938 DOI: 10.1155/2022/4776243] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 04/21/2022] [Accepted: 07/14/2022] [Indexed: 11/18/2022]
Abstract
Acute kidney injury (AKI) is still a puzzling clinical problem; its pathophysiology is not completely understood. Up to now, an effective treatment for AKI is lacking. Ferroptosis is a novel form of regulated cell death characterized by the lethal accumulation of lipid hydroperoxides that are dependent on iron and reactive oxygen species and mitochondrial dysfunction. Recently, ferroptosis was shown to play a vital role in AKI such as ischemia-reperfusion kidney injury and folic acid-induced AKI. Melatonin (MT) is an antioxidant that regulates the sleep-wake cycle. While the therapeutic effect of melatonin on AKI has been reported, its mechanism for the treatment of renal ferroptosis remains unclear. We found that melatonin treatment significantly alleviated the serum biochemistry index and histopathological alterations in vivo AKI models induced by bilateral renal artery ischemia reperfusion and folic acid in mice. Ferroptosis induced by hypoxia and reoxygenation or erastin (Era) in mouse tubular epithelial cells (MTEC) was also rescued by melatonin treatment. RNA sequence analysis of ferroptosis-related genes showed that melatonin affects oxidative stress responses by inhibiting hypoxia and reoxygenation- (HR-) mediated downregulation of NRF2 and upregulation of Slc7a11 in MTEC. Specific knockdown of NRF2 increased the sensitivity of cells to ferroptosis, and melatonin failed to protect against ferroptosis in the HR condition. Together, our data indicate that melatonin prevents ferroptosis in AKI by acting on the NRF2/Slc7a11 axis.
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24
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Yao S, Wei X, Deng W, Wang B, Cai J, Huang Y, Lai X, Qiu Y, Wang Y, Guan Y, Wang J. Nestin-dependent mitochondria-ER contacts define stem Leydig cell differentiation to attenuate male reproductive ageing. Nat Commun 2022; 13:4020. [PMID: 35821241 PMCID: PMC9276759 DOI: 10.1038/s41467-022-31755-w] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Accepted: 06/30/2022] [Indexed: 11/09/2022] Open
Abstract
Male reproductive system ageing is closely associated with deficiency in testosterone production due to loss of functional Leydig cells, which are differentiated from stem Leydig cells (SLCs). However, the relationship between SLC differentiation and ageing remains unknown. In addition, active lipid metabolism during SLC differentiation in the reproductive system requires transportation and processing of substrates among multiple organelles, e.g., mitochondria and endoplasmic reticulum (ER), highlighting the importance of interorganelle contact. Here, we show that SLC differentiation potential declines with disordered intracellular homeostasis during SLC senescence. Mechanistically, loss of the intermediate filament Nestin results in lower differentiation capacity by separating mitochondria-ER contacts (MERCs) during SLC senescence. Furthermore, pharmacological intervention by melatonin restores Nestin-dependent MERCs, reverses SLC differentiation capacity and alleviates male reproductive system ageing. These findings not only explain SLC senescence from a cytoskeleton-dependent MERCs regulation mechanism, but also suggest a promising therapy targeting SLC differentiation for age-related reproductive system diseases. The regulatory mechanisms contributing to male reproductive ageing are unknown. Here, the authors show that Nestin-dependent mito-ER contacts (MERCs) regulate stem Leydig cell (SLC) senescence and provide insights into SLCs-targeting therapies.
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Affiliation(s)
- Senyu Yao
- Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, China.,Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Xiaoyue Wei
- Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, China.,Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Wenrui Deng
- Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, China.,Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Boyan Wang
- Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, China.,Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Jianye Cai
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, 510080, China.,Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital, Organ Transplantation Institute, Sun Yat-Sen University, Guangzhou, 510630, China
| | - Yinong Huang
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, 510080, China.,Department of Endocrinology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, China
| | - Xiaofan Lai
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, 510080, China.,Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Yuan Qiu
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Yi Wang
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Yuanjun Guan
- Core Facility of Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Jiancheng Wang
- Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, China. .,Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, 510080, China. .,Department of Hematology, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518107, China.
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25
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Qin S, Tian Z, Boidin M, Buckley BJR, Thijssen DHJ, Lip GYH. Irisin is an Effector Molecule in Exercise Rehabilitation Following Myocardial Infarction (Review). Front Physiol 2022; 13:935772. [PMID: 35845994 PMCID: PMC9276959 DOI: 10.3389/fphys.2022.935772] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Accepted: 06/01/2022] [Indexed: 11/29/2022] Open
Abstract
Background: Regular exercise is an effective non-pharmacological therapy for treatment and prevention of cardiovascular disease (CVD). The therapeutic benefits of exercise are mediated partly through improved vascular and increase in metabolic health. Release of exercise-responsive myokines, including irisin, is associated with beneficial effects of exercise in CVD patients. Observations: The present review provides an overview of the role of exercise in cardiac rehabilitation of patients with myocardial infarction (MI). Further, the role of irisin as a motion-responsive molecule in improving vascular and metabolic health is explored. Possible mechanism of cardioprotective effect of irisin-mediated exercise on myocardial infarction are also summarized in this review. Conclusion and significance of the review: Irisin is associated with reduced inflammation, antioxidant properties, and anti-apoptotic effect, implying that it is a potential key mediator of the beneficial effects of exercise on vascular and metabolic health. The findings show that irisin is a promising therapeutic target for treatment of patients with cardiovascular disease, particularly post-MI. Further research should be conducted to elucidate the potential mechanisms of cardioprotective effects of irisin and explored whether irisin induced by exercise exerts rehabilitation effects post-MI.
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Affiliation(s)
- Shuguang Qin
- Institute of Sports and Exercise Biology, School of Physical Education, Shaanxi Normal University, Xi’an, China
- Department of Cardiology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Zhenjun Tian
- Institute of Sports and Exercise Biology, School of Physical Education, Shaanxi Normal University, Xi’an, China
- *Correspondence: Zhenjun Tian,
| | - Maxime Boidin
- Liverpool Centre for Cardiovascular Science, Liverpool John Moores University, Liverpool, United Kingdom
- Cardiovascular Prevention and Rehabilitation (EPIC) Center, Montreal Heart Institute, Montreal, QC, Canada
- School of Kinesiology and Exercise Science, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada
| | - Benjamin J. R. Buckley
- Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart and Chest Hospital, Liverpool, United Kingdom
- Cardiovascular and Metabolic Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, United Kingdom
| | - Dick H. J. Thijssen
- Liverpool Centre for Cardiovascular Science, Liverpool John Moores University, Liverpool, United Kingdom
- Research Institute for Sport and Exercise Sciences, Liverpool John Moores University, Liverpool, United Kingdom
| | - Gregory Y. H. Lip
- Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart and Chest Hospital, Liverpool, United Kingdom
- Cardiovascular and Metabolic Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, United Kingdom
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26
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Zhuo X, Jiang H. Protective effects of melatonin in cisplatin-induced cardiac toxicity: possible role of BDNF-TNF-α signaling pathway. Acta Cir Bras 2022; 37:e370208. [PMID: 35507972 PMCID: PMC9064185 DOI: 10.1590/acb370208] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Accepted: 11/22/2021] [Indexed: 11/22/2022] Open
Abstract
Purpose: The present study explored the role of melatonin in cisplatin-induced cardiac injury along with the possible role of brain-derived neurotrophic factor (BDNF) in melatonin-mediated effects. Methods: Wistar rats were administered cisplatin (10 mg/kg), and cardiac injury was assessed by measuring the levels of cardiac troponin (cTnT) and lactate dehydrogenase (LDH-1).The extent of apoptosis was measured by measuring caspase-3 (pro-apoptotic) and Bcl-2 (anti-apoptotic) in hearts. The levels of BDNF, tumour necrosis factor α (TNF-α) and reduced glutathione were measured in heart. Melatonin (5 and 10 mg/kg) was administered for 15 days, and the role of BDNF was identified by co-administering BDNF inhibitor, ANA-12 (0.25 and 0.5 mg/kg). Results: Melatonin attenuated cTnT and LDH-1 levels along with reduction in caspase-3 and increase in Bcl-2. It also increased cisplatin-induced decrease in BDNF, increase in TNF-α and decrease in reduced glutathione levels. Moreover, ANA-12 abolished the cardioprotective effects, anti-inflammatory and antioxidant effects of melatonin suggesting the role of BDNF in melatonin-mediated effects in cisplatin-induced cardiac injury. Conclusions: Melatonin is useful in cisplatin-induced cardiac injury, which may be due to an increase in BDNF, decrease in inflammation and increase in antioxidant activities.
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27
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Reiter RJ, Sharma R, Rosales-Corral S, de Campos Zuccari DAP, de Almeida Chuffa LG. Melatonin: A mitochondrial resident with a diverse skill set. Life Sci 2022; 301:120612. [PMID: 35523285 DOI: 10.1016/j.lfs.2022.120612] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 04/25/2022] [Accepted: 04/30/2022] [Indexed: 12/12/2022]
Abstract
Melatonin is an ancient molecule that originated in bacteria. When these prokaryotes were phagocytized by early eukaryotes, they eventually developed into mitochondria and chloroplasts. These new organelles retained the melatonin synthetic capacity of their forerunners such that all present-day animal and plant cells may produce melatonin in their mitochondria and chloroplasts. Melatonin concentrations are higher in mitochondria than in other subcellular compartments. Isolated mouse oocyte mitochondria form melatonin when they are incubated with serotonin, a necessary precursor. Oocyte mitochondria subsequently give rise to these organelles in all adult vertebrate cells where they continue to synthesize melatonin. The enzymes that convert serotonin to melatonin, i.e., arylalkylamine-N-acetyltransferase (AANAT) and acetylserotonin-O-methyltransferase, have been identified in brain mitochondria which, when incubated with serotonin, also form melatonin. Melatonin is a potent antioxidant and anti-cancer agent and is optimally positioned in mitochondria to aid in the maintenance of oxidative homeostasis and to reduce cancer cell transformation. Melatonin stimulates the transfer of mitochondria from healthy cells to damaged cells via tunneling nanotubes. Melatonin also regulates the major NAD+-dependent deacetylase, sirtuin 3, in the mitochondria. Disruptions of mitochondrial melatonin synthesis may contribute to a number of mitochondria-related diseases, as discussed in this review.
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Affiliation(s)
- Russel J Reiter
- Department of Cell Systems and Anatomy, UT Health, San Antonio, TX 78229, USA.
| | - Ramaswamy Sharma
- Department of Cell Systems and Anatomy, UT Health, San Antonio, TX 78229, USA.
| | - Sergio Rosales-Corral
- Centro de Investigacion Biomedica de Occidente, Instituto Mexicano del Seguro Social, Guadalajara, Jalisco CP45150, Mexico
| | | | - Luiz Gustavo de Almeida Chuffa
- Department of Structural and Functional Biology, Institute of Biosciences, UNESP-São Paulo State University, Botucatu, São Paulo 18618-689, Brazil
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28
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Zheng Y, Tao Y, Zhan X, Wu Q. Nuclear receptor 4A1 (NR4A1) silencing protects hepatocyte against hypoxia-reperfusion injury in vitro by activating liver kinase B1 (LKB1)/AMP-activated protein kinase (AMPK) signaling. Bioengineered 2022; 13:8349-8359. [PMID: 35311465 PMCID: PMC9161842 DOI: 10.1080/21655979.2022.2053804] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 03/08/2022] [Accepted: 03/10/2022] [Indexed: 02/03/2023] Open
Abstract
The nuclear receptor 4A1 (NR4A1) is widely involved in the regulation of cell survival and is related to ischemic injury in several organs. This research examined the emerging role and mechanism of NR4A1 in hepatocyte ischemia-reperfusion injury (IRI). BRL-3A cells were subjected to hypoxia-reperfusion (H/R) to simulate an IRI model in vitro. The expression of NR4A1 and liver kinase B1 (LKB1)/AMP-activated protein kinase (AMPK) pathway-related proteins (LKB1, AMPK, and ACC) was detected by western blotting or RT-qPCR under H/R condition after NR4A1 overexpression or silencing. Then, radicicol, an inhibitor of LKB1 pathway, was used to determine the role of NR4A1 in hepatocyte H/R injury by regulating LKB1. Under the help of CCK-8 assay, cell viability was assessed. The levels of ROS, MDA, and SOD were determined with corresponding kits to evaluate oxidative stress. Additionally, RT-qPCR was employed to analyze the releases of the inflammatory factors. Flow cytometry was applied to estimate the apoptosis and its related proteins, and autophagy-associated proteins were assayed by western blotting. Results indicated that NR4A1 was highly expressed, while proteins in LKB1/AMPK signaling was downregulated in BRL-3A cells exposed to H/R. The activation of LKB1/AMPK pathway could be negatively regulated by NR4A1. Moreover, NR4A1 depletion conspicuously promoted cell viability, inhibited oxidative stress as well as inflammation, and induced apoptosis and autophagy in H/R-stimulated BRL-3A cells, which were reversed after radicicol intervention. Collectively, NR4A1/LKB1/AMPK axis is a new protective pathway involved in hepatocyte IRI, shedding new insights into the improvement of hepatocyte IRI.
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Affiliation(s)
- Yu Zheng
- Hepatobiliary Pancreatic Surgery Department, Tongde Hospital of Zhejiang Province, Hangzhou, China
| | - Yingying Tao
- Emergency Intensive Care Unit, Hangzhou Ninth People’s Hospital, Hangzhou, China
| | - Xiaobo Zhan
- Hepatobiliary Pancreatic Surgery Department, Tongde Hospital of Zhejiang Province, Hangzhou, China
| | - Qi Wu
- Hepatobiliary Pancreatic Surgery Department, Tongde Hospital of Zhejiang Province, Hangzhou, China
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Ergenc M, Ozacmak HS, Turan I, Ozacmak VH. Melatonin reverses depressive and anxiety like-behaviours induced by diabetes: involvement of oxidative stress, age, rage and S100B levels in the hippocampus and prefrontal cortex of rats. Arch Physiol Biochem 2022; 128:402-410. [PMID: 31726890 DOI: 10.1080/13813455.2019.1684954] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Diabetes is associated with depression and anxiety symptoms. The current investigation was designed to explore the effect of melatonin on depressive and anxiety like-behaviours, oxidative stress, levels of AGE, RAGE and S100B in streptozotocin-induced diabetic rats. The animals were divided into four groups: Normoglycemic; Normoglycemic + melatonin; diabetic; diabetic + melatonin (10 mg/kg, for 4 weeks). The malondialdehyde (MDA), reduced glutathione (GSH), AGE, RAGE and S100B were measured and the depressive and anxiety like-behaviours were assessed by forced swimming and elevated plus maze tests, respectively. Melatonin ameliorates depressive and anxiety like-behaviours. Concomitantly, melatonin reversed diabetes induced increase of MDA, AGE and decrease of GSH and S100B levels in the hippocampus and prefrontal cortex. In conclusion, our results showed that melatonin administration may exert antidepressant-like and anxiolytic effects in diabetic rats through normalising of AGE/RAGE, S100B and oxidative stress in the prefrontal cortex and hippocampus.
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Affiliation(s)
- Meryem Ergenc
- Faculty of Medicine, Department of Physiology, Zonguldak Bulent Ecevit University, Zonguldak, Turkey
| | - Hale Sayan Ozacmak
- Faculty of Medicine, Department of Physiology, Zonguldak Bulent Ecevit University, Zonguldak, Turkey
| | - Inci Turan
- Faculty of Medicine, Department of Physiology, Zonguldak Bulent Ecevit University, Zonguldak, Turkey
| | - Veysel Haktan Ozacmak
- Faculty of Medicine, Department of Physiology, Zonguldak Bulent Ecevit University, Zonguldak, Turkey
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30
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Melatonin-Induced Postconditioning Suppresses NMDA Receptor through Opening of the Mitochondrial Permeability Transition Pore via Melatonin Receptor in Mouse Neurons. Int J Mol Sci 2022; 23:ijms23073822. [PMID: 35409182 PMCID: PMC8998233 DOI: 10.3390/ijms23073822] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Revised: 03/02/2022] [Accepted: 03/28/2022] [Indexed: 12/29/2022] Open
Abstract
Mitochondrial membrane potential regulation through the mitochondrial permeability transition pore (mPTP) is reportedly involved in the ischemic postconditioning (PostC) phenomenon. Melatonin is an endogenous hormone that regulates circadian rhythms. Its neuroprotective effects via mitochondrial melatonin receptors (MTs) have recently attracted attention. However, details of the neuroprotective mechanisms associated with PostC have not been clarified. Using hippocampal CA1 pyramidal cells from C57BL mice, we studied the involvement of MTs and the mPTP in melatonin-induced PostC mechanisms similar to those of ischemic PostC. We measured changes in spontaneous excitatory postsynaptic currents (sEPSCs), intracellular calcium concentration, mitochondrial membrane potential, and N-methyl-D-aspartate receptor (NMDAR) currents after ischemic challenge, using the whole-cell patch-clamp technique. Melatonin significantly suppressed increases in sEPSCs and intracellular calcium concentrations. The NMDAR currents were significantly suppressed by melatonin and the MT agonist, ramelteon. However, this suppressive effect was abolished by the mPTP inhibitor, cyclosporine A, and the MT antagonist, luzindole. Furthermore, both melatonin and ramelteon potentiated depolarization of mitochondrial membrane potentials, and luzindole suppressed depolarization of mitochondrial membrane potentials. This study suggests that melatonin-induced PostC via MTs suppressed the NMDAR that was induced by partial depolarization of mitochondrial membrane potential by opening the mPTP, reducing excessive release of glutamate and inducing neuroprotection against ischemia-reperfusion injury.
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31
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Zhang Y, Yang N, Huang X, Zhu Y, Gao S, Liu Z, Cao F, Wang Y. Melatonin Engineered Adipose-Derived Biomimetic Nanovesicles Regulate Mitochondrial Functions and Promote Myocardial Repair in Myocardial Infarction. Front Cardiovasc Med 2022; 9:789203. [PMID: 35402545 PMCID: PMC8985816 DOI: 10.3389/fcvm.2022.789203] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Accepted: 01/31/2022] [Indexed: 12/22/2022] Open
Abstract
Myocardial infarction (MI), one type of ischemic heart disease, is a major cause of disability and mortality worldwide. Currently, extracellular vesicles (EVs) derived from adipose-derived stem cells (ADSC) have been proven to be a potentially promising therapeutic treatment for MI. However, the inconvenience of isolation, the low productivity, and the high cost of EVs greatly limits their application in clinic. In this study, we constructed novel biomimetic ADSC-derived nanovesicles (ADSC NVs) to achieve cell-free therapy for MI. Here, we firstly developed a novel Mel@NVs delivery system consisting of engineered ADSC NVs with melatonin (Mel). Then, the characterization and properties of Mel@NVs were performed. The effect of Mel@NVs on cellular oxidative stress and myocardial infarction repair was conducted. The results showed that Mel@NVs treatment under ischemia mimic condition reduced cell apoptosis from 42.59 ± 2.69% to 13.88 ± 1.77%. Moreover, this novel engineered Mel@NVs could ameliorate excessive ROS generation, promote microvessel formation, and attenuate cardiac fibrosis, which further alleviates mitochondrial dysfunction and finally enhance myocardial repair. Hence, the engineered NVs show a potential strategy for MI therapy.
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Affiliation(s)
- Yang Zhang
- Department of Cardiology, The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese People's Liberation Army General Hospital and Medical School of Chinese People's Liberation Army, Beijing, China
| | - Ning Yang
- Department of Cardiology, The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese People's Liberation Army General Hospital and Medical School of Chinese People's Liberation Army, Beijing, China
| | - Xu Huang
- Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Yan Zhu
- Department of Cardiology, The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese People's Liberation Army General Hospital and Medical School of Chinese People's Liberation Army, Beijing, China
- Nankai University School of Medicine, Nankai University, Tianjin, China
| | - Shan Gao
- Department of Cardiology, The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese People's Liberation Army General Hospital and Medical School of Chinese People's Liberation Army, Beijing, China
| | - Zhongyang Liu
- Department of Orthopedics, The Fourth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Feng Cao
- Department of Cardiology, The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese People's Liberation Army General Hospital and Medical School of Chinese People's Liberation Army, Beijing, China
- Feng Cao
| | - Yabin Wang
- Department of Cardiology, The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese People's Liberation Army General Hospital and Medical School of Chinese People's Liberation Army, Beijing, China
- *Correspondence: Yabin Wang
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32
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Li J, Peng Q, Yang R, Li K, Zhu P, Zhu Y, Zhou P, Szabó G, Zheng S. Application of Mesenchymal Stem Cells During Machine Perfusion: An Emerging Novel Strategy for Organ Preservation. Front Immunol 2022; 12:713920. [PMID: 35024039 PMCID: PMC8744145 DOI: 10.3389/fimmu.2021.713920] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 12/03/2021] [Indexed: 12/24/2022] Open
Abstract
Although solid organ transplantation remains the definitive management for patients with end-stage organ failure, this ultimate treatment has been limited by the number of acceptable donor organs. Therefore, efforts have been made to expand the donor pool by utilizing marginal organs from donation after circulatory death or extended criteria donors. However, marginal organs are susceptible to ischemia-reperfusion injury (IRI) and entail higher requirements for organ preservation. Recently, machine perfusion has emerged as a novel preservation strategy for marginal grafts. This technique continually perfuses the organs to mimic the physiologic condition, allows the evaluation of pretransplant graft function, and more excitingly facilitates organ reconditioning during perfusion with pharmacological, gene, and stem cell therapy. As mesenchymal stem cells (MSCs) have anti-oxidative, immunomodulatory, and regenerative properties, mounting studies have demonstrated the therapeutic effects of MSCs on organ IRI and solid organ transplantation. Therefore, MSCs are promising candidates for organ reconditioning during machine perfusion. This review provides an overview of the application of MSCs combined with machine perfusion for lung, kidney, liver, and heart preservation and reconditioning. Promising preclinical results highlight the potential clinical translation of this innovative strategy to improve the quality of marginal grafts.
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Affiliation(s)
- Jiale Li
- Department of Cardiovascular Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Qinbao Peng
- Department of Cardiovascular Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Ronghua Yang
- Department of Burn Surgery and Skin Regeneration, The First People's Hospital of Foshan, Foshan, China
| | - Kunsheng Li
- Department of Cardiothoracic Surgery, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, China
| | - Peng Zhu
- Department of Cardiovascular Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yufeng Zhu
- Laboratory Animal Research Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Pengyu Zhou
- Department of Cardiovascular Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Gábor Szabó
- Department of Cardiac Surgery, Heidelberg University Hospital, Heidelberg, Germany.,Department of Cardiac Surgery, University Hospital Halle (Saale), Halle, Germany
| | - Shaoyi Zheng
- Department of Cardiovascular Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
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33
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STING Induces Liver Ischemia-Reperfusion Injury by Promoting Calcium-Dependent Caspase 1-GSDMD Processing in Macrophages. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:8123157. [PMID: 35281468 PMCID: PMC8906939 DOI: 10.1155/2022/8123157] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/18/2021] [Revised: 10/26/2021] [Accepted: 01/15/2022] [Indexed: 12/31/2022]
Abstract
Objectives Although a recent study reported that stimulator of interferon genes (STING) in macrophages has an important regulatory effect on liver ischemia-reperfusion injury (IRI), the underlying mechanism of STING-dependent innate immune activation in liver macrophages (Kupffer cells, KCs) remains unclear. Here, we investigated the effect of STING on liver macrophage pyroptosis and the associated regulatory mechanism of liver IRI. Methods Clodronate liposomes were used to block liver macrophages. AAV-STING-RNAi-F4/80-EGFP, an adenoassociated virus (AAV), was transfected into the portal vein of mice in vivo, and the liver IRI model was established 14 days later. In vitro, liver macrophages were treated with STING-specific siRNA, and a hypoxia-reoxygenation (H/R) model was established. The level of STING was detected via Western blotting (WB), RT-PCR, and immunostaining. Liver tissue and blood samples were collected. Pathological changes in liver tissue were detected by hematoxylin and eosin (H&E) staining. Macrophage pyroptosis was detected by WB, confocal laser scanning microscopy (CLSM), transmission electron microscopy (TEM), and enzyme-linked immunosorbent assay (ELISA). The calcium concentration was measured by immunofluorescence and analyzed with a fluorescence microplate reader. Results The expression of STING increased with liver IRI but decreased significantly after the clodronate liposome blockade of liver macrophages. After knockdown of STING, the activation of caspase 1-GSDMD in macrophages and liver IRI was alleviated. More interestingly, hypoxia/reoxygenation (H/R) increased the calcium concentration in liver macrophages, but the calcium concentration was decreased after STING knockdown. Furthermore, after the inhibition of calcium in H/R-induced liver macrophages by BAPTA-AM, pyroptosis was significantly reduced, but the expression of STING was not significantlydecreased. Conclusions Knockdown of STING reduces calcium-dependent macrophage caspase 1-GSDMD-mediated liver IRI, representing a potential therapeutic approach in the clinic.
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Mirza-Aghazadeh-Attari M, Mihanfar A, Yousefi B, Majidinia M. Nanotechnology-based advances in the efficient delivery of melatonin. Cancer Cell Int 2022; 22:43. [PMID: 35093076 PMCID: PMC8800219 DOI: 10.1186/s12935-022-02472-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 01/16/2022] [Indexed: 01/09/2023] Open
Abstract
N-[2-(5-methoxy-1H-indol-3-yl) ethyl] or simply melatonin is a biogenic amine produced by pineal gland and recently recognized various other organs. Because of a broad range of biological function melatonin is considered as a therapeutic agent with high efficacy in the treatment of multiple disorders, such as cancer, degenerative disorders and immune disease. However, since melatonin can affect receptors on the cellular membrane, in the nucleus and can act as an anti-oxidant molecule, some unwanted effects may be observed after administration. Therefore, the entrapment of melatonin in biocompatible, biodegradable and safe nano-delivery systems can prevent its degradation in circulation; decrease its toxicity with increased half-life, enhanced pharmacokinetic profile leading to improved patient compliance. Because of this, nanoparticles have been used to deliver melatonin in multiple studies, and the present article aims to cumulatively illustrate their findings.
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Affiliation(s)
| | - Ainaz Mihanfar
- Department of Biochemistry, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Bahman Yousefi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Majidinia
- Solid Tumor Research Center, Cellular and Molecular Medicine Institute, Urmia University of Medical Sciences, Orjhans Street, Resalat Blvd, Urmia, Iran.
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35
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Mao XL, Cai Y, Chen YH, Wang Y, Jiang XX, Ye LP, Li SW. Novel Targets and Therapeutic Strategies to Protect Against Hepatic Ischemia Reperfusion Injury. Front Med (Lausanne) 2022; 8:757336. [PMID: 35059411 PMCID: PMC8764312 DOI: 10.3389/fmed.2021.757336] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Accepted: 12/08/2021] [Indexed: 12/16/2022] Open
Abstract
Hepatic ischemia reperfusion injury (IRI), a fascinating topic that has drawn a lot of interest in the last few years, is a major complication caused by a variety of clinical situations, such as liver transplantation, severe trauma, vascular surgery, and hemorrhagic shock. The IRI process involves a series of complex events, including mitochondrial deenergization, metabolic acidosis, adenosine-5'-triphosphate depletion, Kupffer cell activation, calcium overload, oxidative stress, and the upregulation of pro-inflammatory cytokine signal transduction. A number of protective strategies have been reported to ameliorate IRI, including pharmacological therapy, ischemic pre-conditioning, ischemic post-conditioning, and machine reperfusion. However, most of these strategies are only at the stage of animal model research at present, and the potential mechanisms and exact therapeutic targets have yet to be clarified. IRI remains a main cause of postoperative liver dysfunction, often leading to postoperative morbidity or even mortality. Very recently, it was reported that the activation of peroxisome proliferator-activated receptor γ (PPARγ), a member of a superfamily of nuclear transcription factors activated by agonists, can attenuate IRI in the liver, and FAM3A has been confirmed to mediate the protective effect of PPARγ in hepatic IRI. In addition, non-coding RNAs, like LncRNAs and miRNAs, have also been reported to play a pivotal role in the liver IRI process. In this review, we presented an overview of the latest advances of treatment strategies and proposed potential mechanisms behind liver IRI. We also highlighted the role of several important molecules (PPARγ, FAM3A, and non-coding RNAs) in protecting against hepatic IRI. Only after achieving a comprehensive understanding of potential mechanisms and targets behind IRI can we effectively ameliorate IRI in the liver and achieve better therapeutic effects.
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Affiliation(s)
- Xin-Li Mao
- Key Laboratory of Minimally Invasive Techniques and Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China.,Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China.,Institute of Digestive Disease, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Yue Cai
- Key Laboratory of Minimally Invasive Techniques and Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China.,Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China.,Institute of Digestive Disease, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Ya-Hong Chen
- Health Management Center, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Yi Wang
- Key Laboratory of Minimally Invasive Techniques and Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China.,Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China.,Institute of Digestive Disease, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Xiu-Xiu Jiang
- Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Li-Ping Ye
- Key Laboratory of Minimally Invasive Techniques and Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China.,Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China.,Institute of Digestive Disease, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Shao-Wei Li
- Key Laboratory of Minimally Invasive Techniques and Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China.,Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China.,Institute of Digestive Disease, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
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Bai Y, Yang Y, Cui B, Lin D, Wang Z, Ma J. Temporal Effect of Melatonin Posttreatment on Anoxia/Reoxygenation Injury in H9c2 Cells. Cell Biol Int 2022; 46:637-648. [PMID: 34989460 DOI: 10.1002/cbin.11759] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Revised: 11/06/2021] [Accepted: 01/01/2022] [Indexed: 11/07/2022]
Abstract
Melatonin has been proven to reduce myocardial ischemia-reperfusion (MI/R) injury. However, in most studies, melatonin was administered prior to MI/R, thus, the results lack clinical significance in patients with acute myocardial infarction. We hypothesize that melatonin posttreatment at different times has different curative effects. Administered of Melatonin (150 μM) at different times after the onset of reoxygenation (t=-15, 0, 5, 10, 15, 30 min). Cellular apoptosis, oxidative stress and mitochondrial function were assessed. Mitophagy-related protein levels, the mitochondrial membrane potential (MMP) and mitochondrial permeability transition pore (mPTP) activity were also measured. A/R injury upregulated mitophagy, which was associated with increased cellular apoptosis, oxidative stress and mitochondrial dysfunction. Melatonin posttreatment (t= -15, 0, 5, 10, 15, 30 min) significantly inhibited excessive mitophagy after A/R injury, reduced cellular apoptosis and oxidative stress, restored mitochondrial function and MMP, and restrained mPTP opening. The therapeutic time window in which melatonin posttreatment protected H9c2 cells against A/R injury was large (from -15 to 30 min after the onset of reperfusion), but the earlier the melatonin administration was, the better its protective effect was. This mechanism is likely due to a reduction in mPTP activity and MMP collapse, which lead to the inhibition of mitophagy. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Yang Bai
- Department of Anesthesiology, Beijing Anzhen Hospital, Capital Medical University-Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, People's Republic of China
| | - Yanli Yang
- Department of Anesthesiology, Beijing Anzhen Hospital, Capital Medical University-Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, People's Republic of China
| | - Boqun Cui
- Department of Anesthesiology, Beijing Anzhen Hospital, Capital Medical University-Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, People's Republic of China
| | - Duomao Lin
- Department of Anesthesiology, Beijing Anzhen Hospital, Capital Medical University-Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, People's Republic of China
| | - Zhaoqi Wang
- Department of Anesthesiology, Beijing Anzhen Hospital, Capital Medical University-Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, People's Republic of China
| | - Jun Ma
- Department of Anesthesiology, Beijing Anzhen Hospital, Capital Medical University-Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, People's Republic of China
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Abdollahzade N, Majidinia M, Babri S. Melatonin: a pleiotropic hormone as a novel potent therapeutic candidate in arsenic toxicity. Mol Biol Rep 2021; 48:6603-6618. [PMID: 34453671 DOI: 10.1007/s11033-021-06669-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2021] [Accepted: 08/18/2021] [Indexed: 12/28/2022]
Abstract
BACKGROUND Arsenic is a natural element which exists in the environment in inorganic and organic forms. In humans, the main reason for the toxicity of arsenic is its uptake via water sources. As polluted water and the problems associated with it can be found in many countries. Therefore, considering all these positive effects of melatonin, this review is aimed at melatonin supplementation therapy on arsenic toxicity which seems to be a suitable therapeutic agent to eliminate the adverse effects of arsenic. METHODS AND RESULTS It is seen in previous studies that chronic exposure to arsenic could cause serious dys functions of organs and induce different degrees of toxicities that is one of the first hazardous materials in the classification of substances by the United States Environmental Protection Agency so leads to costly cleanup operations burdening the economy. Arsenic harmfulness degree depends on the bioavailability, chemical form, valence state, detoxification, and metabolism of human body. The oxidative stress has a major role in arsenic-induced toxicity; on the other hand, it was discovered that melatonin is a powerful scavenger for free radical and it's an extensive-spectrum antioxidant. CONCLUSION Due to its highly lipophilic and small size properties, melatonin accesses all intracellular organs by easily passing via the cell membrane and prevents protein, DNA damage, and lipid peroxidation. In particular, melatonin, by protecting and reducing oxidative stress in mitochondria, can normalize homeostasis and mitochondrial function and ultimately prevent apoptosis and cell death.
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Affiliation(s)
- Naseh Abdollahzade
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Physiology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Majidinia
- Solid Tumor Research Center, Urmia University of Medical Sciences, Urmia, Iran.
| | - Shirin Babri
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. .,Department of Physiology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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Wang XP, Zheng WC, Bai Y, Li Y, Xin Y, Wang JZ, Chang YL, Zhang LM. Carbon Monoxide-Releasing Molecule-3 Alleviates Kupffer Cell Pyroptosis Induced by Hemorrhagic Shock and Resuscitation via sGC-cGMP Signal Pathway. Inflammation 2021; 44:1330-1344. [PMID: 33575924 DOI: 10.1007/s10753-021-01419-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 11/30/2020] [Accepted: 01/11/2021] [Indexed: 12/23/2022]
Abstract
Following hepatic ischemia-reperfusion injury, Kupffer cells could be activated by inflammatory factors released from damaged hepatocytes. Carbon monoxide (CO)-releasing molecule (CORM)-3, a water-soluble transition metal carbonyl, exhibits excellent anti-inflammatory and anti-pyroptosis properties. We investigated whether CORM-3 attenuated hemorrhagic shock and resuscitation (HSR)-induced pyroptosis of Kupffer cells through the soluble guanylate-cyclase (sGC)-cyclic guanosine monophosphate (cGMP) signal pathway. NS2028 (10 mg/kg), a blocker of sGC, was administrated at the onset of hemorrhage, but CORM-3 (4 mg/kg) was infused after resuscitation via femoral vein. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) levels, tumor necrosis Factor-α (TNF-α), and interleukin-1β (IL-1β) were measured at 3, 6, 12, and 24 h after HSR, respectively. Six hours post-HSR, liver injury, pyroptosis of Kupffer cells, and expressions in total caspase-1, cleaved caspase-1, gasdermin D (GSDMD) N-terminal fragment, IL-1β, and IL-18 were measured by hematoxylin-eosin (H&E), immunofluorescence and western blot assays, respectively (Fig. 1). The rats exposed to HSR exhibited significant upregulated levels of serum ALT, AST, TNF-α, and IL-1β, elevated liver injury score, increased pyroptosis of Kupffer cells, and accumulated expressions of pyroptosis-associated protein including cleaved caspase-1, GSDMD N-terminal fragment, IL-1β, and IL-18 than sham-treated rats. However, CORM-3 administration markedly reduced liver injury and pyroptosis of Kupffer cells, whereas these protective effects could be partially blocked by NS2028. CORM-3 can mitigate pyroptosis of Kupffer cells in a blood loss and re-infusion model of rats via sGC-cGMP signal pathway.
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Affiliation(s)
- Xu-Peng Wang
- Department of Anesthesiology, Cangzhou Central Hospital, Cangzhou, China
| | - Wei-Chao Zheng
- Department of Anesthesiology, Cangzhou Central Hospital, Hebei Medical University, Cangzhou, China
| | - Yang Bai
- Department of Anesthesiology, Cangzhou Central Hospital, Cangzhou, China
| | - Yan Li
- Department of Anesthesiology, Cangzhou Central Hospital, Cangzhou, China
| | - Yue Xin
- Department of Anesthesiology, Cangzhou Central Hospital, Hebei Medical University, Cangzhou, China
| | - Jing-Zhou Wang
- Department of Neurosurgery, Cangzhou Central Hospital, Hebei Medical University, Cangzhou, China
| | - Yu-Lin Chang
- Department of Anesthesiology, Cangzhou Central Hospital, Cangzhou, China
- Department of Anesthesiology, Cangzhou Central Hospital, Hebei Medical University, Cangzhou, China
| | - Li-Min Zhang
- Department of Anesthesiology, Cangzhou Central Hospital, Cangzhou, China.
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The Role of Mitochondria in Liver Ischemia-Reperfusion Injury: From Aspects of Mitochondrial Oxidative Stress, Mitochondrial Fission, Mitochondrial Membrane Permeable Transport Pore Formation, Mitophagy, and Mitochondria-Related Protective Measures. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:6670579. [PMID: 34285766 PMCID: PMC8275408 DOI: 10.1155/2021/6670579] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Revised: 06/04/2021] [Accepted: 06/11/2021] [Indexed: 02/08/2023]
Abstract
Ischemia-reperfusion injury (IRI) has indeed been shown as a main complication of hepatectomy, liver transplantation, trauma, and hypovolemic shock. A large number of studies have confirmed that microvascular and parenchymal damage is mainly caused by reactive oxygen species (ROS), which is considered to be a major risk factor for IRI. Under normal conditions, ROS as a kind of by-product of cellular metabolism can be controlled at normal levels. However, when IRI occurs, mitochondrial oxidative phosphorylation is inhibited. In addition, oxidative respiratory chain damage leads to massive consumption of adenosine triphosphate (ATP) and large amounts of ROS. Additionally, mitochondrial dysfunction is involved in various organs and tissues in IRI. On the one hand, excessive free radicals induce mitochondrial damage, for instance, mitochondrial structure, number, function, and energy metabolism. On the other hand, the disorder of mitochondrial fusion and fission results in further reduction of the number of mitochondria so that it is not enough to clear excessive ROS, and mitochondrial structure changes to form mitochondrial membrane permeable transport pores (mPTPs), which leads to cell necrosis and apoptosis, organ failure, and metabolic dysfunction, increasing morbidity and mortality. According to the formation mechanism of IRI, various substances have been discovered or synthesized for specific targets and cell signaling pathways to inhibit or slow the damage of liver IRI to the body. Here, based on the development of this field, this review describes the role of mitochondria in liver IRI, from aspects of mitochondrial oxidative stress, mitochondrial fusion and fission, mPTP formation, and corresponding protective measures. Therefore, it may provide references for future clinical treatment and research.
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Ishihara R, Barros MPD, Silva CMD, Borges LDS, Hatanaka E, Lambertucci RH. Melatonin improves the antioxidant capacity in cardiac tissue of Wistar rats after exhaustive exercise. Free Radic Res 2021; 55:776-791. [PMID: 34100318 DOI: 10.1080/10715762.2021.1939024] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
We investigated the effects of melatonin on the onset and resolution of the oxidative stress in the cardiac muscle in melatonin-treated and nontreated rats subjected to an exhaustive exercise session. Forty male rats were divided into: melatonin-treated (20 mg/kg supplemented for 10 d) and control. On the 10th day, each group was subdivided according to euthanasia moments: control or melatonin-treated not exercised (C0h and M0h); immediately after the exercise (CIA and MIA); and 2 h after exercise (C2h and M2h). The heart of animals was removed and the levels of oxidative stress index (OSI) and the formation of thiobarbituric acid reactive substances (TBARS), protein carbonyl, and the activities of aconitase, catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD) were evaluated. Total antioxidant status (TAS), total oxidant status (TOS), and the protein expression of CAT, GPx, and SOD was also measured. Our data revealed significant differences on: (i) OSI (p=.029), CAT activity (p=.016), CAT content (p<.001), GPx content (p=.014), reduced glutathione levels (p<.001), and aconitase activity (p<.001) for interaction of melatonin; (ii) GPx activity (p=.005), reduced glutathione (p=.004), protein carbonyl (p=.035), and TBARS levels (p=.028) between groups, and (iii) TBARS levels (p=.016) for significance between moments. Although the exhaustive exercise protocol imposed mild oxidative stress on the cardiac tissue of rats, melatonin induced antioxidant responses that rebalanced the redox status of the cardiac tissue, especially after exhaustive exercise.
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Affiliation(s)
- Rafael Ishihara
- Department of Biosciences, Federal University of Sao Paulo, Santos, Brazil
| | - Marcelo Paes de Barros
- Institute of Physical Activity Sciences and Sports (ICAFE), Cruzeiro do Sul University, São Paulo, Brazil
| | | | - Leandro da Silva Borges
- Institute of Physical Activity Sciences and Sports (ICAFE), Cruzeiro do Sul University, São Paulo, Brazil
| | - Elaine Hatanaka
- Institute of Physical Activity Sciences and Sports (ICAFE), Cruzeiro do Sul University, São Paulo, Brazil
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Tuncer M, Pehlivanoglu B, Sürücü SH, Isbir T. Melatonin Improves Reduced Activities of Membrane ATPases and Preserves Ultrastructure of Gray and White Matter in the Rat Brain Ischemia/Reperfusion Model. BIOCHEMISTRY. BIOKHIMIIA 2021; 86:540-550. [PMID: 33993861 DOI: 10.1134/s0006297921050035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 03/22/2021] [Accepted: 03/28/2021] [Indexed: 06/12/2023]
Abstract
Ischemia/reperfusion (I/R) is among the most frequent neurological problems and early intervention to limit the damage is crucial in decreasing mortality and morbidity. Based on reports regarding beneficial effects of melatonin, we investigated its impact on Na+-K+/Mg2+ ATPase and Ca2+/Mg2+ ATPase activities and ultrastructure of gray and white matter in the rat forebrain I/R model. Adult Wistar-albino rats (n = 78), were randomized into control, ischemia (I), ischemia/reperfusion (I/R), low (I/R + melatonin 400 µg/kg), moderate (I/R + melatonin 1200 µg/kg), and high (I/R + melatonin 2400 µg/kg) dose melatonin. Two-vessel occlusion combined with hypotension (15 min) induced ischemia and reperfusion (75 min) achieved by blood reinfusion were performed. Activities of the membrane-bound enzyme, brain malondialdehyde levels, and brain matter ultrastructure were examined in frontoparietal cortices. Melatonin lowered production of malondialdehyde in a dose-dependently. The enzyme activities attenuated under I and I/R, improved with melatonin treatment. I and I/R severely disturbed gray and white matter morphology. Melatonin, in all applied doses, decreased ultrastructural damages in both gray and white matter. Favorable effects of melatonin can be attributed to its antioxidant properties suggesting that it could be a promising neuroprotective agent against I/R injury being effective both for gray and white matter due to favorable biological properties.
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Affiliation(s)
- Meltem Tuncer
- Department of Physiology, Hacettepe University Faculty of Medicine, Ankara, 06100, Turkey.
| | - Bilge Pehlivanoglu
- Department of Physiology, Hacettepe University Faculty of Medicine, Ankara, 06100, Turkey
| | - Selçuk H Sürücü
- Department of Anatomy, Koç University School of Medicine, Istanbul, 34450, Turkey
| | - Turgay Isbir
- Department of Medical Biology, Faculty of Medicine, Yeditepe University, Istanbul, 34755, Turkey
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Bilska B, Schedel F, Piotrowska A, Stefan J, Zmijewski M, Pyza E, Reiter RJ, Steinbrink K, Slominski AT, Tulic MK, Kleszczyński K. Mitochondrial function is controlled by melatonin and its metabolites in vitro in human melanoma cells. J Pineal Res 2021; 70:e12728. [PMID: 33650175 DOI: 10.1111/jpi.12728] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 02/19/2021] [Accepted: 02/23/2021] [Indexed: 12/16/2022]
Abstract
Melanoma is a leading cause of cancer deaths worldwide. Although immunotherapy has revolutionized the treatment for some patients, resistance towards therapy and unwanted side effects remain a problem for numerous individuals. Broad anti-cancer activities of melatonin are recognized; however, additional investigations still need to be elucidated. Herein, using various human melanoma cell models, we explore in vitro the new insights into the regulation of melanoma by melatonin and its metabolites which possess, on the other side, high safety profiles and biological meaningful. In this study, using melanotic (MNT-1) and amelanotic (A375, G361, Sk-Mel-28) melanoma cell lines, the comparative oncostatic responses, the impact on melanin content (for melanotic MNT-1 melanoma cells) as well as the mitochondrial function controlled by melatonin, its precursor (serotonin), a kynuric (N1 -acetyl-N2 -formyl-5-methoxykynuramine, AFMK) and indolic pathway (6-hydroxymelatonin, 6(OH)MEL and 5-methoxytryptamine, 5-MT) metabolites were assessed. Namely, significant disturbances were observed in bioenergetics as follows: (i) uncoupling of oxidative phosphorylation (OXPHOS), (ii) attenuation of glycolysis, (iii) dissipation of mitochondrial transmembrane potential (mtΔΨ) accompanied by (iv) massive generation of reactive oxygen species (ROS), and (v) decrease of glucose uptake. Collectively, these results together with previously published reports provide a new biological potential and make an imperative to consider using melatonin or its metabolites for complementary future treatments of melanoma-affected patients; however, these associations should be additionally investigated in clinical setting.
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Affiliation(s)
- Bernadetta Bilska
- Department of Cell Biology and Imaging, Institute of Zoology and Biomedical Research, Jagiellonian University, Kraków, Poland
| | - Fiona Schedel
- Department of Dermatology, University of Münster, Münster, Germany
| | - Anna Piotrowska
- Department of Histology, Medical University of Gdańsk, Gdańsk, Poland
| | - Joanna Stefan
- Department of Oncology, Nicolaus Copernicus University Medical College, Bydgoszcz, Poland
- Department of Dermatology, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Michal Zmijewski
- Department of Histology, Medical University of Gdańsk, Gdańsk, Poland
| | - Elżbieta Pyza
- Department of Cell Biology and Imaging, Institute of Zoology and Biomedical Research, Jagiellonian University, Kraków, Poland
| | - Russel J Reiter
- Department of Cellular and Structural Biology, UT Health, San Antonio, TX, USA
| | | | - Andrzej T Slominski
- Department of Dermatology, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA
- Pathology and Laboratory Medicine Service, VA Medical Center, Birmingham, AL, USA
| | - Meri K Tulic
- Université Côte d'Azur, INSERM U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Nice, France
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Promotion of Momordica Charantia polysaccharides on neural stem cell proliferation by increasing SIRT1 activity after cerebral ischemia/reperfusion in rats. Brain Res Bull 2021; 170:254-263. [PMID: 33647420 DOI: 10.1016/j.brainresbull.2021.02.016] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 01/22/2021] [Accepted: 02/16/2021] [Indexed: 11/24/2022]
Abstract
The deacetylase SIRT1 has been reported to play a critical role in regulating neurogenesis, which may be an adaptive processes contributing to recovery after stroke. Our previous work showed that the antioxidant capacity of Momordica charantia polysaccharides (MCPs) could protect against cerebral ischemia/reperfusion (I/R) after stroke. However, whether the protective effect of MCPs on I/R injury is related to neural stem cell (NSC) proliferation remains unclear. In the present study, we designed invivo and invitro experiments to elucidate the underlying mechanisms by which MCPs promote endogenous NSC proliferation during cerebral I/R. Invivo results showed that MCPs rescued the memory and learning abilities of rats after I/R damage and enhanced NSC proliferation in the rat subventricular zone (SVZ) and subgrannular zone (SGZ) during I/R. Invitro experiments demonstrated that MCPs could stimulate the proliferation of C17.2 cells under oxygen-glucose deprivation (OGD) conditions. Further studies revealed that the proliferation-promoting mechanism of MCPs relied on increasing the activity of SIRT1, decreasing the level of acetylation of β-catenin in the cytoplasm, and then triggering the translocation of β-catenin into the nucleus. These data provide experimental evidence that the up-regulation of SIRT1 activity by MCPs led to an increased cytoplasmic deacetylation of β-catenin, which promoted translocation of β-catenin to the nucleus to participate in the signaling pathway involved in NSC proliferation. The present study reveals that MCPs function as a therapeutic drug to promote stroke recovery by increasing the activity of SIRT1, decreasing the level of acetylated β-catenin, promoting the nuclear translocation of β-catenin and thereby increasing endogenous NSC proliferation.
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Reiter RJ, Ma Q, Sharma R. Melatonin in Mitochondria: Mitigating Clear and Present Dangers. Physiology (Bethesda) 2021; 35:86-95. [PMID: 32024428 DOI: 10.1152/physiol.00034.2019] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
In cancer cells, glucose is primarily metabolized to pyruvate and then to lactate in the cytosol. By allowing the conversion of pyruvate to acetyl-CoA in mitochondria, melatonin reprograms glucose metabolism in cancer cells to a normal cell phenotype. Acetyl-CoA in the mitochondria also serves as a necessary co-factor for the rate-limiting enzyme in melatonin synthesis, thus ensuring melatonin production in mitochondria of normal cells.
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Affiliation(s)
- Russel J Reiter
- Department of Cell Systems and Anatomy, University of Texas Health San Antonio, San Antonio, Texas
| | - Qiang Ma
- Department of Cell Systems and Anatomy, University of Texas Health San Antonio, San Antonio, Texas
| | - Ramaswamy Sharma
- Department of Cell Systems and Anatomy, University of Texas Health San Antonio, San Antonio, Texas
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Apoptosis: A friend or foe in mesenchymal stem cell-based immunosuppression. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2021. [PMID: 34090619 DOI: 10.1016/bs.apcsb.2021.01.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/10/2023]
Abstract
Mesenchymal stem cells (MSC) are adult stem cells which reside in almost all postnatal tissue where, in juxtacrine and paracrine manner, regulate phenotype and function of immune cells, maintain tissue homeostasis, attenuate on-going inflammation and promote repair and regeneration of injured tissues. Due to their capacity to suppress detrimental immune response, MSC have been considered as potentially new therapeutic agents in the treatment of autoimmune and inflammatory diseases. It was recently revealed that apoptosis may increase anti-inflammatory properties of MSC by enhancing their capacity to induce generation of immunosuppressive phenotype in macrophages and dendritic cells. Upon phagocytosis, apoptotic MSC induce generation of immunosuppressive phenotype in monocytes/macrophages and promote production of anti-inflammatory cytokines and growth factors that attenuate inflammation and facilitate repair and regeneration of injured tissues. Importantly, immunomodulation mediated by apoptotic MSC was either similar or even better than immunomodulation accomplished by viable MSC. In contrast to viable MSC, which obtain either pro- or anti-inflammatory phenotype upon engraftment in different tissue microenvironments, apoptotic MSC were not subject to changes in their immunomodulatory characteristics upon diverse stimuli, indicating their potential for clinical use. In this chapter, we summarized current knowledge about beneficial effects of apoptotic MSC in the suppression of detrimental local and systemic immune response, and we emphasized their therapeutic potential in the treatment of inflammatory diseases.
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Yasojima EY, Domingues RJDS, Silva RC, Sousa LFFD, Trindade Júnior SC. Comparison of remote and local postconditioning against hepatic ischemic-reperfusion injury in rats. Acta Cir Bras 2021; 36:e360101. [PMID: 33533826 PMCID: PMC7853697 DOI: 10.1590/acb360101] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2020] [Accepted: 12/11/2020] [Indexed: 02/07/2023] Open
Abstract
Purpose: The aim of this study is to compare the hepatic protective effect of both
remote and local postconditioning (POS). Methods: Twenty-eight Wistar rats were assigned into four groups: sham group(SHAM),
ischemia-reperfusion group (IR), local ischemic POS group (lPOS) and remote
ischemic POS group (rPOS). Animals were subjected to liver ischemia for 30
min. Local ischemic POS group consisted of four cycles of 5 min liver
ischemia, followed by 5 min reperfusion (40 min). Remote ischemic POS group
consisted of four cycles of 5 min hind limb ischemia, followed by 5 min hind
limb perfusion after the main liver ischemia period. After 190 minutes
median and left liver lobes were harvested for biochemical and
histopathology analysis. Results: All the conditioning techniques were able to increase the level of
bothglutathione reductase and peroxidase, showing higher values in the rPOS
group when compared to the lPOS. Also, thiobarbituric acid reactive
substances were higher in all intervention groups when compared to SHAM, but
rPOS had the lower rates of increase, showing the best result. The
histopathology analysis showed that all groups had worst injury levels than
SHAM, but rPOS had lower degrees of damage when compared to the lPOS,
although it was not statistically significant. Conclusion: Remote postconditioning is a promising technique to reduce liver
ischemia-reperfusion injury, once it increased antioxidants substances and
reduced the damage.
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Kopustinskiene DM, Bernatoniene J. Molecular Mechanisms of Melatonin-Mediated Cell Protection and Signaling in Health and Disease. Pharmaceutics 2021; 13:129. [PMID: 33498316 PMCID: PMC7909293 DOI: 10.3390/pharmaceutics13020129] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 01/14/2021] [Accepted: 01/18/2021] [Indexed: 01/07/2023] Open
Abstract
Melatonin, an endogenously synthesized indolamine, is a powerful antioxidant exerting beneficial action in many pathological conditions. Melatonin protects from oxidative stress in ischemic/reperfusion injury, neurodegenerative diseases, and aging, decreases inflammation, modulates the immune system, inhibits proliferation, counteracts the Warburg effect, and promotes apoptosis in various cancer models. Melatonin stimulates antioxidant enzymes in the cells, protects mitochondrial membrane phospholipids, especially cardiolipin, from oxidation thus preserving integrity of the membranes, affects mitochondrial membrane potential, stimulates activity of respiratory chain enzymes, and decreases the opening of mitochondrial permeability transition pore and cytochrome c release. This review will focus on the molecular mechanisms of melatonin effects in the cells during normal and pathological conditions and possible melatonin clinical applications.
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Affiliation(s)
- Dalia M. Kopustinskiene
- Institute of Pharmaceutical Technologies, Faculty of Pharmacy, Medical Academy, Lithuanian University of Health Sciences, Sukileliu pr. 13, LT-50161 Kaunas, Lithuania;
| | - Jurga Bernatoniene
- Institute of Pharmaceutical Technologies, Faculty of Pharmacy, Medical Academy, Lithuanian University of Health Sciences, Sukileliu pr. 13, LT-50161 Kaunas, Lithuania;
- Department of Drug Technology and Social Pharmacy, Faculty of Pharmacy, Medical Academy, Lithuanian University of Health Sciences, Sukileliu pr. 13, LT-50161 Kaunas, Lithuania
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Hardeland R. Sirtuins, melatonin, and the relevance of circadian oscillators. SIRTUIN BIOLOGY IN MEDICINE 2021:137-151. [DOI: 10.1016/b978-0-12-814118-2.00011-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Kalyoncu Ş, Yilmaz B, Demir M, Tuncer M, Bozdağ Z, Ince O, Bozdayi MA, Ulusal H, Taysi S. Melatonin attenuates ovarian ischemia reperfusion injury in rats by decreasing oxidative stress index and peroxynitrite. Turk J Med Sci 2020; 50:1513-1522. [PMID: 32927928 PMCID: PMC7605088 DOI: 10.3906/sag-2004-135] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Accepted: 09/08/2020] [Indexed: 12/17/2022] Open
Abstract
Background/aim To evaluate the protective effect of melatonin on ovarian ischemia reperfusion injury in a rat model. Materials and methods Forty-eight rats were separated equally into 6 groups. Group 1: sham; Group 2: surgical control with 3-h bilateral ovarian torsion and detorsion; Group 3: intraperitoneal 5% ethanol (1 mL) just after detorsion (as melatonin was dissolved in ethanol); Group 4: 10 mg/kg intraperitoneal melatonin 30 min before 3-h torsion; Group 5:10 mg/kg intraperitoneal melatonin just after detorsion; Group 6:10 mg/kg intraperitoneal melatonin 30 min before torsion and just after detorsion. Both ovaries and blood samples were obtained 7 days after detorsion for histopathological and biochemical analysis. Results In Group 1, serum levels of total oxidant status (TOS) (μmol H2O2 equivalent/g wet tissue)were significantly lower than in Group2 (P = 0.0023), while tissue TOS levels were lower than in Group 3 (P = 0.0030). Similarly, serum and tissue levels of peroxynitrite in Group 6were significantly lower than those ofGroup 2 (P = 0.0023 and P = 0.040, respectively). Moreover, serum oxidative stress index (OSI) (arbitrary unit) levels were significantly increased in Group 2 when compared to groups 1 and 6 (P = 0.0023 and P= 0.0016, respectively) and in Group 3 with respect to groups 1, 4, 5, and 6 (P = 0.0023, P = 0.0026, P = 0.0008, and P = 0.0011, respectively). Furthermore, there was a significant decrease in histopathological scores including follicular degeneration, vascular congestion, hemorrhage, and inflammation in the melatonin and sham groups in comparison with control groups. Additionally, primordial follicle count was significantly higher in Group 6 than in Group 2 (P = 0.0002). Conclusion Melatonin attenuates ischemia reperfusion damage in a rat torsion/detorsion model by improving histopathological and biochemical findings including OSI and peroxynitrite.
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Affiliation(s)
- Şenol Kalyoncu
- Department of Obstetrics and Gynecology, TOBB ETU University Hospital, Ankara, Turkey
| | - Bülent Yilmaz
- Department of Obstetrics and Gynecology, Faculty of Medicine, Recep Tayyip Erdoğan University, Rize, Turkey
| | - Mustafa Demir
- Department of Obstetrics and Gynecology, ANKA Hospital, Gaziantep, Turkey
| | - Meltem Tuncer
- Department of Physiology, Faculty of Medicine, Hacettepe University, Ankara, Turkey
| | - Zehra Bozdağ
- Department of Pathology, Faculty of Medicine, Gaziantep University, Gaziantep, Turkey
| | - Onur Ince
- Department of Obstetrics and Gynecology, Faculty of Medicine, Health Science University, Kütahya, Turkey
| | - Mehmet Akif Bozdayi
- Department of Biochemistry, Faculty of Medicine, Gaziantep University, Gaziantep, Turkey
| | - Hasan Ulusal
- Department of Biochemistry, Faculty of Medicine, Gaziantep University, Gaziantep, Turkey
| | - Seyithan Taysi
- Department of Biochemistry, Faculty of Medicine, Gaziantep University, Gaziantep, Turkey
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Ajoolabady A, Aslkhodapasandhokmabad H, Aghanejad A, Zhang Y, Ren J. Mitophagy Receptors and Mediators: Therapeutic Targets in the Management of Cardiovascular Ageing. Ageing Res Rev 2020; 62:101129. [PMID: 32711157 DOI: 10.1016/j.arr.2020.101129] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2020] [Revised: 07/10/2020] [Accepted: 07/19/2020] [Indexed: 12/17/2022]
Abstract
Mitophagy serves as a cardinal regulator in the maintenance of mitochondrial integrity, function, and cardiovascular homeostasis, through the fine control and governance of cellular metabolism, ATP production, redox balance, and mitochondrial quality and quantity control. As a unique form of selective autophagy, mitophagy specifically recognizes and engulfs long-lived or damaged (depolarized) mitochondria through formation of the double-membraned intracellular organelles - mitophagosomes, ultimately resulting in lysosomal degradation. Levels of mitophagy are reported to be altered in pathological settings including cardiovascular diseases and biological ageing although the precise nature of mitophagy change in ageing and ageing-associated cardiovascular deterioration remains poorly defined. Ample clinical and experimental evidence has depicted a convincing tie between cardiovascular ageing and altered mitophagy. In particular, ageing perturbs multiple enigmatic various signal machineries governing mitophagy, mitochondrial quality, and mitochondrial function, contributing to ageing-elicited anomalies in the cardiovascular system. This review will update novel regulatory mechanisms of mitophagy especially in the perspective of advanced ageing, and discuss how mitophagy dysregulation may be linked to cardiovascular abnormalities in ageing. We hope to pave the way for development of new therapeutic strategies against the growing health and socieconomical issue of cardiovascular ageing through targeting mitophagy.
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