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Ran Y, Guo Z, Zhang L, Li H, Zhang X, Guan X, Cui X, Chen H, Cheng M. Mitochondria‑derived peptides: Promising microproteins in cardiovascular diseases (Review). Mol Med Rep 2025; 31:127. [PMID: 40084698 PMCID: PMC11924172 DOI: 10.3892/mmr.2025.13492] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Accepted: 02/27/2025] [Indexed: 03/16/2025] Open
Abstract
Mitochondria‑derived peptides (MDPs) are a unique class of peptides encoded by short open reading frames in mitochondrial DNA, including the mitochondrial open reading frame of the 12S ribosomal RNA type‑c (MOTS‑c). Recent studies suggest that MDPs offer therapeutic benefits in various diseases, including neurodegenerative disorders and types of cancer, due to their ability to increase cellular resilience. Mitochondrial dysfunction is a key factor in the onset and progression of cardiovascular diseases (CVDs), such as atherosclerosis and heart failure, as it disrupts energy metabolism, increases oxidative stress and promotes inflammation. MDPs such as humanin and MOTS‑c have emerged as important regulators of mitochondrial health, as they show protective effects against these processes. Recent studies have shown that MDPs can restore mitochondrial function, reduce oxidative damage and alleviate inflammation, thus counteracting the pathological mechanisms that drive CVDs. Therefore, MDPs hold promise as therapeutic agents that are capable of slowing, stopping, or even reversing CVD progression and their use presents a promising strategy for future treatments. However, the clinical application of MDPs remains challenging due to their low bioavailability, poor stability and high synthesis costs. Thus, it is necessary to improve drug delivery systems to enhance the bioavailability of MDPs. Moreover, integrating basic research with clinical trials is essential to bridge the gap between experimental findings and clinical applications.
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Affiliation(s)
- Yutong Ran
- School of Basic Medicine Sciences, Shandong Second Medical University, Weifang, Shandong 261053, P.R. China
| | - Zhiliang Guo
- Department of Spinal Surgery, The 80th Group Army Hospital of Chinese PLA, Weifang, Shandong 261021, P.R. China
| | - Lijuan Zhang
- Stroke Centre, Second People's Hospital, Weifang, Shandong 261041, P.R. China
| | - Hong Li
- School of Basic Medicine Sciences, Shandong Second Medical University, Weifang, Shandong 261053, P.R. China
| | - Xiaoyun Zhang
- School of Basic Medicine Sciences, Shandong Second Medical University, Weifang, Shandong 261053, P.R. China
| | - Xiumei Guan
- School of Basic Medicine Sciences, Shandong Second Medical University, Weifang, Shandong 261053, P.R. China
| | - Xiaodong Cui
- School of Basic Medicine Sciences, Shandong Second Medical University, Weifang, Shandong 261053, P.R. China
| | - Hao Chen
- School of Basic Medicine Sciences, Shandong Second Medical University, Weifang, Shandong 261053, P.R. China
| | - Min Cheng
- School of Basic Medicine Sciences, Shandong Second Medical University, Weifang, Shandong 261053, P.R. China
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Kelestemur MM, Bulut F, Bılgın B, Hekım MG, Adam M, Ozcan S, Beker MC, Kaya Tektemur N, Tekin S, Canpolat S, Ozcan M. Humanin's impact on pain markers and neuronal viability in diabetic neuropathy model. Arch Physiol Biochem 2024; 130:898-908. [PMID: 38599217 DOI: 10.1080/13813455.2024.2336922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 01/31/2024] [Accepted: 03/26/2024] [Indexed: 04/12/2024]
Abstract
OBJECTIVE This study investigates the impact of chronic humanin (HN) treatment on pain-related markers (NMDA, substance P, TRPV1, and IL-1β) in diabetic mice's dorsal root ganglia (DRG). Additionally, we assess the effects of HN on cellular viability in DRG neurons. METHODS In vivo experiments involved 15 days of HN administration (4 mg/kg) to diabetic mice (n = 10). Protein levels of NMDA, IL-1β, TRPV1, and substance P were measured in diabetic DRG. In vitro experiments explored HN's impact on apoptosis and cellular viability, focusing on the JAK2/STAT3 pathway. RESULTS Humanin significantly reduced the elevated expression of NMDA, IL-1β, TRPV1, and substance P induced by diabetes (p < .05). Furthermore, HN treatment increased cellular viability in DRG neurons through JAK2/STAT3 pathway activation (p < .05). CONCLUSION These findings highlight the significance of understanding mitochondrial function and pain markers, as well as apoptosis in diabetes. The study provides insights for managing the condition and its complications.
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Affiliation(s)
| | - Ferah Bulut
- Department of Biophysics, School of Medicine, University of Firat, Elazig, Turkey
| | - Batuhan Bılgın
- Department of Biophysics, School of Medicine, Gaziantep Islam Science and Technology University, Gaziantep, Turkey
| | - Munevver Gizem Hekım
- Department of Physiology, School of Medicine, University of Firat, Elazig, Turkey
| | - Muhammed Adam
- Department of Biophysics, School of Medicine, University of Firat, Elazig, Turkey
| | - Sibel Ozcan
- Department of Anaesthesiology and Reanimation, School of Medicine, University of Firat, Elazig, Turkey
| | - Mustafa Caglar Beker
- Department of Physiology, School of Medicine, University of Medipol, Istanbul, Turkey
| | - Nalan Kaya Tektemur
- Department of Histology and Embryology, School of Medicine, University of Firat, Elazig, Turkey
| | - Suat Tekin
- Department of Physiology, School of Medicine, University of Inonu, Malatya, Turkey
| | - Sinan Canpolat
- Department of Physiology, School of Medicine, University of Firat, Elazig, Turkey
| | - Mete Ozcan
- Department of Biophysics, School of Medicine, University of Firat, Elazig, Turkey
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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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Shi Q, Xiao Z, Cai W, Chen Y, Liang H, Ye Z, Li Z, Liang X. Quantitative proteomics analysis reveals the protective role of S14G-humanin in septic acute kidney injury using 4D-label-free and PRM Approaches. Biochem Biophys Res Commun 2024; 733:150630. [PMID: 39332154 DOI: 10.1016/j.bbrc.2024.150630] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 08/29/2024] [Accepted: 08/29/2024] [Indexed: 09/29/2024]
Abstract
Mitochondrial dysfunction contributes to septic acute kidney injury (S-AKI), making mitochondrial protection a potential therapeutic strategy. This study investigates the effects of S14G-humanin (HNG) in S-AKI, utilizing 4D-label-free and parallel reaction monitoring (PRM) techniques for proteomic analysis. An S-AKI model was created in male C57BL/6 mice using lipopolysaccharide (LPS) injection, followed by HNG administration. After 24 h, kidney tissues were analyzed for histology, biochemistry, mitochondrial function, and proteomics. HNG treatment improved renal function, reduced tubular injury, and decreased pro-inflammatory cytokines and oxidative stress markers. Proteomic analysis identified 5900 proteins, with 5111 quantifiable. HNG altered the expression of 132 proteins, with 18 selected for PRM validation. Ten of these proteins were linked to key pathways, including fatty acid degradation and PPAR signaling. This study is the first to show HNG's protective effects in S-AKI, providing insights into its mechanisms through advanced proteomic techniques.
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Affiliation(s)
- Qingying Shi
- Department of Nephrology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 106th, Zhongshan Road II, Guangzhou, 510080, China
| | - Zhenmeng Xiao
- Blood Purification Center, the People's Hospital of Zhengzhou University, No. 7 Weiwu Road, Zhengzhou, 450003, China
| | - Wenjing Cai
- Department of Nephrology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 106th, Zhongshan Road II, Guangzhou, 510080, China
| | - Yuanhan Chen
- Department of Nephrology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 106th, Zhongshan Road II, Guangzhou, 510080, China; Guangdong-Hong Kong Joint Laboratory on Immunological and Genetic Kidney Diseases, 106th, Zhongshan Road II, Guangzhou, 510080, China
| | - Huaban Liang
- Department of Nephrology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 106th, Zhongshan Road II, Guangzhou, 510080, China; Guangdong-Hong Kong Joint Laboratory on Immunological and Genetic Kidney Diseases, 106th, Zhongshan Road II, Guangzhou, 510080, China
| | - Zhiming Ye
- Department of Nephrology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 106th, Zhongshan Road II, Guangzhou, 510080, China; Guangdong-Hong Kong Joint Laboratory on Immunological and Genetic Kidney Diseases, 106th, Zhongshan Road II, Guangzhou, 510080, China
| | - Zhilian Li
- Department of Nephrology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 106th, Zhongshan Road II, Guangzhou, 510080, China; Guangdong-Hong Kong Joint Laboratory on Immunological and Genetic Kidney Diseases, 106th, Zhongshan Road II, Guangzhou, 510080, China.
| | - Xinling Liang
- Department of Nephrology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 106th, Zhongshan Road II, Guangzhou, 510080, China; Guangdong-Hong Kong Joint Laboratory on Immunological and Genetic Kidney Diseases, 106th, Zhongshan Road II, Guangzhou, 510080, China.
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Lu Y, Bartoszek EM, Cortada M, Bodmer D, Levano Huaman S. Mitochondrial-derived peptides, HNG and SHLP3, protect cochlear hair cells against gentamicin. Cell Death Discov 2024; 10:445. [PMID: 39433756 PMCID: PMC11493991 DOI: 10.1038/s41420-024-02215-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Revised: 10/10/2024] [Accepted: 10/14/2024] [Indexed: 10/23/2024] Open
Abstract
Preservation of hair cells is critical for maintaining hearing function, as damage to sensory cells potentially leads to irreparable sensorineural hearing loss. Hair cell loss is often associated with inflammation and oxidative stress. One promising class of bioactive peptides is mitochondrial-derived peptides (MDPs), which have already been proven to protect various tissues from cellular stresses and delay aging processes. Humanin (HN) is one of the best-known members of this family, and recently, we have shown its protective effect in hair cells. The synthetic derivate HN S14G (HNG) has a more potent protective effect than natural HN making it a more useful peptide candidate to promote cytoprotection. A less-known MDP is small humanin-like peptide 3 (SHLP3), which has cytoprotective effects similar to HN, but likely acts through different signaling pathways. Therefore, we examined the effect of exogenous HNG and SHLP3 in auditory hair cells and investigated the molecular mechanisms involved. For this purpose, explants of the organ of Corti (OC) were treated with gentamicin in the presence and absence of HNG or SHLP3. Administration of HNG and SHLP3 reduced gentamicin-induced hair cell loss. The protective mechanisms of HNG and SHLP3 in OC explants included, in part, modulation of AKT and AMPKα. In addition, treatment with HNG and SHLP3 reduced gentamicin-induced oxidative stress and inflammatory gene overexpression. Overall, our data show that HNG and SHLP3 protect hair cells from gentamicin-induced toxicity. This offers new perspectives for the development of therapeutic strategies with MDPs against hearing loss.
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Affiliation(s)
- Yu Lu
- Department of Biomedicine, University of Basel Hospital, Basel, Switzerland
| | | | - Maurizio Cortada
- Department of Biomedicine, University of Basel Hospital, Basel, Switzerland
- Department of Otolaryngology, Head and Neck Surgery, University of Basel Hospital, Basel, Switzerland
| | - Daniel Bodmer
- Department of Biomedicine, University of Basel Hospital, Basel, Switzerland
- Department of Otolaryngology, Head and Neck Surgery, University of Basel Hospital, Basel, Switzerland
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Wang F, Huynh PM, An YA. Mitochondrial Function and Dysfunction in White Adipocytes and Therapeutic Implications. Compr Physiol 2024; 14:5581-5640. [PMID: 39382163 DOI: 10.1002/cphy.c230009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/10/2024]
Abstract
For a long time, white adipocytes were thought to function as lipid storages due to the sizeable unilocular lipid droplet that occupies most of their space. However, recent discoveries have highlighted the critical role of white adipocytes in maintaining energy homeostasis and contributing to obesity and related metabolic diseases. These physiological and pathological functions depend heavily on the mitochondria that reside in white adipocytes. This article aims to provide an up-to-date overview of the recent research on the function and dysfunction of white adipocyte mitochondria. After briefly summarizing the fundamental aspects of mitochondrial biology, the article describes the protective role of functional mitochondria in white adipocyte and white adipose tissue health and various roles of dysfunctional mitochondria in unhealthy white adipocytes and obesity. Finally, the article emphasizes the importance of enhancing mitochondrial quantity and quality as a therapeutic avenue to correct mitochondrial dysfunction, promote white adipocyte browning, and ultimately improve obesity and its associated metabolic diseases. © 2024 American Physiological Society. Compr Physiol 14:5581-5640, 2024.
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Affiliation(s)
- Fenfen Wang
- Department of Anesthesiology, Critical Care, and Pain Medicine, Center for Perioperative Medicine, McGovern Medical School, UT Health Science Center at Houston, Houston, Texas, USA
| | - Phu M Huynh
- Department of Anesthesiology, Critical Care, and Pain Medicine, Center for Perioperative Medicine, McGovern Medical School, UT Health Science Center at Houston, Houston, Texas, USA
| | - Yu A An
- Department of Anesthesiology, Critical Care, and Pain Medicine, Center for Perioperative Medicine, McGovern Medical School, UT Health Science Center at Houston, Houston, Texas, USA
- Center for Metabolic and Degenerative Diseases, The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, McGovern Medical School, UT Health Science Center at Houston, Houston, Texas, USA
- Department of Biochemistry and Molecular Biology, McGovern Medical School, UT Health Science Center at Houston, Houston, Texas, USA
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Li Y, Li Z, Ren Y, Lei Y, Yang S, Shi Y, Peng H, Yang W, Guo T, Yu Y, Xiong Y. Mitochondrial-derived peptides in cardiovascular disease: Novel insights and therapeutic opportunities. J Adv Res 2024; 64:99-115. [PMID: 38008175 PMCID: PMC11464474 DOI: 10.1016/j.jare.2023.11.018] [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: 09/20/2023] [Revised: 11/14/2023] [Accepted: 11/17/2023] [Indexed: 11/28/2023] Open
Abstract
BACKGROUND Mitochondria-derived peptides (MDPs) represent a recently discovered family of peptides encoded by short open reading frames (ORFs) found within mitochondrial genes. This group includes notable members including humanin (HN), mitochondrial ORF of the 12S rDNA type-c (MOTS-c), and small humanin-like peptides 1-6 (SHLP1-6). MDPs assume pivotal roles in the regulation of diverse cellular processes, encompassing apoptosis, inflammation, and oxidative stress, which are all essential for sustaining cellular viability and normal physiological functions. Their emerging significance extends beyond this, prompting a deeper exploration into their multifaceted roles and potential applications. AIM OF REVIEW This review aims to comprehensively explore the biogenesis, various types, and diverse functions of MDPs. It seeks to elucidate the central roles and underlying mechanisms by which MDPs participate in the onset and development of cardiovascular diseases (CVDs), bridging the connections between cell apoptosis, inflammation, and oxidative stress. Furthermore, the review highlights recent advancements in clinical research related to the utilization of MDPs in CVD diagnosis and treatment. KEY SCIENTIFIC CONCEPTS OF REVIEW MDPs levels are diminished with aging and in the presence of CVDs, rendering them potential new indicators for the diagnosis of CVDs. Also, MDPs may represent a novel and promising strategy for CVD therapy. In this review, we delve into the biogenesis, various types, and diverse functions of MDPs. We aim to shed light on the pivotal roles and the underlying mechanisms through which MDPs contribute to the onset and advancement of CVDs connecting cell apoptosis, inflammation, and oxidative stress. We also provide insights into the current advancements in clinical research related to the utilization of MDPs in the treatment of CVDs. This review may provide valuable information with MDPs for CVD diagnosis and treatment.
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Affiliation(s)
- Yang Li
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, College of Life Sciences, Northwest University, Xi'an 710069, Shaanxi, PR China
| | - Zhuozhuo Li
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, College of Life Sciences, Northwest University, Xi'an 710069, Shaanxi, PR China
| | - Yuanyuan Ren
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, College of Life Sciences, Northwest University, Xi'an 710069, Shaanxi, PR China
| | - Ying Lei
- School of Medicine, Northwest University, Xi'an 710069, Shaanxi, PR China
| | - Silong Yang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, College of Life Sciences, Northwest University, Xi'an 710069, Shaanxi, PR China
| | - Yuqi Shi
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, College of Life Sciences, Northwest University, Xi'an 710069, Shaanxi, PR China
| | - Han Peng
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, College of Life Sciences, Northwest University, Xi'an 710069, Shaanxi, PR China
| | - Weijie Yang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, College of Life Sciences, Northwest University, Xi'an 710069, Shaanxi, PR China
| | - Tiantian Guo
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, College of Life Sciences, Northwest University, Xi'an 710069, Shaanxi, PR China
| | - Yi Yu
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, College of Life Sciences, Northwest University, Xi'an 710069, Shaanxi, PR China; School of Medicine, Northwest University, Xi'an 710069, Shaanxi, PR China.
| | - Yuyan Xiong
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, College of Life Sciences, Northwest University, Xi'an 710069, Shaanxi, PR China; Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi'an No.3 Hospital, The Affiliated Hospital of Northwest University, 710018 Xi'an, Shaanxi, PR China.
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Ibrahim AGE, Ciullo A, Yamaguchi S, Li C, Antes T, Jones X, Li L, Murali R, Maslennikov I, Sundararaman N, Soetkamp D, Cingolani E, Van Eyk J, Marbán E. A novel micropeptide, Slitharin, exerts cardioprotective effects in myocardial infarction. Proteomics Clin Appl 2024; 18:e2300128. [PMID: 38444254 PMCID: PMC11374934 DOI: 10.1002/prca.202300128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Revised: 02/19/2024] [Accepted: 02/21/2024] [Indexed: 03/07/2024]
Abstract
PURPOSE Micropeptides are an emerging class of proteins that play critical roles in cell signaling. Here, we describe the discovery of a novel micropeptide, dubbed slitharin (Slt), in conditioned media from Cardiosphere-derived cells (CDCs), a therapeutic cardiac stromal cell type. EXPERIMENTAL DESIGN We performed mass spectrometry of peptide-enriched fractions from the conditioned media of CDCs and a therapeutically inert cell type (human dermal fibrobasts). We then evaluated the therapeutic capacity of the candidate peptide using an in vitro model of cardiomyocyte injury and a rat model of myocardial infarction. RESULTS We identified a novel 24-amino acid micropeptide (dubbed Slitharin [Slt]) with a non-canonical leucine start codon, arising from long intergenic non-coding (LINC) RNA 2099. Neonatal rat ventricular myocytes (NRVMs) exposed to Slt were protected from hypoxic injury in vitro compared to a vehicle or scrambled control. Transcriptomic analysis of cardiomyocytes exposed to Slt reveals cytoprotective capacity, putatively through regulation of stress-induced MAPK-ERK. Slt also exerted cardioprotective effects in rats with myocardial infarction as shown by reduced infarct size 48 h post-injury. Conclusions and clinical relavance: Thus, Slt is a non-coding RNA-derived micropeptide, identified in the extracellular space, with a potential cardioprotective function.
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Affiliation(s)
- Ahmed G E Ibrahim
- Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Alessandra Ciullo
- Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Shukuro Yamaguchi
- Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Chang Li
- Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Travis Antes
- Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Xaviar Jones
- Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Liang Li
- Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Ramachandran Murali
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | | | - Niveda Sundararaman
- Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Daniel Soetkamp
- Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Eugenio Cingolani
- Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Jennifer Van Eyk
- Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Eduardo Marbán
- Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
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Koenis DS, Evers-van Gogh IJA, van Loenen PB, Zwart W, Kalkhoven E, de Vries CJM. Nuclear receptor Nur77 and Yin-Yang 1 synergistically increase mitochondrial abundance and activity in macrophages. FEBS Lett 2024; 598:1715-1729. [PMID: 38825601 DOI: 10.1002/1873-3468.14942] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 05/07/2024] [Accepted: 05/09/2024] [Indexed: 06/04/2024]
Abstract
Mitochondrial biogenesis requires precise regulation of both mitochondrial-encoded and nuclear-encoded genes. Nuclear receptor Nur77 is known to regulate mitochondrial metabolism in macrophages and skeletal muscle. Here, we compared genome-wide Nur77 binding site and target gene expression in these two cell types, which revealed conserved regulation of mitochondrial genes and enrichment of motifs for the transcription factor Yin-Yang 1 (YY1). We show that Nur77 and YY1 interact, that YY1 increases Nur77 activity, and that their binding sites are co-enriched at mitochondrial ribosomal protein gene loci in macrophages. Nur77 and YY1 co-expression synergistically increases Mrpl1 expression as well as mitochondrial abundance and activity in macrophages but not skeletal muscle. As such, we identify a macrophage-specific Nur77-YY1 interaction that enhances mitochondrial metabolism.
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Affiliation(s)
- Duco S Koenis
- Department of Medical Biochemistry, Amsterdam UMC, Amsterdam Cardiovascular Sciences, University of Amsterdam, Amsterdam, The Netherlands
- Amsterdam Cardiovascular Sciences (ACS), Atherosclerosis & Ischemic Syndromes, Amsterdam UMC, Amsterdam, The Netherlands
- Amsterdam Institute for Infection and Immunity (AII), Inflammatory Diseases, Amsterdam UMC, Amsterdam, The Netherlands
| | - Inkie J A Evers-van Gogh
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Pieter B van Loenen
- Department of Medical Biochemistry, Amsterdam UMC, Amsterdam Cardiovascular Sciences, University of Amsterdam, Amsterdam, The Netherlands
- Amsterdam Cardiovascular Sciences (ACS), Atherosclerosis & Ischemic Syndromes, Amsterdam UMC, Amsterdam, The Netherlands
- Amsterdam Institute for Infection and Immunity (AII), Inflammatory Diseases, Amsterdam UMC, Amsterdam, The Netherlands
| | - Wilbert Zwart
- Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Eric Kalkhoven
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Carlie J M de Vries
- Department of Medical Biochemistry, Amsterdam UMC, Amsterdam Cardiovascular Sciences, University of Amsterdam, Amsterdam, The Netherlands
- Amsterdam Cardiovascular Sciences (ACS), Atherosclerosis & Ischemic Syndromes, Amsterdam UMC, Amsterdam, The Netherlands
- Amsterdam Institute for Infection and Immunity (AII), Inflammatory Diseases, Amsterdam UMC, Amsterdam, The Netherlands
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Aksu F, Akkoc RF, Savur E, Çelik C. Effects of N-Acetylcysteine on Humanin and Endostatin in Rats Exposed to Formaldehyde. Cureus 2024; 16:e61354. [PMID: 38947691 PMCID: PMC11214271 DOI: 10.7759/cureus.61354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/29/2024] [Indexed: 07/02/2024] Open
Abstract
INTRODUCTION People are constantly exposed to formaldehyde, a volatile and poisonous gas, in indoor environments. In particular, anatomists, pathologists, histologists, and those involved in embalming are exposed to higher amounts of formaldehyde continuously due to their work. This study aimed to investigate the effect of N-acetylcysteine on endostatin and humanin values in male rats exposed to experimental formaldehyde. METHODS In the study, 28 male Spraque-Dawley rats aged 12-14 weeks (seven animals in each group: control group, formaldehyde group, N-acetylcysteine group, formaldehyde+N-acetylcysteine group) were used. Four weeks later, the animals were sacrificed by decapitation. Following decapitation, endostatin and humanin levels in the serum of rats were studied by the enzyme-linked immunoassay (ELISA) method. In all analyses, p<0.05 was accepted as statistically significant. RESULTS Humanin and endostatin values were checked in the serum of rats. When humanin levels were compared between groups, a statistically significant difference was found between the formaldehyde group and both the control group (p<0.05) and the N-acetylcysteine group (p<0.05). In the formaldehyde+N-acetylcysteine group, it was determined that the humanin level was impaired due to formaldehyde exposure, approaching the control group values with the administered N-acetylcysteine. When the endostatin level was compared between the groups, a statistical significance (p<0.05) was found only between the formaldehyde group and the N-acetylcysteine group. In the formaldehyde+N-acetylcysteine group, it was determined that the endostatin level was impaired due to formaldehyde exposure, approaching the control group values with the administered N-acetylcysteine. CONCLUSION In this study, the effects of N-acetylcysteine on humanin and endostatin on rats exposed to formaldehyde were demonstrated for the first time. Formaldehyde exposure negatively affected humanin and endostatin levels in rat sera. N-acetylcysteine ameliorated the negative effects of formaldehyde, bringing humanin and endostatin levels closer to the healthy control group.
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Affiliation(s)
- Feyza Aksu
- Department of Anatomy, Faculty of Medicine, Firat University, Elazig, TUR
| | | | - Ezgi Savur
- College of Medicine, Faculty of Medicine, Firat University, Elazig, TUR
| | - Celal Çelik
- College of Medicine, Faculty of Medicine, Firat University, Elazig, TUR
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Chen L, Yang X, Wang K, Guo L, Zou C. Humanin inhibits lymphatic endothelial cells dysfunction to alleviate myocardial infarction-reperfusion injury via BNIP3-mediated mitophagy. Free Radic Res 2024; 58:180-193. [PMID: 38535980 DOI: 10.1080/10715762.2024.2333074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Accepted: 02/20/2024] [Indexed: 05/02/2024]
Abstract
OBJECTIVE Acute myocardial infarction (AMI) ranks among the top contributors to sudden death and disability worldwide. It should be noted that current therapies always cause increased reperfusion damage. Evidence suggests that humanin (HN) reduces mitochondrial dysfunction to have cardio-protective effects against MI-reperfusion injury. In this context, we hypothesized that HN may attenuate MI-reperfusion injury by alleviating lymphatic endothelial cells dysfunction through the regulation of mitophagy. MATERIALS AND METHODS In this study, primary lymphatic endothelial cells were selected as the experimental model. Cells were maintained under 1% O2 to induce a hypoxic phenotype. For in vivo experiments, the left coronary arteries of C57/BL6 mice were clamped for 45 min followed by 24 h reperfusion to develop MI-reperfusion injury. The volume of infarcted myocardium in MI-reperfusion injury mouse models were TTC staining. PCR and western blot were used to quantify the expression of autophagy-, mitophagy- and mitochondria-related markers. The fibrosis and apoptosis in the ischemic area were evaluated for Masson staining and TUNEL respectively. We also used western blot to analyze the expression of VE-Cadherin in lymphatic endothelial cells. RESULTS We firstly exhibited a specific mechanism by which HN mitigates MI-reperfusion injury. We demonstrated that HN effectively reduces such injury in vivo and also inhibits dysfunction in lymphatic endothelial cells in vitro. Importantly, this inhibitory effect is mediated through BNIP3-associated mitophagy. CONCLUSIONS In conclusion, HN alleviates myocardial infarction-reperfusion injury by inhibiting lymphatic endothelial cells dysfunction, primarily through BNIP3-mediated mitophagy.
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Affiliation(s)
- Lu Chen
- Department of Cardiology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Center for Cardiovascular Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaohua Yang
- Central Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Kai Wang
- Central Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Lina Guo
- Center for Cardiovascular Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Cao Zou
- Department of Cardiology, The First Affiliated Hospital of Soochow University, Suzhou, China
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Zou L, Huang J, Zhang Q, Mo H, Xia W, Zhu C, Rao M. The humanin analogue (HNG) alleviates intrauterine adhesions by inhibiting endometrial epithelial cells ferroptosis: a rat model-based study. Hum Reprod 2023; 38:2422-2432. [PMID: 37814907 DOI: 10.1093/humrep/dead196] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 09/11/2023] [Indexed: 10/11/2023] Open
Abstract
STUDY QUESTION Does a humanin analogue (HNG) have a therapeutic effect on intrauterine adhesions (IUAs) caused by uterine cavity surgery in a rat model? SUMMARY ANSWER HNG supplementation attenuated the development of endometrial fibrosis and IUAs, improved fertility, and contributed to the regulation of endometrial fibrosis by inhibiting endometrial ferroptosis in rats with IUAs. WHAT IS KNOWN ALREADY IUAs, which are characterized by endometrial fibrosis, are a common cause of female infertility. Humanin (rattin in rats) is a mitochondrial-derived peptide that is widely expressed in multiple tissues. S14G-humanin (HNG) is an HNG that has been reported to have a protective effect against myocardial fibrosis. STUDY DESIGN, SIZE, DURATION Endometrial tissues from three patients with IUAs and three controls were tested for humanin expression. Two animal models were used to evaluate the modelling effect of IUAs and the preventive effect of HNG against IUAs. In the first model, 40 rats were equally randomized to control and Day 7, 14, and 21 groups to establish the IUA model. In the second model, 66 rats were equally randomized to the control, IUA, and IUA + humanin analogue (HNG) groups. Erastin was used to induce ferroptosis in the Ishikawa cell line. PARTICIPANTS/MATERIALS, SETTING, METHODS The endometrium was scraped with a surgical spatula, combined with lipopolysaccharide treatment, to establish the rat model of IUAs. Rats were intraperitoneally injected with 5 mg/kg/day HNG for 21 consecutive days beginning from the day of operation to evaluate the therapeutic effect on IUAs. Haematoxylin-eosin and Masson's trichrome staining were used to assess endometrial morphology and evaluate fibrosis. Ferroptosis-related markers, namely nuclear factor E2-related factor 2 (Nrf2), acyl-CoA synthetase long-chain family member 4 (ACSL4), haeme oxygenase-1 (HO-1), solute carrier family 7 member 11 (SLC7A11), glutathione peroxidase 4 (GPX4), and ferritin, were measured by immunohistochemistry and western blotting to determine whether ferroptosis was involved in the development of IUAs and to assess the attenuative effect of HNG on ferroptosis. Additionally, the female rats were mated with male rats with normal fertility to assess fertility. MAIN RESULTS AND THE ROLE OF CHANCE Humanin was widely expressed in endometrial cells, including epithelial and stromal cells, in both humans and rats. Humanin expression levels were downregulated in the endometria of patients and rats with IUAs relative to the endometria of controls. Endometrial thickness and the number of glands were significantly decreased on Day 7, 14, and 21 after endometrial scraping when compared with the controls (all P < 0.05), whereas the fibrotic area was significantly increased (P < 0.05). Among the tested ferroptosis markers, the expression levels of Nrf2, SLC7A11, and GPX4 were significantly downregulated and those of ACSL4, HO-1, and ferritin were significantly upregulated after endometrial scraping relative to their expression levels in controls (all P < 0.05). The mating rates in the control, IUA, and IUA + HNG groups were 100% (10/10), 40% (4/10), and 80% (8/10), respectively. The number of embryos in rats with IUAs (mean ± SD: 1.6 ± 2.1) was significantly less than the number in the controls (11.8 ± 1.5). HNG supplementation significantly attenuated this decrease in the number of implanted embryos (6.3 ± 4.5) (P < 0.01). Further results showed that HNG significantly attenuated the altered expression levels of proteins involved in ferroptosis in the endometria of rats with IUAs. Moreover, in vitro experiments showed that HNG significantly attenuated the erastin-induced decrease in the viability of the Ishikawa cell line and also attenuated the increase in reactive oxygen species production and the downregulation of GPX4. LARGE SCALE DATA None. LIMITATIONS, REASONS FOR CAUTION The findings of this study showed that HNG inhibited ferroptosis and reduced fibrosis in a rat model of IUAs. However, we could not establish a causal relationship between ferroptosis and the development of IUAs. WIDER IMPLICATIONS OF THE FINDINGS HNG may be effective at alleviating fibrosis during the development of IUAs, and the inhibition of ferroptosis is a promising new strategy for IUA therapy. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by the National Natural Science Foundation of China (No. 82171647); the '1000 Talent Plan' of Yunnan Province (No. RLQN20200001); and the Basic Research Project of the Yunnan Province-Outstanding Youth Foundation (No. 202101AW070018). The authors declare no competing financial interests.
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Affiliation(s)
- Liping Zou
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jin Huang
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qiaoling Zhang
- Department of Reproduction and Genetics, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Hui Mo
- Department of Reproduction and Genetics, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Wei Xia
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Changhong Zhu
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Meng Rao
- Department of Reproduction and Genetics, The First Affiliated Hospital of Kunming Medical University, Kunming, China
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Zhao Q, Cai MM, Li D, Zhao BY, Zhou SS, Wu ZR, Shi YJ, Su L. S14G-humanin confers cardioprotective effects against chronic adrenergic and pressure overload-induced heart failure in mice. Heliyon 2023; 9:e21892. [PMID: 38045183 PMCID: PMC10692773 DOI: 10.1016/j.heliyon.2023.e21892] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 09/18/2023] [Accepted: 10/31/2023] [Indexed: 12/05/2023] Open
Abstract
S14G-humanin (HNG), an analog of the mitochondria-derived peptide humanin, has demonstrated protective effects against various cardiovascular diseases. However, the specific pharmacological effects of HNG in heart failure (HF) have not been previously reported. Therefore, in this study, we aimed to investigate the potential protective effect of HNG in HF using a mouse model. HF was induced in mice through intraperitoneal injection of isoproterenol or transverse aortic constriction, followed by separate administration of HNG to assess its therapeutic impact. Our results revealed that HNG treatment significantly delayed the onset of cardiac dysfunction and structural remodeling in the HF mouse model. Furthermore, HNG administration was associated with reduced infiltration of inflammatory cells, improved myocardial fibrosis, and attenuation of cardiomyocyte apoptosis in the treated cardiac tissues. Additionally, we identified the involvement of the transforming growth factor-beta signaling pathway in the beneficial effects of HNG in isoproterenol-induced HF mice. Collectively, these findings underscore the therapeutic potential of HNG in preventing the progression of HF, as demonstrated in two distinct HF mouse models.
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Affiliation(s)
- Qi Zhao
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China
| | - Ming-Ming Cai
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China
| | - Dan Li
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China
| | - Bin-Yi Zhao
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China
| | - Shuang-Shan Zhou
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China
| | - Zhen-Ru Wu
- Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Yu-Jun Shi
- Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Li Su
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China
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ONAT E, ÖNALAN E, ÖZDEM B, KAVAK BALGETİR M, KULOĞLU T. Effect of humanine on the Notch signaling pathway in myocardial infarction. Turk J Med Sci 2023; 53:1658-1666. [PMID: 38813496 PMCID: PMC10760541 DOI: 10.55730/1300-0144.5734] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 12/12/2023] [Accepted: 10/25/2023] [Indexed: 05/31/2024] Open
Abstract
Background/aim By applying humanin (HN) before myocardial infarction (MI), its protection in myocardial injury and the possible roles of its cellular mechanism in the Notch pathway were investigated. Materials and methods The study was carried out at Fırat University Experimental Research Center (12/24/2018-12/23/2019). Spraque-Dawley rats were divided into 10 groups: I (control) (n = 6), II (HN 6 h) (n = 6), III (HN 24 h) (n = 6), IV (HN day 7) (n = 6), V (MI 6 h) (n = 7), VI (MI 24 h) (n = 7), VII (MI day 7) (n = 7), VIII (MI+HN 6 h) (n = 7), IX (MI+HN 24 h) (n = 7), and X (MI+HN day 7) (n = 7). To create MI, 200 mg/kg of isoproterenol (ISO) was administered to the rats subcutaneously. Moreover, 252 μg/kg of HN was given intraperitoneally (ip) to the rats on its own and before MI. Molecular parameters Notch1, Notch2, Hes1, Hes2, Jagged1, Jagged2, DLL1, and DLL4 were examined using polymerase chain reaction in the heart tissue, Notch1, Hes1, and DLL4 were examined using western blot, while heart tissue was taken for histochemical examinations. Results The mRNA expression levels of the Notch signaling members (Notch1, Notch2, Hes1, Hes2, Jagged1, Jagged2, DLL1, and DLL4) tended to decrease after MI. The Notch signaling members increased more significantly, especially toward day 7 after HN application before MI. In the western blot anylyses, the Notch1, Hes1, and DLL4 protein levels increased significantly toward day 7 in the groups given HN before MI. Moreover, the serum AST, LDH, CK-MB, and troponin I levels tended to decrease with the application of HN before MI and there was a significant decrease in edema, hemorrhage, and mononuclear cells in the heart tissue at 24 h post-MI and fibrosis on day 7 post-MI. Conclusion HN administration before MI has a cardioprotective effect on rats via the Notch signaling pathway.
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Affiliation(s)
- Elif ONAT
- Department of Medical Pharmacology, Faculty of Medicine, Adıyaman University, Adıyaman,
Turkiye
| | - Ebru ÖNALAN
- Department of Medical Biology, Faculty of Medicine, Fırat University, Elazığ,
Turkiye
| | - Berna ÖZDEM
- Department of Medical Biology and Genetics, Faculty of Medicine, İnönü University, Malatya,
Turkiye
| | | | - Tuncay KULOĞLU
- Department of Histology and Embryology, Faculty of Medicine, Fırat University, Elazığ,
Turkiye
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Thamarai Kannan H, Issac PK, Dey N, Guru A, Arockiaraj J. A Review on Mitochondrial Derived Peptide Humanin and Small Humanin-Like Peptides and Their Therapeutic Strategies. Int J Pept Res Ther 2023; 29:86. [DOI: 10.1007/s10989-023-10558-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/26/2023] [Indexed: 10/16/2023]
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Onat E, Kocaman N, Hancer S. The protective effects of humanin in rats with experimental myocardial infarction: The role of asprosin and spexin. Heliyon 2023; 9:e18739. [PMID: 37576267 PMCID: PMC10412837 DOI: 10.1016/j.heliyon.2023.e18739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 07/09/2023] [Accepted: 07/26/2023] [Indexed: 08/15/2023] Open
Abstract
Objective In this study, by applying humanin (HN) before myocardial infarction (MI) in rats, its protection in MI and the possible roles in asprosin and spexin were investigated. Materials and methods The rats were divided into 7 groups each with 6 rats (group I (control), group II (HN 48th hour), group III (HN 7th day), group IV (MI 48th hour), group V (MI 7th day), group VI (MI + HN 48th hour), group VII (MI + HN 7th day). To create MI, 200 mg/kg isoproterenol (ISO) was administered subcutaneously to the rats. 2 mg/kg HN was given intraperitoneally (ip) to rats alone and before MI. Molecular parameters asprosin and spexin were examined by immunohistochemical in heart tissue. Biochemical parameters (aspartate aminotransferase (AST), lactate dehydrogenase (LDH), creatine kinase MB (CK-MB), Troponin I) were studied in serum by enzyme-linked immunosorbent assay (ELISA) method. Results It was found in the study that the levels of spexin elevated especially towards the 7th day after MI and decreased more significantly towards the 7th day, after HN application before MI. Asprosin elevated significantly towards the 7th day after MI and decreased especially on the 7th day after HN application before MI. Also, serum AST, LDH, CK-MB, and Troponin I levels tended to decrease and a significant decrease was detected in congested veins in the heart tissue at the 48th hour of MI and erythrocyte extravasation, congested veins and necrotic muscle fibers at the 7th day of MI in rats given HN before MI. Conclusion It was concluded that HN has a cardioprotective effect in MI and asprosin and spexin might mediate this effect.
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Affiliation(s)
- Elif Onat
- Department of Medical Pharmacology, Faculty of Medicine, Adiyaman University, Adiyaman, 02040, Turkey
| | - Nevin Kocaman
- Department of Histology and Embryology, Faculty of Medicine, Firat University, Elazig, 23119, Turkey
| | - Serhat Hancer
- Department of Histology and Embryology, Faculty of Medicine, Firat University, Elazig, 23119, Turkey
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Wagner ML, Ammann A, Piraino G, Wolfe V, O’Connor M, Lahni P, Ziady A, Zingarelli B. PROTECTIVE EFFECTS OF HUMANIN-G IN HEMORRHAGIC SHOCK IN FEMALE MICE VIA AMPKα1-INDEPENDENT MECHANISMS. Shock 2023; 60:64-74. [PMID: 37079467 PMCID: PMC10523894 DOI: 10.1097/shk.0000000000002134] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/21/2023]
Abstract
ABSTRACT Introduction: Despite therapeutic advances in hemorrhagic shock, mortality from multiple organ failure remains high. We previously showed that the α1 subunit of AMP-activated protein kinase (AMPK), a crucial regulator of mitochondrial function, exerts a protective role in hemorrhagic shock. Humanin is a mitochondrial peptide with cytoprotective properties against cellular stress. Here, we investigated whether AMPKα1 influences systemic levels of endogenous humanin in hemorrhagic shock and whether treatment with the synthetic analog humanin-G affords beneficial effects. Methods: AMPKα1 wild-type (WT) and knockout (KO) female mice were subjected to hemorrhagic shock followed by resuscitation with blood and lactated Ringer's solution. In short-term studies, mice were treated with humanin-G or vehicle and sacrificed at 3 h after resuscitation; in survival studies, mice were treated with PEGylated humanin-G and monitored for 7 days. Results: Compared with the vehicle WT group, KO mice exhibited severe hypotension, cardiac mitochondrial damage, and higher plasma levels of Th17 cytokines but had similar lung injury and similar plasma elevation of endogenous humanin. Treatment with humanin-G improved lung injury, mean arterial blood pressure, and survival in both WT and KO mice, without affecting systemic cytokine or humanin levels. Humanin-G also ameliorated cardiac mitochondrial damage and increased adenosine triphosphate levels in KO mice. Beneficial effects of humanin-G were associated with lung cytoplasmic and nuclear activation of the signal transducer and activator of transcription-3 (STAT3) in AMPKα1-independent manner with marginal or no effects on mitochondrial STAT3 and complex I subunit GRIM-19. Conclusions: Our data indicate that circulating levels of humanin increase during hemorrhagic shock in AMPKα1-independent fashion as a defense mechanism to counteract metabolic derangement and that administration of humanin-G affords beneficial effects through STAT3 activation even in the absence of a functional AMPKα1.
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Affiliation(s)
- Monica L. Wagner
- Department of Surgery, University of Cincinnati College of Medicine, Cincinnati Ohio, USA
| | - Allison Ammann
- Department of Surgery, University of Cincinnati College of Medicine, Cincinnati Ohio, USA
| | - Giovanna Piraino
- Division of Critical Care Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati Ohio, USA
| | - Vivian Wolfe
- Division of Critical Care Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati Ohio, USA
| | - Michael O’Connor
- Division of Critical Care Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati Ohio, USA
| | - Patrick Lahni
- Division of Critical Care Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati Ohio, USA
| | - Assem Ziady
- Division of Bone Marrow Transplantation & Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati Ohio, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati Ohio, USA
| | - Basilia Zingarelli
- Division of Critical Care Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati Ohio, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati Ohio, USA
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Xia Y, Zhang HY, Ma S, Zhou F. Age-related Changes in Humanin Expression in the Ovarian Tissue of Rat. Curr Med Sci 2023:10.1007/s11596-023-2732-7. [PMID: 37115400 DOI: 10.1007/s11596-023-2732-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Accepted: 08/19/2022] [Indexed: 04/29/2023]
Abstract
OBJECTIVE This study examined humanin expression in rat ovarian tissue, its cellular localization, and its correlation with rat age under physiological conditions. METHODS A total of 40 Sprague-Dawley rats of various ages (2, 12, 30, and 60 days old and 1 year old) were grouped by age. Immunofluorescence and immunohistochemical techniques were used to observe humanin expression and cellular location in the ovarian tissues of rats from each age group. In addition, Western blotting and Real-time quantitative reverse transcription PCR (qRT-PCR) techniques were used to measure humanin expression level in the ovarian tissues of rats from each age group. RESULTS The immunofluorescence and immunohistochemical results confirmed that humanin was expressed in rat ovarian tissues. In addition, cellular localization analysis showed that humanin was expressed in the cytoplasm of oocytes, interstitial cells, granulosa cells and theca cells in all levels of follicles after the primary follicles, and in the corpus luteum. The qRT-PCR results revealed that the level of humanin expression in the ovarian tissues of 12-day-old rats was non-significantly higher than that in the ovarian tissues of 2-day-old rats (P>0.05), whereas the levels of humanin expression in the ovarian tissues of 30-day-old, 60-day-old, and 1-year-old rats were significantly lower than that in the ovarian tissues of 2-day-old rats (P<0.05). The Western blotting results demonstrated that the levels of humanin protein expression in the ovarian tissues of 60-day-old and 1-year-old rats were significantly lower than those of 2-day-old rats (P<0.01), whereas there was no significant difference in the level of humanin protein expression between the ovarian tissues of 12-day-old and 30-day-old rats. CONCLUSION This study confirmed that humanin is expressed in the cytoplasm of various cells in rat ovarian tissues. Moreover, the level of humanin expression was highest in the ovarian tissues of 12-day-old rats, and it subsequently decreased with age. The changes in the expression of humanin in the ovary of rats at different ages will lay the foundation for the role of humanin in ovarian aging. The effect of humanin on ovarian function is worthy of further study in the future.
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Affiliation(s)
- Yi Xia
- The Second Clinical Medical College, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Han-Yong Zhang
- School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Sha Ma
- Department of Reproductive Center, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430015, China.
| | - Fang Zhou
- Department of Reproductive Medicine, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430070, China.
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Moin H, Shafi R, Ishtiaq A, Liaquat A, Majeed S, Zaidi NN. Effectiveness of analog of Humanin in ameliorating streptozotocin-induced diabetic nephropathy in Sprague Dawley rats. Peptides 2023; 165:171014. [PMID: 37119975 DOI: 10.1016/j.peptides.2023.171014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 04/24/2023] [Accepted: 04/26/2023] [Indexed: 05/01/2023]
Abstract
Diabetes mellitus(DM) is associated with numerous complications, including nephropathy, which principally occur due to hyperglycemia-induced oxidative stress and inflammation. Humanin(HN), a novel peptide generated from mitochondria, has anti-oxidant and anti-inflammatory potential as observed in different disease models. However, role of HN in diabetic nephropathy (DN) has not yet been explored. This study aimed to evaluate biochemical and molecular aspects of the effects of HN analog, Humanin-glycine([S14G]-humanin) on streptozotocin (STZ)-induced rat model of DN. Ninety Sprague Dawley (SD) rats were randomly segregated into three groups - A (control), B (disease control) and C (treatment). DM type-I was induced in group B and C via single intra-peritoneal dose of STZ (45mg/Kg). Seven days following STZ injection, rats were deemed diabetic if their blood glucose level was >250mg/dL. Subsequently, diabetic rats in group C were injected with [S14G]-humanin intra-peritoneally (0.4mg/Kg/day) for sixteen weeks. Biochemical analysis revealed that diabetic rats had markedly elevated levels of serum glucose, creatinine, BUN, TNF-α, and kidney tissue SOD. Whereas, significant decline was detected in serum insulin and albumin levels. All these parameters were significantly reversed in group C after administering [S14G]-humanin. Moreover, qRT-PCR analysis displayed up-regulation of pro-inflammatory (IL-18, IL-6, IL-1α, IL-1β, TNF-α) and down-regulation of anti-inflammatory cytokines (IL-10, IL-1RN, IL-4) in diabetic rats (group B). [S14G]-humanin treatment significantly reversed the expression IL-18 and IL-1α, however, change in relative expression of IL-6, IL-1β, TNF-α and anti-inflammatory cytokines was insignificant(group C). Conclusively, the findings of this study depicted potential therapeutic role of [S14G]-humanin in pre-clinical rodent model of DN.
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Affiliation(s)
- Hira Moin
- Department of Physiology, Shifa College of Medicine, Shifa Tameer-e-Millat University, Islamabad 45550, Pakistan.
| | - Riffat Shafi
- Department of Physiology, Shifa College of Medicine, Shifa Tameer-e-Millat University, Islamabad 45550, Pakistan.
| | - Ayesha Ishtiaq
- Signal Transduction Lab, Department of Biochemistry, Faculty of Biological Sciences, Quaid-I-Azam University, Islamabad 45320, Pakistan.
| | - Afrose Liaquat
- Dr. Qamar Alam Research Lab, Department of Biochemistry, Shifa College of Medicine Shifa Tameer-e-Millat University, Islamabad 45550, Pakistan.
| | - Sadaf Majeed
- Department of Physiology, Shifa College of Medicine, Shifa Tameer-e-Millat University, Islamabad 45550, Pakistan.
| | - Nilofar Nasir Zaidi
- Department of Physiology, Shifa College of Medicine, Shifa Tameer-e-Millat University, Islamabad 45550, Pakistan.
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20
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Coradduzza D, Congiargiu A, Chen Z, Cruciani S, Zinellu A, Carru C, Medici S. Humanin and Its Pathophysiological Roles in Aging: A Systematic Review. BIOLOGY 2023; 12:558. [PMID: 37106758 PMCID: PMC10135985 DOI: 10.3390/biology12040558] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/12/2023] [Revised: 04/03/2023] [Accepted: 04/03/2023] [Indexed: 04/29/2023]
Abstract
BACKGROUND Senescence is a cellular aging process in all multicellular organisms. It is characterized by a decline in cellular functions and proliferation, resulting in increased cellular damage and death. These conditions play an essential role in aging and significantly contribute to the development of age-related complications. Humanin is a mitochondrial-derived peptide (MDP), encoded by mitochondrial DNA, playing a cytoprotective role to preserve mitochondrial function and cell viability under stressful and senescence conditions. For these reasons, humanin can be exploited in strategies aiming to counteract several processes involved in aging, including cardiovascular disease, neurodegeneration, and cancer. Relevance of these conditions to aging and disease: Senescence appears to be involved in the decay in organ and tissue function, it has also been related to the development of age-related diseases, such as cardiovascular conditions, cancer, and diabetes. In particular, senescent cells produce inflammatory cytokines and other pro-inflammatory molecules that can participate to the development of such diseases. Humanin, on the other hand, seems to contrast the development of such conditions, and it is also known to play a role in these diseases by promoting the death of damaged or malfunctioning cells and contributing to the inflammation often associated with them. Both senescence and humanin-related mechanisms are complex processes that have not been fully clarified yet. Further research is needed to thoroughly understand the role of such processes in aging and disease and identify potential interventions to target them in order to prevent or treat age-related conditions. OBJECTIVES This systematic review aims to assess the potential mechanisms underlying the link connecting senescence, humanin, aging, and disease.
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Affiliation(s)
| | | | - Zhichao Chen
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy
| | - Sara Cruciani
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy
| | - Angelo Zinellu
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy
| | - Ciriaco Carru
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy
- Control Quality Unit, Azienda-Ospedaliera Universitaria (AOU), 07100 Sassari, Italy
| | - Serenella Medici
- Department of Chemical, Physical, Mathematical and Natural Sciences, University of Sassari, 07100 Sassari, Italy
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21
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Ozgul M, Nesburn AB, Nasralla N, Katz B, Taylan E, Kuppermann BD, Kenney MC. Stability Determination of Intact Humanin-G with Characterizations of Oxidation and Dimerization Patterns. Biomolecules 2023; 13:biom13030515. [PMID: 36979450 PMCID: PMC10046509 DOI: 10.3390/biom13030515] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 02/23/2023] [Accepted: 02/25/2023] [Indexed: 03/14/2023] Open
Abstract
Humanin is the first identified mitochondrial-derived peptide. Humanin-G (HNG) is a variant of Humanin that has significantly higher cytoprotective properties. Here, we describe the stability features of HNG in different conditions and characterize HNG degradation, oxidation, and dimerization patterns over short-term and long-term periods. HNG solutions were prepared in high-performance liquid chromatography (HPLC) water or MO formulation and stored at either 4 °C or 37 °C. Stored HNG samples were analyzed using HPLC and high-resolution mass spectrometry (HRMS). Using HPLC, full-length HNG peptides in HPLC water decreased significantly with time and higher temperature, while HNG in MO formulation remained stable up to 95% at 4 °C on day 28. HNG peptides in HPLC water, phosphate-buffered saline (PBS) and MO formulation were incubated at 37 °C and analyzed at day 1, day 7 and day 14 using HRMS. Concentrations of full-length HNG peptide in HPLC water and PBS declined over time with a corresponding appearance of new peaks that increased over time. These new peaks were identified to be singly oxidized HNG, doubly oxidized HNG, homodimerized HNG, singly oxidized homodimerized HNG, and doubly oxidized homodimerized HNG. Our results may help researchers improve the experimental design to further understand the critical role of HNG in human diseases.
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Affiliation(s)
- Mustafa Ozgul
- Department of Ophthalmology, Gavin Herbert Eye Institute, University of California Irvine, Irvine, CA 92617, USA
- Correspondence: (M.O.); (M.C.K.)
| | - Anthony B. Nesburn
- Department of Ophthalmology, Gavin Herbert Eye Institute, University of California Irvine, Irvine, CA 92617, USA
- Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | | | - Benjamin Katz
- Department of Chemistry, University of California Irvine, Irvine, CA 92697, USA
| | - Enes Taylan
- Department of Obstetrics and Gynecology, University of California Los Angeles, Los Angeles, CA 90095, USA
| | - Baruch D. Kuppermann
- Department of Ophthalmology, Gavin Herbert Eye Institute, University of California Irvine, Irvine, CA 92617, USA
| | - Maria Cristina Kenney
- Department of Ophthalmology, Gavin Herbert Eye Institute, University of California Irvine, Irvine, CA 92617, USA
- Department of Pathology and Laboratory Medicine, University of California Irvine, Irvine, CA 92617, USA
- Correspondence: (M.O.); (M.C.K.)
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22
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Çakmak T, Yaşar E, Çakmak E, Tekin S, Karakuş Y, Türkoğlu C, Yüksel F. Evaluation of Coronary Flow Level with Mots-C in Patients with STEMI Undergoing Primary PCI. Arq Bras Cardiol 2022; 120:e20220358. [PMID: 36629605 PMCID: PMC9833276 DOI: 10.36660/abc.20220358] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Accepted: 09/01/2022] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND The protective effects of mitochondrial open reading frame of the 12S rRNA-c (MOTS-C) on cardiovascular diseases have been shown in numerous studies. However, there is little documentation of the relationship between MOTS-C and coronary blood flow in ST-segment elevation myocardial infarction (STEMI). OBJECTIVE We aimed to investigate the role of MOTS-C, which is known to have cytoprotective properties in the pathogenesis of the no-reflow phenomenon, by comparing the coronary flow rate and MOTS-C levels in patients with STEMI submitted to primary PCI. METHODS 52 patients with STEMI and 42 patients without stenosis >50% in the coronary arteries were included in the study. The STEMI group was divided into two groups according to post-PCI TIMI (Thrombolysis In Myocardial Infarction) flow grade:(i) No-reflow: grade 0, 1, and 2 and (ii) grade 3(angiographic success). A p value of <0.05 was considered significant. RESULTS MOTS-C levels were significantly lower in the STEMI group compared to the control group (91.9 ± 8.9 pg/mL vs. 171.8±12.5 pg/mL, p<0.001). In addition, the Receiver Operating Characteristics (ROC) curve analysis indicated that serum MOTS-C levels had a diagnostic value in predicting no-reflow (Area Under the ROC curve [AUC]:0.95, 95% CI:0.856-0.993, p<0.001). A MOTS-C ≥84.15 pg/mL measured at admission was shown to have 95.3% sensitivity and 88.9% specificity in predicting no-reflow. CONCLUSION MOTS-C is a strong and independent predictor of no-reflow and in-hospital MACE in patients with STEMI. It was also noted that low MOTS-C levels may be an important prognostic marker of and may have a role in the pathogenesis of STEMI.
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Affiliation(s)
- Tolga Çakmak
- Departamento de CardiologiaBalikesir Atatürk City HospitalBalikesirTurquiaDepartamento de Cardiologia – Balikesir Atatürk City Hospital, Balikesir – Turquia
| | - Erdoğan Yaşar
- Departamento de CardiologiaMalatya Training and Research HospitalMalatyaTurquiaDepartamento de Cardiologia – Malatya Training and Research Hospital, Malatya – Turquia
| | - Esin Çakmak
- Departamento de Saúde PúblicaBalikesir Provincial Health DepartmentBalikesirTurquiaDepartamento de Saúde Pública – Balikesir Provincial Health Department, Balikesir – Turquia
| | - Suat Tekin
- Departamento de FisiologiaInonu UniversityMedical FacultyMalatyaTurquiaDepartamento de Fisiologia – Inonu University Medical Faculty, Malatya – Turquia
| | - Yasin Karakuş
- Departamento de CardiologiaMalatya Training and Research HospitalMalatyaTurquiaDepartamento de Cardiologia – Malatya Training and Research Hospital, Malatya – Turquia
| | - Caner Türkoğlu
- Departamento de CardiologiaMalatya Training and Research HospitalMalatyaTurquiaDepartamento de Cardiologia – Malatya Training and Research Hospital, Malatya – Turquia
| | - Furkan Yüksel
- Departamento de FisiologiaInonu UniversityMedical FacultyMalatyaTurquiaDepartamento de Fisiologia – Inonu University Medical Faculty, Malatya – Turquia
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23
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Katiyar R, Ghosh SK, Karikalan M, Kumar A, Pande M, Gemeda AI, Rautela R, Dhara SK, Bhure SK, Srivastava N, Patra MK, Chandra V, Devi HL, Singh M. An evidence of Humanin-like peptide and Humanin mediated cryosurvival of spermatozoa in buffalo bulls. Theriogenology 2022; 194:13-26. [PMID: 36183493 DOI: 10.1016/j.theriogenology.2022.09.013] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 08/12/2022] [Accepted: 09/10/2022] [Indexed: 11/16/2022]
Abstract
Buffalo spermatozoa are vulnerable to cryo-injuries due to inherent deficiency of endogenous antioxidants, high polyunsaturated fatty acids (PUFA) content in plasma membrane and low cholesterol/phospholipid (C/P) ratio. Humanin is a potent cytoprotective agent that protects the cells against oxidative stress and apoptosis. The present study was designed to establish the presence of Humanin in buffalo and effect of Humanin supplementation on freezability of buffalo spermatozoa. Indirect immunofluorescence test revealed presence of Humanin in ejaculated and epididymal spermatozoa, and, elongated spermatids and interstitial space in the testicular tissue section. Humanin levels in seminal plasma were significantly and positively correlated with sperm concentration and individual progressive motility (IPM) in good (n = 22; IPM >70%) and poor (n = 10; IPM <50%) quality ejaculates. For supplementation studies, a total of 24 ejaculates (IPM ≥70%) were collected and each ejaculate was then divided into four aliquots. First aliquot was diluted with egg yolk-tris-glycerol (EYTG) extender without Humanin and served as control group (Group I). Rest three aliquots were diluted with extender containing 2 (Group II), 5 (Group III) and 10 μM Humanin (Group IV), respectively. Semen was cryopreserved using standard protocol and evaluated at pre-freeze for lipid peroxidation (LPO) and post-thaw stages for spermatozoa kinematics, LPO, mitochondrial membrane potential (MMP), capacitation, apoptotic status and DNA integrity. The treatment group that showed best results (5 μM) was compared with control group for in vitro fertility assessment by homologous zona binding assay. The LPO levels were lower (p < 0.05) in 5 and 10 μM Humanin supplemented group. The MMP and DNA integrity were higher (p < 0.05) in 5 μM group than other groups. F-pattern was higher (p < 0.05) and B-pattern was lower (p < 0.05) in 5 and 10 μM Humanin supplemented groups. Lower apoptotic and higher viable spermatozoa (p < 0.05) were observed in 5 μM Humanin group. The mean number of spermatozoa bound to zona pellucida was higher (p < 0.05) in 5 μM Humanin treated group than the control group. The study established the presence of Humanin in buffalo spermatozoa and seminal plasma for very first time and concluded that Humanin supplementation at 5 μM concentration improves the freezability and in vitro fertility of buffalo spermatozoa.
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Affiliation(s)
- Rahul Katiyar
- Division of Animal Reproduction, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, 243122, Uttar Pradesh, India.
| | - Subrata Kumar Ghosh
- Division of Animal Reproduction, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, 243122, Uttar Pradesh, India.
| | - M Karikalan
- Centre for Wildlife, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, 243122, Uttar Pradesh, India
| | - Abhishek Kumar
- Division of Animal Reproduction, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, 243122, Uttar Pradesh, India
| | - Megha Pande
- Division of Animal Reproduction, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, 243122, Uttar Pradesh, India
| | - Amare Ishetu Gemeda
- Division of Animal Reproduction, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, 243122, Uttar Pradesh, India
| | - Rupali Rautela
- Division of Animal Reproduction, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, 243122, Uttar Pradesh, India
| | - S K Dhara
- Division of Veterinary Biotechnology, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, 243122, Uttar Pradesh, India
| | - S K Bhure
- Division of Veterinary Biochemistry, ICAR-Indian Veterinary Research Institute, Bengaluru Campus, India
| | - Neeraj Srivastava
- Division of Animal Reproduction, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, 243122, Uttar Pradesh, India
| | - M K Patra
- Division of Animal Reproduction, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, 243122, Uttar Pradesh, India
| | - Vikash Chandra
- Division of Physiology & Climatology, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, 243122, Uttar Pradesh, India
| | - Huidrom Lakshmi Devi
- Division of Physiology & Climatology, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, 243122, Uttar Pradesh, India
| | - Mahak Singh
- ICAR Research Complex for N.E.H.Region, Nagaland Centre, Medziphema, Nagaland, 797106, India
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24
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Kaorop W, Maneechote C, Kumfu S, Chattipakorn SC, Chattipakorn N. Mitochondrial-derived peptides as a novel intervention for obesity and cardiac diseases: bench evidence for potential bedside application. J Clin Pathol 2022; 75:jclinpath-2022-208321. [PMID: 35863886 DOI: 10.1136/jcp-2022-208321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Accepted: 07/11/2022] [Indexed: 11/04/2022]
Abstract
Currently, obesity is the most common major health problem for people worldwide. Obesity is known to be a significant risk factor for several diseases, including metabolic syndrome, insulin resistance and type 2 diabetes, eventually leading to the development of chronic systemic disorders. Previous studies showed that mitochondrial dysfunction could be one of the potential mechanisms for obesity progression. Most interventions used for combating obesity have also been reported to modulate mitochondrial function, suggesting the potential role of mitochondria in the pathology of the obese condition. Recent studies have shown that peptides produced by mitochondria, mitochondrial-derived peptides (MDPs), potentially improve metabolic function and exert benefits in obesity-associated diabetes and various heart pathologies. In this review, the roles of MDPs in the metabolic pathways and their use in the treatment of various adverse effects of obesity are comprehensively summarised based on collective evidence from in vitro, in vivo and clinical studies. The roles of MDPs as novel therapeutic interventions for cardiac dysfunction caused by various stresses or toxicities are also presented and discussed. This review aims to summarise the knowledge regarding the effects of MDPs on obesity, with a particular emphasis on their potential protective effects on the impaired cardiac function associated with obesity. The information from this review will also encourage further clinical investigations to warrant the potential application of MDP interventions in the clinical setting in the future.
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Affiliation(s)
- Wichida Kaorop
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
- Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, Thailand
| | - Chayodom Maneechote
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, Thailand
| | - Sirinart Kumfu
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
- Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, Thailand
| | - Siriporn C Chattipakorn
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, Thailand
- Department of Oral Biology and Diagnostic Sciences, Faculty of Dentistry, Chiang Mai University, Chiang Mai, Thailand
| | - Nipon Chattipakorn
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
- Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, Thailand
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25
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Abstract
The mechanisms that explain mitochondrial dysfunction in aging and healthspan continue to be studied, but one element has been unexplored: microproteins. Small open reading frames in circular mitochondria DNA can encode multiple microproteins, called mitochondria-derived peptides (MDPs). Currently, eight MDPs have been published: humanin, MOTS-c, and SHLPs 1–6. This Review describes recent advances in microprotein discovery with a focus on MDPs. It discusses what is currently known about MDPs in aging and how this new understanding could add to the way we understand age-related diseases including type 2 diabetes, cancer, and neurodegenerative diseases at the genomic, proteomic, and drug-development levels.
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26
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Thiankhaw K, Chattipakorn K, Chattipakorn SC, Chattipakorn N. Roles of humanin and derivatives on the pathology of neurodegenerative diseases and cognition. Biochim Biophys Acta Gen Subj 2022; 1866:130097. [DOI: 10.1016/j.bbagen.2022.130097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 01/13/2022] [Accepted: 01/20/2022] [Indexed: 10/19/2022]
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27
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Boutari C, Pappas PD, Theodoridis TD, Vavilis D. Humanin and diabetes mellitus: A review of in vitro and in vivo studies. World J Diabetes 2022; 13:213-223. [PMID: 35432758 PMCID: PMC8984571 DOI: 10.4239/wjd.v13.i3.213] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 10/24/2021] [Accepted: 02/23/2022] [Indexed: 02/06/2023] Open
Abstract
Humanin (HN) is a 24-amino acid mitochondrial-derived polypeptide with cyto-protective and anti-apoptotic effects that regulates the mitochondrial functions under stress conditions. Accumulating evidence suggests the role of HN against age-related diseases, such as Alzheimer’s disease. The decline in insulin action is a metabolic feature of aging and thus, type 2 diabetes mellitus is considered an age-related disease, as well. It has been suggested that HN increases insulin sensitivity, improves the survival of pancreatic beta cells, and delays the onset of diabetes, actions that could be deployed in the treatment of diabetes. The aim of this review is to present the in vitro and in vivo studies that examined the role of HN in insulin resistance and diabetes and to discuss its newly emerging role as a therapeutic option against those conditions.
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Affiliation(s)
- Chrysoula Boutari
- Second Propedeutic Department of Internal Medicine, Hippocration Hospital, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
| | - Panagiotis D Pappas
- First Department of Obstetrics and Gynaecology, Papageorgiou Hospital, Aristotle University of Thessaloniki, Thessaloniki 56429, Greece
| | - Theodoros D Theodoridis
- First Department of Obstetrics and Gynaecology, Papageorgiou Hospital, Aristotle University of Thessaloniki, Thessaloniki 56429, Greece
| | - Dimitrios Vavilis
- First Department of Obstetrics and Gynaecology, Papageorgiou Hospital, Aristotle University of Thessaloniki, Thessaloniki 56429, Greece
- Medical School, University of Cyprus, Nicosia, Cyprus 20537 1678, Cyprus
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28
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Targeting AMPK signaling in ischemic/reperfusion injury: From molecular mechanism to pharmacological interventions. Cell Signal 2022; 94:110323. [DOI: 10.1016/j.cellsig.2022.110323] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 03/23/2022] [Accepted: 03/24/2022] [Indexed: 12/16/2022]
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29
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Fernandez Rico C, Konate K, Josse E, Nargeot J, Barrère-Lemaire S, Boisguérin P. Therapeutic Peptides to Treat Myocardial Ischemia-Reperfusion Injury. Front Cardiovasc Med 2022; 9:792885. [PMID: 35252383 PMCID: PMC8891520 DOI: 10.3389/fcvm.2022.792885] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Accepted: 01/07/2022] [Indexed: 12/13/2022] Open
Abstract
Cardiovascular diseases (CVD) including acute myocardial infarction (AMI) rank first in worldwide mortality and according to the World Health Organization (WHO), they will stay at this rank until 2030. Prompt revascularization of the occluded artery to reperfuse the myocardium is the only recommended treatment (by angioplasty or thrombolysis) to decrease infarct size (IS). However, despite beneficial effects on ischemic lesions, reperfusion leads to ischemia-reperfusion (IR) injury related mainly to apoptosis. Improvement of revascularization techniques and patient care has decreased myocardial infarction (MI) mortality however heart failure (HF) morbidity is increasing, contributing to the cost-intense worldwide HF epidemic. Currently, there is no treatment for reperfusion injury despite promising results in animal models. There is now an obvious need to develop new cardioprotective strategies to decrease morbidity/mortality of CVD, which is increasing due to the aging of the population and the rising prevalence rates of diabetes and obesity. In this review, we will summarize the different therapeutic peptides developed or used focused on the treatment of myocardial IR injury (MIRI). Therapeutic peptides will be presented depending on their interacting mechanisms (apoptosis, necroptosis, and inflammation) reported as playing an important role in reperfusion injury following myocardial ischemia. The search and development of therapeutic peptides have become very active, with increasing numbers of candidates entering clinical trials. Their optimization and their potential application in the treatment of patients with AMI will be discussed.
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Affiliation(s)
- Carlota Fernandez Rico
- Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, France
- Laboratory of Excellence Ion Channel Science and Therapeutics, Valbonne, France
| | - Karidia Konate
- PHYMEDEXP, Université de Montpellier, CNRS, INSERM, Montpellier, France
| | - Emilie Josse
- PHYMEDEXP, Université de Montpellier, CNRS, INSERM, Montpellier, France
| | - Joël Nargeot
- Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, France
- Laboratory of Excellence Ion Channel Science and Therapeutics, Valbonne, France
| | - Stéphanie Barrère-Lemaire
- Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, France
- Laboratory of Excellence Ion Channel Science and Therapeutics, Valbonne, France
| | - Prisca Boisguérin
- PHYMEDEXP, Université de Montpellier, CNRS, INSERM, Montpellier, France
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30
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Gong Z, Goetzman E, Muzumdar RH. Cardio-protective role of Humanin in myocardial ischemia-reperfusion. Biochim Biophys Acta Gen Subj 2022; 1866:130066. [PMID: 34896254 DOI: 10.1016/j.bbagen.2021.130066] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 11/18/2021] [Accepted: 12/02/2021] [Indexed: 01/07/2023]
Abstract
Mitochondria-derived peptides (MDPs) are bioactive peptides encoded by and secreted from the mitochondria. To date, a few MDPs including humanin, MOTS-c and SHLP1-6, and their diverse biological functions have been identified. The first and most studied MDP is humanin, a 24-amino-acid poly peptide. It was first identified in 2001 in the surviving neurons of patient with Alzheimer's disease, and since then has been well characterized for its neuro-protective effect through inhibition of apoptosis. Over the past two decades, humanin has been reported to play critical roles in aging as well as multiple diseases including metabolic disorders, cardiovascular diseases, and autoimmune disease. Humanin has been shown to modulate multiple biological processes including autophagy, ER stress, cellular metabolism, oxidative stress, and inflammation. A role for humanin has been shown in a wide range of cardiovascular diseases, such as coronary heart disease, atherosclerosis, and myocardial fibrosis. In this minireview, we will summarize the literature demonstrating a role for humanin in cardio-protection following myocardial ischemia-reperfusion induced injury and the potential mechanisms that mediate it.
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Affiliation(s)
- Zhenwei Gong
- Division of Endocrinology, Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA
| | - Eric Goetzman
- Division of Genetic and Genomic Medicine, Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Radhika H Muzumdar
- Division of Endocrinology, Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA.
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31
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Kattawy M D HAE, Abozaid ER, Abdullah DM. Humanin ameliorates late-onset hypogonadism in aged male rats. Curr Mol Pharmacol 2022; 15:996-1008. [PMID: 35086467 DOI: 10.2174/1874467215666220127115602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 11/08/2021] [Accepted: 11/29/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND The reproductive potential declines with age. Late-onset hypogonadism is characterized by reduced serum testosterone. Humanin is a mitochondrial-derived signaling peptide encoded by short open reading frames within the mitochondrial genome. It may protect against some age-related diseases such as atherosclerosis by its cytoprotective effects. OBJECTIVE it aimed to investigate the potential anti-aging effects of humanin on the testicular architecture, oxidative stress, some apoptotic and inflammatory markers in the hypogonadal aged male rats. METHODS Forty male albino rats were divided into 4 groups: normal adult controls, aged vehicle-treated group, aged testosterone-treated group, and aged humanin-treated group. Twenty-month-old male rats with declined serum testosterone were selected to be the animal models of late-onset hypogonadism. Testicular weights, serum testosterone, and some sperm parameters were measured. Testicular tissue IL-6 and TNF-α, superoxide dismutase activity, glutathione peroxidase, and malondialdehyde were assessed. The activity of caspase-3, BCL2, PCNA, and the nuclear factor erythroid 2-related factor 2-antioxidant response element pathway were evaluated. Testes were subjected to histopathological and immunohistochemical examination. Statistical analysis was executed using One Way Analysis of variance (ANOVA) followed by Post hoc (LSD) test to compare means among all studied groups. RESULTS humanin treatment significantly improved serum testosterone, some sperm characteristics, and antioxidant defenses. It decreased active caspase-3, pro-apoptotic BAX expression, and increased antiapoptotic BCL2 and proliferating cell nuclear antigen (PCNA) possibly via activating the (Nrf2-ARE) pathway. CONCLUSION humanin might be a promising therapeutic modality in late-onset hypogonadism as it ameliorated some age-related testicular and hormonal adverse effects.
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Affiliation(s)
- Hany A El Kattawy M D
- Department of Basic Medical Sciences, College of Medicine, Almaarefa University, P.O. Box 71666, Riyadh, Saudi Arabia
- Medical Physiology Department, College of Medicine, Zagazig University, Egypt
| | - Eman R Abozaid
- Department of Basic Medical Sciences, College of Medicine, Almaarefa University, P.O. Box 71666, Riyadh, Saudi Arabia
| | - Doaa M Abdullah
- Clinical Pharmacology Department, College of Medicine, Zagazig University, Egypt
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Rochette L, Rigal E, Dogon G, Malka G, Zeller M, Vergely C, Cottin Y. Mitochondrial-derived peptides: New markers for cardiometabolic dysfunction. Arch Cardiovasc Dis 2022; 115:48-56. [PMID: 34972639 DOI: 10.1016/j.acvd.2021.10.013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 10/21/2021] [Accepted: 10/25/2021] [Indexed: 02/07/2023]
Abstract
Great attention is being paid to the evaluation of new markers in blood circulation for the estimation of tissue metabolism disturbance. This endogenous disturbance may contribute to the onset and progression of cardiometabolic disease. In addition to their role in energy production and metabolism, mitochondria play a main function in cellular mechanisms, including apoptosis, oxidative stress and calcium homeostasis. Mitochondria produce mitochondrial-derived peptides that mediate the transcriptional stress response by translocating into the nucleus and interacting with deoxyribonucleic acid. This class of peptides includes humanin, mitochondrial open reading frame of the 12S ribosomal ribonucleic acid type c (MOTS-c) and small humanin-like peptides. Mitochondrial-derived peptides are regulators of metabolism, exerting cytoprotective effects through antioxidative stress, anti-inflammatory responses and antiapoptosis; they are emerging biomarkers reflecting mitochondrial function, and the circulating concentration of these proteins can be used to diagnose cardiometabolic dysfunction. The aims of this review are: (1) to describe the emerging role for mitochondrial-derived peptides as biomarkers; and (2) to discuss the therapeutic application of these peptides.
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Affiliation(s)
- Luc Rochette
- Équipe d'Accueil (EA 7460), physiopathologie et épidémiologie cérébro-cardiovasculaires (PEC2), faculté des sciences de santé, université de Bourgogne-Franche Comté, 21000 Dijon, France.
| | - Eve Rigal
- Équipe d'Accueil (EA 7460), physiopathologie et épidémiologie cérébro-cardiovasculaires (PEC2), faculté des sciences de santé, université de Bourgogne-Franche Comté, 21000 Dijon, France
| | - Geoffrey Dogon
- Équipe d'Accueil (EA 7460), physiopathologie et épidémiologie cérébro-cardiovasculaires (PEC2), faculté des sciences de santé, université de Bourgogne-Franche Comté, 21000 Dijon, France
| | - Gabriel Malka
- Centre interface applications médicales (CIAM), université Mohammed VI Polytechnique, 43150 Ben Guerir, Morocco
| | - Marianne Zeller
- Équipe d'Accueil (EA 7460), physiopathologie et épidémiologie cérébro-cardiovasculaires (PEC2), faculté des sciences de santé, université de Bourgogne-Franche Comté, 21000 Dijon, France
| | - Catherine Vergely
- Équipe d'Accueil (EA 7460), physiopathologie et épidémiologie cérébro-cardiovasculaires (PEC2), faculté des sciences de santé, université de Bourgogne-Franche Comté, 21000 Dijon, France
| | - Yves Cottin
- Cardiology Unit, CHU de Dijon-Bourgogne, 21000 Dijon, France
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Xie Y, Zhang J, Zhang M, Jiang L. [Gly14]-Humanin inhibits an angiotensin II-induced vascular smooth muscle cell phenotypic switch via ameliorating intracellular oxidative stress. Hum Exp Toxicol 2022; 41:9603271221136208. [PMID: 36289015 DOI: 10.1177/09603271221136208] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/08/2023]
Abstract
Angiotensin II (AngII) is involved in the pathogenesis of hypertensive artery remodeling by inducing a phenotypic switch in vascular smooth muscle cells [Gly14]-Humanin (HNG), a humanin analogue, exerts potent cytoprotective effects both in vitro and in vivo. This study aimed to investigate the effects of HNG on an AngII-induced phenotypic switch in VSMCs and the potential mechanisms underlying these effects. The roles of [Gly14]-Humanin in AngII-stimulated VSMCs proliferation and migration was detected by CCK-8 assay, Cell cycle analysis, wound healing assay, trsnswell assay and western blot. The mechanism by which [Gly14]-Humanin regulates VSMC phenotypic switch was determined by intracellular oxidative stress detection, transcriptomic analysis and qRT-PCR. The results showed that HNG inhibited AngII-induced VSMC proliferation and migration and maintained a stable VSMC contractile phenotype. In addition, HNG reduced the level of AngII-induced oxidative stress in vascular smooth muscle cells. This process could be accomplished by inhibiting nicotinamide adenine dinucleotide phosphate oxidase activity. In conclusion, the results suggested that HNG ameliorated intracellular oxidative stress by inhibiting NAD(P)H oxidase activity, thereby suppressing the AngII-induced VSMC phenotype switch. Thus, HNG is a potential drug to ameliorate artery remodeling in hypertension.
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Affiliation(s)
- Yi Xie
- Division of Cardiology, Tongren Hospital, 537229Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jin Zhang
- Division of Cardiology, Tongren Hospital, 537229Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of General Surgery, Tongren Hospital, 537229Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Min Zhang
- Division of Cardiology, Tongren Hospital, 537229Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Li Jiang
- Division of Cardiology, Tongren Hospital, 537229Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Robson B. Computers and preventative diagnosis. A survey with bioinformatics examples of mitochondrial small open reading frame peptides as portents of a new generation of powerful biomarkers. Comput Biol Med 2022; 140:105116. [PMID: 34896883 DOI: 10.1016/j.compbiomed.2021.105116] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2021] [Accepted: 12/02/2021] [Indexed: 12/27/2022]
Abstract
The present brief survey is to alert developers in datamining, machine learning, inference methods, and other approaches in relation to diagnostic, predictive, and risk assessment medicine about a relatively new class of bioactive messaging peptides in which there is escalating interest. They provide patterns of communication and cross-chatter about states of health and disease within and, importantly, between cells (they also appear extracellularly in biological fluids). This chatter needs to be analyzed somewhat in the manner of the decryption of the Enigma code in the Second World War. It could lead not only to improved diagnosis but to predictive diagnosis, prediction of organ failure, and preventative medicine. This involves peptide products of short reading frames that have been previously somewhat neglected as unlikely gene products, with probably many examples in nuclear DNA, but certainly several known in the mitochondrial DNA. There is a great deal of knowledge now becoming available about the latter and itis believed thatthat the mRNA can be translated both by standard cytosolic and mitochondrial genetic codes, resulting in different peptides, adding a further level of complexity to the applications of bioinformatics and computational biology but a higher level of detail and sophistication to preventative diagnosis. The code to crack could be sophisticated and combinatorically complex to analyze by computers. Mitochondria may have combined with proto-eucaryotic cells some 2 billion years ago, only about a 7th of the age of the universe. Cells appeared some 2 billion years before that, also with possible signaling based on similar ideas. This makes life small in space but huge in time, refinement of which centrally involves these signaling processes.
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Affiliation(s)
- Barry Robson
- Ingine Inc. Viginia, USA and the Dirac Foundation OxfordShire UK.
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Kim SJ, Devgan A, Miller B, Lee SM, Kumagai H, Wilson KA, Wassef G, Wong R, Mehta HH, Cohen P, Yen K. Humanin-induced autophagy plays important roles in skeletal muscle function and lifespan extension. Biochim Biophys Acta Gen Subj 2022; 1866:130017. [PMID: 34624450 PMCID: PMC8595716 DOI: 10.1016/j.bbagen.2021.130017] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 09/10/2021] [Accepted: 09/20/2021] [Indexed: 01/18/2023]
Abstract
BACKGROUND Autophagy, a highly conserved homeostatic mechanism, is essential for cell survival. The decline of autophagy function has been implicated in various diseases as well as aging. Although mitochondria play a key role in the autophagy process, whether mitochondrial-derived peptides are involved in this process has not been explored. METHODS We developed a high through put screening method to identify potential autophagy inducers among mitochondrial-derived peptides. We used three different cell lines, mice, c.elegans, and a human cohort to validate the observation. RESULTS Humanin, a mitochondrial-derived peptide, increases autophagy and maintains autophagy flux in several cell types. Humanin administration increases the expression of autophagy-related genes and lowers accumulation of harmful misfolded proteins in mice skeletal muscle, suggesting that humanin-induced autophagy potentially contributes to the improved skeletal function. Moreover, autophagy is a critical role in humanin-induced lifespan extension in C. elegans. CONCLUSIONS Humanin is an autophagy inducer. GENERAL SIGNIFICANCE This paper presents a significant, novel discovery regarding the role of the mitochondrial derived peptide humanin in autophagy regulation and as a possible therapeutic target for autophagy in various age-related diseases.
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Affiliation(s)
- Su-Jeong Kim
- The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA
| | - Anjali Devgan
- The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA
| | - Brendan Miller
- The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA
| | - Sam Mool Lee
- The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA
| | - Hiroshi Kumagai
- The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA
| | | | - Gabriella Wassef
- The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA
| | - Richard Wong
- The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA
| | - Hemal H Mehta
- The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA
| | - Pinchas Cohen
- The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA.
| | - Kelvin Yen
- The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA
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Urban C, Hayes HV, Piraino G, Wolfe V, Lahni P, O'Connor M, Phares C, Zingarelli B. Colivelin, a synthetic derivative of humanin, ameliorates endothelial injury and glycocalyx shedding after sepsis in mice. Front Immunol 2022; 13:984298. [PMID: 36119052 PMCID: PMC9478210 DOI: 10.3389/fimmu.2022.984298] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Accepted: 08/15/2022] [Indexed: 11/19/2022] Open
Abstract
Endothelial dysfunction plays a central role in the pathogenesis of sepsis-mediated multiple organ failure. Several clinical and experimental studies have suggested that the glycocalyx is an early target of endothelial injury during an infection. Colivelin, a synthetic derivative of the mitochondrial peptide humanin, has displayed cytoprotective effects in oxidative conditions. In the current study, we aimed to determine the potential therapeutic effects of colivelin in endothelial dysfunction and outcomes of sepsis in vivo. Male C57BL/6 mice were subjected to a clinically relevant model of polymicrobial sepsis by cecal ligation and puncture (CLP) and were treated with vehicle or colivelin (100-200 µg/kg) intraperitoneally at 1 h after CLP. We observed that vehicle-treated mice had early elevation of plasma levels of the adhesion molecules ICAM-1 and P-selectin, the angiogenetic factor endoglin and the glycocalyx syndecan-1 at 6 h after CLP when compared to control mice, while levels of angiopoietin-2, a mediator of microvascular disintegration, and the proprotein convertase subtilisin/kexin type 9, an enzyme implicated in clearance of endotoxins, raised at 18 h after CLP. The early elevation of these endothelial and glycocalyx damage biomarkers coincided with lung histological injury and neutrophil inflammation in lung, liver, and kidneys. At transmission electron microscopy analysis, thoracic aortas of septic mice showed increased glycocalyx breakdown and shedding, and damaged mitochondria in endothelial and smooth muscle cells. Treatment with colivelin ameliorated lung architecture, reduced organ neutrophil infiltration, and attenuated plasma levels of syndecan-1, tumor necrosis factor-α, macrophage inflammatory protein-1α and interleukin-10. These therapeutic effects of colivelin were associated with amelioration of glycocalyx density and mitochondrial structure in the aorta. At molecular analysis, colivelin treatment was associated with inhibition of the signal transducer and activator of transcription 3 and activation of the AMP-activated protein kinase in the aorta and lung. In long-term outcomes studies up to 7 days, co-treatment of colivelin with antimicrobial agents significantly reduced the disease severity score when compared to treatment with antibiotics alone. In conclusion, our data support that damage of the glycocalyx is an early pathogenetic event during sepsis and that colivelin may have therapeutic potential for the treatment of sepsis-associated endothelial dysfunction.
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Affiliation(s)
- Catherine Urban
- Division of Pediatric Critical Care, Stony Brook Children's, Stony Brook University, Stony Brook, NY, United States
| | - Hannah V Hayes
- Department of Surgery, College of Medicine, University of Cincinnati, Cincinnati, OH, United States
| | - Giovanna Piraino
- 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
| | - Patrick Lahni
- 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
| | - Ciara Phares
- Department of Systems Biology and Physiology, College of Medicine, University of Cincinnati, 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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Wu D, Kampmann E, Qian G. Novel Insights Into the Role of Mitochondria-Derived Peptides in Myocardial Infarction. Front Physiol 2021; 12:750177. [PMID: 34777013 PMCID: PMC8582487 DOI: 10.3389/fphys.2021.750177] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Accepted: 09/28/2021] [Indexed: 01/02/2023] Open
Abstract
Mitochondria-derived peptides (MDPs) are a new class of bioactive peptides encoded by small open reading frames (sORFs) within known mitochondrial DNA (mtDNA) genes. MDPs may affect the expression of nuclear genes and play cytoprotective roles against chronic and age-related diseases by maintaining mitochondrial function and cell viability in the face of metabolic stress and cytotoxic insults. In this review, we summarize clinical and experimental findings indicating that MDPs act as local and systemic regulators of glucose homeostasis, immune and inflammatory responses, mitochondrial function, and adaptive stress responses, and focus on evidence supporting the protective effects of MDPs against myocardial infarction. These insights into MDPs actions suggest their potential in the treatment of cardiovascular diseases and should encourage further research in this field.
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Affiliation(s)
- Dan Wu
- Department of Cardiology, The First Medical Center, Chinese People's Liberation Army Hospital, Medical School of Chinese People's Liberation Army, Beijing, China
| | - Enny Kampmann
- School of Life Sciences, City College of San Francisco, San Francisco, CA, United States
| | - Geng Qian
- Department of Cardiology, The First Medical Center, Chinese People's Liberation Army Hospital, Medical School of Chinese People's Liberation Army, Beijing, China
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Hosseinabadi M, Abdolmaleki Z, Beheshtiha SHS. Cardiac aorta-derived extracellular matrix scaffold enhances critical mediators of angiogenesis in isoproterenol-induced myocardial infarction mice. JOURNAL OF MATERIALS SCIENCE. MATERIALS IN MEDICINE 2021; 32:134. [PMID: 34704139 PMCID: PMC8550234 DOI: 10.1007/s10856-021-06611-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/22/2020] [Accepted: 10/07/2021] [Indexed: 06/13/2023]
Abstract
An incapability to improve lost cardiac muscle caused by acute ischemic injury remains the most important deficiency of current treatments to prevent heart failure. We investigated whether cardiomyocytes culturing on cardiac aorta-derived extracellular matrix scaffold has advantageous effects on cardiomyocytes survival and angiogenesis biomarkers' expression. Ten male NMRI mice were randomly divided into two groups: (1) control (healthy mice) and (2) myocardial infarction (MI)-induced model group (Isoproterenol/subcutaneously injection/single dose of 85 mg/kg). Two days after isoproterenol injection, all animals were sacrificed to isolate cardiomyocytes from myocardium tissues. The fresh thoracic aorta was obtained from male NMRI mice and decellularized using 4% sodium deoxycholate and 2000 kU DNase-I treatments. Control and MI-derived cardiomyocytes were seeded on decellularized cardiac aorta (DCA) considered three-dimensional (3D) cultures. To compare, the isolated cardiomyocytes from control and MI groups were also cultured as a two-dimensional (2D) culture system for 14 days. The cell viability was examined by MTT assay. The expression levels of Hif-1α and VEGF genes and VEGFR1 protein were tested by real-time PCR and western blotting, respectively. Moreover, the amount of VEGF protein was evaluated in the conditional media of the 2D and 3D systems. The oxidative stress was assessed via MDA assay. Hif-1α and VEGF genes were downregulated in MI groups compared to controls. However, the resulting data showed that decellularized cardiac aorta matrices positively affect the expression of Hif-1α and VEGF genes. The expression level of VEGFR1 protein was significantly (p ≤ 0.01) upregulated in both MI and healthy cell groups cultured on decellularized cardiac aorta matrices as a 3D system compared to the MI cell group cultured in the 2D systems. Furthermore, MDA concentration significantly decreased in 3D-cultured cells (MI and healthy cell groups) rather than the 2D-cultured MI group (p ≤ 0.015). The findings suggest that cardiac aorta-derived extracellular scaffold by preserving VEGF, improving the cell viability, and stimulating angiogenesis via upregulating Hif-1α, VEGF, and VEGFR1 in cardiomyocytes could be considered as a potential approach along with another therapeutic method to reduce the complications of myocardial infarction and control the progressive pathological conditions related to MI.
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Affiliation(s)
- Mahara Hosseinabadi
- Department of Pharmacology, Karaj Branch, Islamic Azad University, Karaj, Iran
| | - Zohreh Abdolmaleki
- Department of Pharmacology, Karaj Branch, Islamic Azad University, Karaj, Iran.
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He F, Wu Z, Wang Y, Yin L, Lu S, Dai L. Downregulation of tripartite motif protein 11 attenuates cardiomyocyte apoptosis after ischemia/reperfusion injury via DUSP1-JNK1/2. Cell Biol Int 2021; 46:148-157. [PMID: 34694031 PMCID: PMC9299661 DOI: 10.1002/cbin.11716] [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: 06/23/2021] [Revised: 10/09/2021] [Accepted: 10/16/2021] [Indexed: 11/11/2022]
Abstract
Currently, the prevention of ischemic diseases such as myocardial infarction associated with ischemia/reperfusion (I/R) injury remains to be a challenge. Thus, this study was designed to explore the effects of tripartite motif protein 11 (TRIM11) on cardiomyocytes I/R injury and its underlying mechanism. Cardiomyocytes AC16 were used to establish an I/R injury cell model. After TRIM11 downregulation in I/R cells, cell proliferation (0, 12, 24, and 48 h) and apoptosis at 48 h as well as the related molecular changes in oxidative stress‐related pathways was detected. Further, after the treatment of TRIM11 overexpression, SP600125, or DUSP1 overexpression, cell proliferation, apoptosis, and related genes were detected again. As per our findings, it was determined that TRIM11 was highly expressed in the cardiomyocytes AC16 after I/R injury. Downregulation of TRIM11 was determined to have significantly reduced I/R‐induced proliferation suppression and apoptosis. Besides, I/R‐activated c‐Jun N‐terminal kinase (JNK) signaling and cleaved caspase 3 and Bax expression were significantly inhibited by TRIM11 downregulation. In addition, the overexpression of TRIM11 significantly promoted apoptosis in AC16 cells, and JNK1/2 inhibition and DUSP1 overexpression potently counteracted the induction of TRIM11 overexpression in AC16 cells. These suggested that the downregulation of TRIM11 attenuates apoptosis in AC16 cells after I/R injury probably through the DUSP1‐JNK1/2 pathways.
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Affiliation(s)
- Fang He
- Shanghai Changning Mental Health Center, Shanghai, China
| | - Zheqian Wu
- Department of Emergency, Shidong Hospital of Yangpu District, Shanghai, China
| | - Yong Wang
- Department of Emergency, Shidong Hospital of Yangpu District, Shanghai, China
| | - Lili Yin
- Department of Emergency, Shidong Hospital of Yangpu District, Shanghai, China
| | - Shijie Lu
- Department of Emergency, Shidong Hospital of Yangpu District, Shanghai, China
| | - Lihua Dai
- Department of Emergency, Shidong Hospital of Yangpu District, Shanghai, China
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Lei H, Rao M. The role of humanin in the regulation of reproduction. Biochim Biophys Acta Gen Subj 2021; 1866:130023. [PMID: 34626748 DOI: 10.1016/j.bbagen.2021.130023] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 10/04/2021] [Accepted: 10/04/2021] [Indexed: 10/20/2022]
Abstract
Humanin, a mitochondria-derived peptide, has been found to exert variously protective function in many tissues, especially in the nervous tissues. However, relatively limited studies have focused on the role of humanin in the regulation of reproduction. Current observations indicate that humanin plays an important role in regulating the response of the cell to oxidative stress and apoptosis in ovaries and testes via the modulation of several signaling pathways, especially when the body is in an abnormal state. Even so, the detailed mechanism of humanin function needs to be explored urgently. In this passage, we demonstrate how humanin exerts its protective role in female and male reproduction and raise several questions that need further investigations. Given humanin's new frontier for the design of novel therapeutic approaches for male infertility, male contraception, female infertility, and glucose metabolism in polycystic ovary syndrome, it is worthy of further study on its protective effects and clinical applications in reproductive function.
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Affiliation(s)
- Hui Lei
- Gynecology Department, Taikang Tongji (Wuhan) Hospital, Wuhan 430000, China
| | - Meng Rao
- Department of Reproduction and Genetics, the First Affiliated Hospital of Kunming Medical University, Kunming 650032, China.
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Cai H, Cao P, Sun W, Shao W, Li R, Wang L, Zou L, Forno E, Muzumdar R, Gong Z, Zheng Y. Circulating humanin is lower in coronary artery disease and is a prognostic biomarker for major cardiac events in humans. Biochim Biophys Acta Gen Subj 2021; 1866:130010. [PMID: 34525397 DOI: 10.1016/j.bbagen.2021.130010] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 08/24/2021] [Accepted: 08/31/2021] [Indexed: 01/24/2023]
Abstract
BACKGROUND Humanin is an endogenous mitochondria-derived peptide that plays critical roles in oxidative stress, inflammation and CAD. In this study, we measured the levels of circulating humanin, markers of oxidative stress and inflammation in patients with unstable angina and MI and studied the relationship between these parameters and major adverse cardiac events (MACE). METHODS A total of 327 subjects were recruited from the inpatient department at First Hospital of Jilin University and divided into 3 groups [control, angina and myocardial infarction (MI)] based on the clinical data and the results of the angiography. Serum humanin and thiobarbituric acid reactive substances (TBARS) were measured at the time of initial admission. The hospitalization data and MACE of all patients were collected. RESULTS Circulating humanin levels were lower in the angina group compared to controls [124.22 ± 63.02 vs. 157.77 ± 99.93 pg/ml, p < 0.05] and even lower in MI patients [67.17 ± 24.35 pg/ml, p < 0.05 vs controls] and oxidative stress marker were higher in MI patients compared to the control and angina groups [12.94 ± 4.55 vs. 8.26 ± 1.66 vs. 9.06 ± 2.47 umol/ml, p < 0.05]. Lower circulating humanin levels was an independent risk factor of MI patients. Circulating humanin levels could be used to predict MACE in angina group. CONCLUSIONS Lower circulating humanin levels was an independent risk factor for CAD, and a potential prognostic marker for mild CAD. GENERAL SIGNIFICANCE Humanin may become a new index for the diagnosis and treatment of CAD.
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Affiliation(s)
- He Cai
- The Cardiovascular Center, First Hospital of Jilin University, 71 Xinmin Road, Changchun, Jilin 130021, China
| | - Pengyu Cao
- The Cardiovascular Center, First Hospital of Jilin University, 71 Xinmin Road, Changchun, Jilin 130021, China.
| | - Wanqing Sun
- National Center for Cardiovascular Diseases China, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Wangshu Shao
- The Cardiovascular Center, First Hospital of Jilin University, 71 Xinmin Road, Changchun, Jilin 130021, China
| | - Rongyu Li
- The Cardiovascular Center, First Hospital of Jilin University, 71 Xinmin Road, Changchun, Jilin 130021, China
| | - Lin Wang
- The Cardiovascular Center, First Hospital of Jilin University, 71 Xinmin Road, Changchun, Jilin 130021, China
| | - Lin Zou
- The Cardiovascular Center, First Hospital of Jilin University, 71 Xinmin Road, Changchun, Jilin 130021, China
| | - Erick Forno
- Division of Pulmonology, Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA
| | - Radhika Muzumdar
- Division of Endocrinology, Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA
| | - Zhenwei Gong
- Division of Endocrinology, Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA.
| | - Yang Zheng
- The Cardiovascular Center, First Hospital of Jilin University, 71 Xinmin Road, Changchun, Jilin 130021, China.
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Chang E, Chang JS, Kong ID, Baik SK, Kim MY, Park KS. Multidimensional Biomarker Analysis Including Mitochondrial Stress Indicators for Nonalcoholic Fatty Liver Disease. Gut Liver 2021; 16:171-189. [PMID: 34420934 PMCID: PMC8924798 DOI: 10.5009/gnl210106] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 06/15/2021] [Accepted: 06/22/2021] [Indexed: 11/22/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is accompanied by a complex and multifactorial pathogenesis with sequential progressions from inflammation to fibrosis and then to cancer. This heterogeneity interferes with the development of precise diagnostic and prognostic strategies for NAFLD. The current approach for the diagnosis of simple steatosis, steatohepatitis, and cirrhosis mainly consists of ultrasonography, magnetic resonance imaging, elastography, and various serological analyses. However, individual dry and wet biomarkers have limitations demanding an integrative approach for the assessment of disease progression. Here, we review diagnostic strategies for simple steatosis, steatohepatitis and hepatic fibrosis, followed by potential biomarkers associated with fat accumulation and mitochondrial stress. For mitochondrial stress indicators, we focused on fibroblast growth factor 21 (FGF21), growth differentiation factor 15 (GDF15), angiopoietin-related growth factor and mitochondrial-derived peptides. Each biomarker may not strongly indicate the severity of steatosis or steatohepatitis. Instead, multidimensional analysis of different groups of biomarkers based on pathogenic mechanisms may provide decisive diagnostic/prognostic information to develop a therapeutic plan for patients with NAFLD. For this purpose, mitochondrial stress indicators, such as FGF21 or GDF15, could be an important component in the multiplexed and contextual interpretation of NAFLD. Further validation of the integrative evaluation of mitochondrial stress indicators combined with other biomarkers is needed in the diagnosis/prognosis of NAFLD.
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Affiliation(s)
- Eunha Chang
- Department of Physiology, Yonsei University Wonju College of Medicine, Wonju, Korea.,Department of Mitohormesis Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Jae Seung Chang
- Department of Mitohormesis Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - In Deok Kong
- Department of Physiology, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Soon Koo Baik
- Department of Mitohormesis Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea.,Department of Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Moon Young Kim
- Department of Mitohormesis Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea.,Department of Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Kyu-Sang Park
- Department of Physiology, Yonsei University Wonju College of Medicine, Wonju, Korea.,Department of Mitohormesis Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea
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Feng Y, Huang W, Paul C, Liu X, Sadayappan S, Wang Y, Pauklin S. Mitochondrial nucleoid in cardiac homeostasis: bidirectional signaling of mitochondria and nucleus in cardiac diseases. Basic Res Cardiol 2021; 116:49. [PMID: 34392401 PMCID: PMC8364536 DOI: 10.1007/s00395-021-00889-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Accepted: 07/20/2021] [Indexed: 01/11/2023]
Abstract
Metabolic function and energy production in eukaryotic cells are regulated by mitochondria, which have been recognized as the intracellular 'powerhouses' of eukaryotic cells for their regulation of cellular homeostasis. Mitochondrial function is important not only in normal developmental and physiological processes, but also in a variety of human pathologies, including cardiac diseases. An emerging topic in the field of cardiovascular medicine is the implication of mitochondrial nucleoid for metabolic reprogramming. This review describes the linear/3D architecture of the mitochondrial nucleoid (e.g., highly organized protein-DNA structure of nucleoid) and how it is regulated by a variety of factors, such as noncoding RNA and its associated R-loop, for metabolic reprogramming in cardiac diseases. In addition, we highlight many of the presently unsolved questions regarding cardiac metabolism in terms of bidirectional signaling of mitochondrial nucleoid and 3D chromatin structure in the nucleus. In particular, we explore novel techniques to dissect the 3D structure of mitochondrial nucleoid and propose new insights into the mitochondrial retrograde signaling, and how it regulates the nuclear (3D) chromatin structures in mitochondrial diseases.
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Affiliation(s)
- Yuliang Feng
- Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Old Road, University of Oxford, Oxford, OX3 7LD, UK
| | - Wei Huang
- Department of Pathology and Laboratory Medicine, Regenerative Medicine Research, University of Cincinnati College of Medicine, 231 Albert Sabin Way, CincinnatiCincinnati, OH, 45267-0529, USA
| | - Christian Paul
- Department of Pathology and Laboratory Medicine, Regenerative Medicine Research, University of Cincinnati College of Medicine, 231 Albert Sabin Way, CincinnatiCincinnati, OH, 45267-0529, USA
| | - Xingguo Liu
- Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Hefei Institute of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
- Guangzhou Regenerative Medicine and Health Guangdong Laboratory, CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Hefei Institute of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Guangzhou Medical University, Guangzhou, 510530, China
- Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Institute for Stem Cell and Regeneration, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
| | - Sakthivel Sadayappan
- Heart, Lung and Vascular Institute, Division of Cardiovascular Health and Disease, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH, 45267, USA
| | - Yigang Wang
- Department of Pathology and Laboratory Medicine, Regenerative Medicine Research, University of Cincinnati College of Medicine, 231 Albert Sabin Way, CincinnatiCincinnati, OH, 45267-0529, USA.
| | - Siim Pauklin
- Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Old Road, University of Oxford, Oxford, OX3 7LD, UK.
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Wang Y, Zeng Z, Zhao S, Tang L, Yan J, Li N, Zou L, Fan X, Xu C, Huang J, Xia W, Zhu C, Rao M. Humanin Alleviates Insulin Resistance in Polycystic Ovary Syndrome: A Human and Rat Model-Based Study. Endocrinology 2021; 162:bqab056. [PMID: 33693742 DOI: 10.1210/endocr/bqab056] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Indexed: 11/19/2022]
Abstract
Polycystic ovary syndrome (PCOS), the most common endocrine disorder in women of reproductive age, is characterized by hyperandrogenism and insulin resistance (IR); however, the pathogenesis of local ovarian IR in PCOS remains largely unclear. Humanin, a mitochondria-derived peptide, has been reported to be associated with IR. Our previous study confirmed that humanin is expressed in multiple cell types in the ovary and is present in follicular fluid. However, it remains unknown whether humanin participates in the pathogenesis of local ovarian IR or whether humanin supplementation can improve IR in PCOS patients. In this study, we compared humanin concentrations in follicular fluid from PCOS patients with and without IR. We further investigated the effect of humanin analogue (HNG) supplementation on IR in a rat model of dehydroepiandrosterone-induced PCOS. Humanin concentrations in the follicular fluid were found to be significantly lower in PCOS patients with IR than in those without IR. HNG supplementation attenuated both the increases in the levels of fasting plasma glucose and fasting insulin in rats with PCOS and the decreases in phosphorylation of IRS1, PI3K, AKT, and GLUT4 proteins in the granulosa cells of these rats. Combined supplementation with HNG and insulin significantly improved glucose consumption in normal and humanin-siRNA-transfected COV434 cells. In conclusion, downregulated humanin in the ovaries may be involved in the pathogenesis of IR in PCOS, and exogenous supplementation with HNG improved local ovarian IR through modulation of the IRS1/PI3K/Akt signaling pathway in a rat model. This finding supports the potential future use of HNG as a therapeutic drug for PCOS.
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Affiliation(s)
- Yingying Wang
- Reproductive Health Institute, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Zhengyan Zeng
- Department of General Medicine, the First Affiliated Hospital of Kunming Medical University, Kunming 650032, China
| | - Shuhua Zhao
- Department of Reproduction and Genetics, the First Affiliated Hospital of Kunming Medical University, Kunming 650032, China
| | - Li Tang
- Department of Reproduction and Genetics, the First Affiliated Hospital of Kunming Medical University, Kunming 650032, China
| | - Jin Yan
- Department of Reproduction and Genetics, the First Affiliated Hospital of Kunming Medical University, Kunming 650032, China
| | - Nianyu Li
- Reproductive Health Institute, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Liping Zou
- Reproductive Health Institute, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Xiaorong Fan
- Reproductive Health Institute, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Chengcheng Xu
- Reproductive Health Institute, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Jin Huang
- Reproductive Health Institute, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Wei Xia
- Reproductive Health Institute, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Reproductive Medicine Centre, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Changhong Zhu
- Reproductive Health Institute, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Reproductive Medicine Centre, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Meng Rao
- Department of Reproduction and Genetics, the First Affiliated Hospital of Kunming Medical University, Kunming 650032, China
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Jia Y, Swerdloff RS, Lue Y, Dai-Ju J, Surampudi P, Cohen P, Wang C. The IL-27 component EBI-3 and its receptor subunit IL-27Rα are essential for the cytoprotective action of humanin on male germ cells†. Biol Reprod 2021; 104:717-730. [PMID: 33330922 PMCID: PMC8527998 DOI: 10.1093/biolre/ioaa225] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 11/19/2020] [Accepted: 12/08/2020] [Indexed: 12/28/2022] Open
Abstract
Humanin (HN) is a mitochondrial-derived peptide that protects many cells/tissues from damage. We previously demonstrated that HN reduces stress-induced male germ cell apoptosis in rodents. HN action in neuronal cells is mediated through its binding to a trimeric cell membrane receptor composed of glycoprotein 130 (gp130), IL-27 receptor subunit (IL-27R, also known as WSX-1/TCCR), and ciliary neurotrophic factor receptor subunit (CNTFR). The mechanisms of HN action in testis remain unclear. We demonstrated in ex-vivo seminiferous tubules culture that HN prevented heat-induced germ cell apoptosis was blocked by specific anti-IL-27R, anti-gp130, and anti-EBI-3, but not by anti-CNTFR antibodies significantly. The cytoprotective action of HN was studied by using groups of il-27r-/- or ebi-3-/- mice administered the following treatment: (1) vehicle; (2) a single intraperitoneal (IP) injection of HN peptide; (3) testicular hyperthermia; and (4) testicular hyperthermia plus HN. We demonstrated that HN inhibited heat-induced germ cell apoptosis in wildtype but not in il-27r-/- or ebi-3-/- mice. HN restored heat-suppressed STAT3 phosphorylation in wildtype but not il-27r-/- or ebi-3-/- mice. Dot blot analyses showed the direct interaction of HN with IL-27R or EBI-3 peptide. Immunofluorescence staining showed the co-localization of IL-27R with HN and gp130 in Leydig cells and germ cells. We conclude that the anti-apoptotic effects of HN in mouse testes are mediated through interaction with EBI-3, IL-27R, and activation of gp130, whereas the role of CNTFR needs further studies. This suggests a multicomponent tissue-specific receptor for HN in the testis and links HN action with the IL-12/IL-27 family of cytokines.
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Affiliation(s)
- Yue Jia
- Division of Endocrinology, Department of Medicine, The Lundquist Research Institute and Harbor-UCLA Medical Center, Torrance, CA, USA
- Department of Pathology, Harbor-UCLA Medical Center, Torrance, CA, USA
| | - Ronald S Swerdloff
- Division of Endocrinology, Department of Medicine, The Lundquist Research Institute and Harbor-UCLA Medical Center, Torrance, CA, USA
| | - YanHe Lue
- Division of Endocrinology, Department of Medicine, The Lundquist Research Institute and Harbor-UCLA Medical Center, Torrance, CA, USA
| | - Jenny Dai-Ju
- Division of Endocrinology, Department of Medicine, The Lundquist Research Institute and Harbor-UCLA Medical Center, Torrance, CA, USA
| | - Prasanth Surampudi
- Division of Endocrinology, Department of Medicine, The Lundquist Research Institute and Harbor-UCLA Medical Center, Torrance, CA, USA
| | - Pinchas Cohen
- USC Davis School of Gerontology, Ethel Percy Andrus Gerontology Center, University of Southern California, Los Angeles, CA, USA
| | - Christina Wang
- Division of Endocrinology, Department of Medicine, The Lundquist Research Institute and Harbor-UCLA Medical Center, Torrance, CA, USA
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From Mitochondria to Atherosclerosis: The Inflammation Path. Biomedicines 2021; 9:biomedicines9030258. [PMID: 33807807 PMCID: PMC8000234 DOI: 10.3390/biomedicines9030258] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 02/26/2021] [Accepted: 02/27/2021] [Indexed: 12/11/2022] Open
Abstract
Inflammation is a key process in metazoan organisms due to its relevance for innate defense against infections and tissue damage. However, inflammation is also implicated in pathological processes such as atherosclerosis. Atherosclerosis is a chronic inflammatory disease of the arterial wall where unstable atherosclerotic plaque rupture causing platelet aggregation and thrombosis may compromise the arterial lumen, leading to acute or chronic ischemic syndromes. In this review, we will focus on the role of mitochondria in atherosclerosis while keeping inflammation as a link. Mitochondria are the main source of cellular energy. Under stress, mitochondria are also capable of controlling inflammation through the production of reactive oxygen species (ROS) and the release of mitochondrial components, such as mitochondrial DNA (mtDNA), into the cytoplasm or into the extracellular matrix, where they act as danger signals when recognized by innate immune receptors. Primary or secondary mitochondrial dysfunctions are associated with the initiation and progression of atherosclerosis by elevating the production of ROS, altering mitochondrial dynamics and energy supply, as well as promoting inflammation. Knowing and understanding the pathways behind mitochondrial-based inflammation in atheroma progression is essential to discovering alternative or complementary treatments.
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Su Q, Xu Y, Cai R, Dai R, Yang X, Liu Y, Kong B. miR-146a inhibits mitochondrial dysfunction and myocardial infarction by targeting cyclophilin D. MOLECULAR THERAPY. NUCLEIC ACIDS 2021; 23:1258-1271. [PMID: 33717647 PMCID: PMC7907681 DOI: 10.1016/j.omtn.2021.01.034] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Accepted: 01/28/2021] [Indexed: 12/18/2022]
Abstract
Increasing evidence suggests that mitochondrial microRNAs (miRNAs) are implicated in the pathogenesis of cardiovascular diseases; however, their roles in ischemic heart disease remain unclear. Herein, we demonstrate that miR-146a is enriched in the mitochondrial fraction of cardiomyocytes, and its level significantly decreases after ischemic reperfusion (I/R) challenge. Cardiomyocyte-specific knockout of miR-146a aggravated myocardial infarction, apoptosis, and cardiac dysfunction induced by the I/R injury. Overexpression of miR-146a suppressed anoxia/reoxygenation-induced cardiomyocyte apoptosis by inhibiting the mitochondria-dependent apoptotic pathway and increasing the Bcl-2/Bax ratio. miR-146a overexpression also blocked mitochondrial permeability transition pore opening and attenuated the loss of mitochondrial membrane potential and cytochrome c leakage; meanwhile, miR-146a knockdown elicited the opposite effects. Additionally, miR-146a overexpression decreased cyclophilin D protein, not mRNA, expression. The luciferase reporter assay revealed that miR-146a binds to the coding sequence of the cyclophilin D gene. Restoration of cyclophilin D reversed the inhibitory action of miR-146a on cardiomyocyte apoptosis. Furthermore, cardiomyocyte-specific cyclophilin D deletion completely abolished the exacerbation of myocardial infarction and apoptosis observed in miR-146a cardiomyocyte-deficient mice. Collectively, these findings demonstrate that nuclear miR-146a translocates into the mitochondria and regulates mitochondrial function and cardiomyocyte apoptosis. Our study unveils a novel role for miR-146a in ischemic heart disease.
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Affiliation(s)
- Qiang Su
- Department of Cardiology, The Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi, China
| | - Yuli Xu
- Department of Cardiology, The Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi, China
| | - Ruping Cai
- Department of Cardiology, The Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi, China
| | - Rixin Dai
- Department of Cardiology, The Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi, China
| | - Xiheng Yang
- Department of Cardiology, The Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi, China
| | - Yang Liu
- Department of Cardiology, The Second People’s Hospital of Nanning City, The Third Affiliated Hospital of Guangxi Medical University, Nanning 530031, Guangxi, China
| | - Binghui Kong
- Department of Cardiology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi, China
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Wang Y, Li N, Zeng Z, Tang L, Zhao S, Zhou F, Zhou L, Xia W, Zhu C, Rao M. Humanin regulates oxidative stress in the ovaries of polycystic ovary syndrome patients via the Keap1/Nrf2 pathway. Mol Hum Reprod 2021; 27:gaaa081. [PMID: 33337472 DOI: 10.1093/molehr/gaaa081] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 11/18/2020] [Indexed: 02/06/2023] Open
Abstract
Polycystic ovary syndrome (PCOS) is the most common endocrinological pathology among women of reproductive age, whereas the pathogenesis is still not fully understood. Systemic and ovarian oxidative stress (OS) imbalance is a pivotal feature of PCOS. Humanin, a mitochondria-derived peptide, has been reported to function as an antioxidant in cardiomyocytes, pancreatic beta cells and other cells, but how this function is regulated remains unclear. In this study, we investigated whether humanin expression differs in the granulosa cells (GCs) of PCOS patients versus controls, and whether humanin alleviates OS in PCOS ovaries. Sixteen PCOS patients and 28 age- and BMI-matched controls undergoing IVF were recruited, and their serum, follicular fluid and GCs were collected for humanin analysis. Dehydroepiandrosterone-induced rat PCOS models, and vitamin K3-induced OS COV434 cell lines were applied to investigate the mechanism. Humanin expression was significantly down-regulated in the ovaries of PCOS patients relative to those of non-PCOS patients. Exogenous humanin supplementation significantly attenuated body weight gain, ovarian morphological abnormalities, endocrinological disorders and ovarian and systemic OS in PCOS rat models. Our study further demonstrated that this attenuation effect was involved in the modulation of the Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor-erythroid 2-related factor 2 (Nrf2) signalling pathway. In summary, this study reported for the first time that decreased expression of humanin in the GCs was associated with oxidative imbalance in PCOS. Humanin alleviates OS in ovarian GCs of PCOS patients via modulation of the Keap1/Nrf2 signalling pathway.
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Affiliation(s)
- Yingying Wang
- Family Planning Research Institute, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Nianyu Li
- Family Planning Research Institute, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhengyan Zeng
- Department of Neurology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Li Tang
- Department of Reproduction and Genetics, The First affiliated Hospital of Kunming Medical University, Kunming, China
| | - Shuhua Zhao
- Department of Reproduction and Genetics, The First affiliated Hospital of Kunming Medical University, Kunming, China
| | - Fang Zhou
- Family Planning Research Institute, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Liping Zhou
- Family Planning Research Institute, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wei Xia
- Family Planning Research Institute, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Reproductive Medicine Center, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Changhong Zhu
- Family Planning Research Institute, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Reproductive Medicine Center, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Meng Rao
- Department of Reproduction and Genetics, The First affiliated Hospital of Kunming Medical University, Kunming, China
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Kim J, Choi JW, Namkung J. Expression Profile of Mouse Gm20594, Nuclear-Encoded Humanin-Like Gene. J Lifestyle Med 2021; 11:13-22. [PMID: 33763338 PMCID: PMC7957044 DOI: 10.15280/jlm.2021.11.1.13] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Accepted: 11/29/2020] [Indexed: 12/21/2022] Open
Abstract
Background Mitochondrial-derived peptides (MDPs) such as MOTS-c and humanin have been studied for their cytoprotective functions. In mice, humanin-encoding Mtrnr2 is a mitochondrial pseudogene, and the humanin-like peptide is encoded by the nuclear Gm20594 gene. However, endogenous tissue-specific expression profiles of Gm20594 have not yet been identified. Methods Mtrnr1 and Gm20594 expression was profiled via reverse transcription using only oligo(dT) primers from tissues of C57BL6/J mice. To analyze altered expression upon mitochondrial biogenesis, C2C12 myocytes and brown adipocytes were differentiated. Mitochondrial DNA copy numbers were quantified for normalization. Results Both Mtrnr1 and Gm20594 were highly expressed in brown adipose tissue. When normalized against mitochondrial content, Mtrnr1 was identified as being highly expressed in the duodenum, followed by the jejunum. In models of mitochondrial biogenesis, both Mtrnr1 and Gm20594 were upregulated during myocyte and brown adipocyte differentiation. Increased Mtrnr1 expression during brown adipocyte differentiation remained significant after normalization against mitochondrial DNA copy number, whereas myocyte differentiation exhibited biphasic upregulation and downregulation in early and late phases, respectively. Conclusion Nuclear-encoded Gm20594 showed similar expression patterns of mitochondrial-encoded Mtrnr1. Brown adipose tissue presented the highest basal expression levels of Gm20594 and Mtrnr1. When normalized against mitochondrial DNA copy number, gut tissues exhibited the highest expression of Mtrnr1. Upregulation of Mtrnr1 during mitochondrial biogenesis is independent of mitochondrial content.
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Affiliation(s)
- Jihye Kim
- Department of Biochemistry, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Jong-Whan Choi
- Department of Biochemistry, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Jun Namkung
- Department of Biochemistry, Yonsei University Wonju College of Medicine, Wonju, Korea
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Wu Y, Sun L, Zhuang Z, Hu X, Dong D. Mitochondrial-Derived Peptides in Diabetes and Its Complications. Front Endocrinol (Lausanne) 2021; 12:808120. [PMID: 35185787 PMCID: PMC8851315 DOI: 10.3389/fendo.2021.808120] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Accepted: 12/23/2021] [Indexed: 12/14/2022] Open
Abstract
The changes of mitochondrial function are closely related to diabetes and its complications. Here we describe the effects of mitochondrial-derived peptides (MDPs), short peptides formed by transcription and translation of the open reading frame site in human mitochondrial DNA (mtDNA), on diabetes and its complications. We mainly focus on MDPs that have been discovered so far, such as Humanin (HN), mitochondrial open reading frame of the 12S rRNA-c (MOTS-c) and Small humanin-like peptides (SHLP 1-6), and elucidated the role of MDPs in diabetes and its major complications stroke and myocardial infarction by improving insulin resistance, inhibiting inflammatory response and anti-apoptosis. It provides more possibilities for the clinical application of mitochondrial derived peptides.
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Affiliation(s)
- Ying Wu
- Key Laboratory of Pathobiology, Ministry of Education, Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Liankun Sun
- Key Laboratory of Pathobiology, Ministry of Education, Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Zhoudao Zhuang
- Clinical Medical College of Jilin University, The First Hospital of Jilin University, Changchun, China
| | - Xiaoqing Hu
- Department of Ophthalmology, The First Hospital of Jilin University, Changchun, China
- *Correspondence: Xiaoqing Hu, ; Delu Dong,
| | - Delu Dong
- Key Laboratory of Pathobiology, Ministry of Education, Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, China
- *Correspondence: Xiaoqing Hu, ; Delu Dong,
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