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1
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Devine AJ, Smith NJ, Joshi R, Brooks-Patton B, Dunham J, Varisco AN, Goodman EM, Fan Q, Zingarelli B, Varisco BM. KF4 Anti-Chymotrypsin-like Elastase 1 Antibody and Purified Alpha-1 Antitrypsin Have Similar but Not Additive Efficacy in Preventing Emphysema in Murine Alpha-1 Antitrypsin Deficiency. CHRONIC OBSTRUCTIVE PULMONARY DISEASES (MIAMI, FLA.) 2025; 12:12-22. [PMID: 39636054 PMCID: PMC11925070 DOI: 10.15326/jcopdf.2024.0535] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/07/2024]
Abstract
Background Alpha-1 antitrypsin (AAT) deficiency is the most common genetic cause of emphysema. Chymotrypsin-like elastase 1 (CELA1) is a serine protease neutralized by AAT and is important in emphysema progression. Cela1-deficiency is protective in murine models of AAT-deficient emphysema. KF4 anti-CELA1 antibody prevented emphysema in porcine pancreatic elastase (PPE) and cigarette smoke models in wild-type mice. Methods We evaluated potential toxicities of KF4 and its ability to prevent emphysema in AAT deficiency. We found Cela1 protein expression in mouse lungs, pancreas, small intestine, spleen, and bone marrow. In toxicity studies, mice treated with KF4 25mg/kg weekly for 4 weeks showed an elevation in blood urea nitrogen and slower weight gain compared to lower doses or equivalent dose immunoglobin G (IgG). By histologic grading of tissue injury of the lung, kidney, liver, and heart, there was some evidence of liver injury with KF4 25mg/kg, but in all tissues, injury was less than in control mice subjected to cecal ligation and puncture. In efficacy studies, KF4 doses as low as 0.5mg/kg reduced the lung elastase activity of AAT-/- mice treated with 0.2 units of PPE. Results In this injury model, AAT-/- mice treated with KF4 1mg/kg weekly, human purified AAT 60mg/kg weekly, and combined KF4 and AAT treatment had less emphysema than mice treated with IgG 1mg/kg weekly. However, the efficacy of KF4, AAT, or KF4 and AAT was similar. Conclusion While KF4 might be an alternative to AAT replacement, combined KF4 and AAT replacement does not confer additional benefit.
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Affiliation(s)
- Andrew J Devine
- Heritage College of Osteopathic Medicine, Ohio University, Athens, Ohio, United States
| | - Noah J Smith
- College of Medicine, University of Cincinnati, Cincinnati, Ohio, United States
| | - Rashika Joshi
- Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
| | | | - Jenna Dunham
- Northern Kentucky University, Highland Heights, Kentucky, United States
| | - Ansley N Varisco
- University of Arkansas at Little Rock, Little Rock, Arkansas, United States
| | - Emily M Goodman
- University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States
| | - Qiang Fan
- Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
| | - Basilia Zingarelli
- College of Medicine, University of Cincinnati, Cincinnati, Ohio, United States
- Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
| | - Brian M Varisco
- College of Medicine, University of Cincinnati, Cincinnati, Ohio, United States
- Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
- University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States
- Arkansas Children's Research Institute, Little Rock, Arkansas, United States
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Amman AM, Wolfe V, Piraino G, Ziady A, Zingarelli B. Humanin-G Ameliorates Hemorrhage-Induced Acute Lung Injury in Mice Through AMPKα1-Dependent and -Independent Mechanisms. Biomedicines 2024; 12:2615. [PMID: 39595179 PMCID: PMC11592305 DOI: 10.3390/biomedicines12112615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Revised: 11/06/2024] [Accepted: 11/13/2024] [Indexed: 11/28/2024] Open
Abstract
Background/Objectives: The severity of acute lung injury is significantly impacted by age and sex in patients with hemorrhagic shock. AMP-activated protein kinase (AMPK) is a crucial regulator of energy metabolism but its activity declines with aging. Humanin is a mitochondrial peptide that exerts cytoprotective effects in response to oxidative stressors and is associated with longevity. Using a mouse model of hemorrhagic shock that mimics the clinical condition of adult patients, we investigated whether treatment with a humanin analog, humanin-G, mitigates lung injury and whether its mechanisms of action are dependent on the catalytic AMPKα1 subunit activation. Methods: Male and female AMPKα1 wild-type (WT) and knock-out (KO) mice (8-13 months old) were subjected to hemorrhagic shock by blood withdrawal, followed by resuscitation with shed blood and lactated Ringer's solution. The mice were treated with PEGylated humanin-G or vehicle and euthanized 3 h post-resuscitation. Results: Sex- and genotype-related differences were observed after hemorrhagic shock as lung neutrophil infiltration was more pronounced in the male AMPKα1 WT mice than the female WT mice; also, the male AMPKα1 KO mice experienced a significant decline in mean arterial blood pressure when compared to the male WT mice after resuscitation. The scores of histological lung injury were similarly elevated in all the male and female AMPKα1 WT and KO mice when compared to the control mice. At molecular analysis, acute lung injury was associated with the downregulation of AMPKα1/α2 catalytic subunits in the WT mice, whereas an increased activation of the signal transducer and activator of transcription-3 (STAT3) was observed in all the vehicle-treated groups. The in vivo administration of humanin-G ameliorated histological lung damage in all the groups of animals and ameliorated mean arterial blood pressure in the male AMPKα1 KO mice. The in vivo administration of humanin-G lowered lung neutrophil infiltration in the male and female AMPKα1 WT mice only but not in the KO mice. The beneficial results of humanin-G correlated with the lung cytosolic and nuclear activation of AMPKα in the male and female AMPKα1 WT groups, whereas STAT3 activation was not modified. Conclusions: In adult age, hemorrhage-induced acute lung injury manifests with sex-dependent characteristics. Humanin-G has therapeutic potential and the AMPKα1subunit is an important requisite for its inhibitory effects on lung leucosequestration, but not for the amelioration of lung alveolar structure or the hemodynamic effects of the peptide.
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Affiliation(s)
- Allison M. Amman
- Department of Surgery, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267, USA;
| | - Vivian Wolfe
- Department of Pediatrics, University of Cincinnati College of Medicine, Division of Critical Care Medicine, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA; (V.W.); (G.P.)
| | - Giovanna Piraino
- Department of Pediatrics, University of Cincinnati College of Medicine, Division of Critical Care Medicine, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA; (V.W.); (G.P.)
| | - Assem Ziady
- Department of Pediatrics, University of Cincinnati College of Medicine, Division of Bone Marrow Transplantation & Immune Deficiency, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA;
| | - Basilia Zingarelli
- Department of Pediatrics, University of Cincinnati College of Medicine, Division of Critical Care Medicine, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA; (V.W.); (G.P.)
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Yumoto T, Coopersmith CM. Targeting AMP-activated protein kinase in sepsis. Front Endocrinol (Lausanne) 2024; 15:1452993. [PMID: 39469575 PMCID: PMC11513325 DOI: 10.3389/fendo.2024.1452993] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Accepted: 09/30/2024] [Indexed: 10/30/2024] Open
Abstract
Sepsis is a global health challenge marked by limited clinical options and high mortality rates. AMP-activated protein kinase (AMPK) is a cellular energy sensor that mediates multiple crucial metabolic pathways that may be an attractive therapeutic target in sepsis. Pre-clinical experimental studies have demonstrated that pharmacological activation of AMPK can offer multiple potential benefits during sepsis, including anti-inflammatory effects, induction of autophagy, promotion of mitochondrial biogenesis, enhanced phagocytosis, antimicrobial properties, and regulation of tight junction assembly. This review aims to discuss the existing evidence supporting the therapeutic potential of AMPK activation in sepsis management.
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Affiliation(s)
- Tetsuya Yumoto
- Department of Surgery and Emory Critical Care Center, Emory University School of Medicine, Atlanta, GA, United States
- Department of Emergency, Critical Care and Disaster Medicine, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Craig M. Coopersmith
- Department of Surgery and Emory Critical Care Center, Emory University School of Medicine, Atlanta, GA, United States
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Bai G, Ling J, Lu J, Fang M, Yu S. Adiponectin receptor agonist AdipoRon alleviates memory impairment in the hippocampus of septic mice. Behav Brain Res 2024; 472:115174. [PMID: 39098398 DOI: 10.1016/j.bbr.2024.115174] [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: 05/21/2024] [Revised: 07/20/2024] [Accepted: 08/01/2024] [Indexed: 08/06/2024]
Abstract
Sepsis-associated encephalopathy (SAE) is a common and severe clinical feature of sepsis; however, therapeutic approaches are limited because of the unclear pathogenesis. Adiponectin receptor agonist (AdipoRon) is a small-molecule agonist of the adiponectin receptor that exhibits anti-inflammatory and memory-improving effects in various diseases. In the present study, we established lipopolysaccharide (LPS)-induced mice models of SAE and found that Adiponectin receptor 1 (AdipoR1) was significantly decreased in the hippocampus. Administration of AdipoRon improves memory impairment, mitigates synaptic damage, and alleviates neuronal death. Furthermore, AdipoRon reduces the number of microglia. More importantly, AdipoRon promotes the phosphorylation of adenosine 5 '-monophosphate activated protein kinase (pAMPK). In conclusion, AdipoRon is protective against SAE-induced memory decline and brain injury in the SAE models via activating the hippocampal adenosine 5 '-monophosphate activated protein kinase (AMPK).
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Affiliation(s)
- Guangyang Bai
- Department of Emergency Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China; Department of Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China
| | - Jianmin Ling
- Department of Emergency Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China; Department of Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China
| | - Jun Lu
- Department of Emergency Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China; Department of Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China
| | - Minghao Fang
- Department of Emergency Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China; Department of Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China.
| | - Shanshan Yu
- Department of Emergency Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China; Department of Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China.
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Liu BH, Xu CZ, Liu Y, Lu ZL, Fu TL, Li GR, Deng Y, Luo GQ, Ding S, Li N, Geng Q. Mitochondrial quality control in human health and disease. Mil Med Res 2024; 11:32. [PMID: 38812059 PMCID: PMC11134732 DOI: 10.1186/s40779-024-00536-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Accepted: 05/07/2024] [Indexed: 05/31/2024] Open
Abstract
Mitochondria, the most crucial energy-generating organelles in eukaryotic cells, play a pivotal role in regulating energy metabolism. However, their significance extends beyond this, as they are also indispensable in vital life processes such as cell proliferation, differentiation, immune responses, and redox balance. In response to various physiological signals or external stimuli, a sophisticated mitochondrial quality control (MQC) mechanism has evolved, encompassing key processes like mitochondrial biogenesis, mitochondrial dynamics, and mitophagy, which have garnered increasing attention from researchers to unveil their specific molecular mechanisms. In this review, we present a comprehensive summary of the primary mechanisms and functions of key regulators involved in major components of MQC. Furthermore, the critical physiological functions regulated by MQC and its diverse roles in the progression of various systemic diseases have been described in detail. We also discuss agonists or antagonists targeting MQC, aiming to explore potential therapeutic and research prospects by enhancing MQC to stabilize mitochondrial function.
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Affiliation(s)
- Bo-Hao Liu
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China
- Department of Thoracic Surgery, First Hospital of Jilin University, Changchun, 130021, China
| | - Chen-Zhen Xu
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Yi Liu
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Zi-Long Lu
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Ting-Lv Fu
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Guo-Rui Li
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Yu Deng
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Guo-Qing Luo
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Song Ding
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Ning Li
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
| | - Qing Geng
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
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Devine AJ, Smith NJ, Joshi R, Brooks-Patton B, Dunham J, Varisco AN, Goodman EM, Fan Q, Zingarelli B, Varisco BM. KF4 anti-CELA1 Antibody and Purified α1-Antitrypsin Have Similar but Not Additive Efficacy in Preventing Emphysema in Murine α1-Antitrypsin Deficiency. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.05.07.592994. [PMID: 38766202 PMCID: PMC11100728 DOI: 10.1101/2024.05.07.592994] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/22/2024]
Abstract
Alpha-1 antitrypsin (AAT) deficiency is the most common genetic cause of emphysema. Chymotrypsin-like Elastase 1 (CELA1) is a serine protease neutralized by AAT and is important in emphysema progression. Cela1-deficiency is protective in a murine models of AAT-deficient emphysema. KF4 anti-CELA1 antibody prevented emphysema in PPE and cigarette smoke models in wild type mice. We evaluated potential toxicities of KF4 and its ability to prevent emphysema in AAT deficiency. We found Cela1 protein expression in mouse lung, pancreas, small intestine, and spleen. In toxicity studies, mice treated with KF4 25 mg/kg weekly for four weeks showed an elevation in blood urea nitrogen and slower weight gain compared to lower doses or equivalent dose IgG. In histologic grading of tissue injury of the lung, kidney, liver, and heart, there was some evidence of liver injury with KF4 25 mg/kg, but in all tissues, injury was less than in control mice subjected to cecal ligation and puncture. In efficacy studies, KF4 doses as low as 0.5 mg/kg reduced the lung elastase activity of AAT-/- mice treated with 0.2 units of PPE. In this injury model, AAT-/- mice treated with KF4 1 mg/kg weekly, human purified AAT 60 mg/kg weekly, and combined KF4 and AAT treatment had less emphysema than mice treated with IgG 1 mg/kg weekly. However, the efficacy of KF4, AAT, or KF4 & AAT was similar. While KF4 might be an alternative to AAT replacement, combined KF4 and AAT replacement does not confer additional benefit.
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Affiliation(s)
- Andrew J. Devine
- Ohio University Heritage College of Osteopathic Medicine, Athens, OH, USA
| | - Noah J. Smith
- College of Medicine, University of Cincinnati, Cincinnati, OH, USA
| | - Rashika Joshi
- Critical Care Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
| | | | - Jenna Dunham
- Northern Kentucky University, Covington, KY, USA
| | | | - Emily M. Goodman
- University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Qiang Fan
- Critical Care Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
| | - Basilia Zingarelli
- Critical Care Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
| | - Brian M. Varisco
- Ohio University Heritage College of Osteopathic Medicine, Athens, OH, USA
- College of Medicine, University of Cincinnati, Cincinnati, OH, USA
- University of Arkansas for Medical Sciences, Little Rock, AR, USA
- Arkansas Children’s Research Institute, Little Rock, AR, USA
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Liu L, Lin L, Wang Y, Yan X, Li R, He M, Li H, Zhuo C, Li L, Zhang D, Wang X, Huang W, Li X, Mao Y, Chen H, Wu S, Jiang W, Zhu L. L-AP Alleviates Liver Injury in Septic Mice by Inhibiting Macrophage Activation via Suppressing NF-κB and NLRP3 Inflammasome/Caspase-1 Signal Pathways. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:8460-8475. [PMID: 38564364 DOI: 10.1021/acs.jafc.3c02781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/04/2024]
Abstract
Liver injury and progressive liver failure are severe life-threatening complications in sepsis, further worsening the disease and leading to death. Macrophages and their mediated inflammatory cytokine storm are critical regulators in the occurrence and progression of liver injury in sepsis, for which effective treatments are still lacking. l-Ascorbic acid 6-palmitate (L-AP), a food additive, can inhibit neuroinflammation by modulating the phenotype of the microglia, but its pharmacological action in septic liver damage has not been fully explored. We aimed to investigate L-AP's antisepticemia action and the possible pharmacological mechanisms in attenuating septic liver damage by modulating macrophage function. We observed that L-AP treatment significantly increased survival in cecal ligation and puncture-induced WT mice and attenuated hepatic inflammatory injury, including the histopathology of the liver tissues, hepatocyte apoptosis, and the liver enzyme levels in plasma, which were comparable to NLRP3-deficiency in septic mice. L-AP supplementation significantly attenuated the excessive inflammatory response in hepatic tissues of septic mice in vivo and in cultured macrophages challenged by both LPS and ATP in vitro, by reducing the levels of NLRP3, pro-IL-1β, and pro-IL-18 mRNA expression, as well as the levels of proteins for p-I-κB-α, p-NF-κB-p65, NLRP3, cleaved-caspase-1, IL-1β, and IL-18. Additionally, it impaired the inflammasome ASC spot activation and reduced the inflammatory factor contents, including IL-1β and IL-18 in plasma/cultured superannuants. It also prevented the infiltration/migration of macrophages and their M1-like inflammatory polarization while improving their M2-like polarization. Overall, our findings revealed that L-AP protected against sepsis by reducing macrophage activation and inflammatory cytokine production by suppressing their activation in NF-κB and NLRP3 inflammasome signal pathways in septic liver.
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Affiliation(s)
- Linling Liu
- Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, and Department of Pharmacology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, PR China
| | - Lan Lin
- Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, and Department of Pharmacology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, PR China
| | - Yingling Wang
- Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, and Department of Pharmacology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, PR China
| | - Xin Yan
- Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, and Department of Pharmacology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, PR China
- Department of Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China
| | - Ruli Li
- Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, and Department of Pharmacology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, PR China
| | - Min He
- Department of Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China
| | - He Li
- Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, and Department of Pharmacology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, PR China
| | - Caili Zhuo
- Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, and Department of Pharmacology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, PR China
| | - Lingyu Li
- Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, and Department of Pharmacology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, PR China
| | - Die Zhang
- Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, and Department of Pharmacology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, PR China
| | - Xuemei Wang
- Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, and Department of Pharmacology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, PR China
| | - Wenjing Huang
- Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, and Department of Pharmacology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, PR China
| | - Xinyue Li
- Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, and Department of Pharmacology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, PR China
| | - Yan Mao
- Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, and Department of Pharmacology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, PR China
| | - Hongying Chen
- Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, and Department of Pharmacology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, PR China
- Core Facilities, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China
| | - Sisi Wu
- Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, and Department of Pharmacology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, PR China
- Core Facilities, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China
| | - Wei Jiang
- Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, and Department of Pharmacology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, PR China
| | - Ling Zhu
- Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, and Department of Pharmacology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, PR China
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Bruno MEC, Mukherjee S, Sturgill JL, Cornea V, Yeh P, Hawk GS, Saito H, Starr ME. PAI-1 as a critical factor in the resolution of sepsis and acute kidney injury in old age. Front Cell Dev Biol 2024; 11:1330433. [PMID: 38304613 PMCID: PMC10830627 DOI: 10.3389/fcell.2023.1330433] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Accepted: 12/27/2023] [Indexed: 02/03/2024] Open
Abstract
Elevated plasma levels of plasminogen activator inhibitor type 1 (PAI-1) are documented in patients with sepsis and levels positively correlate with disease severity and mortality. Our prior work demonstrated that PAI-1 in plasma is positively associated with acute kidney injury (AKI) in septic patients and mice. The objective of this study was to determine if PAI-1 is causally related to AKI and worse sepsis outcomes using a clinically-relevant and age-appropriate murine model of sepsis. Sepsis was induced by cecal slurry (CS)-injection to wild-type (WT, C57BL/6) and PAI-1 knockout (KO) mice at young (5-9 months) and old (18-22 months) age. Survival was monitored for at least 10 days or mice were euthanized for tissue collection at 24 or 48 h post-insult. Contrary to our expectation, PAI-1 KO mice at old age were significantly more sensitive to CS-induced sepsis compared to WT mice (24% vs. 65% survival, p = 0.0037). In comparison, loss of PAI-1 at young age had negligible effects on sepsis survival (86% vs. 88% survival, p = 0.8106) highlighting the importance of age as a biological variable. Injury to the kidney was the most apparent pathological consequence and occurred earlier in aged PAI-1 KO mice. Coagulation markers were unaffected by loss of PAI-1, suggesting thrombosis-independent mechanisms for PAI-1-mediated protection. In summary, although high PAI-1 levels are clinically associated with worse sepsis outcomes, loss of PAI-1 rendered mice more susceptible to kidney injury and death in a CS-induced model of sepsis using aged mice. These results implicate PAI-1 as a critical factor in the resolution of sepsis in old age.
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Affiliation(s)
- Maria E. C. Bruno
- Department of Surgery, University of Kentucky, Lexington, KY, United States
| | - Sujata Mukherjee
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY, United States
| | - Jamie L. Sturgill
- Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky, Lexington, KY, United States
| | - Virgilius Cornea
- Department of Pathology, University of Kentucky, Lexington, KY, United States
| | - Peng Yeh
- Department of Statistics, University of Kentucky, Lexington, KY, United States
| | - Gregory S. Hawk
- Department of Statistics, University of Kentucky, Lexington, KY, United States
| | - Hiroshi Saito
- Department of Surgery, University of Kentucky, Lexington, KY, United States
- Department of Physiology, University of Kentucky, Lexington, KY, United States
- Department of Pharmacology and Nutritional Sciences, Graduate Faculty of Nutritional Sciences, University of Kentucky, Lexington, KY, United States
| | - Marlene E. Starr
- Department of Surgery, University of Kentucky, Lexington, KY, United States
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY, United States
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Le TV, Truong NH, Holterman AXL. Autophagy modulates physiologic and adaptive response in the liver. LIVER RESEARCH (BEIJING, CHINA) 2023; 7:304-320. [PMID: 39958781 PMCID: PMC11792069 DOI: 10.1016/j.livres.2023.12.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 07/20/2023] [Accepted: 11/14/2023] [Indexed: 01/03/2025]
Abstract
Autophagy is a physiological process that is ubiquitous and essential to the disposal or recycling of damaged cellular organelles and misfolded proteins to maintain organ homeostasis and survival. Its importance in the regulation of liver function in normal and pathological conditions is increasingly recognized. This review summarizes how autophagy regulates epithelial cell- and non-epithelial cell-specific function in the liver and how it differentially participates in hepatic homeostasis, hepatic injury response to stress-induced liver damage such as cholestasis, sepsis, non-alcoholic and alcohol-associated liver disease, viral hepatitis, hepatic fibrosis, hepatocellular and cholangiocellular carcinoma, and aging. Autophagy-based interventional studies for liver diseases that are currently registered in clinicatrials.gov are summarized. Given the broad and multidirectional autophagy response in the liver, a more refined understanding of the liver cell-specific autophagy activities in a context-dependent manner is necessary.
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Affiliation(s)
- Trinh Van Le
- Laboratory of Stem Cell Research and Application, University of Science-VNUHCM, Ho Chi Minh City, Vietnam
- Vietnam National University, Ho Chi Minh City, Vietnam
| | - Nhung Hai Truong
- Faculty of Biology and Biotechnology, University of Science-VNUHCM, Ho Chi Minh City, Vietnam
| | - Ai Xuan L. Holterman
- Department of Pediatrics and Surgery, University of Illinois College of Medicine, Chicago and Peoria, IL, USA
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10
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Yin L, Yuan L, Tang Y, Luo Z, Lin X, Wang S, Liang P, Jiang B. NUCLEOLIN PROMOTES AUTOPHAGY THROUGH PGC-1Α IN LPS-INDUCED MYOCARDIAL INJURY. Shock 2023; 60:227-237. [PMID: 37249064 DOI: 10.1097/shk.0000000000002152] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/31/2023]
Abstract
ABSTRACT As a multifunctional protein, nucleolin can participate in a variety of cellular processes. Nucleolin also has multiple protective effects on heart disease. Previous studies have shown that nucleolin could not only resist oxidative stress damage and inflammatory damage, but also regulate autophagy to play a protective role in cardiac ischemia. However, the specific mechanism has not been fully elucidated in LPS-induced myocardial injury. Therefore, the aim of this study is to explore the underlying mechanism by which nucleolin regulates autophagy to protect against LPS-induced myocardial injury in vivo and in vitro . In our study, we found that nucleolin could bind to PGC-1α, and we predicted that this interaction could promote autophagy and played a role in inhibiting cardiomyocyte apoptosis. Downregulation of nucleolin in H9C2 cells resulted in decreased autophagy and increased cell apoptosis during LPS-induced myocardial injury, while upregulation of PGC-1α had the opposite protective effect. Upregulation of nucleolin expression in cardiomyocytes could increase the level of autophagy during LPS-induced myocardial injury. In contrast, interference with PGC-1α expression resulted in a decrease in the protective effect of nucleolin, leading to reduced autophagy and thus increasing apoptosis. By using tandem fluorescent-tagged LC3 autophagic flux detection system, we observed autophagic flux and determined that PGC-1α interference could block autophagic lysosomal progression. We further tested our hypothesis in the nucleolin cardiac-specific knockout mice. Finally, we also found that inhibition of autophagy can reduce mitochondrial biogenesis as well as increase apoptosis, which demonstrated the importance of autophagy. Therefore, we can speculate that nucleolin can protect LPS-induced myocardial injury by regulating autophagy, and this protective effect may be mediated by the interaction with PGC-1α, which can positively regulate the ULK1, an autophagy-related protein. Our study provides a new clue for the cardioprotective effect of nucleolin, and may provide new evidence for the treatment of LPS-induced myocardial injury through the regulation of autophagy.
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Affiliation(s)
| | | | | | | | | | | | - Pengfei Liang
- Department of Burns and Plastic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
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11
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Hussain I, Sureshkumar HK, Bauer M, Rubio I. Starvation Protects Hepatocytes from Inflammatory Damage through Paradoxical mTORC1 Signaling. Cells 2023; 12:1668. [PMID: 37371138 PMCID: PMC10297036 DOI: 10.3390/cells12121668] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 06/12/2023] [Accepted: 06/16/2023] [Indexed: 06/29/2023] Open
Abstract
Background and aims: Sepsis-related liver failure is associated with a particularly unfavorable clinical outcome. Calorie restriction is a well-established factor that can increase tissue resilience, protect against liver failure and improve outcome in preclinical models of bacterial sepsis. However, the underlying molecular basis is difficult to investigate in animal studies and remains largely unknown. METHODS We have used an immortalized hepatocyte line as a model of the liver parenchyma to uncover the role of caloric restriction in the resilience of hepatocytes to inflammatory cell damage. In addition, we applied genetic and pharmacological approaches to investigate the contribution of the three major intracellular nutrient/energy sensor systems, AMPK, mTORC1 and mTORC2, in this context. RESULTS We demonstrate that starvation reliably protects hepatocytes from cellular damage caused by pro-inflammatory cytokines. While the major nutrient- and energy-related signaling pathways AMPK, mTORC2/Akt and mTORC1 responded to caloric restriction as expected, mTORC1 was paradoxically activated by inflammatory stress in starved, energy-deprived hepatocytes. Pharmacological inhibition of mTORC1 or genetic silencing of the mTORC1 scaffold Raptor, but not its mTORC2 counterpart Rictor, abrogated the protective effect of starvation and exacerbated inflammation-induced cell death. Remarkably, mTORC1 activation in starved hepatocytes was uncoupled from the regulation of autophagy, but crucial for sustained protein synthesis in starved resistant cells. CONCLUSIONS AMPK engagement and paradoxical mTORC1 activation and signaling mediate protection against pro-inflammatory stress exerted by caloric restriction in hepatocytes.
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Affiliation(s)
- Iqra Hussain
- Department for Anesthesiology & Intensive Care Medicine, Jena University Hospital, Member of the Leibniz Center for Photonics in Infection Research (LPI), 07747 Jena, Germany; (I.H.)
| | - Harini K. Sureshkumar
- Department for Anesthesiology & Intensive Care Medicine, Jena University Hospital, Member of the Leibniz Center for Photonics in Infection Research (LPI), 07747 Jena, Germany; (I.H.)
| | - Michael Bauer
- Department for Anesthesiology & Intensive Care Medicine, Jena University Hospital, Member of the Leibniz Center for Photonics in Infection Research (LPI), 07747 Jena, Germany; (I.H.)
- Integrated Research and Treatment Center, Center for Sepsis Control and Care, Jena University Hospital, 07747 Jena, Germany
| | - Ignacio Rubio
- Department for Anesthesiology & Intensive Care Medicine, Jena University Hospital, Member of the Leibniz Center for Photonics in Infection Research (LPI), 07747 Jena, Germany; (I.H.)
- Integrated Research and Treatment Center, Center for Sepsis Control and Care, Jena University Hospital, 07747 Jena, Germany
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12
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Zhang Y, Wu F, Teng F, Guo S, Li H. Deficiency of S100A9 Alleviates Sepsis-Induced Acute Liver Injury through Regulating AKT-AMPK-Dependent Mitochondrial Energy Metabolism. Int J Mol Sci 2023; 24:2112. [PMID: 36768433 PMCID: PMC9916677 DOI: 10.3390/ijms24032112] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 01/15/2023] [Accepted: 01/18/2023] [Indexed: 01/25/2023] Open
Abstract
Acute liver injury (ALI) is recognized as a serious complication of sepsis in patients in intensive care units (ICUs). S100A8/A9 is known to promote inflammation and immune responses. However, the role of S100A8/A9 in the regulation of sepsis-induced ALI remains known. Our results indicated that S100A8/A9 expression was significantly upregulated in the livers of septic mice 24 h after cecal ligation and a puncture (CLP) operation. Moreover, S100A9-KO in mice markedly attenuated CLP-induced liver dysfunction and injury, promoting the AMPK/ACC/GLUT4-mediated increases in fatty acid and glucose uptake as well as the improvement in mitochondrial function and ATP production. In contrast, treatment with the AMPK inhibitor Compound C reversed the inhibitory effects of S100A9 KO on CLP-induced liver dysfunction and injury in vivo. Finally, the administration of the S100A9 inhibitor Paquinimod (Paq) to WT mice protected against CLP-induced mortality, liver injury and mitochondrial dysfunction. In summary, our findings demonstrate for the first time that S100A9 plays an important pro-inflammatory role in sepsis-mediated ALI by regulating AKT-AMPK-dependent mitochondrial energy metabolism and highlights that targeting S100A9 may be a promising new approach for the prevention and treatment of sepsis-related liver injury.
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Affiliation(s)
| | | | | | - Shubin Guo
- Beijing Key Laboratory of Cardiopulmonary Cerebral Resuscitation, Department of Emergency Medicine, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China
| | - Huihua Li
- Beijing Key Laboratory of Cardiopulmonary Cerebral Resuscitation, Department of Emergency Medicine, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China
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13
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Wang Z, Xiao D, Ji Q, Li Y, Cai Z, Fang L, Huo H, Zhou G, Yan X, Shen L, He B. Jujuboside A attenuates sepsis-induced cardiomyopathy by inhibiting inflammation and regulating autophagy. Eur J Pharmacol 2022; 947:175451. [PMID: 36502962 DOI: 10.1016/j.ejphar.2022.175451] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 12/02/2022] [Accepted: 12/07/2022] [Indexed: 12/13/2022]
Abstract
BACKGROUND Jujuboside A (JuA), as a main effective component of Jujubogenin, has long been known as a sedative-hypnotic drug. The aim of the current study was to investigate the potential effect of JuA on sepsis-induced cardiomyopathy (SIC) induced by lipopolysaccharide (LPS). METHOD Wide type C57BL/6 mice and neonatal rat cardiomyocytes (NRCMs) were exposed to LPS to establish myocardial toxicity models. Cardiac function of septic mice was detected by echocardiography. Moreover, the survival rate was calculated for 7 days. ELISA assays were used to analyze inflammatory factors in serum. Furthermore, western blotting, flow cytometry and TUNEL staining were performed to assess cell apoptosis and transmission electron microscopy detect the number of autophagosomes in myocardium. Finally, the expression of proteins related to pyroptosis, autophagy and oxidative stress was analyzed by western blotting and immunohistochemistry staining. RESULTS Results showed that JuA pretreatment significantly improved the survival rate and cardiac function, and suppressed systemic inflammatory response in septic mice. Further study revealed that JuA could decrease cell apoptosis and pyroptosis; instead, it strengthened autophagy in SIC. Moreover, JuA also significantly decreased oxidative stress and nitrodative stress, as evidenced by suppressing the superoxide production and downregulating iNOS and gp91 expression in vivo. In addition, the autophagy inhibitor 3-MA significantly abolished the effect of JuA on autophagic activity in SIC. CONCLUSION In conclusion, the findings indicated that JuA attenuates cardiac function via blocking inflammasome-mediated apoptosis and pyroptosis, at the same time by enhancing autophagy in SIC, heralding JuA as a potential therapy for sepsis.
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14
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Liu LL, Yan X, Xue KY, Wang XM, Li LY, Chen HY, Li RL, Li H, Lan J, Xin JJ, Li X, Zhuo CL, Wu Z, Zhang D, Huang WJ, Wang YL, Li XY, Jiang W, Zhang HY. Prim-O-glucosycimifugin attenuates liver injury in septic mice by inhibiting NLRP3 inflammasome/caspase-1 signaling cascades in macrophages. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2022; 106:154427. [PMID: 36088791 DOI: 10.1016/j.phymed.2022.154427] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 08/28/2022] [Accepted: 08/31/2022] [Indexed: 06/15/2023]
Abstract
BACKGROUND Liver dysfunction and liver failure are serious complications of sepsis, directly leading to septic progression and death. Now, there is no specific therapeutics available for sepsis-related liver dysfunction. Prim-O-glucosylcimifugin (POG), a chromone richest in the roots of Saposhnikovia divaricata (Turcz.) Schischk, is usually used to treat headache, rheumatoid arthritis and tetanus. While, the underlying mechanisms of POG against sepsis-induced liver damage and dysfunction are still not clear. PURPOSE To study the anti-sepsis effect of POG, and its pharmacological mechanism to protect liver injury by weakening the function of macrophages in septic livers through inhibiting NOD-like receptor protein 3 (NLRP3) inflammasome pathway. METHOD In vivo experiments, septic mouse model was induced by cecal ligation and puncture (CLP), and then the mortality was detected, liver inflammatory damages and plasma biomarkers of liver injury were evaluated by histopathological staining and biochemical assays, respectively. In vitro experiments, mouse primary peritoneal macrophages were treated with lipopolysaccharide (LPS) and ATP, and then the activated-inflammasomes, macrophage migration and polarization were detected by ASC immunofluorescence staining, transwell and flow cytometry assays, respectively. NLRP3 inflammasome components NLRP3, caspase-1, IL-1β and IL-18 protein expressions were detected using western blot assays, and the contents of IL-1β and IL-18 were measured by ELISA assays. RESULTS POG treatment significantly decreased the mortality, liver inflammatory damages, hepatocyte apoptosis and plasma biomarkers of liver injury in CLP-challenged male WT mice, which were comparable to those in ibuprofen (a putative anti-inflammatory drug)-supplemented septic male WT mice and septic NLRP3 deficient-male mice. POG supplementation significantly suppressed NLRP3 inflammasome activation in septic liver tissues and cultured macrophages, by significantly reducing NLRP3, cleaved-caspase-1, IL-1β and IL-18 levels, the activated-inflammasome ASC specks, and macrophage infiltration and migration, as well as M1-like polarization, but significantly increasing M2-like polarization. These findings were similar to the pharmacological effects of ibuprofen, NLRP3 deficiency, and a special NLRP3 inhibitor, MCC950. CONCLUSION POG protected against sepsis by inhibiting NLRP3 inflammasome-mediated macrophage activation in septic liver and attenuating liver inflammatory injury, indicating that it may be a potential anti-sepsis drug candidate.
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Affiliation(s)
- Lin-Ling Liu
- Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China; School of Preclinical and Forensic Medicine, Sichuan University, Chengdu 610041, PR China
| | - Xin Yan
- Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China
| | - Kun-Yue Xue
- Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China
| | - Xue-Mei Wang
- Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China
| | - Ling-Yu Li
- Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China
| | - Hong-Ying Chen
- Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China; Core Facilities, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China
| | - Ru-Li Li
- Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China
| | - He Li
- Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China
| | - Jie Lan
- Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China
| | - Juan-Juan Xin
- Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China
| | - Xue Li
- Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China
| | - Cai-Li Zhuo
- Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China
| | - Zhuang Wu
- Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China
| | - Die Zhang
- Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China
| | - Wen-Jing Huang
- Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China
| | - Ying-Ling Wang
- Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China
| | - Xin-Yue Li
- Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China
| | - Wei Jiang
- Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China.
| | - Heng-Yu Zhang
- Department of Cardiology, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, PR China.
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Song B, Zhou W. Amarogentin has protective effects against sepsis-induced brain injury via modulating the AMPK/SIRT1/NF-κB pathway. Brain Res Bull 2022; 189:44-56. [PMID: 35985610 DOI: 10.1016/j.brainresbull.2022.08.018] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 06/21/2022] [Accepted: 08/14/2022] [Indexed: 02/05/2023]
Abstract
Amarogentin (AMA), a secoiridoid glycoside that is mainly derived from SwertiaandGentiana roots, has been confirmed to exhibit antioxidative, tumor-suppressive and anti-diabetic properties. This research intends to investigate the protective effect of AMA against sepsis-induced brain injury and its mechanism. NSC-34 and HT22 cells were treated with lipopolysaccharide (LPS) to induce an in-vitro sepsis model and then treated with varying concentrations (1, 5, 10 µM) of AMA. Cell proliferation and apoptosis were evaluated. The intensity of inflammation and oxidative stress were assessed by different methods. The AMPK/SIRT1/NF-κB pathway expression was determined by WB. An in-vitro sepsis model was set up with cecal ligation and puncture (CLP) in adult C57/BL6J mice, and different concentrations (25, 50, 100 mg/kg) of AMA were applied for treatment. Neurological function was evaluated using the modified neurological severity scores (mNSS), and the brain tissue damage was measured using hematoxylin-eosin (H&E) staining and Nissl staining. Tissue apoptosis was tested using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. Then, the AMPK inhibitor Compound C (CC) was administered to confirm AMA-mediated mechanism. Our finding illustrated that AMA mitigated LPS-induced neuronal damage, inflammation and oxidative stress, activated the AMPK/SIRT1 pathway and choked NF-κB phosphorylation. Furthermore, AMA improved neurological functions of sepsis mice by reliving neuroinflammation and oxidative stress. Inhibition of AMPK attenuated the protective effect of AMA on neurons or the mice's brain tissues. In conclusion, AMA protected against sepsis-induced brain injury by modulating the AMPK/SIRT1/NF-κB pathway.
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Affiliation(s)
- Bihui Song
- Emergency Department, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, China
| | - Wenhao Zhou
- Emergency Department, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, China.
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Zhao Y, Yu D, Wang H, Jin W, Li X, Hu Y, Qin Y, Kong D, Li G, Ellen A, Wang H. Galectin-9 Mediates the Therapeutic Effect of Mesenchymal Stem Cells on Experimental Endotoxemia. Front Cell Dev Biol 2022; 10:700702. [PMID: 35252164 PMCID: PMC8893172 DOI: 10.3389/fcell.2022.700702] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 01/03/2022] [Indexed: 12/19/2022] Open
Abstract
Endotoxemia remains a major cause of mortality in the intensive care unit, but the therapeutic strategy is still lacking. Mesenchymal stem cell (MSC) was reported with a tissue-oriented differentiation ability and an excellent immunoregulatory capacity. However, the immunity signaling pathways that govern MSC modulation effect are not completely understood. In our current study, MSCs (2.5 × 105 /ml) were obtained and stimulated with IFN-γ (20 ng/ml) for 72 h. Gal-9 expression on MSCs was measured by ELISA, RT-PCR, flow cytometry, and immunofluorescence, respectively. Experimental endotoxemia was induced by LPS injection (10 mg/kg, i. p.) followed by the treatment with Gal-9 high-expressing MSCs, unmodified MSCs, and Gal-9 blocking MSCs. Therapeutic effects of MSCs were assessed by monitoring murine sepsis score, survival rate, splenocyte proportion rate, inflammatory mediator levels, and pathological manifestations. The results showed that Gal-9 expressed in MSCs, and this expression was increased in a dose-dependent manner after pre-stimulating with IFN-γ. Adoptive transfer of Gal-9 high-expressing MSCs into modeling mice significantly alleviated endotoxemia symptoms and multi-organ pathological damages. Splenocyte analysis indicated that Gal-9 high-expressing MSCs could promote macrophage polarization to M2-subtype and boost Treg generation. Moreover, there were also attenuated pro-inflammatory mediator expressions (TNF-α, IL-1β, IFN-γ, and iNOS), and increased anti-inflammatory mediator expressions (T-SOD and IL-35) in the sera and damaged organ homogenates. Additionally, we found a higher expression of Gal-9 in liver, lung, and kidney homogenate. Taken together, this study reveals that the optimized immunoregulatory effect of MSCs is strongly correlated with Gal-9 high expression, which provides a novel idea for the investigation of MSC immunomodulatory mechanisms and offers a potential strategy for the treatment of endotoxemia in clinical settings.
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Affiliation(s)
- Yiming Zhao
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Tianjin General Surgery Institute, Tianjin, China
| | - Dingding Yu
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
- Tianjin General Surgery Institute, Tianjin, China
| | - Hongda Wang
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
- Tianjin General Surgery Institute, Tianjin, China
| | - Wang Jin
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
- Tianjin General Surgery Institute, Tianjin, China
| | - Xiang Li
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
- Tianjin General Surgery Institute, Tianjin, China
| | - Yonghao Hu
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
- Tianjin General Surgery Institute, Tianjin, China
| | - Yafei Qin
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
- Tianjin General Surgery Institute, Tianjin, China
| | - Dejun Kong
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
- Tianjin General Surgery Institute, Tianjin, China
| | - Guangming Li
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
- Tianjin General Surgery Institute, Tianjin, China
| | - Acheampong Ellen
- Department of Pathology, Massachusetts General Hospital, Boston, MA, United States
| | - Hao Wang
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
- Tianjin General Surgery Institute, Tianjin, China
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He D, Li N, Lu X, Li W, Chen Y, Sun Z, Zhang L, Guo L, Cui X, Song G, Niu W, Zhang Q. Association of mitochondrial respiratory chain enzymes with the risk and mortality of sepsis among Chinese children. BMC Infect Dis 2022; 22:34. [PMID: 34991517 PMCID: PMC8740061 DOI: 10.1186/s12879-021-07014-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 12/23/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Sepsis is a leading cause of pediatric morbidity and mortality worldwide. The aim of this study was to explore the association of decreased mitochondrial respiratory chain enzyme activities with the risk for pediatric sepsis, and explore their association with mortality among affected children. METHODS A total of 50 incident cases with sepsis and 49 healthy controls participated in this study. The level of serum coenzyme Q10 was measured by high-performance liquid chromatography, and selected mitochondrial respiratory chain enzymes in WBC were measured using spectrophotometric. Logistic regression models were used to estimate odds ratio (OR) and 95% confidence interval (CI). RESULTS The levels of CoQ10, complex II, complex I + III and FoF1-ATPase were significantly higher in healthy controls than in children with sepsis (p < 0.001, = 0.004, < 0.001 and < 0.001, respectively). In children with sepsis, levels of CoQ10 and complex I + III were significantly higher in survived cases than in deceased cases (p < 0.001). Per 0.05 μmol/L, 50 nmol/min.mg and 100 nmol/min.mg increment in CoQ10, complex I + III and FoF1-ATPase were associated with significantly lowered risk of having sepsis, even after adjusting for confounding factors (OR = 0.85, 0.68 and 0.04, p = 0.001, < 0.001 and < 0.001, respectively). Per 0.05 μmol/L and 50 nmol/min.mg increment in CoQ10 and complex I + III was associated with significantly lowered risk of dying from sepsis during hospitalization, and significance retained after adjustment (OR = 0.73 and 0.76, 95% CI: 0.59 to 0.90 and 0.64 to 0.89, p = 0.004 and 0.001, respectively) in children with sepsis. CONCLUSIONS Our findings indicate the promising predictive contribution of low serum CoQ10 and complex I + III to the risk of pediatric sepsis and its associated mortality during hospitalization among Chinese children. Trial registration The trial was registered with www.chictr.org.cn , number ChiCTR-IOR-15006446 on May 05, 2015. Retrospectively registered.
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Affiliation(s)
- Danni He
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, No. 2 Yinghua East Street, Chaoyang District, Beijing, 100029, China.,Department of Pediatrics, China-Japan Friendship Hospital, No.2 Yinghua East Street, Chaoyang District, Beijing, 100029, China
| | - Ning Li
- Intensive Care Unit, Affiliated Children's Hospital of Capital Institute of Pediatrics, Beijing, China
| | - Xiuxiu Lu
- Intensive Care Unit, Affiliated Children's Hospital of Capital Institute of Pediatrics, Beijing, China
| | - Wei Li
- Intensive Care Unit, Affiliated Children's Hospital of Capital Institute of Pediatrics, Beijing, China
| | - Yuanmei Chen
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, No. 2 Yinghua East Street, Chaoyang District, Beijing, 100029, China
| | - Zhongyuan Sun
- Intensive Care Unit, Affiliated Children's Hospital of Capital Institute of Pediatrics, Beijing, China
| | - Lipeng Zhang
- Department of Pediatrics, China-Japan Friendship Hospital, No.2 Yinghua East Street, Chaoyang District, Beijing, 100029, China.,Graduate School of Peking Union Medical College and Chinese Academy of Medical Science, Beijing, China
| | - Linying Guo
- Intensive Care Unit, Affiliated Children's Hospital of Capital Institute of Pediatrics, Beijing, China
| | - Xiaodai Cui
- Central Laboratory, Capital Institute of Pediatrics, Beijing, China
| | - Guowei Song
- Central Laboratory, Capital Institute of Pediatrics, Beijing, China
| | - Wenquan Niu
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, No. 2 Yinghua East Street, Chaoyang District, Beijing, 100029, China.
| | - Qi Zhang
- Department of Pediatrics, China-Japan Friendship Hospital, No.2 Yinghua East Street, Chaoyang District, Beijing, 100029, China.
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Carvajal FJ, Cerpa W. Regulation of Phosphorylated State of NMDA Receptor by STEP 61 Phosphatase after Mild-Traumatic Brain Injury: Role of Oxidative Stress. Antioxidants (Basel) 2021; 10:antiox10101575. [PMID: 34679709 PMCID: PMC8533270 DOI: 10.3390/antiox10101575] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 09/14/2021] [Accepted: 09/28/2021] [Indexed: 01/21/2023] Open
Abstract
Traumatic Brain Injury (TBI) mediates neuronal death through several events involving many molecular pathways, including the glutamate-mediated excitotoxicity for excessive stimulation of N-methyl-D-aspartate receptors (NMDARs), producing activation of death signaling pathways. However, the contribution of NMDARs (distribution and signaling-associated to the distribution) remains incompletely understood. We propose a critical role of STEP61 (Striatal-Enriched protein tyrosine phosphatase) in TBI; this phosphatase regulates the dephosphorylated state of the GluN2B subunit through two pathways: by direct dephosphorylation of tyrosine-1472 and indirectly via dephosphorylation and inactivation of Fyn kinase. We previously demonstrated oxidative stress’s contribution to NMDAR signaling and distribution using SOD2+/− mice such a model. We performed TBI protocol using a controlled frontal impact device using C57BL/6 mice and SOD2+/− animals. After TBI, we found alterations in cognitive performance, NMDAR-dependent synaptic function (decreased synaptic form of NMDARs and decreased synaptic current NMDAR-dependent), and increased STEP61 activity. These changes are reduced partially with the STEP61-inhibitor TC-2153 treatment in mice subjected to TBI protocol. This study contributes with evidence about the role of STEP61 in the neuropathological progression after TBI and also the alteration in their activity, such as an early biomarker of synaptic damage in traumatic lesions.
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Affiliation(s)
- Francisco J. Carvajal
- Laboratorio de Función y Patología Neuronal, Centro de Envejecimiento y Regeneración (CARE), Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile;
- Centro de Excelencia en Biomedicina de Magallanes (CEBIMA), Universidad de Magallanes, Punta Arenas 6200000, Chile
| | - Waldo Cerpa
- Laboratorio de Función y Patología Neuronal, Centro de Envejecimiento y Regeneración (CARE), Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile;
- Centro de Excelencia en Biomedicina de Magallanes (CEBIMA), Universidad de Magallanes, Punta Arenas 6200000, Chile
- Correspondence: ; Tel.: +56-2-2354-2656; Fax: +56-2-2354-2660
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19
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Hayes HV, Wolfe V, O’Connor M, Levinsky NC, Piraino G, Zingarelli B. Deficiency of AMPKα1 Exacerbates Intestinal Injury and Remote Acute Lung Injury in Mesenteric Ischemia and Reperfusion in Mice. Int J Mol Sci 2021; 22:9911. [PMID: 34576076 PMCID: PMC8468919 DOI: 10.3390/ijms22189911] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 09/04/2021] [Accepted: 09/08/2021] [Indexed: 01/13/2023] Open
Abstract
Mesenteric ischemia and reperfusion (I/R) injury can ensue from a variety of vascular diseases and represents a major cause of morbidity and mortality in intensive care units. It causes an inflammatory response associated with local gut dysfunction and remote organ injury. Adenosine monophosphate-activated protein kinase (AMPK) is a crucial regulator of metabolic homeostasis. The catalytic α1 subunit is highly expressed in the intestine and vascular system. In loss-of-function studies, we investigated the biological role of AMPKα1 in affecting the gastrointestinal barrier function. Male knock-out (KO) mice with a systemic deficiency of AMPKα1 and wild-type (WT) mice were subjected to a 30 min occlusion of the superior mesenteric artery. Four hours after reperfusion, AMPKα1 KO mice exhibited exaggerated histological gut injury and impairment of intestinal permeability associated with marked tissue lipid peroxidation and a lower apical expression of the junction proteins occludin and E-cadherin when compared to WT mice. Lung injury with neutrophil sequestration was higher in AMPKα1 KO mice than WT mice and paralleled with higher plasma levels of syndecan-1, a biomarker of endothelial injury. Thus, the data demonstrate that AMPKα1 is an important requisite for epithelial and endothelial integrity and has a protective role in remote organ injury after acute ischemic events.
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Affiliation(s)
- Hannah V. Hayes
- Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA; (H.V.H.); (N.C.L.)
| | - Vivian Wolfe
- Division of Critical Care Medicine, Cincinnati Children’s Hospital Medical Center, and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA; (V.W.); (M.O.); (G.P.)
| | - Michael O’Connor
- Division of Critical Care Medicine, Cincinnati Children’s Hospital Medical Center, and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA; (V.W.); (M.O.); (G.P.)
| | - Nick C. Levinsky
- Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA; (H.V.H.); (N.C.L.)
| | - Giovanna Piraino
- Division of Critical Care Medicine, Cincinnati Children’s Hospital Medical Center, and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA; (V.W.); (M.O.); (G.P.)
| | - Basilia Zingarelli
- Division of Critical Care Medicine, Cincinnati Children’s Hospital Medical Center, and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA; (V.W.); (M.O.); (G.P.)
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20
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Abstract
Mitochondria have been studied for decades from the standpoint of metabolism and ATP generation. However, in recent years mitochondrial dynamics and its influence on bioenergetics and cellular homeostasis is also being appreciated. Mitochondria undergo regular cycles of fusion and fission regulated by various cues including cellular energy requirements and pathophysiological stimuli, and the network of critical proteins and membrane lipids involved in mitochondrial dynamics is being revealed. Hepatocytes are highly metabolic cells which have abundant mitochondria suggesting a biologically relevant role for mitochondrial dynamics in hepatocyte injury and recovery. Here we review information on molecular mediators of mitochondrial dynamics and their alteration in drug-induced liver injury. Based on current information, it is evident that changes in mitochondrial fusion and fission are hallmarks of liver pathophysiology ranging from acetaminophen-induced or cholestatic liver injury to chronic liver diseases. These alterations in mitochondrial dynamics influence multiple related mitochondrial responses such as mitophagy and mitochondrial biogenesis, which are important adaptive responses facilitating liver recovery in several contexts, including drug-induced liver injury. The current focus on characterization of molecular mechanisms of mitochondrial dynamics is of immense relevance to liver pathophysiology and have the potential to provide significant insight into mechanisms of liver recovery and regeneration after injury.
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21
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Dabravolski SA, Bezsonov EE, Orekhov AN. The role of mitochondria dysfunction and hepatic senescence in NAFLD development and progression. Biomed Pharmacother 2021; 142:112041. [PMID: 34411916 DOI: 10.1016/j.biopha.2021.112041] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 07/29/2021] [Accepted: 08/09/2021] [Indexed: 02/07/2023] Open
Abstract
Senescence is a crucial player in several metabolic disorders and chronic inflammatory diseases. Recent data prove the involvement of hepatocyte senescence in the development of NAFLD (non-alcoholic fatty liver disease). As the main energy and ROS (reactive oxygen species) producing organelle, mitochondria play the central role in accelerated senescence and diseases development. In this review, we focus on the role of regulation of mitochondrial Ca2+ homeostasis, NAD+/NADH ratio, UPRmt (mitochondrial unfolded protein response), phospholipids and fatty acid oxidation in hepatic senescence, lifespan and NAFLD disease susceptibility. Additionally, the involvement of mitochondrial and nuclear mutations in lifespan-modulation and NAFLD development is discussed. While nuclear and mitochondria DNA mutations and SNPs (single nucleotide polymorphisms) can be used as effective diagnostic markers and targets for treatments, advanced age should be considered as an independent risk factor for NAFLD development.
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Affiliation(s)
- Siarhei A Dabravolski
- Department of Clinical Diagnostics, Vitebsk State Academy of Veterinary Medicine [UO VGAVM], 7/11 Dovatora str., 210026 Vitebsk, Belarus.
| | - Evgeny E Bezsonov
- Laboratory of Cellular and Molecular Pathology of Cardiovascular System, Institute of Human Morphology, 3 Tsyurupa Street, 117418 Moscow, Russia; Laboratory of Angiopathology, The Institute of General Pathology and Pathophysiology, 8 Baltiyskaya Street, 125315 Moscow, Russia.
| | - Alexander N Orekhov
- Laboratory of Cellular and Molecular Pathology of Cardiovascular System, Institute of Human Morphology, 3 Tsyurupa Street, 117418 Moscow, Russia; Laboratory of Angiopathology, The Institute of General Pathology and Pathophysiology, 8 Baltiyskaya Street, 125315 Moscow, Russia; Department of Basic Research, Institute for Atherosclerosis Research, Moscow 121609, Russia.
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22
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AMPK activates Parkin independent autophagy and improves post sepsis immune defense against secondary bacterial lung infections. Sci Rep 2021; 11:12387. [PMID: 34117280 PMCID: PMC8196038 DOI: 10.1038/s41598-021-90573-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Accepted: 05/12/2021] [Indexed: 02/06/2023] Open
Abstract
Metabolic and bioenergetic plasticity of immune cells is essential for optimal responses to bacterial infections. AMPK and Parkin ubiquitin ligase are known to regulate mitochondrial quality control mitophagy that prevents unwanted inflammatory responses. However, it is not known if this evolutionarily conserved mechanism has been coopted by the host immune defense to eradicate bacterial pathogens and influence post-sepsis immunosuppression. Parkin, AMPK levels, and the effects of AMPK activators were investigated in human leukocytes from sepsis survivors as well as wild type and Park2−/− murine macrophages. In vivo, the impact of AMPK and Parkin was determined in mice subjected to polymicrobial intra-abdominal sepsis and secondary lung bacterial infections. Mice were treated with metformin during established immunosuppression. We showed that bacteria and mitochondria share mechanisms of autophagic killing/clearance triggered by sentinel events that involve depolarization of mitochondria and recruitment of Parkin in macrophages. Parkin-deficient mice/macrophages fail to form phagolysosomes and kill bacteria. This impairment of host defense is seen in the context of sepsis-induced immunosuppression with decreased levels of Parkin. AMPK activators, including metformin, stimulate Parkin-independent autophagy and bacterial killing in leukocytes from post-shock patients and in lungs of sepsis-immunosuppressed mice. Our results support a dual role of Parkin and AMPK in the clearance of dysfunctional mitochondria and killing of pathogenic bacteria, and explain the immunosuppressive phenotype associated Parkin and AMPK deficiency. AMPK activation appeared to be a crucial therapeutic target for the macrophage immunosuppressive phenotype and to reduce severity of secondary bacterial lung infections and respiratory failure.
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23
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Ke L, Li Q, Song J, Jiao W, Ji A, Chen T, Pan H, Song Y. The mitochondrial biogenesis signaling pathway is a potential therapeutic target for myasthenia gravis via energy metabolism (Review). Exp Ther Med 2021; 22:702. [PMID: 34007311 PMCID: PMC8120506 DOI: 10.3892/etm.2021.10134] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Accepted: 07/21/2020] [Indexed: 02/06/2023] Open
Abstract
Myasthenia gravis (MG) is an autoantibody-mediated autoimmune disease that is characterized by muscle weakness and fatigue. Traditional treatments for MG target the neuromuscular junction (NMJ) or the immune system. However, the efficacy of such treatments is limited, and novel therapeutic options for MG are urgently required. In the current review, a new therapeutic strategy is proposed based on the mitochondrial biogenesis and energy metabolism pathway, as stimulating mitochondrial biogenesis and the energy metabolism might alleviate myasthenia gravis. A number of cellular sensors of the energy metabolism were investigated, including AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1). AMPK and SIRT1 are sensors that regulate cellular energy homeostasis and maintain energy metabolism by balancing anabolism and catabolism. Peroxisome proliferator-activated receptor γ coactivator 1α and its downstream transcription factors nuclear respiratory factors 1, nuclear respiratory factors 2, and transcription factor A are key sensors of mitochondrial biogenesis, which can restore mitochondrial DNA and produce new mitochondria. These processes help to control muscle contraction and relieve the symptoms of MG, including muscle weakness caused by dysfunctional NMJ transmission. Therefore, the present review provides evidence for the therapeutic potential of targeting mitochondrial biogenesis for the treatment of MG.
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Affiliation(s)
- Lingling Ke
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510405, P.R. China.,Institute of Pi-Wei, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510405, P.R. China
| | - Qing Li
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510405, P.R. China.,Institute of Pi-Wei, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510405, P.R. China
| | - Jingwei Song
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510405, P.R. China.,Institute of Pi-Wei, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510405, P.R. China
| | - Wei Jiao
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510405, P.R. China.,Institute of Pi-Wei, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510405, P.R. China
| | - Aidong Ji
- Clinical Medical College of Acupuncture, Moxibustion and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, P.R. China
| | - Tongkai Chen
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510405, P.R. China.,Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510405, P.R. China
| | - Huafeng Pan
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510405, P.R. China
| | - Yafang Song
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510405, P.R. China.,Institute of Pi-Wei, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510405, P.R. China
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24
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Jiang Y, Chen D, Gong Q, Xu Q, Pan D, Lu F, Tang Q. Elucidation of SIRT-1/PGC-1α-associated mitochondrial dysfunction and autophagy in nonalcoholic fatty liver disease. Lipids Health Dis 2021; 20:40. [PMID: 33902605 PMCID: PMC8077826 DOI: 10.1186/s12944-021-01461-5] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Accepted: 04/01/2021] [Indexed: 02/06/2023] Open
Abstract
Background Nonalcoholic fatty liver disease (NAFLD) can lead to chronic liver diseases associated with mitochondrial damages. However, the exact mechanisms involved in the etiology of the disease are not clear. Methods To gain new insights, the changes affecting sirtuin 1 (SIRT-1) during liver fat accumulation was investigated in a NAFLD mouse model. In addition, the in vitro research investigated the regulation operated by SIRT-1 on mitochondrial structures, biogenesis, functions, and autophagy. Results In mice NAFLD, high-fat-diet (HFD) increased body weight gain, upregulated serum total cholesterol, triglycerides, aspartate aminotransferase, alanine aminotransferase, blood glucose, insulin levels, and liver malondialdehyde, and decreased liver superoxide dismutase activity. In liver, the levels of SIRT-1 and peroxisome proliferator-activated receptor-gamma coactivator -1α (PGC-1α) decreased. The expression of peroxisome proliferator-activated receptor-α and Beclin-1 proteins was also reduced, while p62/SQSTM1 expression increased. These results demonstrated SIRT-1 impairment in mouse NAFLD. In a well-established NAFLD cell model, exposure of the HepG2 hepatocyte cell line to oleic acid (OA) for 48 h caused viability reduction, apoptosis, lipid accumulation, and reactive oxygen species production. Disturbance of SIRT-1 expression affected mitochondria. Pre-treatment with Tenovin-6, a SIRT-1 inhibitor, aggravated the effect of OA on hepG2, while this effect was reversed by CAY10602, a SIRT-1 activator. Further investigation demonstrated that SIRT-1 activity was involved in mitochondrial biogenesis through PGC-1α and participated to the balance of autophagy regulatory proteins. Conclusion In conclusion, in high-fat conditions, SIRT-1 regulates multiple cellular properties by influencing on mitochondrial physiology and lipid autophagy via the PGC-1α pathway. The SIRT-1/PGC-1α pathway could be targeted to develop new NAFLD therapeutic strategies.
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Affiliation(s)
- Yan Jiang
- Medical College of Guangxi University, Nanning, 530004, Guangxi, China.,YouJiang Medical University for Nationalities, Baise, 533000, Guangxi, China
| | - Duankai Chen
- YouJiang Medical University for Nationalities, Baise, 533000, Guangxi, China
| | - Qiming Gong
- YouJiang Medical University for Nationalities, Baise, 533000, Guangxi, China
| | - Qunqing Xu
- YouJiang Medical University for Nationalities, Baise, 533000, Guangxi, China
| | - Dong Pan
- YouJiang Medical University for Nationalities, Baise, 533000, Guangxi, China
| | - Feiyan Lu
- YouJiang Medical University for Nationalities, Baise, 533000, Guangxi, China
| | - Qianli Tang
- Medical College of Guangxi University, Nanning, 530004, Guangxi, China. .,YouJiang Medical University for Nationalities, Baise, 533000, Guangxi, China.
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25
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Lei W, Liu D, Sun M, Lu C, Yang W, Wang C, Cheng Y, Zhang M, Shen M, Yang Z, Chen Y, Deng C, Yang Y. Targeting STAT3: A crucial modulator of sepsis. J Cell Physiol 2021; 236:7814-7831. [PMID: 33885157 DOI: 10.1002/jcp.30394] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Revised: 03/14/2021] [Accepted: 04/05/2021] [Indexed: 12/12/2022]
Abstract
Signal transducer and activator of transcription 3 (STAT3) is a cellular signal transcription factor that has recently attracted a great deal of attention. It can trigger a variety of genes transcription in response to cytokines and growth factors stimulation, which plays an important role in many cellular biological processes involved in anti/proinflammatory responses. Sepsis is a life-threatening organ dysfunction resulting from dysregulated host responses to infection. As a converging point of multiple inflammatory responses pathways, accumulating studies have presented the elaborate network of STAT3 in sepsis pathophysiology; these results generally indicate a promising therapeutic application for targeting STAT3 in the treatment of sepsis. In the present review, we evaluated the published literature describing the use of STAT3 in the treatment of experimental and clinical sepsis. The information presented here may be useful for the design of future studies and may highlight the potential of STAT3 as a future biomarker and therapeutic target for sepsis.
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Affiliation(s)
- Wangrui Lei
- Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi'an No.3 Hospital, School of Life Sciences and Medicine, Northwest University, Xi'an, China.,Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences, Northwest University, Xi'an, China
| | - Dianxiao Liu
- Department of Cardiac Surgery, Binzhou Medical University Hospital, Binzhou, China
| | - Meng Sun
- Department of Cardiology, The First Hospital of Shanxi Medical University, Taiyuan, China
| | - Chenxi Lu
- Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi'an No.3 Hospital, School of Life Sciences and Medicine, Northwest University, Xi'an, China.,Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences, Northwest University, Xi'an, China
| | - Wenwen Yang
- Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi'an No.3 Hospital, School of Life Sciences and Medicine, Northwest University, Xi'an, China.,Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences, Northwest University, Xi'an, China
| | - Changyu Wang
- Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi'an No.3 Hospital, School of Life Sciences and Medicine, Northwest University, Xi'an, China.,Department of Cardiology, School of Life Sciences and Medicine, Xi'an No.3 Hospital, Northwest University, Xi'an, China
| | - Ye Cheng
- Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi'an No.3 Hospital, School of Life Sciences and Medicine, Northwest University, Xi'an, China.,Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences, Northwest University, Xi'an, China
| | - Meng Zhang
- Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi'an No.3 Hospital, School of Life Sciences and Medicine, Northwest University, Xi'an, China.,Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences, Northwest University, Xi'an, China
| | - Mingzhi Shen
- Hainan Hospital of PLA General Hospital, The Second School of Clinical Medicine, Southern Medical University, Sanya, Hainan, China
| | - Zhi Yang
- Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi'an No.3 Hospital, School of Life Sciences and Medicine, Northwest University, Xi'an, China.,Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences, Northwest University, Xi'an, China
| | - Yin Chen
- Department of Hematology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Chao Deng
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yang Yang
- Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi'an No.3 Hospital, School of Life Sciences and Medicine, Northwest University, Xi'an, China
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26
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Xu F, Li Y, Cao Z, Zhang J, Huang W. AFB 1-induced mice liver injury involves mitochondrial dysfunction mediated by mitochondrial biogenesis inhibition. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2021; 216:112213. [PMID: 33838459 DOI: 10.1016/j.ecoenv.2021.112213] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 03/24/2021] [Accepted: 03/29/2021] [Indexed: 06/12/2023]
Abstract
Aflatoxin B1 (AFB1) pollutes foodstuffs and feeds, causing a food safety problem and seriously endangering human and animal health. Liver is the principal organ for AFB1 accumulation and biotransformation, during which AFB1 can cause acute and chronic liver damage, however, the specific mechanism is not completely clear. Mitochondria are the primary organelle of cellular bio-oxidation, providing 95% energy for liver to execute its multiple functions. Therefore, we speculated that mitochondrial dysfunction is involved in AFB1-induced liver injury. To verify the hypothesis, a total of eighty healthy male mice were randomly divided into four groups on average, and exposed with 0, 0.375, 0.75 and 1.5 mg/kg body weight AFB1 by intragastric administration for 30 d. The results displayed that AFB1 triggered liver injury accompanied by oxidative stress. AFB1 exposure also damaged mitochondria structure, decreased mitochondrial membrane potential (MMP), as well as increased cytoplasmic cytochrome c (Cyt-c) protein expression, Bax, p53, Caspase-3/9 protein and/or mRNA expression levels and terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine-5'-triphosphate (dUTP) nick end labeling (TUNEL) staining positive cells in mice liver. Meanwhile, AFB1 exposure elevated pyruvate content, inhibited tricarboxylic acid (TCA) cycle rate-limiting enzymes and electron transport chain (ETC) complexes I-V activities, disturbed ETC complexes I-V subunits mRNA expression levels and reduced adenosine triphosphate (ATP) level in mice liver. These results indicated that AFB1 destroyed mitochondrial structure, activated mitochondrion-dependent apoptosis and induced mitochondrial dysfunction. In addition, AFB1 disrupted mitochondrial biogenesis, presented as the abnormalities of protein and/or gene expression levels of voltage dependent anion channel protein 1 (VDAC1), peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), nuclear respiratory factor 1 (Nrf1) and mitochondrial transcription factor A (Tfam). This may contribute to hepatic and mitochondrial lesions induced by AFB1. These results provide a new perspective for elucidating the mechanisms of AFB1 hepatotoxicity.
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Affiliation(s)
- Feibo Xu
- Department of Histology and Embryology, College of Basic Medicine, Binzhou Medical University, 346 Guanhai Road, Yantai 246003, Shandong, China; Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China.
| | - Yanfei Li
- Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China
| | - Zheng Cao
- Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China
| | - Jian Zhang
- Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China
| | - Wanyue Huang
- Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China
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27
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Yuan X, Chen G, Guo D, Xu L, Gu Y. Polydatin Alleviates Septic Myocardial Injury by Promoting SIRT6-Mediated Autophagy. Inflammation 2021; 43:785-795. [PMID: 32394287 DOI: 10.1007/s10753-019-01153-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Sepsis is a life-threatening condition. Polydatin (PD), a small natural compound from Polygonum cuspidatum, possesses antioxidant and anti-inflammatory properties. However, the protective mechanism of PD on sepsis-induced acute myocardial damage is still unclear. The aim of this study was to investigate the effect and mechanism of action of PD on lipopolysaccharide (LPS)-induced H9c2 cells and in a rat model of sepsis, and explored the role of PD-upregulated sirtuin (SIRT)6. LPS-induced H9c2 cells were used to simulate sepsis. Cecal ligation and puncture (CLP)-induced sepsis in rats were used to verify the protective effect of PD. ELISA, western blotting, immunofluorescence, immunohistochemistry, and flow cytometry were used to study the protective mechanism of PD against septic myocardial injury. PD pretreatment suppressed LPS-induced H9c2 cell apoptosis by promotion of SIRT6-mediated autophagy. Downregulation of SIRT6 or inhibition of autophagy reversed the protective effect of PD on LPS-induced apoptosis. PD pretreatment also suppressed LPS-induced inflammatory factor expression. CLP-induced sepsis in rats showed that PD pretreatment decreased CLP-induced myocardial apoptosis and serum tumor necrosis factor-α, interleukin (IL)-1β, and IL-6 expression. 3-Methyladenine (autophagy inhibitor) pretreatment prevented the protective effect of PD on septic cardiomyopathy. SIRT6 expression was increased with PD treatment, which confirmed that PD attenuates septic cardiomyopathy by promotion of SIRT6-mediated autophagy. All these results indicate that PD has potential therapeutic effects that alleviate septic myocardial injury by promotion of SIRT6-mediated autophagy.
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Affiliation(s)
- Xiaoyan Yuan
- Department of Emergency Medicine, Shanghai Gongli Hospital, 219 Miao-Pu Road, Shanghai, 200135, China.,Ningxia Medical University, No.1160, Shengli Street, Xingqing District, Yinchuan, Ningxia, 750004, China
| | - Guo Chen
- Department of Emergency Medicine, Shanghai Gongli Hospital, 219 Miao-Pu Road, Shanghai, 200135, China
| | - Dongfeng Guo
- Department of Emergency Medicine, Shanghai Gongli Hospital, 219 Miao-Pu Road, Shanghai, 200135, China.
| | - Lei Xu
- Department of Emergency Medicine, Shanghai Gongli Hospital, 219 Miao-Pu Road, Shanghai, 200135, China.
| | - Yongfeng Gu
- Department of Emergency Medicine, Shanghai Gongli Hospital, 219 Miao-Pu Road, Shanghai, 200135, China.
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28
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Kouroumalis E, Voumvouraki A, Augoustaki A, Samonakis DN. Autophagy in liver diseases. World J Hepatol 2021; 13:6-65. [PMID: 33584986 PMCID: PMC7856864 DOI: 10.4254/wjh.v13.i1.6] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 12/10/2020] [Accepted: 12/26/2020] [Indexed: 02/06/2023] Open
Abstract
Autophagy is the liver cell energy recycling system regulating a variety of homeostatic mechanisms. Damaged organelles, lipids and proteins are degraded in the lysosomes and their elements are re-used by the cell. Investigations on autophagy have led to the award of two Nobel Prizes and a health of important reports. In this review we describe the fundamental functions of autophagy in the liver including new data on the regulation of autophagy. Moreover we emphasize the fact that autophagy acts like a two edge sword in many occasions with the most prominent paradigm being its involvement in the initiation and progress of hepatocellular carcinoma. We also focused to the implication of autophagy and its specialized forms of lipophagy and mitophagy in the pathogenesis of various liver diseases. We analyzed autophagy not only in well studied diseases, like alcoholic and nonalcoholic fatty liver and liver fibrosis but also in viral hepatitis, biliary diseases, autoimmune hepatitis and rare diseases including inherited metabolic diseases and also acetaminophene hepatotoxicity. We also stressed the different consequences that activation or impairment of autophagy may have in hepatocytes as opposed to Kupffer cells, sinusoidal endothelial cells or hepatic stellate cells. Finally, we analyzed the limited clinical data compared to the extensive experimental evidence and the possible future therapeutic interventions based on autophagy manipulation.
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Affiliation(s)
- Elias Kouroumalis
- Liver Research Laboratory, University of Crete Medical School, Heraklion 71110, Greece
| | - Argryro Voumvouraki
- 1 Department of Internal Medicine, AHEPA University Hospital, Thessaloniki 54636, Greece
| | - Aikaterini Augoustaki
- Department of Gastroenterology and Hepatology, University Hospital of Crete, Heraklion 71110, Greece
| | - Dimitrios N Samonakis
- Department of Gastroenterology and Hepatology, University Hospital of Crete, Heraklion 71110, Greece.
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29
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Angiotensin-(1-7) Prevents Lipopolysaccharide-Induced Autophagy via the Mas Receptor in Skeletal Muscle. Int J Mol Sci 2020; 21:ijms21249344. [PMID: 33302427 PMCID: PMC7762589 DOI: 10.3390/ijms21249344] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 11/27/2020] [Accepted: 12/04/2020] [Indexed: 12/18/2022] Open
Abstract
Skeletal muscle atrophy, which occurs in lipopolysaccharide (LPS)-induced sepsis, causes a severe muscle function reduction. The increased autophagy contributes to sepsis-induced skeletal muscle atrophy in a model of LPS injection, increasing LC3II/LC3I ratio, autophagy flux, and autophagosomes. Angiotensin-(1-7) (Ang-(1-7)) has anti-atrophic effects via the Mas receptor in skeletal muscle. However, the impact of Ang-(1-7) on LPS-induced autophagy is unknown. In this study, we determined the effect of Ang-(1-7) on sepsis-induced muscle autophagy. C57BL6 wild-type (WT) mice and mice lacking the Mas receptor (KO Mas) were injected with LPS together with the systemic administration of Ang-(1-7) to determine autophagy in skeletal muscle. We also evaluated autophagy and p38 and c-Jun N-terminal kinase (JNK)activation. Our results show that Ang-(1-7) prevents LPS-induced autophagy in the diaphragm, tibialis anterior, and gastrocnemius of WT mice, which is demonstrated by a decrease in the LC3II/LC3I ratio and mRNA levels of lc3b and ctsl. This effect was lost in KO Mas mice, suggesting the role of the Mas receptor. The results in C2C12 cells show that Ang-(1-7) reduces several LPS-dependent effects, such as autophagy (LC3II/LC3I ratio, autophagic flux, and autophagosomes), activation of p38 and JNK, B-cell lymphoma-2 (BCL2) phosphorylation, and disassembly of the Beclin1/BCL2 complex. In conclusion, Ang-(1-7)/Mas receptor reduces LPS-induced autophagy in skeletal muscle. In vitro assays indicate that Ang-(1-7) prevents LPS-induced autophagy and modifies the MAPK signaling and the disassembly of a complex involved at the beginning of autophagy.
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Activation of AMP-Activated Protein Kinase by A769662 Ameliorates Sepsis-Induced Acute Lung Injury in Adult Mice. Shock 2020; 52:540-549. [PMID: 30562237 DOI: 10.1097/shk.0000000000001303] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
A serious consequence of sepsis is acute lung injury, whose severity is particularly impacted by the age of the patient. AMP-activated protein kinase (AMPK) is a crucial regulator of cellular metabolism, which controls mitochondrial biogenesis and autophagy. Here, we investigated the effect of pharmacological activation of AMPK with A769662 on lung injury by using a model that would preferably mimic the clinical condition of adult patients. Male C57BL/6 retired breeder mice (7-9 months old) were subjected to sepsis by cecal ligation and puncture (CLP). Mice received vehicle or A769662 (10 mg/kg) intraperitoneally at 1 h after CLP. At 6 h after CLP, vehicle-treated mice exhibited severe lung injury and elevation of plasma pro-inflammatory cytokines when compared with control mice. At molecular analysis, lung injury was associated with downregulation of AMPKα1/α2 catalytic subunits and reduced phosphorylation of AMPKβ1 regulatory subunit. Treatment with A769662 ameliorated lung architecture, reduced bacterial load in lung and blood, and attenuated plasma levels of interleukin-6. This protective effect was associated with nuclear phosphorylation of AMPKα1/α2 and AMPKβ1, increased nuclear expression of peroxisome proliferator-activated receptor γ co-activator-α and increased autophagy, as evaluated by the light-chain (LC)3B-I and LC3B-II content, without changes in sirtuin-1 cellular dynamics. Treatment with A769662 alone or in combination with the antimicrobial agent imipenem (25 mg/kg) increased survival rate (29% and 51%, respectively) when compared with vehicle treatment (10%) at 7 days after CLP. These data suggest that pharmacological activation of AMPK might be a beneficial approach for the treatment of sepsis in adult population.
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AMPK, Mitochondrial Function, and Cardiovascular Disease. Int J Mol Sci 2020; 21:ijms21144987. [PMID: 32679729 PMCID: PMC7404275 DOI: 10.3390/ijms21144987] [Citation(s) in RCA: 144] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 07/04/2020] [Accepted: 07/06/2020] [Indexed: 12/12/2022] Open
Abstract
Adenosine monophosphate-activated protein kinase (AMPK) is in charge of numerous catabolic and anabolic signaling pathways to sustain appropriate intracellular adenosine triphosphate levels in response to energetic and/or cellular stress. In addition to its conventional roles as an intracellular energy switch or fuel gauge, emerging research has shown that AMPK is also a redox sensor and modulator, playing pivotal roles in maintaining cardiovascular processes and inhibiting disease progression. Pharmacological reagents, including statins, metformin, berberine, polyphenol, and resveratrol, all of which are widely used therapeutics for cardiovascular disorders, appear to deliver their protective/therapeutic effects partially via AMPK signaling modulation. The functions of AMPK during health and disease are far from clear. Accumulating studies have demonstrated crosstalk between AMPK and mitochondria, such as AMPK regulation of mitochondrial homeostasis and mitochondrial dysfunction causing abnormal AMPK activity. In this review, we begin with the description of AMPK structure and regulation, and then focus on the recent advances toward understanding how mitochondrial dysfunction controls AMPK and how AMPK, as a central mediator of the cellular response to energetic stress, maintains mitochondrial homeostasis. Finally, we systemically review how dysfunctional AMPK contributes to the initiation and progression of cardiovascular diseases via the impact on mitochondrial function.
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Cao K, Lv W, Hu S, Gao J, Liu J, Feng Z. Punicalagin Activates AMPK/PGC-1α/Nrf2 Cascade in Mice: The Potential Protective Effect against Prenatal Stress. Mol Nutr Food Res 2020; 64:e2000312. [PMID: 32475051 DOI: 10.1002/mnfr.202000312] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 05/20/2020] [Indexed: 12/11/2022]
Abstract
SCOPE Prenatal stress is closely associated with poor health outcomes for offspring, yet the specific mechanisms and effective interventions remain limited. METHODS AND RESULTS In the present study, both male and female rat offspring exposed to prenatal restraint stress (PRS) are confirmed to have impaired spatial learning and memory, accompanied by reduced AMP-activated protein kinase (AMPK) activity and decreased protein expression of mitochondrial biogenesis and antioxidant pathways in the hippocampus. Interestingly, a deficiency in the AMPK cascade also occurs in liver, heart, and adipose tissues, suggesting that the systemic deactivation of AMPK in the offspring is potentially attributed to increased maternal glucocorticoid levels under PRS. Punicalagin (PU), a major ellagitannin in pomegranate, is found to effectively induce mitochondrial biogenesis and phase II enzymes through activation of AMPK in both HT22 and primary hippocampal neurons, thereby inhibiting glutamate-induced cell viability and mitochondrial membrane potential loss. Meanwhile, the activation of AMPK cascade is also confirmed in mice administrated with PU for three days. CONCLUSIONS Altogether, these results indicate that the systemic deficiency of the AMPK cascade can be the key factor that contributes to poor outcomes of PRS, and PU may be used as an effective maternal nutritional intervention.
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Affiliation(s)
- Ke Cao
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi, 710049, China
| | - Weiqiang Lv
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi, 710049, China
| | - Shaoqin Hu
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi, 710049, China
| | - Jing Gao
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi, 710049, China
| | - Jiankang Liu
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi, 710049, China.,Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi, 710049, China
| | - Zhihui Feng
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi, 710049, China.,Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi, 710049, China
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33
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Stromal Cell-Derived Factor-1 Enhances the Therapeutic Effects of Human Endometrial Regenerative Cells in a Mouse Sepsis Model. Stem Cells Int 2020; 2020:4820543. [PMID: 32256608 PMCID: PMC7103048 DOI: 10.1155/2020/4820543] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2019] [Revised: 02/09/2020] [Accepted: 02/25/2020] [Indexed: 12/17/2022] Open
Abstract
Endometrial regenerative cells (ERCs) are mesenchymal-like stromal cells obtained from human menstrual blood, whose positive therapeutic effects have been validated in several experimental models. Stromal cell-derived factor-1 (SDF-1), the ligand for CXCR4, plays an important role in the migration of mesenchymal stromal cells. The purpose of this study was to investigate the role of the SDF-1/CXCR4 pathway in the therapeutic effects of ERCs in a mouse sepsis model. Through preexperiment and confirmation, wild-type C57BL/6 mice were intraperitoneally injected with 10 mg/kg lipopolysaccharide (LPS). The therapeutic effects of ERCs with different pretreatments were evaluated by assessing sepsis-related symptoms, detecting tissue damage and measuring levels of inflammatory and oxidative stress-related factors. The in vitro experiments demonstrated that there was a much higher CXCR4 expression on ERCs when they were cocultured with SDF-1. The ex vivo experiment results showed that SDF-1 expression significantly increased in mouse tissues. Further experiments also confirmed that, compared with the unmodified ERC treatment group, SDF-1 pretreatment significantly enhanced the therapeutic effects of ERCs on alleviating sepsis symptoms, ameliorating pathological changes, reducing Bax level, and increasing Bcl-2 and PCNA expressions in mouse liver tissues. Furthermore, it was also found that SDF-1-pretreated ERCs contributed to reducing the levels of proinflammatory cytokines (TNF-α, IL-1β) and increasing the levels of anti-inflammatory factors (IL-4, IL10) in mouse serum, liver, and lung. Moreover, SDF-1-pretreated ERCs could also significantly decrease the levels of iNOS and MDA and increase the expression of Nrf2, HO-1, and SOD in liver tissues. Taken together, these results indicate that SDF-1 pretreatment plays a key role in improving the therapeutic effects of ERCs in alleviating sepsis-related symptoms, reducing tissue damage, regulating inflammatory imbalance, and relieving oxidative stress in a mouse sepsis model, which provides more possibilities for the clinical application of ERCs in sepsis and relevant diseases.
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Kikuchi S, Piraino G, O'Connor M, Wolfe V, Ridings K, Lahni P, Zingarelli B. Hepatocyte-Specific Deletion of AMPKα1 Results in Worse Outcomes in Mice Subjected to Sepsis in a Sex-Specific Manner. Front Immunol 2020; 11:210. [PMID: 32117320 PMCID: PMC7031478 DOI: 10.3389/fimmu.2020.00210] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Accepted: 01/27/2020] [Indexed: 12/25/2022] Open
Abstract
Alterations in the energy homeostasis contribute to sepsis-mediated multiple organ failure. The liver plays a central role in metabolism and participates to the innate immune and inflammatory responses of sepsis. Several clinical and experimental studies have suggested that females are less susceptible to the adverse outcome of sepsis. However, underlying mechanisms of organ damage in sepsis remain largely undefined. AMP-activated protein kinase (AMPK) is an important regulator of mitochondrial quality control. The AMPK catalytic α1 isoform is abundantly expressed in the liver. Here, we determined the role of hepatocyte AMPKα1 in sepsis by using hepatocyte-specific AMPKα1 knockout mice (H-AMPKα1 KO) generated with Cre-recombinase expression under the control of the albumin promoter. Using a clinically relevant model of polymicrobial sepsis by cecal ligation and puncture (CLP), we observed that male H-AMPKα1 KO mice had higher plasma levels of tumor necrosis factor-α and interleukin-6 and exhibited a more severe liver and lung injury than male H-AMPKα1 WT mice, as evaluated by histology and neutrophil infiltration at 18 h after CLP. Plasma levels of interleukin-10 and the keratinocyte-derived chemokine were similarly elevated in both KO and WT male mice. At transmission electron microscopy analysis, male H-AMPKα1 KO mice exhibited higher liver mitochondrial damage, which was associated with a significant decrease in liver ATP levels when compared to WT mice at 18 h after sepsis. Mortality rate was significantly higher in the male H-AMPKα1 KO group (91%) when compared to WT mice (60%) at 7 days after CLP. Female H-AMPKα1 WT mice exhibited a similar degree of histological liver and lung injury, but significantly milder liver mitochondrial damage and higher autophagy when compared to male WT mice after CLP. Interestingly, H-AMPKα1 KO female mice had lower organ neutrophil infiltration, lower liver mitochondrial damage and lower levels of cytokines than WT female mice. There was no significant difference in survival rate between WT and KO mice in the female group. In conclusion, our study demonstrates that AMPKα1 is a crucial hepatoprotective enzyme during sepsis. Furthermore, our results suggest that AMPK-dependent liver metabolic functions may influence the susceptibility to multiple organ injury in a sex-dependent manner.
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Affiliation(s)
- Satoshi Kikuchi
- Department of Emergency Medicine, Ehime University, Toon, Japan
| | - Giovanna Piraino
- Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
| | - Michael O'Connor
- Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
| | - Vivian Wolfe
- Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
| | - Kiana Ridings
- Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
| | - Patrick Lahni
- Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
| | - Basilia Zingarelli
- Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States.,Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH, United States
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35
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Inata Y, Piraino G, Hake PW, O'Connor M, Lahni P, Wolfe V, Schulte C, Moore V, James JM, Zingarelli B. Reply to Angé et al. Am J Physiol Heart Circ Physiol 2020; 316:H936-H937. [PMID: 30946605 DOI: 10.1152/ajpheart.00095.2019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Affiliation(s)
- Yu Inata
- Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center , Cincinnati, Ohio
| | - Giovanna Piraino
- Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center , Cincinnati, Ohio
| | - Paul W Hake
- Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center , Cincinnati, Ohio
| | - Michael O'Connor
- Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center , Cincinnati, Ohio
| | - Patrick Lahni
- Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center , Cincinnati, Ohio
| | - Vivian Wolfe
- Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center , Cincinnati, Ohio
| | - Christine Schulte
- Cardiovascular Imaging Core of the Heart Institute, Cincinnati Children's Hospital Medical Center , Cincinnati, Ohio
| | - Victoria Moore
- Cardiovascular Imaging Core of the Heart Institute, Cincinnati Children's Hospital Medical Center , Cincinnati, Ohio
| | - Jeanne M James
- Division of Cardiology, Department of Pediatrics, Medical College of Wisconsin , Milwaukee, Wisconsin
| | - Basilia Zingarelli
- Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center , Cincinnati, Ohio.,Department of Pediatrics, College of Medicine, University of Cincinnati , Cincinnati, Ohio
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36
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Li L, Tian FY, Yuan Y, Zhang T, Yang WB, Kong R, Wang G, Chen H, Chen HZ, Hu JS, Zhang GQ, Zhao ZJ, Wang XL, Li GQ, Sun B. HYAL-1-induced autophagy facilitates pancreatic fistula for patients who underwent pancreaticoduodenectomy. FASEB J 2020; 34:2524-2540. [PMID: 31908026 DOI: 10.1096/fj.201901583r] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Revised: 11/10/2019] [Accepted: 12/03/2019] [Indexed: 12/20/2022]
Abstract
The main mechanism of hyaluronidase 1(HYAL-1) in the development of postoperative pancreatic fistula (POPF) after pancreatoduodenectomy (PD) was unknown. In this study, a comprehensive inventory of pre-, intra-, and postoperative clinical and biological data of two cohorts (62 pancreatic cancer [PCa] and 111 pancreatic ductal adenocarcinoma [PDAC]) which could induce POPF were retrospectively analyzed. Then, a total of 7644 genes correlated with HYAL-1 was predicted in PDAC tissues and the enriched pathway, kinase targets and biological process of those correlated genes were evaluated. Finally, a mouse pancreatic fistula (PF) model was first built and in vitro studies were performed to investigate the effects of HYAL-1 on PF progression. Our data indicated that preoperative serum HYAL-1 level, pancreatic fibrosis score, and pancreatic duct size were valuable factors for detecting POPF of Grade B and C. The serum HYAL-1 level of 2.07 mg/ml and pancreatic fibrosis score of 2.5 were proposed as the cutoff values for indicating POPF. The bioinformatic analysis and in vitro and in vivo studies demonstrated that HYAL-1 facilitates pancreatic acinar cell autophagy via the dephosphorylation of adenosine 5'-monophosphate-activated protein kinase (AMPK) and signal transducers and activators of transcription 3 (STAT3) signaling pathways, which exacerbate pancreatic secretion and inflammation. In summary, the preoperative serum HYAL-1 was a significant predictor for POPF in patients who underwent PD. Tumor-induced HYAL-1 is one of core risk in accelerating PF and then promoting pancreatic secretion and acute inflammation response through the AMPK and STAT3-induced autophagy.
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Affiliation(s)
- Le Li
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Feng-Yu Tian
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yue Yuan
- Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Tao Zhang
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Wen-Bo Yang
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Rui Kong
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Gang Wang
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Hua Chen
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Hong-Ze Chen
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Ji-Sheng Hu
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Guang-Quan Zhang
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Zhong-Jie Zhao
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xin-Long Wang
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Guan-Qun Li
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Bei Sun
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
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Yin X, Xin H, Mao S, Wu G, Guo L. The Role of Autophagy in Sepsis: Protection and Injury to Organs. Front Physiol 2019; 10:1071. [PMID: 31507440 PMCID: PMC6716215 DOI: 10.3389/fphys.2019.01071] [Citation(s) in RCA: 69] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2019] [Accepted: 08/05/2019] [Indexed: 12/12/2022] Open
Abstract
Sepsis is a systemic inflammatory disease with infection, and autophagy has been shown to play an important role in sepsis. This review summarizes the main regulatory mechanisms of autophagy in sepsis and its latest research. Recent studies have shown that autophagy can regulate innate immune processes and acquired immune processes, and the regulation of autophagy in different immune cells is different. Mitophagy can select damaged mitochondria and remove it to deal with oxidative stress damage. The process of mitophagy is regulated by other factors. Non-coding RNA is also an important factor in the regulation of autophagy. In addition, more and more studies in recent years have shown that autophagy plays different roles in different organs. It tends to be protective in the lungs, heart, kidneys, and brain, and tends to be damaging in skeletal muscle. We also mentioned that some drugs can regulate autophagy. The process of modulating autophagy through drug intervention appears to be a new potential hope for the treatment of sepsis.
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Affiliation(s)
- Xin Yin
- Department of Critical Care Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Huang Xin
- Department of Critical Care Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Shuai Mao
- Department of Critical Care Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Guangping Wu
- Department of Critical Care Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Liheng Guo
- Department of Critical Care Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
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Maurice NM, Bedi B, Yuan Z, Goldberg JB, Koval M, Hart CM, Sadikot RT. Pseudomonas aeruginosa Induced Host Epithelial Cell Mitochondrial Dysfunction. Sci Rep 2019; 9:11929. [PMID: 31417101 PMCID: PMC6695387 DOI: 10.1038/s41598-019-47457-1] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Accepted: 07/07/2019] [Indexed: 02/06/2023] Open
Abstract
The pathogenicity of P. aeruginosa is dependent on quorum sensing (QS), an inter-bacterial communication system that can also modulate host biology. The innate immune function of the lung mucosal barrier is dependent on proper mitochondrial function. The purpose of this study was to define the mechanism by which bacterial factors modulate host lung epithelial cell mitochondrial function and to investigate novel therapies that ameliorate this effect. 3-oxo-C12-HSL disrupts mitochondrial morphology, attenuates mitochondrial bioenergetics, and induces mitochondrial DNA oxidative injury. Mechanistically, we show that 3-oxo-C12-HSL attenuates expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), a master regulator of mitochondrial biogenesis, antioxidant defense, and cellular respiration, and its downstream effectors in both BEAS-2B and primary lung epithelial cells. Overexpression of PGC-1α attenuates the inhibition in cellular respiration caused by 3-oxo-C12-HSL. Pharmacologic activation of PGC-1α restores barrier integrity in cells treated with 3-oxo-C12-HSL. These data demonstrate that the P. aeruginosa QS molecule, 3-oxo-C12-HSL, alters mitochondrial pathways critical for lung mucosal immunity. Genetic and pharmacologic strategies that activate the PGC-1α pathway enhance host epithelial cell mitochondrial function and improve the epithelial innate response to P. aeruginosa. Therapies that rescue PGC-1α function may provide a complementary approach in the treatment of P. aeruginosa infection.
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Affiliation(s)
- Nicholas M Maurice
- Department of Medicine, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA.,Atlanta Veterans Affairs Health Care System, Decatur, GA, 30033, USA
| | - Brahmchetna Bedi
- Department of Medicine, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA.,Atlanta Veterans Affairs Health Care System, Decatur, GA, 30033, USA
| | - Zhihong Yuan
- Department of Medicine, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA.,Atlanta Veterans Affairs Health Care System, Decatur, GA, 30033, USA
| | - Joanna B Goldberg
- Department of Pediatrics, Division of Pulmonology, Allergy/Immunology, Cystic Fibrosis, and Sleep, Emory University, Atlanta, GA, 30322, USA.,Children's Healthcare of Atlanta, Center for CF and Airways Disease Research Atlanta, Atlanta, GA, USA
| | - Michael Koval
- Department of Medicine, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA.,Department of Cell Biology, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - C Michael Hart
- Department of Medicine, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA.,Atlanta Veterans Affairs Health Care System, Decatur, GA, 30033, USA
| | - Ruxana T Sadikot
- Department of Medicine, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA. .,Atlanta Veterans Affairs Health Care System, Decatur, GA, 30033, USA.
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Jiang L, Chen Q, Wu M, Ji T, Liu S, Zhu F, Shi D. Short-term high salt intake impairs hepatic mitochondrial bioenergetics and biosynthesis in SIRT3 knockout mice. Free Radic Res 2019; 53:387-396. [PMID: 31044629 DOI: 10.1080/10715762.2019.1580499] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
High salt intake (HS) is an important factor in the development of many metabolic diseases. The liver is the metabolic center in the body. However, the effect of short-term HS on the liver mitochondria and its mechanism are still unclear. In this study, we investigated the effects of short-term HS on liver mitochondrial function. We found that HS reduced Sirtuin3 (SIRT3) protein level, increasing protein carbonylation in mice liver. HS intake decreased ATP production, mitochondrial transcription factor A (TFAM), and complex I level. SIRT3 knockout (SKO) mice exhibited similar results with HS-treated wild-type mice but with a less extent of carbonylation and ATP reduction. Our study shows that short-term HS led to increased hepatic oxidative state, impaired mitochondrial biosynthesis, and bioenergetics. HS-treated mice could still maintain hepatic glucose homeostasis by compensatory activation of Adenosine 5'-monophosphate-activated protein kinase (AMPK). However, in HS-treated SKO mice, AMPK was not activated, instead, the glycogen synthase activity increased, which caused an exceptionally increased glycogen accumulation. This study provides evidence that short-term HS intake could cause the early hepatic metabolic changes, highlighting the importance of controlling salt intake especially in those patients with defects in SIRT3. Highlights High salt intake down-regulates SIRT3 protein level and increases oxidation. High salt intake activates AMPK via AMP-dependent pathway. High salt intake impairs energy metabolism. High salt combined with SIRT3 knockout results in glycogen accumulation.
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Affiliation(s)
- Lihan Jiang
- a Department of Biochemistry and Molecular Biology , School of Basic Medical Sciences, Fudan University , Shanghai , People's Republic of China
| | - Qinghua Chen
- b Department of Food Hygiene and Nutrition , School of Public Health, Shanghai University of Traditionnal Chinese Medicine , Shanghai , People's Republic of China
| | - Meiling Wu
- a Department of Biochemistry and Molecular Biology , School of Basic Medical Sciences, Fudan University , Shanghai , People's Republic of China
| | - Tingting Ji
- c Department of Nephrology, Qingpu Branch , Zhongshan Hospital, Fudan University , Shanghai , People's Republic of China
| | - Shanlin Liu
- d Free Radical Regulation and Application Research Center, Fudan University , Shanghai , People's Republic of China
| | - Fengge Zhu
- e Department of Nephrology , Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases , Beijing , People's Republic of China
| | - Dongyun Shi
- a Department of Biochemistry and Molecular Biology , School of Basic Medical Sciences, Fudan University , Shanghai , People's Republic of China
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Wu Y, Yao YM, Lu ZQ. Mitochondrial quality control mechanisms as potential therapeutic targets in sepsis-induced multiple organ failure. J Mol Med (Berl) 2019; 97:451-462. [PMID: 30788535 DOI: 10.1007/s00109-019-01756-2] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2018] [Revised: 12/24/2018] [Accepted: 02/06/2019] [Indexed: 02/07/2023]
Abstract
Sepsis is a dysregulated response to severe infection characterized by life-threatening organ failure and is the leading cause of mortality worldwide. Multiple organ failure is the central characteristic of sepsis and is associated with poor outcome of septic patients. Ultrastructural damage to the mitochondria and mitochondrial dysfunction are reported in sepsis. Mitochondrial dysfunction with subsequent ATP deficiency, excessive reactive oxygen species (ROS) release, and cytochrome c release are all considered to contribute to organ failure. Consistent mitochondrial dysfunction leads to reduced mitochondrial quality control capacity, which eliminates dysfunctional and superfluous mitochondria to maintain mitochondrial homeostasis. Mitochondrial quality is controlled through a series of processes including mitochondrial biogenesis, mitochondrial dynamics, mitophagy, and transport processes. Several studies have indicated that multiple organ failure is ameliorated by restoring mitochondrial quality control mechanisms and is further amplified by defective quality control mechanisms. This review will focus on advances concerning potential mechanisms in regulating mitochondrial quality control and impacts of mitochondrial quality control on the progression of sepsis.
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Affiliation(s)
- You Wu
- Emergency Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China.,Wenzhou Municipal Key Laboratory of Emergency, Critical Care and Disaster Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Yong-Ming Yao
- Emergency Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China. .,Trauma Research Center, First Hospital Affiliated to the Chinese PLA General Hospital, Beijing, People's Republic of China.
| | - Zhong-Qiu Lu
- Emergency Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China. .,Wenzhou Municipal Key Laboratory of Emergency, Critical Care and Disaster Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China. .,College of Nursing, Wenzhou Medical University, Wenzhou, People's Republic of China.
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41
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Kohoutová M, Dejmek J, Tůma Z, Kuncová J. Variability of mitochondrial respiration in relation to sepsis-induced multiple organ dysfunction. Physiol Res 2019; 67:S577-S592. [PMID: 30607965 DOI: 10.33549/physiolres.934050] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Ample experimental evidence suggests that sepsis could interfere with any mitochondrial function; however, the true role of mitochondrial dysfunction in the pathogenesis of sepsis-induced multiple organ dysfunction is still a matter of controversy. This review is primarily focused on mitochondrial oxygen consumption in various animal models of sepsis in relation to human disease and potential sources of variability in experimental results documenting decrease, increase or no change in mitochondrial respiration in various organs and species. To date, at least three possible explanations of sepsis-associated dysfunction of the mitochondrial respiratory system and consequently impaired energy production have been suggested: 1. Mitochondrial dysfunction is secondary to tissue hypoxia. 2. Mitochondria are challenged by various toxins or mediators of inflammation that impair oxygen utilization (cytopathic hypoxia). 3. Compromised mitochondrial respiration could be an active measure of survival strategy resembling stunning or hibernation. To reveal the true role of mitochondria in sepsis, sources of variability of experimental results based on animal species, models of sepsis, organs studied, or analytical approaches should be identified and minimized by the use of appropriate experimental models resembling human sepsis, wider use of larger animal species in preclinical studies, more detailed mapping of interspecies differences and organ-specific features of oxygen utilization in addition to use of complex and standardized protocols evaluating mitochondrial respiration.
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Affiliation(s)
- M Kohoutová
- Institute of Physiology, Faculty of Medicine in Plzeň, Charles University, Plzeň, Czech Republic.
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42
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Zingarelli B, Coopersmith CM, Drechsler S, Efron P, Marshall JC, Moldawer L, Wiersinga WJ, Xiao X, Osuchowski MF, Thiemermann C. Part I: Minimum Quality Threshold in Preclinical Sepsis Studies (MQTiPSS) for Study Design and Humane Modeling Endpoints. Shock 2019; 51:10-22. [PMID: 30106874 PMCID: PMC6296871 DOI: 10.1097/shk.0000000000001243] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Preclinical animal studies are mandatory before new treatments can be tested in clinical trials. However, their use in developing new therapies for sepsis has been controversial because of limitations of the models and inconsistencies with the clinical conditions. In consideration of the revised definition for clinical sepsis and septic shock (Sepsis-3), a Wiggers-Bernard Conference was held in Vienna in May 2017 to propose standardized guidelines on preclinical sepsis modeling. The participants conducted a literature review of 260 most highly cited scientific articles on sepsis models published between 2003 and 2012. The review showed, for example, that mice were used in 79% and euthanasia criteria were defined in 9% of the studies. Part I of this report details the recommendations for study design and humane modeling endpoints that should be addressed in sepsis models. The first recommendation is that survival follow-up should reflect the clinical time course of the infectious agent used in the sepsis model. Furthermore, it is recommended that therapeutic interventions should be initiated after the septic insult replicating clinical care. To define an unbiased and reproducible association between a new treatment and outcome, a randomization and blinding of treatments as well as inclusion of all methodological details in scientific publications is essential. In all preclinical sepsis studies, the high standards of animal welfare must be implemented. Therefore, development and validation of specific criteria for monitoring pain and distress, and euthanasia of septic animals, as well as the use of analgesics are recommended. A set of four considerations is also proposed to enhance translation potential of sepsis models. Relevant biological variables and comorbidities should be included in the study design and sepsis modeling should be extended to mammalian species other than rodents. In addition, the need for source control (in case of a defined infection focus) should be considered. These recommendations and considerations are proposed as "best practices" for animal models of sepsis that should be implemented.
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Affiliation(s)
- Basilia Zingarelli
- Department of Pediatrics, Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, College of Medicine, University of Cincinnati, Cincinnati, Ohio
| | | | - Susanne Drechsler
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology in the AUVA Research Center, Vienna, Austria
| | - Philip Efron
- Sepsis and Critical Illness Research Center, University of Florida College of Medicine, Gainesville, Florida
| | - John C Marshall
- Keenan Research Centre for Biomedical Science, St. Michael's Hospital, University of Toronto, Toronto, Canada
| | - Lyle Moldawer
- Sepsis and Critical Illness Research Center, University of Florida College of Medicine, Gainesville, Florida
| | - W Joost Wiersinga
- Division of Infectious Diseases, Center for Experimental and Molecular Medicine, The Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Xianzhong Xiao
- Xiangya School of Medicine, Central South University, Chagnsha, Hunan, China
| | - Marcin F Osuchowski
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology in the AUVA Research Center, Vienna, Austria
| | - Christoph Thiemermann
- The William Harvey Research Institute, Barts and London School of Medicine & Dentistry, Queen Mary University of London, London, United Kingdom
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Dymkowska D, Drabarek B, Michalik A, Nowak N, Zabłocki K. TNFα stimulates NO release in EA.hy926 cells by activating the CaMKKβ-AMPK-eNOS pathway. Int J Biochem Cell Biol 2019; 106:57-67. [PMID: 30471424 DOI: 10.1016/j.biocel.2018.11.010] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Revised: 11/06/2018] [Accepted: 11/20/2018] [Indexed: 12/28/2022]
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Wei Y, Meng M, Tian Z, Xie F, Yin Q, Dai C, Wang J, Zhang Q, Liu Y, Liu C, Yan F, Jiang F, Guo X. Pharmacological preconditioning with the cellular stress inducer thapsigargin protects against experimental sepsis. Pharmacol Res 2018; 141:114-122. [PMID: 30579975 DOI: 10.1016/j.phrs.2018.12.017] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 12/12/2018] [Accepted: 12/19/2018] [Indexed: 02/08/2023]
Abstract
Previous studies have shown that pretreatment with thapsigargin (TG), a cellular stress inducer, produced potent protective actions against various pathologic injuries. So far there is no information on the effects of TG on the development of bacterial sepsis. Using lipopolysaccharides- and cecal ligation/puncture-induced sepsis models in mice, we demonstrated that preconditioning with a single bolus administration of TG conferred significant improvements in survival. The beneficial effects of TG were not mediated by ER stress induction or changes in Toll-like receptor 4 signaling. In vivo and in cultured macrophages, we identified that TG reduced the protein production of pro-inflammatory cytokines, but exhibited no significant effects on steady state levels of their transcriptions. Direct measurement on the fraction of polysome-bound mRNAs revealed that TG reduced the translational efficiency of pro-inflammatory cytokines in macrophages. Moreover, we provided evidence suggesting that repression of the mTOR (the mammalian target of rapamycin) signaling pathway, but not activation of the PERK (protein kinase R-like endoplasmic reticulum kinase)-eIF2α (eukaryotic initiation factor 2α) pathway, might be involved in mediating the TG effects on cytokine production. In summary, our results support that pharmacological preconditioning with TG may represent a novel strategy to prevent sepsis-induced mortality and organ injuries.
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Affiliation(s)
- Yaping Wei
- Department of Physiology and Pathophysiology, School of Basic Medicine, Shandong University, Jinan, Shandong Province, China
| | - Mei Meng
- Department of Critical Care Medicine, Shandong Provincial Hospital Affiliated, Shandong University, Jinan, Shandong Province, China
| | - Zhenyu Tian
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Fubo Xie
- Department of Radiology, Qilu Hospital of Shandong University, Jinan, Shandong Province, China
| | - Qihui Yin
- Department of Physiology and Pathophysiology, School of Basic Medicine, Shandong University, Jinan, Shandong Province, China
| | - Chaochao Dai
- Department of Physiology and Pathophysiology, School of Basic Medicine, Shandong University, Jinan, Shandong Province, China
| | - Jingjing Wang
- Department of Physiology and Pathophysiology, School of Basic Medicine, Shandong University, Jinan, Shandong Province, China
| | - Qunye Zhang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Yu Liu
- Department of Physiology and Pathophysiology, School of Basic Medicine, Shandong University, Jinan, Shandong Province, China
| | - Chang Liu
- Department of Physiology and Pathophysiology, School of Basic Medicine, Shandong University, Jinan, Shandong Province, China
| | - Feng Yan
- Department of Emergency, Qilu Hospital of Shandong University, Jinan, Shandong Province, China
| | - Fan Jiang
- Department of Physiology and Pathophysiology, School of Basic Medicine, Shandong University, Jinan, Shandong Province, China; The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China.
| | - Xiaosun Guo
- Department of Physiology and Pathophysiology, School of Basic Medicine, Shandong University, Jinan, Shandong Province, China.
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Zhang H, Feng YW, Yao YM. Potential therapy strategy: targeting mitochondrial dysfunction in sepsis. Mil Med Res 2018; 5:41. [PMID: 30474573 PMCID: PMC6260865 DOI: 10.1186/s40779-018-0187-0] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2018] [Accepted: 11/08/2018] [Indexed: 12/21/2022] Open
Abstract
Recently, the definition of sepsis was concluded to be a life-threatening organ dysfunction caused by a dysregulated host response to infection. Severe patients always present with uncorrectable hypotension or hyperlactacidemia, which is defined as septic shock. The new definition emphasizes dysregulation of the host response and multiple organ dysfunction, which is partially attributed to metabolic disorders induced by energy crisis and oxidative stress. Mitochondria are a cellular organelle that are well known as the center of energy production, and mitochondrial damage or dysfunction is commonly induced in septic settings and is a predominant factor leading to a worse prognosis. In the present review, we determine the major mitochondrial disorders from morphology to functions in sepsis. In the following, several clinical or pre-clinical assays for monitoring mitochondrial function are demonstrated according to accumulated evidence, which is the first step of specific therapy targeting to modulate mitochondrial function. Accordingly, various reagents used for regulating mitochondrial enzyme activities and promoting biogenesis have been documented, among which mitochondria-targeted cation, TPP-conjugated antioxidants are the most valuable for future trials and clinical treatment to improve mitochondrial function as they may take advantage of the prognosis associated with septic complications.
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Affiliation(s)
- Hui Zhang
- Trauma Research Center, First Hospital Affiliated to the Chinese PLA General Hospital, Fucheng Road 51, Haidian District, Beijing, 100048, China
| | - Yong-Wen Feng
- Department of Critical Care Medicine, The Second People's Hospital of Shenzhen, Shenzhen, 518035, China
| | - Yong-Ming Yao
- Trauma Research Center, First Hospital Affiliated to the Chinese PLA General Hospital, Fucheng Road 51, Haidian District, Beijing, 100048, China.
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Inata Y, Piraino G, Hake PW, O'Connor M, Lahni P, Wolfe V, Schulte C, Moore V, James JM, Zingarelli B. Age-dependent cardiac function during experimental sepsis: effect of pharmacological activation of AMP-activated protein kinase by AICAR. Am J Physiol Heart Circ Physiol 2018; 315:H826-H837. [PMID: 29979626 DOI: 10.1152/ajpheart.00052.2018] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Age represents a major risk factor for multiple organ failure, including cardiac dysfunction, in patients with sepsis. AMP-activated protein kinase (AMPK) is a crucial regulator of energy homeostasis that controls mitochondrial biogenesis by activation of peroxisome proliferator-activated receptor-γ coactivator-1α and disposal of defective organelles by autophagy. We investigated whether AMPK dysregulation contributes to age-dependent cardiac injury in young (2-3 mo) and mature adult (11-13 mo) male mice subjected to sepsis by cecal ligation and puncture and whether AMPK activation by 5-amino-4-imidazole carboxamide riboside affords cardioprotective effects. Plasma proinflammatory cytokines and myokine follistatin were similarly elevated in vehicle-treated young and mature adult mice at 18 h after sepsis. However, despite equivalent troponin I and T levels compared with similarly treated young mice, vehicle-treated mature adult mice exhibited more severe cardiac damage by light and electron microscopy analyses with more marked intercellular edema, inflammatory cell infiltration, and mitochondrial derangement. Echocardiography revealed that vehicle-treated young mice exhibited left ventricular dysfunction after sepsis, whereas mature adult mice exhibited a reduction in stroke volume without apparent changes in load-dependent indexes of cardiac function. At molecular analysis, phosphorylation of the catalytic subunits AMPK-α1/α2 was associated with nuclear translocation of peroxisome proliferator-activated receptor-γ coactivator-1α in vehicle-treated young but not mature adult mice. Treatment with 5-amino-4-imidazole carboxamide riboside ameliorated cardiac architecture derangement in mice of both ages. These cardioprotective effects were associated with attenuation of the systemic inflammatory response and amelioration of cardiac dysfunction in young mice only, not in mature adult animals. NEW & NOTEWORTHY Our data suggest that sepsis-induced cardiac dysfunction manifests with age-dependent characteristics, which are associated with a distinct regulation of AMP-activated protein kinase-dependent metabolic pathways. Consistent with this age-related deterioration, pharmacological activation of AMP-activated protein kinase may afford cardioprotective effects allowing a partial recovery of cardiac function in young but not mature age.
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Affiliation(s)
- Yu Inata
- Division of Critical Care Medicine, College of Medicine, University of Cincinnati , Cincinnati, Ohio
| | - Giovanna Piraino
- Division of Critical Care Medicine, College of Medicine, University of Cincinnati , Cincinnati, Ohio
| | - Paul W Hake
- Division of Critical Care Medicine, College of Medicine, University of Cincinnati , Cincinnati, Ohio
| | - Michael O'Connor
- Division of Critical Care Medicine, College of Medicine, University of Cincinnati , Cincinnati, Ohio
| | - Patrick Lahni
- Division of Critical Care Medicine, College of Medicine, University of Cincinnati , Cincinnati, Ohio
| | - Vivian Wolfe
- Division of Critical Care Medicine, College of Medicine, University of Cincinnati , Cincinnati, Ohio
| | - Christine Schulte
- Cardiovascular Imaging Core of the Heart Institute Cincinnati Children's Hospital Medical Center, College of Medicine, University of Cincinnati , Cincinnati, Ohio
| | - Victoria Moore
- Cardiovascular Imaging Core of the Heart Institute Cincinnati Children's Hospital Medical Center, College of Medicine, University of Cincinnati , Cincinnati, Ohio
| | - Jeanne M James
- Division of Cardiology, Department of Pediatrics, Medical College of Wisconsin , Milwaukee, Wisconsin
| | - Basilia Zingarelli
- Division of Critical Care Medicine, College of Medicine, University of Cincinnati , Cincinnati, Ohio.,Department of Pediatrics, College of Medicine, University of Cincinnati , Cincinnati, Ohio
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