|
1
|
Yuxuan H, Sixu R, Chenglin L, Xiufen Z, Cuilin Z. Targeting mitochondria quality control for myocardial ischemia-reperfusion injury. Mitochondrion 2025:102046. [PMID: 40419068 DOI: 10.1016/j.mito.2025.102046] [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: 11/07/2024] [Revised: 04/24/2025] [Accepted: 05/01/2025] [Indexed: 05/28/2025]
Abstract
Cardiovascular disease (CVD) remains the leading global cause of mortality. Acute myocardial infarction (AMI) refers to acute myocardial ischemia resulting from thrombosis secondary to coronary atherosclerosis, which poses a major threat to human health. Clinically, timely revascularization (reperfusion) represents the basis of clinical treatment for AMI. However, secondary myocardial ischemia-reperfusion injury (MIRI) caused by reperfusion often exacerbates damage, representing a major challenge in clinical practice. Mitochondria represent essential organelles for maintaining cardiac function and cellular bioenergetics in MIRI. In recent years, the role of mitochondrial quality control (MQC) in maintaining cell homeostasis and mediating MIRI has been extensively studied. This review provides a concise overview of MQC mechanisms at the molecular, organelle, and cellular levels and their possible complex regulatory network in MIRI. In addition, potential treatment strategies targeting MQC to mitigate MIRI are summarized, highlighting the gap between current preclinical research and clinical transformation. Overall, this review provides theoretical guidance for further research and clinical translational studies.
Collapse
Affiliation(s)
- He Yuxuan
- Department of Cardiovascular Surgery, The Second Hospital of Jilin University, Changchun 130000, China; Norman Bethune Second Clinical Medical College, Jilin University, Changchun 130000, China
| | - Ren Sixu
- Department of Cardiovascular Surgery, The Second Hospital of Jilin University, Changchun 130000, China; Norman Bethune Second Clinical Medical College, Jilin University, Changchun 130000, China
| | - Liu Chenglin
- China-Japan Union Hospital of Jilin University, Changchun City 130033 Jilin Province, China
| | - Zheng Xiufen
- Department of Surgery, Western University, Ontario, Canada
| | - Zhu Cuilin
- Department of Cardiovascular Surgery, The Second Hospital of Jilin University, Changchun 130000, China; Norman Bethune Second Clinical Medical College, Jilin University, Changchun 130000, China.
| |
Collapse
|
|
2
|
Xu E, Wang J, Ding N, Wang H, Liu C, Wang X, Liu C. Nanoarchitectonics with Zinc-Doped Carbon Dots for Mitochondria-Targeted Repair and Regeneration Signaling Amplification in CLI Therapy. ACS APPLIED MATERIALS & INTERFACES 2025. [PMID: 40377343 DOI: 10.1021/acsami.5c03525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/18/2025]
Abstract
Critical limb ischemia (CLI) faces high rates of amputation and mortality. Despite advancements in surgical and endovascular interventions, their invasiveness and restricted applicability leave many CLI patients classified as "no-option" cases. Therapeutic angiogenesis strategies offer prospects for revascularization, but their efficacy remains suboptimal. Herein, we developed a nanomedicine, mitochondria-targeted zinc-doped ascorbic acid-derived carbon dots (TPP-Zn@ACDs), which simultaneously restores mitochondrial function and amplifies regenerative signaling to synergistically boost angiogenesis in ischemic limbs. TPP-Zn@ACDs integrate potent antioxidative properties of carbon dots and the pro-regenerative effects of Zn2+, with triphenylphosphine (TPP) and polyethylene glycol (PEG) functionalization endowing precise mitochondrial targeting and enhanced biocompatibility, thereby localizing therapeutic effects to the core of oxidative stress mitigation and regenerative signaling transduction. In vitro, TPP-Zn@ACDs improved mitochondrial function by reducing reactive oxygen species, restoring mitochondrial membrane potential and enhancing ATP production, through activation of the SIRT1/PGC-1α signaling pathway. Further, the proliferation, migration, and tube formation activities of endothelial cells were increased, while hypoxia-induced apoptosis and necrosis was inhibited effectively. Notably, leveraging mitochondrial restoration in endothelial cells, TPP-Zn@ACDs subsequently reprogrammed macrophages from an M1 pro-inflammatory phenotype to an M2 anti-inflammatory phenotype. In vivo, TPP-Zn@ACDs demonstrated remarkable therapeutic efficacy in a mouse CLI model, achieving robust blood flow recovery, increased microvascular density, and improved immune microenvironment. Together, this study proposes TPP-Zn@ACDs as a versatile engineering nanomedicine for mitochondria-targeted therapy, providing a scalable approach to breakthrough angiogenic efficacy in ischemic diseases.
Collapse
Affiliation(s)
- Erwei Xu
- State Key Laboratory of Bio-fibers and Eco-textiles, Institute of Biochemical Engineering, The Affiliated Qingdao Central Hospital of Qingdao University, College of Materials Science and Engineering, Qingdao University, Qingdao 266071, China
| | - Jianyuan Wang
- State Key Laboratory of Bio-fibers and Eco-textiles, Institute of Biochemical Engineering, The Affiliated Qingdao Central Hospital of Qingdao University, College of Materials Science and Engineering, Qingdao University, Qingdao 266071, China
| | - Ning Ding
- State Key Laboratory of Bio-fibers and Eco-textiles, Institute of Biochemical Engineering, The Affiliated Qingdao Central Hospital of Qingdao University, College of Materials Science and Engineering, Qingdao University, Qingdao 266071, China
| | - Haoran Wang
- State Key Laboratory of Bio-fibers and Eco-textiles, Institute of Biochemical Engineering, The Affiliated Qingdao Central Hospital of Qingdao University, College of Materials Science and Engineering, Qingdao University, Qingdao 266071, China
| | - Chunlei Liu
- State Key Laboratory of Bio-fibers and Eco-textiles, Institute of Biochemical Engineering, The Affiliated Qingdao Central Hospital of Qingdao University, College of Materials Science and Engineering, Qingdao University, Qingdao 266071, China
| | - Xiaoyu Wang
- State Key Laboratory of Bio-fibers and Eco-textiles, Institute of Biochemical Engineering, The Affiliated Qingdao Central Hospital of Qingdao University, College of Materials Science and Engineering, Qingdao University, Qingdao 266071, China
| | - Chunzhao Liu
- State Key Laboratory of Bio-fibers and Eco-textiles, Institute of Biochemical Engineering, The Affiliated Qingdao Central Hospital of Qingdao University, College of Materials Science and Engineering, Qingdao University, Qingdao 266071, China
| |
Collapse
|
|
3
|
Zhang JJ, Cheng L, Qiao Q, Xiao XL, Lin SJ, He YF, Sha RL, Sha J, Ma Y, Zhang HL, Ye XR. Adenosine triphosphate-induced cell death in heart failure: Is there a link? World J Cardiol 2025; 17:105021. [PMID: 40308621 PMCID: PMC12038699 DOI: 10.4330/wjc.v17.i4.105021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Revised: 02/22/2025] [Accepted: 04/02/2025] [Indexed: 04/21/2025] Open
Abstract
Heart failure (HF) has emerged as one of the foremost global health threats due to its intricate pathophysiological mechanisms and multifactorial etiology. Adenosine triphosphate (ATP)-induced cell death represents a novel form of regulated cell deaths, marked by cellular energy depletion and metabolic dysregulation stemming from excessive ATP accumulation, identifying its uniqueness compared to other cell death processes modalities such as programmed cell death and necrosis. Growing evidence suggests that ATP-induced cell death (AICD) is predominantly governed by various biological pathways, including energy metabolism, redox homeostasis and intracellular calcium equilibrium. Recent research has shown that AICD is crucial in HF induced by pathological conditions like myocardial infarction, ischemia-reperfusion injury, and chemotherapy. Thus, it is essential to investigate the function of AICD in the pathogenesis of HF, as this may provide a foundation for the development of targeted therapies and novel treatment strategies. This review synthesizes current advancements in understanding the link between AICD and HF, while further elucidating its involvement in cardiac remodeling and HF progression.
Collapse
Affiliation(s)
- Jing-Jing Zhang
- Department of Cardiovascular Medicine, Fuwai Yunnan Hospital, Chinese Academy Medical Sciences, Kunming 650000, Yunnan Province, China
| | - Lu Cheng
- Department of Cardiovascular Medicine, Fuwai Yunnan Hospital, Chinese Academy Medical Sciences, Kunming 650000, Yunnan Province, China
| | - Qian Qiao
- Department of Cardiovascular Medicine, Fuwai Yunnan Hospital, Chinese Academy Medical Sciences, Kunming 650000, Yunnan Province, China
| | - Xue-Liang Xiao
- Department of Critical Care Medicine, Ninglang Yi Autonomous County People's Hospital, Lijiang 674300, Yunnan Province, China
| | - Shao-Jun Lin
- Department of Critical Care Medicine, Ninglang Yi Autonomous County People's Hospital, Lijiang 674300, Yunnan Province, China
| | - Yue-Fang He
- Department of Critical Care Medicine, Ninglang Yi Autonomous County People's Hospital, Lijiang 674300, Yunnan Province, China
| | - Ren-Luo Sha
- Department of Critical Care Medicine, Ninglang Yi Autonomous County People's Hospital, Lijiang 674300, Yunnan Province, China
| | - Jun Sha
- Department of Critical Care Medicine, Ninglang Yi Autonomous County People's Hospital, Lijiang 674300, Yunnan Province, China
| | - Yin Ma
- Department of Critical Care Medicine, Ninglang Yi Autonomous County People's Hospital, Lijiang 674300, Yunnan Province, China
| | - Hao-Ling Zhang
- Department of Biomedical Science, Advanced Medical and Dental Institute, University Sains Malaysia, Penang 13200, Malaysia.
| | - Xue-Rui Ye
- Department of Cardiovascular Medicine, Fuwai Yunnan Hospital, Chinese Academy Medical Sciences, Kunming 650000, Yunnan Province, China
| |
Collapse
|
|
4
|
Yan S, Bi Y, Liu Q, Song S, Ma L, Ji G. hUC-MSCs Prevent Acute High-Altitude Injury through Apoe/Pdgf-b/p-Erk1/2 Axis in Mice. Stem Cell Rev Rep 2025; 21:834-848. [PMID: 39871082 PMCID: PMC11965259 DOI: 10.1007/s12015-024-10840-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/26/2024] [Indexed: 01/29/2025]
Abstract
BACKGROUND The hypobaric hypoxic atmosphere can cause adverse reactions or sickness. The purpose of this study was to explore the preventive effect and mechanism of human umbilical cord mesenchymal stem cells (hUC-MSCs) on acute pathological injury in mice exposed to high-altitude. METHODS We pretreated C57BL/6 mice with hUC-MSCs via the tail vein injection, and then the mice were subjected to hypobaric hypoxic conditions for five days. The effects of hUC-MSCs on the pathological injury of lung, heart, brain were assessed by biochemical analysis, histopathological testing, quantitative real-time polymerase chain reaction (qPCR), and western blot (WB). Further, transcriptome sequencing was used to screen for the potential therapeutic targets of hUC-MSCs in acute pathological injury, the identified signaling axis was characterized using Apoe-/- mice, qPCR and WB. RESULTS hUC-MSCs administration notably prevented and relieved gastrointestinal symptoms and inflammation of lung and heart, increased blood oxygen saturation and serum superoxide dismutase (SOD) level, decreased serum malondialdehyde (MDA) level, rescued lung tissue injury and myocardial mitochondrial disorder, elevated nissl bodies number in brain tissue and reduced the degree of pulmonary and cerebral edema. Furthermore, hUC-MSCs pretreatment reversed the down-regulated Apoe and up-regulated Pdgf-b and p-Erk1/2 in the lung of hypobaric hypoxic mice. Thus, hUC-MSCs protected against acute pathological injury caused by hypobaric hypoxic condition via the Apoe/Pdgf-b/p-Erk1/2 axis, and the identified pathway was confirmed by the negative results of Apoe-/- mice. CONCLUSION hUC-MSCs possess the preventive effect on acute pathological injury caused by hypobaric hypoxia environment at high-altitude.
Collapse
Affiliation(s)
- Siyu Yan
- Chinese Academy of Medical Sciences & Peking Union Medical College Fuwai Hospital, Beijing, China
| | - Youkun Bi
- Chinese Academy of Medical Sciences & Peking Union Medical College Fuwai Hospital, Beijing, China
- Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
| | - Qun Liu
- Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
| | - Shaole Song
- Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
| | - Lihong Ma
- Chinese Academy of Medical Sciences & Peking Union Medical College Fuwai Hospital, Beijing, China.
| | - Guangju Ji
- Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
- Henan Academy of Sciences, Zhengzhou, 450000, China.
| |
Collapse
|
|
5
|
Abolfazli S, Karav S, Johnston TP, Sahebkar A. Regulatory effects of resveratrol on nitric oxide signaling in cardiovascular diseases. Pharmacol Rep 2025; 77:355-374. [PMID: 39832074 DOI: 10.1007/s43440-025-00694-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Revised: 01/04/2025] [Accepted: 01/06/2025] [Indexed: 01/22/2025]
Abstract
Cardiovascular illnesses are multifactorial disorders and represent the primary reasons for death worldwide, according to the World Health Organization. As a signaling molecule, nitric oxide (NO) is extremely permeable across cellular membranes owing to its unique molecular features, like its small molecular size, lipophilicity, and free radical properties. Some of the biological effects of NO are vasodilation, inhibition in the growth of vascular smooth muscle cells, and functional regulation of cardiac cells. Several therapeutic approaches have been tested to increase the production of NO or some downstream NO signaling pathways. The health benefits of red wine are typically attributed to the polyphenolic phytoalexin, resveratrol (3,5,4'-trihydroxy-trans-stilbene), which is found in several plant species. Resveratrol has beneficial cardiovascular properties, some of which are mediated through endothelial nitric oxide synthase production (eNOS). Resveratrol promotes NO generation from eNOS through various methods, including upregulation of eNOS expression, activation in the enzymatic activity of eNOS, and reversal of eNOS uncoupling. Additionally, by reducing of oxidative stress, resveratrol inhibits the formation of superoxide and inactivation NO, increasing NO bioavailability. This review discusses the scientific literature on resveratrol's beneficial impact on NO signaling and how this effect improves the function of vascular endothelium.
Collapse
Affiliation(s)
- Sajad Abolfazli
- Student Research Committee, School of Pharmacy, Mazandaran University of Medical Science, Sari, Iran
| | - Sercan Karav
- Department of Molecular Biology and Genetics, Canakkale Onsekiz Mart University, Canakkale, 17100, Turkey
| | - Thomas P Johnston
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO, USA
| | - Amirhossein Sahebkar
- Center for Global Health Research, Saveetha Medical College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India.
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
| |
Collapse
|
|
6
|
Zeng L, Zhu L, Fu S, Li Y, Hu K. Mitochondrial Dysfunction-Molecular Mechanisms and Potential Treatment approaches of Hepatocellular Carcinoma. Mol Cell Biochem 2025; 480:2131-2142. [PMID: 39463200 DOI: 10.1007/s11010-024-05144-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Accepted: 10/18/2024] [Indexed: 10/29/2024]
Abstract
Primary liver cancer (PLC), also known as hepatocellular carcinoma (HCC), is a common type of malignant tumor of the digestive system. Its pathological form has a significant negative impact on the patients' quality of life and ability to work, as well as a significant financial burden on society. Current researches had identified chronic hepatitis B virus infection, aflatoxin B1 exposure, and metabolic dysfunction-associated steatotic liver disease (MASLD) as the main causative factors of HCC. Numerous variables, including inflammatory ones, oxidative stress, apoptosis, autophagy, and others, have been linked to the pathophysiology of HCC. On the other hand, autoimmune regulation, inflammatory response, senescence of the hepatocytes, and mitochondrial dysfunction are all closely related to the pathogenesis of HCC. In fact, a growing number of studies have suggested that mitochondrial dysfunction in hepatocytes may be a key factor in the pathogenesis of HCC. In disorders linked to cancer, mitochondrial dysfunction has gained attention in recent 10 years. As the primary producer of adenosine triphosphate (ATP) in liver cells, mitochondria are essential for preserving cell viability and physiological processes. By influencing multiple pathological processes, including mitochondrial fission/fusion, mitophagy, cellular senescence, and cell death, mitochondrial dysfunction contributes to the development of HCC. We review the molecular mechanisms of HCC-associated mitochondrial dysfunction and discuss new directions for quality control of mitochondrial disorders as a treatment for HCC.
Collapse
Affiliation(s)
- Lianlin Zeng
- Department of Rehabilitation Medicine, Suining Central Hospital, Suining, Sichuan Provience, China
| | - Lutao Zhu
- Department of Rehabilitation Medicine, Suining Central Hospital, Suining, Sichuan Provience, China
| | - Shasha Fu
- Department of Rehabilitation Medicine, Suining Central Hospital, Suining, Sichuan Provience, China
| | - Yangan Li
- Department of Rehabilitation Medicine, Suining Central Hospital, Suining, Sichuan Provience, China
| | - Kehui Hu
- Department of Rehabilitation Medicine, Suining Central Hospital, Suining, Sichuan Provience, China.
| |
Collapse
|
|
7
|
Grossini E, Venkatesan S, Ola Pour MM. Mitochondrial Dysfunction in Endothelial Cells: A Key Driver of Organ Disorders and Aging. Antioxidants (Basel) 2025; 14:372. [PMID: 40298614 PMCID: PMC12024085 DOI: 10.3390/antiox14040372] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2025] [Revised: 03/14/2025] [Accepted: 03/19/2025] [Indexed: 04/30/2025] Open
Abstract
Mitochondria are of great importance in cell biology since they are major sites of adenosine triphosphate (ATP) production and are widely involved in different cellular pathways involved in the response to stress. During ATP production, reactive oxygen species (ROS) can be produced. While a small amount of ROS may be important for the regulation of physiological processes, at elevated levels they can turn into harmful agents leading to cellular damage. From a pathological perspective, it could be particularly interesting to focus on mitochondrial function in endothelial cells since they may be involved in the development of aging and in the onset of different diseases, including renal, cardio-metabolic, liver and neurodegenerative ones. However, to date, there are no surveys which address the above issues. To fill this gap, it may be valuable to collect recent findings about the role of mitochondria in the regulation of endothelial function, not only to increase knowledge about it but also for clinical applications. Here, we overview the most recent knowledge about the above issues in the view of characterizing the role of mitochondria in endothelial cells as an innovative potential target for the prevention of aging, as well as the treatment of the above pathological conditions.
Collapse
Affiliation(s)
- Elena Grossini
- Laboratory of Physiology, Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; (S.V.); (M.M.O.P.)
| | | | | |
Collapse
|
|
8
|
Zhuang Q, Chen L, Wu W, Wang Q, Kang C, Xiong Y, Huang X. Scutellarin ameliorates ischemia/reperfusion-mediated endothelial dysfunction by upregulating cathepsin D expression to rescue autophagy-lysosomal function. Front Pharmacol 2025; 16:1538697. [PMID: 40098620 PMCID: PMC11911473 DOI: 10.3389/fphar.2025.1538697] [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: 12/20/2024] [Accepted: 02/12/2025] [Indexed: 03/19/2025] Open
Abstract
Background Endothelial dysfunction-induced microcirculation impairment and the no-reflow phenomenon are the leading causes of cardiac ischemia/reperfusion (I/R) injury. There is an urgent need to elucidate the underlying mechanism of I/R-mediated endothelial dysfunction and to identify effective drugs for treatment. Scutellarin (SCU), a flavonoid compound, has been extensively studied because of its various pharmacological properties, including its potent protective effects on the cardiovascular system. However, the anti-endothelial dysfunction efficacy and mechanisms of action of SCU have not been investigated. Approach and results An in vivo I/R injury model was established using coronary artery ligation and release. An oxygen-glucose deprivation/oxygen-glucose resupply (OGD/OGR) approach was used to establish an in vitro I/R injury model. We evaluated the effects of SCU on endothelial dysfunction under I/R conditions, both in vivo and in vitro. SCU pretreatment promoted vasodilation and reperfusion of blood flow, inhibited myocardial injury and infarction, and improved cardiac function in I/R rats. Additionally, SCU inhibited cell membrane damage, reactive oxygen species (ROS) accumulation, inflammation, nitric oxide (NO) reduction, endothelin 1 (ET-1) elevation and increase in the expression levels of vascular endothelial growth factor (VEGF) and von willebrand factor (vWF) in endothelial cells. Mechanistically, SCU rescued the lysosomal flow and autophagic flux disrupted by I/R through upregulating cathepsin D (CTSD) levels. Knockdown of CTSD or treatment with the CTSD inhibitor pepstatin A (P.A) abrogated the protective effects of SCU on endothelial cells under I/R conditions. Conclusion We demonstrated that SCU, via upregulation of CTSD levels in endothelial cells, rescued autophagy-lysosomal function and alleviated I/R-mediated endothelial dysfunction. Thus, SCU is a potential therapeutic drug for the prevention and treatment of cardiac I/R injury.
Collapse
Affiliation(s)
- Qizhen Zhuang
- The Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Lu Chen
- The Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Wanqian Wu
- The Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Qing Wang
- The Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Chunmin Kang
- Department of Laboratory Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Key Laboratory of Research on Emergency in TCM, Guangzhou, China
| | - Yujuan Xiong
- Department of Laboratory Medicine, Panyu Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xianzhang Huang
- Department of Laboratory Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Key Laboratory of Research on Emergency in TCM, Guangzhou, China
| |
Collapse
|
|
9
|
Pandolfi S, Chirumbolo S, Franzini M, Tirelli U, Valdenassi L. Oxygen-ozone therapy for myocardial ischemic stroke and cardiovascular disorders. Med Gas Res 2025; 15:36-43. [PMID: 39217427 PMCID: PMC11515079 DOI: 10.4103/mgr.medgasres-d-23-00013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Revised: 12/08/2023] [Accepted: 07/10/2024] [Indexed: 09/04/2024] Open
Abstract
Cardiovascular diseases (CVDs) represent a major concern for human health worldwide. Emergencies in this field include wide repertories of studies dealing primarily with CVD prevention. In addition to dietary habits and lifestyles, medical knowledge is fully needed to improve public educational programs toward cardiovascular risk factors and to enrich the endowment of pharmaceutical options and therapies to address CVDs, particularly for ischemic damage due to an impairment in the endothelial-myocardial relationship. Because ozone is a stimulator of the endothelial nitric oxide synthase/nitric oxide pathway, ozone therapy has been widely demonstrated to have the ability to counteract endothelial-cardiac disorders, providing a novel straightforward opportunity to reduce the impact of CVDs, including atrial fibrillation. In this review, we attempt to establish a state-of-the-art method for the use of ozone in CVD, suggesting that future remarks be addressed to provide fundamental insights into this issue. The purpose of this study was to highlight the role of ozone in the adjunctive medical treatment of cardiovascular pathologies such as acute myocardial infarction due to ischemic disorders.
Collapse
Affiliation(s)
- Sergio Pandolfi
- High School Master of Oxygen Ozone Therapy, University of Pavia, Pavia, Italy
- Italian Scientific Society of Oxygen-Ozone Therapy (SIOOT), Gorle, Italy
| | - Salvatore Chirumbolo
- Department of Engineering for Innovation Medicine, University of Verona, Verona, Italy
| | - Marianno Franzini
- High School Master of Oxygen Ozone Therapy, University of Pavia, Pavia, Italy
- Italian Scientific Society of Oxygen-Ozone Therapy (SIOOT), Gorle, Italy
| | | | - Luigi Valdenassi
- High School Master of Oxygen Ozone Therapy, University of Pavia, Pavia, Italy
- Italian Scientific Society of Oxygen-Ozone Therapy (SIOOT), Gorle, Italy
| |
Collapse
|
|
10
|
Morariu-Briciu DM, Bolintineanu SL, Rata A, Semenescu AD, Anton A, Jijie R, Kis A, Hrubaru I, Heghes A. Assessment of the biosafety profile of Galium verum in vitro on myoblasts and in ovo on chorioallantoic membrane. World J Cardiol 2025; 17:102310. [DOI: 10.4330/wjc.v17.i2.102310] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 12/09/2024] [Accepted: 01/03/2025] [Indexed: 02/25/2025] Open
Abstract
BACKGROUND Cardiovascular diseases are the first cause of death in the world. Ischemic heart disease is the main cause of heart failure. New approaches are continuously sought to identify better therapeutic success. Thereby, current research has been drawn to identifying and completing the therapeutic profile of natural sources. Galium species are representatives exhibiting diuretic and antibacterial potential in living organisms and can treat burns, wounds, and skin diseases. Moreover, it was also observed that these plants manifest cardioprotective effects as well as having antihemolytic, antioxidant, antibacterial, anti-inflammatory, immunomodulatory, and antiproliferative potential. In ischemic heart disease, Galium verum (G. verum) extract manifested preservative properties in terms of contractility, systolic and diastolic function maintenance, and reduced damage to the heart after ischemia. In addition, G. verum extract upregulated the activity of antioxidant enzymes alleviating the production of pro-oxidants.
AIM To test the ethanolic extract of G. verum on the H9C2(2-1) cell line by evaluating the in vitro biosafety profile and in ovo irritative potential.
METHODS Cells were tested in vitro for viability (using the MTT test), cellular morphology, cell number, confluence, nuclear morphology (by immunofluorescence staining of cell nuclei and F-actin assay) and in ovo by the hen’s egg chorioallantoic membrane (CAM) test and CAM anti-irritant methods to study the irritation potential on the CAM.
RESULTS The extract demonstrated a dose-dependent stimulatory activity. The viability increased to 170% for the dose of 55 µg/mL and decreased to 135% at 200 µg/mL. The results of cell number, confluence, and morphological analysis did not present significant changes compared with control untreated cells. The immunofluorescence assay showed insignificant apoptotic potential, and the hen’s egg CAM test revealed that the extract was in the weak to moderately irritating category with an irritation score of 5.3. When applying the sample to the CAM, only slight coagulation was observed (128 s). The anti-irritant test revealed the protective potential of the extract in the vascular plexus.
CONCLUSION The ethanolic extract of G. verum manifests a stimulating effect on cardiomyocytes, enhancing cell viability, and maintaining a normal elongated shape, cell number, and confluence, without significant signs of apoptosis and with a weak irritative effect in ovo. In addition, the extract demonstrated a protective effect against hemorrhage, lysis, and coagulation of blood vessels induced by sodium dodecyl sulfate on the CAM.
Collapse
Affiliation(s)
- Diana Maria Morariu-Briciu
- Department of Anatomy and Embryology, “Victor Babes” University of Medicine and Pharmacy, Timisoara 300041, Romania
- Doctoral School, “Victor Babes” University of Medicine and Pharmacy, Timisoara 300041, Romania
| | - Sorin Lucian Bolintineanu
- Department of Anatomy and Embryology, “Victor Babes” University of Medicine and Pharmacy, Timisoara 300041, Romania
| | - Andreea Rata
- Department of Vascular Surgery, “Victor Babes” University of Medicine and Pharmacy, Timisoara 300041, Romania
| | - Alexandra Denisa Semenescu
- Department of Toxicology, Drug Industry, Management and Legislation, “Victor Babes” University of Medicine and Pharmacy, Timisoara 300041, Romania
- Research Center for Pharmaco-Toxicological Evaluations, “Victor Babes” University of Medicine and Pharmacy, Timisoara 300041, Romania
| | - Alina Anton
- Department of Toxicology, Drug Industry, Management and Legislation, “Victor Babes” University of Medicine and Pharmacy, Timisoara 300041, Romania
- Research Center for Pharmaco-Toxicological Evaluations, “Victor Babes” University of Medicine and Pharmacy, Timisoara 300041, Romania
| | - Robert Jijie
- Department of Toxicology, Drug Industry, Management and Legislation, “Victor Babes” University of Medicine and Pharmacy, Timisoara 300041, Romania
- Research Center for Pharmaco-Toxicological Evaluations, “Victor Babes” University of Medicine and Pharmacy, Timisoara 300041, Romania
| | - Andreea Kis
- Department of Toxicology, Drug Industry, Management and Legislation, “Victor Babes” University of Medicine and Pharmacy, Timisoara 300041, Romania
- Research Center for Pharmaco-Toxicological Evaluations, “Victor Babes” University of Medicine and Pharmacy, Timisoara 300041, Romania
| | - Ingrid Hrubaru
- Department of Obstetrics and Gynecology, “Victor Babes” University of Medicine and Pharmacy, Timisoara 300041, Romania
| | - Alina Heghes
- Department of Pharmaceutical Technology, “Victor Babes” University of Medicine and Pharmacy, Timisoara 300041, Romania
| |
Collapse
|
|
11
|
Liu X, Liu H, Wang N, Lai S, Qiu C, Gao S, Huang T, Zhang W. The interactive toxic effect of homocysteine and copper on cardiac microvascular endothelial cells during ischemia-reperfusion injury. Chem Biol Interact 2025; 408:111387. [PMID: 39824432 DOI: 10.1016/j.cbi.2025.111387] [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: 09/10/2024] [Revised: 01/07/2025] [Accepted: 01/14/2025] [Indexed: 01/20/2025]
Abstract
Hyperhomocysteinemia (HHcy) is associated with the development and progression of chronic cardiovascular diseases through the deleterious effects of high levels of homocysteine (Hcy) on the cardiovascular system. However, the exact mechanism of action of Hcy on the acute injury of the cardiovascular system following ischemia/reperfusion (I/R) remains unclear. The present study demonstrated that copper mobilization occurs during cardiac I/R, and the interactive toxic effect of Hcy and mobile Cu2+ during cardiac I/R induces necroptosis of cardiac microvascular endothelial cells (CMECs) and thus enhances cardiac dysfunction. In the present study, we utilized three cardiac I/R model: isolated rat heart, in vivo model as well as cell culture, and demonstrated that copper mobilization occurs during cardiac I/R, and the interactive toxic effect of Hcy and mobile Cu2+ during cardiac I/R induces necroptosis of cardiac microvascular endothelial cells (CMECs) and thus enhances cardiac dysfunction. Furthermore, we proved that the Cu2+ chelator TTM significantly mitigated the deleterious effects of Hcy and Cu2+ on CMECs and cardiac function both in vitro and in vivo. Mechanismly, the combinative effect of Hcy and Cu2+ are associated with the production of reactive oxygen species (ROS) and nitric oxide (NO) by NADPH oxidase (NOX) and endothelial nitric oxide synthase (eNOS), respectively. Subsequently, the overproduction of toxic peroxynitrite (ONOO-) induces CMECs necroptosis. The application of ROS scavengers in CMECs resulted in a notable reduction in necroptosis mediated by Hcy and Cu2+ under hypoxia/reperfusion (H/R) condition. These findings indicate that the mechanism by which Hcy and Cu2+ enhances cardiac dysfunction under I/R condition may be attributed to the stimulation of both NOX and eNOS activity, resulting in the generation of excessive ONOO- and subsequent necroptosis of CMECs.
Collapse
Affiliation(s)
- Xiaoming Liu
- Department of Thoracic Surgery, The 1st Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, PR China; Jiangxi Hospital of China-Japan Friendship Hospital, National Regional Center for Respiratory Medicine, Nanchang, 330000, Jiangxi, PR China; Jiangxi Institute of Respiratory Disease, The 1st Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330000, Jiangxi, PR China
| | - Haipeng Liu
- Department of Thoracic Surgery, The 1st Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, PR China; Jiangxi Hospital of China-Japan Friendship Hospital, National Regional Center for Respiratory Medicine, Nanchang, 330000, Jiangxi, PR China; Jiangxi Institute of Respiratory Disease, The 1st Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330000, Jiangxi, PR China
| | - Ning Wang
- Department of Thoracic Surgery, The 1st Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, PR China; Jiangxi Hospital of China-Japan Friendship Hospital, National Regional Center for Respiratory Medicine, Nanchang, 330000, Jiangxi, PR China; Jiangxi Institute of Respiratory Disease, The 1st Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330000, Jiangxi, PR China
| | - Songqing Lai
- Department of Cardiovascular Surgery, The 1st Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, PR China
| | - Chengpeng Qiu
- Department of Thoracic Surgery, The 1st Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, PR China; Jiangxi Hospital of China-Japan Friendship Hospital, National Regional Center for Respiratory Medicine, Nanchang, 330000, Jiangxi, PR China; Jiangxi Institute of Respiratory Disease, The 1st Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330000, Jiangxi, PR China
| | - Shansong Gao
- Department of Thoracic Surgery, The 1st Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, PR China; Jiangxi Hospital of China-Japan Friendship Hospital, National Regional Center for Respiratory Medicine, Nanchang, 330000, Jiangxi, PR China; Jiangxi Institute of Respiratory Disease, The 1st Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330000, Jiangxi, PR China
| | - Tianxiang Huang
- Department of Thoracic Surgery, The 1st Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, PR China; Jiangxi Hospital of China-Japan Friendship Hospital, National Regional Center for Respiratory Medicine, Nanchang, 330000, Jiangxi, PR China
| | - Wan Zhang
- Department of Thoracic Surgery, The 1st Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, PR China; Jiangxi Hospital of China-Japan Friendship Hospital, National Regional Center for Respiratory Medicine, Nanchang, 330000, Jiangxi, PR China; Jiangxi Institute of Respiratory Disease, The 1st Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330000, Jiangxi, PR China.
| |
Collapse
|
|
12
|
Li W, Li Y, Xiao L, Xie Z, Peng J, Huang W, Li X, Meng Y. Micheliolide attenuates sepsis-induced acute lung injury by suppressing mitochondrial oxidative stress and PFKFB3-driven glycolysis. J Transl Med 2025; 23:181. [PMID: 39953547 PMCID: PMC11829335 DOI: 10.1186/s12967-024-05906-0] [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: 08/02/2024] [Accepted: 11/19/2024] [Indexed: 02/17/2025] Open
Abstract
BACKGROUND Sepsis is a potentially fatal condition with a significant risk of death. Acute lung injury (ALI) is a life-threatening complication of sepsis, and the inflammatory response plays a critical role in sepsis-induced ALI. The protective effects of micheliolide (MCL) against renal fibrosis and leukemia have been demonstrated, but the precise underlying mechanisms remain unclear. METHODS In vitro, lipopolysaccharides (LPS) and interferon-gamma (IFN-γ) were used to stimulate RAW264.7 cells and bone marrow-derived macrophages (BMDMs) to investigate the protective effect of MCL on sepsis-induced ALI. Cecal ligation and puncture (CLP) models were constructed in mice to induce ALI in vivo. The expression of inflammatory factors, macrophage polarization markers, and the glycolysis-related enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) were measured in vivo. Mitochondrial function, oxidative stress, and mitochondrial-related proteins were evaluated in vitro. RESULTS MCL inhibited CLP-induced ALI, as evidenced by improvements in proinflammatory factor levels, lung wet/dry ratios, and histopathological findings. In vitro, MCL treatment significantly suppressed LPS + IFN-γ-induced M1-type polarization of RAW264.7 cells and BMDMs, as well as the production of inflammatory factors and oxidative stress. Mechanistic experiments revealed that MCL suppresses PFKFB3-driven glycolysis to reduce inflammation and activates the mitochondrial unfolded protein response (UPRmt) to alleviate mitochondrial stress. However, the therapeutic effect of MCL was diminished when PFKFB3 was overexpressed in cells. CONCLUSION This study is the first to demonstrate that MCL attenuates sepsis-induced ALI by reducing M1-type macrophage polarization. Its therapeutic effect is closely related to the suppression of oxidative stress and PFKFB3-driven glycolysis.
Collapse
Affiliation(s)
- Wenhan Li
- Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, 510515, China
| | - Yuhan Li
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Linjie Xiao
- Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, 510515, China
| | - Zhanzhan Xie
- Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, 510515, China
| | - Jun Peng
- Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, 510515, China
| | - Wenhui Huang
- Department of Respiratory and Critical Care Medicine, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510000, China
| | - Xu Li
- Department of Emergency Medicine, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, 510515, China.
| | - Ying Meng
- Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, 510515, China.
| |
Collapse
|
|
13
|
Xia T, Yu J, Du M, Chen X, Wang C, Li R. Vascular endothelial cell injury: causes, molecular mechanisms, and treatments. MedComm (Beijing) 2025; 6:e70057. [PMID: 39931738 PMCID: PMC11809559 DOI: 10.1002/mco2.70057] [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: 06/12/2024] [Revised: 12/16/2024] [Accepted: 12/17/2024] [Indexed: 02/13/2025] Open
Abstract
Vascular endothelial cells form a single layer of flat cells that line the inner surface of blood vessels, extending from large vessels to the microvasculature of various organs. These cells are crucial metabolic and endocrine components of the body, playing vital roles in maintaining circulatory stability, regulating vascular tone, and preventing coagulation and thrombosis. Endothelial cell injury is regarded as a pivotal initiating factor in the pathogenesis of various diseases, triggered by multiple factors, including infection, inflammation, and hemodynamic changes, which significantly compromise vascular integrity and function. This review examines the causes, underlying molecular mechanisms, and potential therapeutic approaches for endothelial cell injury, focusing specifically on endothelial damage in cardiac ischemia/reperfusion (I/R) injury, sepsis, and diabetes. It delves into the intricate signaling pathways involved in endothelial cell injury, emphasizing the roles of oxidative stress, mitochondrial dysfunction, inflammatory mediators, and barrier damage. Current treatment strategies-ranging from pharmacological interventions to regenerative approaches and lifestyle modifications-face ongoing challenges and limitations. Overall, this review highlights the importance of understanding endothelial cell injury within the context of various diseases and the necessity for innovative therapeutic methods to improve patient outcomes.
Collapse
Affiliation(s)
- Tian Xia
- Department of Laboratory MedicineThe First Medical Center of Chinese PLA General HospitalBeijingChina
- Department of Laboratory MedicineMedical School of Chinese PLABeijingChina
| | - Jiachi Yu
- Department of Laboratory MedicineThe First Medical Center of Chinese PLA General HospitalBeijingChina
- Department of Laboratory MedicineMedical School of Chinese PLABeijingChina
| | - Meng Du
- Department of Laboratory MedicineThe First Medical Center of Chinese PLA General HospitalBeijingChina
- Department of Clinical LaboratoryHuaian Hospital of Huaian CityHuaianJiangsuChina
| | - Ximeng Chen
- Department of Laboratory MedicineThe First Medical Center of Chinese PLA General HospitalBeijingChina
- Department of Laboratory MedicineMedical School of Chinese PLABeijingChina
| | - Chengbin Wang
- Department of Laboratory MedicineThe First Medical Center of Chinese PLA General HospitalBeijingChina
- Department of Laboratory MedicineMedical School of Chinese PLABeijingChina
| | - Ruibing Li
- Department of Laboratory MedicineThe First Medical Center of Chinese PLA General HospitalBeijingChina
- Department of Laboratory MedicineMedical School of Chinese PLABeijingChina
| |
Collapse
|
|
14
|
Al-Faze R, Ahmed HA, El-Atawy MA, Zagloul H, Alshammari EM, Jaremko M, Emwas AH, Nabil GM, Hanna DH. Mitochondrial dysfunction route as a possible biomarker and therapy target for human cancer. Biomed J 2025; 48:100714. [PMID: 38452973 PMCID: PMC11743316 DOI: 10.1016/j.bj.2024.100714] [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: 01/18/2024] [Revised: 03/02/2024] [Accepted: 03/04/2024] [Indexed: 03/09/2024] Open
Abstract
Mitochondria are vital organelles found within living cells and have signalling, biosynthetic, and bioenergetic functions. Mitochondria play a crucial role in metabolic reprogramming, which is a characteristic of cancer cells and allows them to ensure a steady supply of proteins, nucleotides, and lipids to enable rapid proliferation and development. Their dysregulated activities have been associated with the growth and metastasis of different kinds of human cancer, particularly ovarian carcinoma. In this review, we briefly demonstrated the modified mitochondrial function in cancer, including mutations in mitochondrial DNA (mtDNA), reactive oxygen species (ROS) production, dynamics, apoptosis of cells, autophagy, and calcium excess to maintain cancer genesis, progression, and metastasis. Furthermore, the mitochondrial dysfunction pathway for some genomic, proteomic, and metabolomics modifications in ovarian cancer has been studied. Additionally, ovarian cancer has been linked to targeted therapies and biomarkers found through various alteration processes underlying mitochondrial dysfunction, notably targeting (ROS), metabolites, rewind metabolic pathways, and chemo-resistant ovarian carcinoma cells.
Collapse
Affiliation(s)
- Rawan Al-Faze
- Department of Chemistry, Faculty of Science, Taibah University, Almadinah Almunawarah, Saudi Arabia
| | - Hoda A Ahmed
- Chemistry Department, Faculty of Science at Yanbu, Taibah University, Yanbu, Saudi Arabia; Chemistry Department, Faculty of Science, Cairo University, Giza, Egypt
| | - Mohamed A El-Atawy
- Chemistry Department, Faculty of Science at Yanbu, Taibah University, Yanbu, Saudi Arabia; Chemistry Department, Faculty of Science, Alexandria University, Ibrahemia, Alexandria, Egypt
| | - Hayat Zagloul
- Chemistry Department, Faculty of Science at Yanbu, Taibah University, Yanbu, Saudi Arabia
| | - Eida M Alshammari
- Department of Chemistry, College of Sciences, University of Ha'il, Ha'il, Saudi Arabia
| | - Mariusz Jaremko
- Biological and Environmental Sciences & Engineering Division (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia
| | - Abdul-Hamid Emwas
- Core Labs., King Abdullah University of Science and Technology, Thuwal, Saudi Arabia
| | - Gehan M Nabil
- Department of Chemistry, College of Science and Humanities in Al-Kharj, Prince Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia
| | - Demiana H Hanna
- Chemistry Department, Faculty of Science, Cairo University, Giza, Egypt.
| |
Collapse
|
|
15
|
Wang K, Zhu Q, Liu W, Wang L, Li X, Zhao C, Wu N, Ma C. Mitochondrial apoptosis in response to cardiac ischemia-reperfusion injury. J Transl Med 2025; 23:125. [PMID: 39875870 PMCID: PMC11773821 DOI: 10.1186/s12967-025-06136-8] [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: 10/10/2024] [Accepted: 01/13/2025] [Indexed: 01/30/2025] Open
Abstract
In patients with acute myocardial infarction (AMI), thrombolytic therapy and revascularization strategies allow complete recanalization of occluded epicardial coronary arteries. However, approximately 35% of patients still experience myocardial ischemia/reperfusion (I/R) injury, which contributing to increased AMI mortality. Therefore, an accurate understanding of myocardial I/R injury is important for preventing and treating AMI. The death of each cell (cardiomyocytes, endothelial cells, vascular smooth muscle cells, cardiac fibroblasts, and mesenchymal stem cells) after myocardial ischemia/reperfusion is associated with apoptosis due to mitochondrial dysfunction. Abnormal opening of the mitochondrial permeability transition pore, aberrant mitochondrial membrane potential, Ca2+ overload, mitochondrial fission, and mitophagy can lead to mitochondrial dysfunction, thereby inducing mitochondrial apoptosis. The manifestation of mitochondrial apoptosis varies according to cell type. Here, we reviewed the characteristics of mitochondrial apoptosis in cardiomyocytes, endothelial cells, vascular smooth muscle cells, cardiac fibroblasts, and mesenchymal stem cells following myocardial ischemia/reperfusion.
Collapse
Affiliation(s)
- Kaixin Wang
- Department of Cardiovascular Ultrasound, The First Hospital of China Medical University, Shenyang, China
- Clinical Medical Research Center of Imaging in Liaoning Province, Shenyang, China
| | - Qing Zhu
- Department of Cardiovascular Ultrasound, The First Hospital of China Medical University, Shenyang, China
- Clinical Medical Research Center of Imaging in Liaoning Province, Shenyang, China
| | - Wen Liu
- Department of Cardiovascular Ultrasound, The First Hospital of China Medical University, Shenyang, China
- Clinical Medical Research Center of Imaging in Liaoning Province, Shenyang, China
| | - Linyuan Wang
- Department of Cardiovascular Ultrasound, The First Hospital of China Medical University, Shenyang, China
- Clinical Medical Research Center of Imaging in Liaoning Province, Shenyang, China
| | - Xinxin Li
- Department of Cardiovascular Ultrasound, The First Hospital of China Medical University, Shenyang, China
- Clinical Medical Research Center of Imaging in Liaoning Province, Shenyang, China
| | - Cuiting Zhao
- Department of Cardiovascular Ultrasound, The First Hospital of China Medical University, Shenyang, China
- Clinical Medical Research Center of Imaging in Liaoning Province, Shenyang, China
| | - Nan Wu
- The Central Laboratory of The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Chunyan Ma
- Department of Cardiovascular Ultrasound, The First Hospital of China Medical University, Shenyang, China.
- Clinical Medical Research Center of Imaging in Liaoning Province, Shenyang, China.
| |
Collapse
|
|
16
|
Liu M, Li B, Yin Z, Yin L, Luo Y, Zeng Q, Zhang D, Wu A, Chen L. Targeting mitochondrial dynamics: A promising approach for intracerebral hemorrhage therapy. Life Sci 2025; 361:123317. [PMID: 39674268 DOI: 10.1016/j.lfs.2024.123317] [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: 10/04/2024] [Revised: 12/03/2024] [Accepted: 12/11/2024] [Indexed: 12/16/2024]
Abstract
Intracerebral hemorrhage (ICH) is a major global health issue with high mortality and disability rates. Following ICH, the hematoma exerts direct pressure on brain tissue, and blood entering the brain directly damages neurons and the blood-brain barrier. Subsequently, oxidative stress, inflammatory responses, apoptosis, brain edema, excitotoxicity, iron toxicity, and metabolic dysfunction around the hematoma further exacerbate brain tissue damage, leading to secondary brain injury (SBI). Mitochondria, essential for energy production and the regulation of oxidative stress, are damaged after ICH, resulting in impaired ATP production, excessive reactive oxygen species (ROS) generation, and disrupted calcium homeostasis, all of which contribute to SBI. Therefore, a central factor in SBI is mitochondrial dysfunction. Mitochondrial dynamics regulate the shape, size, distribution, and quantity of mitochondria through fusion and fission, both of which are crucial for maintaining their function. Fusion repairs damaged mitochondria and preserves their health, while fission helps mitochondria adapt to cellular stress and removes damaged mitochondria through mitophagy. When this balance is disrupted following ICH, mitochondrial dysfunction worsens, oxidative stress and metabolic failure are exacerbated, ultimately contributing to SBI. Targeting mitochondrial dynamics offers a promising therapeutic approach to restoring mitochondrial function, reducing cellular damage, and improving recovery. This review explores the latest research on modulating mitochondrial dynamics and highlights its potential to enhance outcomes in ICH patients.
Collapse
Affiliation(s)
- Mengnan Liu
- Department of Cardiovascular Medicine, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou 646000, Sichuan, China.
| | - Binru Li
- Department of Neurology, Minzu Hospital of Guangxi Zhuang Autonomous Region, Nanning 530021, Guangxi, China.
| | - Zhixue Yin
- Southwest Medical University, Luzhou 646000, Sichuan, China.
| | - Lu Yin
- Southwest Medical University, Luzhou 646000, Sichuan, China.
| | - Ye Luo
- Southwest Medical University, Luzhou 646000, Sichuan, China.
| | - Qi Zeng
- Southwest Medical University, Luzhou 646000, Sichuan, China.
| | - Dechou Zhang
- Department of Neurology, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou 646000, Sichuan, China.
| | - Anguo Wu
- Sichuan Key Medical Laboratory of New Drug Discovery and Drugability Evaluation, Department of Cardiology, The Affiliated Hospital of Southwest Medical University and Key Laboratory of Medical Electrophysiology, Ministry of Education, School of Pharmacy, Luzhou 646000, Sichuan, China; Southwest Medical University, Luzhou 646000, Sichuan, China.
| | - Li Chen
- Department of Neurology, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou 646000, Sichuan, China.
| |
Collapse
|
|
17
|
Liu W, Hu J, Wang Y, Gan T, Ding Y, Wang X, Xu Q, Xiong J, Xiong N, Lu S, Wang Y, Wang Z. 9-PAHSA ameliorates microvascular damage during cardiac ischaemia/reperfusion injury by promoting LKB1/AMPK/ULK1-mediated autophagy-dependent STING degradation. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 136:156241. [PMID: 39579609 DOI: 10.1016/j.phymed.2024.156241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Revised: 10/25/2024] [Accepted: 11/07/2024] [Indexed: 11/25/2024]
Abstract
BACKGROUND Considering that cardiac microvascular injury may play a more critical role than cardiomyocyte injury in the pathology of early ischaemia/reperfusion (I/R) injury, therapeutic strategies targeting the microvasculature are highly desirable. Palmitic acid-9-hydroxystearic acid (9-PAHSA) is a new class of bioactive anti-inflammatory lipids widely distributed in vegetables, fruits and medicinal plants, especially broccoli and apple. However, the pharmacological effects and underlying mechanisms of 9-PAHSA in protecting- against cardiac microvascular I/R injury have rarely been studied. PURPOSE This study aimed to explore the potential effects and molecular mechanisms of 9-PAHSA on the coronary microvasculature after cardiac I/R injury. METHODS Immunofluorescence staining, western blotting, and other experimental methods were used to evaluate the role and mechanism of 9-PAHSA in cardiac microvascular I/R injury in vivo and in vitro. RESULTS 9-PAHSA administration significantly attenuated myocardial I/R-induced microvascular damage, as indicated by an impaired microvascular structure, reduced regional blood perfusion and decreased endothelial barrier function. In addition, 9-PAHSA administration protected the structure and function of coronary artery endothelial cells (CMECs) to resist I/R damage, an effect that was at least partially mediated by increased autophagy. Mechanistically, 9-PAHSA activated autophagy through the LKB1/AMPK/ULK1 pathway and promoted STING degradation via the autophagic‒lysosomal pathway. CONCLUSIONS To our best knowledge, this study is the first to report that 9-PAHSA attenuates cardiac microvascular I/R injury, potentially by activating LKB1/AMPK/ULK1-mediated autophagy-dependent STING degradation to suppress apoptosis. Thus, 9-PAHSA may be a promising therapeutic option for alleviating cardiac microvascular I/R injury.
Collapse
Affiliation(s)
- Wenhu Liu
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jing Hu
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Joint International Laboratory of Infection and Immunity, Huazhong University of Science and Technology, Wuhan, China
| | - Ya Wang
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ting Gan
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yan Ding
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xuehua Wang
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qian Xu
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jingjie Xiong
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ni Xiong
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shuai Lu
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yan Wang
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Zhaohui Wang
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| |
Collapse
|
|
18
|
Duan Q, Dong A, Cheng H, Zhang S, Chen W, Yang W. Inhibition of Taurine-upregulated Gene 1 Upregulates MiR-34a-5p to Protect against Myocardial Ischemia/Reperfusion via Autophagy Regulation. Comb Chem High Throughput Screen 2025; 28:110-121. [PMID: 38299288 DOI: 10.2174/0113862073267559231106074309] [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: 06/16/2023] [Revised: 08/23/2023] [Accepted: 09/25/2023] [Indexed: 02/02/2024]
Abstract
BACKGROUND Taurine upregulated gene 1 (TUG1) has been identified on long noncoding RNA (lncRNA); however, its function in myocardial cells following ischemia/ reperfusion (I/R) injury has not been explored. This study aimed to investigate the role of LncTUG1 in I/R injury by focusing on its relationship with autophagy induction by regulating miR-34a-5p expression. METHODS We established a myocardial I/R model and H9C2 hypoxia-ischemic and reoxygenation (HI/R) conditions to induce I/R injury. TTC, Western blot, CCK-8 assay, quantitative reverse transcription PCR, flow cytometry, and confocal microscopy were used to assess the size of myocardial infarct, level of some apoptotic-related and autophagy-associated proteins, cell viability, the level of LncRNA TUG1, apoptosis, and autophagy, respectively. RESULTS The results revealed that a TUG1 knockdown protected against I/R-induced myocardial injury by decreasing the impairment in cardiac function. LncRNA TUG1 expression was increased in a myocardial I/R model and HI/R in H9C2 cells. Moreover, inhibition of LncTUG1 enhanced H9C2 cell viability and protected the cells from HI/R-induced apoptosis. Silencing LncRNA TUG1 promoted HI/R-induced autophagy. Furthermore, TUG1 siRNA upregulated the level of miR-34a-5p compared to the HI/R group. The protective effect of LncRNA TUG1 inhibition on H9C2 cells following HI/R was eliminated by blocking autophagy with an miR-34a-5p inhibitor. CONCLUSION These findings indicated that inhibiting TUG1 may reduce the extent of myocardial I/R injury by regulating miR-34a-5p. Taken together, these results suggest that LncRNA TUG1 may represent a novel therapeutic target for myocardial I/R injury.
Collapse
Affiliation(s)
- Qunjun Duan
- Department of Cardiaovascular Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China
| | - Aiqiang Dong
- Department of Cardiaovascular Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China
| | - Haifeng Cheng
- Department of Cardiaovascular Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China
| | - Shufen Zhang
- Department of Cancer Institute of Integrated Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang 310012, China
| | - Wei Chen
- Department of Cancer Institute of Integrated Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang 310012, China
| | - Weijun Yang
- Department of Cardiaovascular Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China
| |
Collapse
|
|
19
|
Doulamis IP, Tzani A, Alemany VS, Nomoto RS, Celik A, Recco DP, Saeed MY, Guariento A, Plutzky J, Emani SM, Del Nido PJ, McCully JD. Mitochondrial transplantation normalizes transcriptomic and proteomic shift associated with ischemia reperfusion injury in neonatal hearts donated after circulatory death. Sci Rep 2024; 14:31236. [PMID: 39732955 PMCID: PMC11682362 DOI: 10.1038/s41598-024-82578-2] [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: 05/31/2024] [Accepted: 12/06/2024] [Indexed: 12/30/2024] Open
Abstract
Heart transplantation remains the ultimate treatment strategy for neonates and children with medically refractory end-stage heart failure and utilization of donors after circulatory death (DCD) can expand th donor pool. We have previously shown that mitochondrial transplantation preserves myocardial function and viability in neonatal swine DCD hearts to levels similar to that observed in donation after brain death (DBD). Herein, we sought to investigate the transcriptomic and proteomic pathways implicated in these phenotypic changes using ex situ perfused swine hearts. Pathway analysis showed that ATP binding, voltage-gated K channel activity involved in cardiac cell muscle contraction and ribosomal RNA biogenesis were upregulated in the mitochondrial transplantation group, while mitochondria were the predicted source. Promotion of ribosome biogenesis and downregulation of apoptosis were the overlapping mechanisms between transcriptomic and proteomic alterations. Moreover, we showed that mitochondrial transplantation modulates ischemic transcriptomic and proteomic profiles to that of non-ischemia through the mitochondria. Replication of these findings in human in vivo experiments is warranted.
Collapse
Affiliation(s)
- Ilias P Doulamis
- Department of Cardiac Surgery, Boston Children's Hospital, 300 Longwood Ave, Boston, MA, 02115, USA
- Harvard Medical School, Boston, MA, USA
| | - Aspasia Tzani
- Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA, USA
| | - Victor S Alemany
- Department of Cardiac Surgery, Boston Children's Hospital, 300 Longwood Ave, Boston, MA, 02115, USA
- Harvard Medical School, Boston, MA, USA
| | - Rio S Nomoto
- Department of Cardiac Surgery, Boston Children's Hospital, 300 Longwood Ave, Boston, MA, 02115, USA
- Harvard Medical School, Boston, MA, USA
| | - Aybuke Celik
- Department of Cardiac Surgery, Boston Children's Hospital, 300 Longwood Ave, Boston, MA, 02115, USA
- Harvard Medical School, Boston, MA, USA
| | - Dominic P Recco
- Department of Cardiac Surgery, Boston Children's Hospital, 300 Longwood Ave, Boston, MA, 02115, USA
- Harvard Medical School, Boston, MA, USA
| | - Mossab Y Saeed
- Department of Cardiac Surgery, Boston Children's Hospital, 300 Longwood Ave, Boston, MA, 02115, USA
- Harvard Medical School, Boston, MA, USA
| | - Alvise Guariento
- Department of Cardiac Surgery, Boston Children's Hospital, 300 Longwood Ave, Boston, MA, 02115, USA
- Harvard Medical School, Boston, MA, USA
| | - Jorge Plutzky
- Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA, USA
| | - Sitaram M Emani
- Department of Cardiac Surgery, Boston Children's Hospital, 300 Longwood Ave, Boston, MA, 02115, USA
- Harvard Medical School, Boston, MA, USA
| | - Pedro J Del Nido
- Department of Cardiac Surgery, Boston Children's Hospital, 300 Longwood Ave, Boston, MA, 02115, USA
- Harvard Medical School, Boston, MA, USA
| | - James D McCully
- Department of Cardiac Surgery, Boston Children's Hospital, 300 Longwood Ave, Boston, MA, 02115, USA.
- Harvard Medical School, Boston, MA, USA.
| |
Collapse
|
|
20
|
Zhao H, Wang W, Yang Y, Feng C, Lin T, Gong L. Norepinephrine Attenuates Benzalkonium Chloride-Induced Dry Eye Disease by Regulating the PINK1/Parkin Mitophagy Pathway. Ocul Immunol Inflamm 2024:1-15. [PMID: 39731302 DOI: 10.1080/09273948.2024.2447816] [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: 07/11/2024] [Revised: 12/17/2024] [Accepted: 12/21/2024] [Indexed: 12/29/2024]
Abstract
BACKGROUND Increased reactive oxygen species (ROS) are involved in the pathological process of dry eye disease. Our previous results suggested that norepinephrine (NE) has a protective effect on dry eye. PURPOSE This study explored the potential therapeutic role and underlying mechanisms of NE in benzalkonium chloride (BAC)-induced dry eye disease. METHODS BAC-pretreated human corneal epithelial cells (HCEpiC) were cultured with various concentrations of NE. A BAC-induced dry eye mice model was established to explore the role of NE. Alterations in mice corneal tissues, ROS levels, mitochondrial function, and mitophagy levels were analyzed. RESULTS In vitro, our results revealed that BAC-exposed HCEpiC led to mitochondrial malfunction, which involved excessive ROS production, decreased mitochondrial membrane potential (MMP), and promoted mitochondrial fragmentation through increased DRP1 and fission protein 1 (Fis1) expression and reduced mitofusin 2 (Mfn2) expression. Moreover, topical BAC application induced excessive mitophagy. These effects were reversed by NE. Additionally, the increased expression of LC3B, SQSTM1/p62, PINK1, and Parkin, which control mitophagy, in BAC-exposed HCEpiC was suppressed by NE. In BAC-induced C57BL/6J mice, NE resulted in lower fluorescein staining scores, decreased TUNEL-positive cells, and decreased mitochondrial fragmentation. CONCLUSIONS In conclusion, our findings showed that NE therapy prevented HCEpiC following BAC application by regulating mitochondrial quality control, which is controlled by PINK1/Parkin-dependent mitophagy. Our research suggests a potential targeted treatment for dry eye disease.
Collapse
Affiliation(s)
- Han Zhao
- Department of Ophthalmology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Hunan Clinical Research Center of Ophthalmic Disease, Changsha, Hunan, China
| | - Wushuang Wang
- Department of Ophthalmology, Eye, Ear, Nose, and Throat Hospital of Fudan University, Shanghai, China
- Laboratory of Myopia, NHC Key Laboratory of Myopia (Fudan University), Chinese Academy of Medical Sciences, Shanghai, China
| | - Yun Yang
- Department of Ophthalmology, Eye, Ear, Nose, and Throat Hospital of Fudan University, Shanghai, China
- Laboratory of Myopia, NHC Key Laboratory of Myopia (Fudan University), Chinese Academy of Medical Sciences, Shanghai, China
| | - Changming Feng
- Department of Ophthalmology, Eye, Ear, Nose, and Throat Hospital of Fudan University, Shanghai, China
- Laboratory of Myopia, NHC Key Laboratory of Myopia (Fudan University), Chinese Academy of Medical Sciences, Shanghai, China
| | - Tong Lin
- Department of Ophthalmology, Eye, Ear, Nose, and Throat Hospital of Fudan University, Shanghai, China
- Laboratory of Myopia, NHC Key Laboratory of Myopia (Fudan University), Chinese Academy of Medical Sciences, Shanghai, China
| | - Lan Gong
- Department of Ophthalmology, Eye, Ear, Nose, and Throat Hospital of Fudan University, Shanghai, China
- Laboratory of Myopia, NHC Key Laboratory of Myopia (Fudan University), Chinese Academy of Medical Sciences, Shanghai, China
| |
Collapse
|
|
21
|
Qiu B, Xie X, Xi Y. Mitochondrial quality control: the real dawn of intervertebral disc degeneration? J Transl Med 2024; 22:1126. [PMID: 39707402 DOI: 10.1186/s12967-024-05943-9] [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: 03/31/2024] [Accepted: 12/05/2024] [Indexed: 12/23/2024] Open
Abstract
Intervertebral disc degeneration is the most common disease in chronic musculoskeletal diseases and the main cause of low back pain, which seriously endangers social health level and increases people's economic burden. Disc degeneration is characterized by NP cell apoptosis, extracellular matrix degradation and disc structure changes. It progresses with age and under the influence of mechanical overload, oxidative stress and genetics. Mitochondria are not only the energy factories of cells, but also participate in a variety of cellular functions such as calcium homeostasis, regulation of cell proliferation, and control of apoptosis. The mitochondrial quality control system involves many mechanisms such as mitochondrial gene regulation, mitochondrial protein import, mitophagy, and mitochondrial dynamics. A large number of studies have confirmed that mitochondrial dysfunction is a key factor in the pathological mechanism of aging and intervertebral disc degeneration, and balancing mitochondrial quality control is extremely important for delaying and treating intervertebral disc degeneration. In this paper, we first demonstrate the molecular mechanism of mitochondrial quality control in detail by describing mitochondrial biogenesis and mitophagy. Then, we describe the ways in which mitochondrial dysfunction leads to disc degeneration, and review in detail the current research on targeting mitochondria for the treatment of disc degeneration, hoping to draw inspiration from the current research to provide innovative perspectives for the treatment of disc degeneration.
Collapse
Affiliation(s)
- Ba Qiu
- Department of Orthopedics, Spine Surgery, Second Affiliated Hospital of Naval Medical University, Shanghai, 200003, China
| | - Xiaoxing Xie
- Department of Orthopedics, Spine Surgery, Second Affiliated Hospital of Naval Medical University, Shanghai, 200003, China
| | - Yanhai Xi
- Department of Orthopedics, Spine Surgery, Second Affiliated Hospital of Naval Medical University, Shanghai, 200003, China.
| |
Collapse
|
|
22
|
Luo X, Zhang S, Wang L, Li J. Pathological roles of mitochondrial dysfunction in endothelial cells during the cerebral no-reflow phenomenon: A review. Medicine (Baltimore) 2024; 103:e40951. [PMID: 39705421 PMCID: PMC11666140 DOI: 10.1097/md.0000000000040951] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Revised: 11/18/2024] [Accepted: 11/25/2024] [Indexed: 12/22/2024] Open
Abstract
Emergency intravascular interventional therapy is the most effective approach to rapidly restore blood flow and manage occlusion of major blood vessels during the initial phase of acute ischemic stroke. Nevertheless, several patients continue to experience ineffective reperfusion or cerebral no-reflow phenomenon, that is, hypoperfusion of cerebral blood supply after treatment. This is primarily attributed to downstream microcirculation disturbance. As integral components of the cerebral microvascular structure, endothelial cells (ECs) attach importance to regulating microcirculatory blood flow. Unlike neurons and microglia, ECs harbor a relatively low abundance of mitochondria, acting as key sensors of environmental and cellular stress in regulating the viability, structural integrity, and function of ECs rather than generating energy. Mitochondria dysfunction including increased mitochondrial reactive oxygen species levels and disturbed mitochondrial dynamics causes endothelial injury, further causing microcirculation disturbance involved in the cerebral no-reflow phenomenon. Therefore, this review aims to discuss the role of mitochondrial changes in regulating the role of ECs and cerebral microcirculation blood flow during I/R injury. The outcomes of the review will provide promising potential therapeutic targets for future prevention and effective improvement of the cerebral no-reflow phenomenon.
Collapse
Affiliation(s)
- Xia Luo
- Department of Neurology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Laboratory of Neurological Diseases and Brain Function, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Shaotao Zhang
- Department of Neurology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Laboratory of Neurological Diseases and Brain Function, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Longbing Wang
- Department of Neurology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Laboratory of Neurological Diseases and Brain Function, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Jinglun Li
- Department of Neurology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Laboratory of Neurological Diseases and Brain Function, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| |
Collapse
|
|
23
|
Zheng Z, Ke L, Ye S, Shi P, Yao H. Pharmacological Mechanisms of Cryptotanshinone: Recent Advances in Cardiovascular, Cancer, and Neurological Disease Applications. Drug Des Devel Ther 2024; 18:6031-6060. [PMID: 39703195 PMCID: PMC11658958 DOI: 10.2147/dddt.s494555] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Accepted: 11/26/2024] [Indexed: 12/21/2024] Open
Abstract
Cryptotanshinone (CTS) is an important active ingredient of Salvia miltiorrhiza Bge. In recent years, its remarkable pharmacological effects have triggered extensive and in-depth studies. The aim of this study is to retrieve the latest research progress on CTS and provide prospects for future research. The selection of literature for inclusion, data extraction and methodological quality assessment were discussed. Studies included (1) physicochemical and ADME/Tox properties, (2) pharmacological effects and mechanism, (3) conclusion and bioinformatics analysis. A total of 915 titles and abstracts were screened, resulting in 184 papers used in this review; CTS has shown therapeutic effects on a variety of diseases by modulating multiple molecular pathways. For example, CTS primarily targets NF-κB pathway and MAPK pathway to have a therapeutic role in cardiovascular diseases; in cancer, CTS shows superior efficacy through the PI3K/Akt/mTOR pathway and the JAK/STAT pathway; CTS act on the Nrf2/HO-1 pathway to combat neurological diseases. In addition, key targets of CTS were predicted by bioinformatics analysis, referring to disease ontology (DO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene ontology (GO) enrichment analysis, with R Studio; AKT1, MAPK1, STAT3, P53 and EGFR are predicted to be the key targets of CTS against diseases. The key proteins were then docked by Autodock software to preliminarily assess their binding activities. This review provided new insights into research of CTS and its potential applications in the future, and especially the targets and directly binding modes for CTS are waiting to be investigated.
Collapse
Affiliation(s)
- Ziyao Zheng
- Department of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University, Fuzhou, 350122, People’s Republic of China
| | - Liyuan Ke
- Department of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University, Fuzhou, 350122, People’s Republic of China
| | - Shumin Ye
- Department of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University, Fuzhou, 350122, People’s Republic of China
| | - Peiying Shi
- Department of Traditional Chinese Medicine Resource and Bee Products, College of Animal Sciences (College of Bee Science), Fujian Agriculture and Forestry University, Fuzhou, 350002, People’s Republic of China
| | - Hong Yao
- Department of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University, Fuzhou, 350122, People’s Republic of China
- Fujian Key Laboratory of Drug Target Discovery and Structural and Functional Research, Fujian Medical University, Fuzhou, 350122, People’s Republic of China
| |
Collapse
|
|
24
|
Fu Y, Yang L, Liu L, Kong L, Sun H, Sun Y, Yin F, Yan G, Wang X. Rhein: An Updated Review Concerning Its Biological Activity, Pharmacokinetics, Structure Optimization, and Future Pharmaceutical Applications. Pharmaceuticals (Basel) 2024; 17:1665. [PMID: 39770507 PMCID: PMC11679290 DOI: 10.3390/ph17121665] [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: 11/20/2024] [Revised: 12/08/2024] [Accepted: 12/09/2024] [Indexed: 01/11/2025] Open
Abstract
Rhein is a natural active ingredient in traditional Chinese medicine that has attracted much attention due to its wide range of pharmacological activities. However, its clinical application is limited by low water solubility, poor oral absorption, and potential toxicity to the liver and kidneys. Recently, advanced extraction and synthesis techniques have made it possible to develop derivatives of rhein, which have better pharmacological properties and lower toxicity. This article comprehensively summarizes the biological activity and action mechanism of rhein. Notably, we found that TGF-β1 is the target of rhein improving tissue fibrosis, while NF-κB is the main target of its anti-inflammatory effect. Additionally, we reviewed the current research status of the pharmacokinetics, toxicology, structural optimization, and potential drug applications of rhein and found that the coupling and combination therapy of rhein and other active ingredients exhibit a synergistic effect, significantly enhancing therapeutic efficacy. Finally, we emphasize the necessity of further studying rhein's pharmacological mechanisms, toxicology, and development of analogs, aiming to lay the foundation for its widespread clinical application as a natural product and elucidate its prospects in modern medicine.
Collapse
Affiliation(s)
- Yuqi Fu
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin 150040, China; (Y.F.); (L.L.); (L.K.); (F.Y.); (G.Y.)
| | - Le Yang
- State Key Laboratory of Dampness Syndrome, The Second Affiliated Hospital Guangzhou University of Chinese Medicine, Dade Road 111, Guangzhou 510006, China; (L.Y.); (Y.S.)
| | - Lei Liu
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin 150040, China; (Y.F.); (L.L.); (L.K.); (F.Y.); (G.Y.)
| | - Ling Kong
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin 150040, China; (Y.F.); (L.L.); (L.K.); (F.Y.); (G.Y.)
| | - Hui Sun
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin 150040, China; (Y.F.); (L.L.); (L.K.); (F.Y.); (G.Y.)
| | - Ye Sun
- State Key Laboratory of Dampness Syndrome, The Second Affiliated Hospital Guangzhou University of Chinese Medicine, Dade Road 111, Guangzhou 510006, China; (L.Y.); (Y.S.)
| | - Fengting Yin
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin 150040, China; (Y.F.); (L.L.); (L.K.); (F.Y.); (G.Y.)
| | - Guangli Yan
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin 150040, China; (Y.F.); (L.L.); (L.K.); (F.Y.); (G.Y.)
| | - Xijun Wang
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin 150040, China; (Y.F.); (L.L.); (L.K.); (F.Y.); (G.Y.)
- State Key Laboratory of Dampness Syndrome, The Second Affiliated Hospital Guangzhou University of Chinese Medicine, Dade Road 111, Guangzhou 510006, China; (L.Y.); (Y.S.)
| |
Collapse
|
|
25
|
Wang W, Tai S, Tao J, Yang L, Cheng X, Zhou J. Innovative hydrogel-based therapies for ischemia-reperfusion injury： bridging the gap between pathophysiology and treatment. Mater Today Bio 2024; 29:101295. [PMID: 39493810 PMCID: PMC11528235 DOI: 10.1016/j.mtbio.2024.101295] [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: 07/01/2024] [Revised: 09/21/2024] [Accepted: 10/08/2024] [Indexed: 11/05/2024] Open
Abstract
Ischemia-reperfusion injury (IRI) commonly occurs in clinical settings, particularly in medical practices such as organ transplantation, cardiopulmonary resuscitation, and recovery from acute trauma, posing substantial challenges in clinical therapies. Current systemic therapies for IRI are limited by poor drug targeting, short efficacy, and significant side effects. Owing to their exceptional biocompatibility, biodegradability, excellent mechanical properties, targeting capabilities, controlled release potential, and properties mimicking the extracellular matrix (ECM), hydrogels not only serve as superior platforms for therapeutic substance delivery and retention, but also facilitate bioenvironment cultivation and cell recruitment, demonstrating significant potential in IRI treatment. This review explores the pathological processes of IRI and discusses the roles and therapeutic outcomes of various hydrogel systems. By categorizing hydrogel systems into depots delivering therapeutic agents, scaffolds encapsulating mesenchymal stem cells (MSCs), and ECM-mimicking hydrogels, this article emphasizes the selection of polymers and therapeutic substances, and details special crosslinking mechanisms and physicochemical properties, as well as summarizes the application of hydrogel systems for IRI treatment. Furthermore, it evaluates the limitations of current hydrogel treatments and suggests directions for future clinical applications.
Collapse
Affiliation(s)
- Weibo Wang
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Institute of Urology, Anhui Medical University, Hefei, Anhui, China
- Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, Anhui, China
| | - Supeng Tai
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Institute of Urology, Anhui Medical University, Hefei, Anhui, China
- Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, Anhui, China
| | - Junyue Tao
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Institute of Urology, Anhui Medical University, Hefei, Anhui, China
- Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, Anhui, China
| | - Lexing Yang
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Institute of Urology, Anhui Medical University, Hefei, Anhui, China
- Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, Anhui, China
| | - Xi Cheng
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Institute of Urology, Anhui Medical University, Hefei, Anhui, China
- Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, Anhui, China
| | - Jun Zhou
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Institute of Urology, Anhui Medical University, Hefei, Anhui, China
- Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, Anhui, China
| |
Collapse
|
|
26
|
Wu Y, Lin Y, Liu B, Ma J, Xiang Y, Wang Y, Meng S. Shexiang Tongxin dropping pill ameliorates microvascular obstruction via downregulating ALOX12 after myocardial ischemia-reperfusion. Int J Cardiol 2024; 416:132481. [PMID: 39179033 DOI: 10.1016/j.ijcard.2024.132481] [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: 03/29/2024] [Revised: 08/04/2024] [Accepted: 08/20/2024] [Indexed: 08/26/2024]
Abstract
BACKGROUND Microvascular dysfunction (MVD) is common in patients with myocardial infarction receiving reperfusion therapy and is associated with adverse cardiac prognosis. Accumulating evidence suggests a protective role of Shexiang Tongxin dropping pill (STDP) in MVD. However, the specific effects and the underlying mechanisms of STDP in the context of MVD after myocardial ischemia-reperfusion (IR) remains unclear. AIMS We aimed to elucidate the role of STDP in MVD induced by IR and the potential mechanisms involved. METHODS Mice were orally administered with STDP or normal saline for 5 days before receiving myocardial IR. Cardiac function and microvascular obstruction was measured. Proteomics and single-cell RNA sequencing was performed on mouse hearts. In vitro hyoxia/reoxygenation model was established on mouse cardiac microvascular endothelial cells (MCMECs). RESULTS STDP improved cardiac function and decreased microvascular obstruction (MVO) in mice after myocardial IR. Proteomics identified ALOX12 as an important target of STDP. Single-cell RNA sequencing further revealed that downregulation of ALOX12 by STDP mainly occurred in endothelial cells. The involvement of ALOX12 in the effect of STDP on MVO was validated by manipulating ALOX12 via endothelial-specific adeno-associated virus transfection in vivo and in vitro. In vivo, overexpression of ALOX12 increased whereas knockdown of ALOX12 decreased MVO and thrombus formation. STDP treatment alleviated the detrimental effects of overexpression of ALOX12. In vitro, overexpression of ALOX12 increased endothelial cell inflammation and platelet adhesion to endothelial cells, which was abolished by STDP treatment. CONCLUSION Our findings suggest that STDP alleviates MVO after IR, with ALOX12 playing a crucial role.
Collapse
Affiliation(s)
- Yuanhao Wu
- Medical School Of Xinhua Hospital Affiliated To Shanghai Jiao Tong University School Of Medicine, Shanghai, China
| | - Yanjun Lin
- Medical School Of Xinhua Hospital Affiliated To Shanghai Jiao Tong University School Of Medicine, Shanghai, China; Xinhua Hospital Affiliated To Shanghai Jiao Tong University School Of Medicine, Shanghai, China
| | - Bo Liu
- Xinhua Hospital Affiliated To Shanghai Jiao Tong University School Of Medicine, Shanghai, China
| | - Jingqing Ma
- Medical School Of Xinhua Hospital Affiliated To Shanghai Jiao Tong University School Of Medicine, Shanghai, China
| | - Yin Xiang
- Xinhua Hospital Affiliated To Shanghai Jiao Tong University School Of Medicine, Shanghai, China
| | - Yuepeng Wang
- Xinhua Hospital Affiliated To Shanghai Jiao Tong University School Of Medicine, Shanghai, China.
| | - Shu Meng
- Xinhua Hospital Affiliated To Shanghai Jiao Tong University School Of Medicine, Shanghai, China.
| |
Collapse
|
|
27
|
Shan H, Gao L, Zhao S, Dou Z, Pan Y. Bone marrow mesenchymal stem cells with PTBP1 knockdown protect against cerebral ischemia-reperfusion injury by inhibiting ferroptosis via the JNK/P38 pathway in rats. Neuroscience 2024; 560:130-142. [PMID: 39306318 DOI: 10.1016/j.neuroscience.2024.09.038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Revised: 09/17/2024] [Accepted: 09/18/2024] [Indexed: 09/29/2024]
Abstract
Over the years, the neuroprotective potential of bone marrow mesenchymal stem cells (BMSCs) in acute ischemic stroke has attracted significant attention. However, BMSCs face challenges like short metabolic cycles and low survival rates post-transplant. Polypyrimidine tract-binding protein 1 (PTBP1) is an immunomodulatory RNA-binding protein that regulates the cell cycle and increases cell viability. This study investigated the protective effects and underlying mechanism of PTBP1 knockdown in BMSCs (PTBP1KD-BMSCs) following ischemia-reperfusion injury (IRI) in neurons. BMSCs were isolated from Sprague-Dawley rat femurs and characterized through flow cytometry and differentiation induction. PTBP1 knockdown inhibited BMSCs proliferation. Co-culture with PTBP1KD-BMSCs decreased reactive oxygen species (ROS) and malondialdehyde (MDA) levels, while increasing glutathione (GSH) production in oxygen and glucose deprivation/reperfusion-induced PC12 cells. Transcriptome sequencing analysis of PC12 cells suggested that the protective effect of PTBP1KD-BMSCs against injury may involve ferroptosis. Furthermore, western blotting showed upregulation of glutathione synthetase (GSS), glutathione peroxidase 4 (GPX4), and solute carrier family 7 member 11 (SLC7A11) in PTBP1KD-BMSCs, known negative regulators of ferroptosis. Moreover, PTBP1KD-BMSCs inhibited p38MAPK and JNK activation. In addition, PTBP1KD-BMSCs transplantation into middle cerebral artery occlusion/reperfusion (MCAO/R) rats reduced cerebral infarction volume and improved neurological function. Immunofluorescence analysis confirmed the upregulation of GSS expression in neurons of the ischemic cortex, while immunohistochemistry indicated a downregulation of p-P38. These result suggest that PTBP1KD-BMSCs can alleviate neuronal IRI by reducing oxidative stress, inhibiting ferroptosis, and modulating the MAPK pathway, providing a theoretical basis for potential treatment strategies for cerebral IRI.
Collapse
Affiliation(s)
- Hailei Shan
- Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China; Department of Neurology, The Affiliated Hospital of Chengde Medical University, Chengde 067000, China; Hebei Key Laboratory of Panvascular Diseases, The Affiliated Hospital of Chengde Medical University, Chengde, China
| | - Limin Gao
- Department of Neurology, The Affiliated Hospital of Chengde Medical University, Chengde 067000, China
| | - Shuang Zhao
- Department of Neurology, The Affiliated Hospital of Chengde Medical University, Chengde 067000, China
| | - Zhijie Dou
- Department of Neurology, The Affiliated Hospital of Chengde Medical University, Chengde 067000, China.
| | - Yujun Pan
- Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
| |
Collapse
|
|
28
|
Liu C, Qin M, Jiang L, Shan J, Sun Y. Mitochondria-Targetable Cyclometalated Iridium(III) Complex-Based Luminescence Probe for Monitoring and Assessing Treatment Response of Ferroptosis-Mediated Hepatic Ischemia-Reperfusion Injury. Inorg Chem 2024; 63:21627-21636. [PMID: 39473350 DOI: 10.1021/acs.inorgchem.4c03170] [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: 11/12/2024]
Abstract
Ferroptosis plays an essential role in the pathological progression of hepatic ischemia-reperfusion injury (HIRI), which is closely related to iron-dependent lipid peroxidation. Since mitochondria are thought to be the major site of reactive oxygen species (ROS) production and iron storage, monitoring the variations of mitochondrial hypochlorous acid (HClO) (an important member of ROS) has important implications for the assessment of ferroptosis status, as well as the formulation of treatment strategies for HIRI. However, reliable imaging tools for the visualization of mitochondrial HClO and monitoring its dynamic changes in ferroptosis-mediated HIRI are still lacking. Herein, in this work, an HClO-activated near-infrared (NIR) cyclometalated iridium(III) complex-based probe, named NIR-Ir-HClO, was developed for the visual monitoring of the mitochondrial HClO fluxes in ferroptosis-mediated HIRI. The newly prepared probe showed fast response (<30 s), good sensitivity, excellent selectivity, good cell biocompatibility, and satisfactory mitochondrial-targeting performance, making it suitable for accurate monitoring of mitochondrial HClO in living cells. Moreover, visualization of the variations of mitochondrial HClO in ferroptosis-mediated HIRI and monitoring of the treatment response of ferroptosis-mediated HIRI to the ferroptosis inhibitors were achieved for the first time. All these show that probe NIR-Ir-HClO can be utilized as a reliable imaging tool for revealing the pathological mechanism of mitochondrial HClO in ferroptosis-mediated HIRI, as well as for the formulation of new treatment strategies for HIRI.
Collapse
Affiliation(s)
- Chaolong Liu
- Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao 266071, China
| | - Meichun Qin
- Institute of Hybrid Materials, National Center of International Joint Research for Hybrid Materials Technology, National Base of International Sci. & Tech. Cooperation on Hybrid Materials, College of Materials Science and Engineering, Qingdao University, 308 Ningxia Road, Qingdao 266071, China
| | - Lin Jiang
- Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao 266071, China
| | - Jiongchen Shan
- Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao 266071, China
| | - Yong Sun
- Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao 266071, China
| |
Collapse
|
|
29
|
Xu H, Zhao Z, She P, Ren X, Li A, Li G, Wang Y. Salvaging myocardial infarction with nanoenzyme-loaded hydrogels: Targeted scavenging of mitochondrial reactive oxygen species. J Control Release 2024; 375:788-801. [PMID: 39326500 DOI: 10.1016/j.jconrel.2024.09.038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Revised: 09/19/2024] [Accepted: 09/22/2024] [Indexed: 09/28/2024]
Abstract
Myocardial infarction resulting from coronary artery atherosclerosis is the leading cause of heart failure, which represents a significant global health burden. The limitations of conventional pharmacologic thrombolysis and flow reperfusion procedures highlight the urgent need for new therapeutic strategies to effectively treat myocardial infarction. In this study, we present a novel biomimetic approach that integrates polyphenols and metal nanoenzymes, inspired by the structure of pomegranates. We developed tannic acid-coated Mn-Co3O4 (MCT) nanoparticles in combination with an injectable collagen hydrogel for the effective treatment of myocardial infarction. The hydrogel enhanced the infarct microenvironment, while the slow-released MCT targets mitochondria to inhibit the post-infarction surge of reactive oxygen species, providing anti-apoptotic and anti-inflammatory effects. RNA sequencing revealed the potential of hydrogels to serve as an interventional mechanism during the post-infarction inflammatory phase. Notably, we found that the hydrogel, when combined with the nanopomegranate-based therapy, significantly improves adverse ventricular remodeling and restores cardiac function in early infarction management. The MCT hydrogel leverages the unique benefits of both MCT nanopomegranates and collagen, demonstrating a synergistic effect. This approach provides a promising example of the potential cooperation between nanomimetic structures and natural biomaterials in therapeutic applications.
Collapse
Affiliation(s)
- Hong Xu
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan university, Chengdu 610064, China
| | - Zhiyu Zhao
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan university, Chengdu 610064, China
| | - Peiyi She
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan university, Chengdu 610064, China
| | - Xingrong Ren
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan university, Chengdu 610064, China
| | - Annuo Li
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan university, Chengdu 610064, China
| | - Gaocan Li
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan university, Chengdu 610064, China.
| | - Yunbing Wang
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan university, Chengdu 610064, China.
| |
Collapse
|
|
30
|
Li Y, Yu J, Wang Y. Mechanism of Coronary Microcirculation Obstruction after Acute Myocardial Infarction and Cardioprotective Strategies. Rev Cardiovasc Med 2024; 25:367. [PMID: 39484142 PMCID: PMC11522835 DOI: 10.31083/j.rcm2510367] [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: 03/08/2024] [Revised: 06/03/2024] [Accepted: 06/11/2024] [Indexed: 11/03/2024] Open
Abstract
ST-segment elevation myocardial infarction patients are best treated with emergency percutaneous coronary intervention (PCI), while coronary microvascular dysfunction and obstruction (CMVO) are indicated by the absence or slowing of antegrade epicardial flow on angiography, resulting in suboptimal myocardial perfusion despite the lack of mechanical vascular obstruction. CMVO occurs in up to half of patients who undergo PCI for the first time and is associated with poor outcomes. This review summarizes the complex mechanisms leading to CMVO and elaborates on the changes observed at the organism, tissue, organ, cellular, and molecular levels. It also describes the current diagnostic methods and comprehensive treatment methods for CMVO.
Collapse
Affiliation(s)
- Yuyu Li
- Beijing Anzhen Hospital Affiliated to Capital Medical University, 100029 Beijing, China
- Beijing Institute of Heart, Lung and Blood Vessel Disease, 100029 Beijing, China
| | - Jiaqi Yu
- Beijing Anzhen Hospital Affiliated to Capital Medical University, 100029 Beijing, China
- Beijing Institute of Heart, Lung and Blood Vessel Disease, 100029 Beijing, China
| | - Yuan Wang
- Beijing Anzhen Hospital Affiliated to Capital Medical University, 100029 Beijing, China
- Beijing Institute of Heart, Lung and Blood Vessel Disease, 100029 Beijing, China
| |
Collapse
|
|
31
|
Liao L, Wang T, Zhang L, Wei Y, Fan X. Protective Mechanisms of SGLTi in Ischemic Heart Disease. J Cardiovasc Transl Res 2024; 17:1018-1035. [PMID: 38767796 DOI: 10.1007/s12265-024-10513-x] [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: 12/28/2023] [Accepted: 04/11/2024] [Indexed: 05/22/2024]
Abstract
Ischemic heart disease (IHD) is a common clinical cardiovascular disease with high morbidity and mortality. Sodium glucose cotransporter protein inhibitor (SGLTi) is a novel hypoglycemic drug. To date, both clinical trials and animal experiments have shown that SGLTi play a protective role in IHD, including myocardial infarction (MI) and ischemia/reperfusion (I/R). The protective effects may be involved in mechanisms of energy metabolic conversion, anti-inflammation, anti-fibrosis, ionic homeostasis improvement, immune cell development, angiogenesis and functional regulation, gut microbiota regulation, and epicardial lipids. Thus, this review summarizes the above mechanisms and aims to provide theoretical evidence for therapeutic strategies for IHD.
Collapse
Affiliation(s)
- Lei Liao
- Department of Cardiology, the Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Tong Wang
- Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Lu Zhang
- Department of Cardiology, the Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Yan Wei
- Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, 646000, Sichuan, China.
| | - Xinrong Fan
- Department of Cardiology, the Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China.
- Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, 646000, Sichuan, China.
| |
Collapse
|
|
32
|
Zhang CH, Lu DC, Liu Y, Wang L, Sethi G, Ma Z. The role of extracellular vesicles in pyroptosis-mediated infectious and non-infectious diseases. Int Immunopharmacol 2024; 138:112633. [PMID: 38986299 DOI: 10.1016/j.intimp.2024.112633] [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: 04/06/2024] [Revised: 06/22/2024] [Accepted: 07/02/2024] [Indexed: 07/12/2024]
Abstract
Pyroptosis, a lytic and pro-inflammatory cell death, is important in various pathophysiological processes. Host- and bacteria-derived extracellular vesicles (EVs), as natural nanocarriers messengers, are versatile mediators of intercellular communication between different types of cells. Recently, emerging research has suggested that EVs exhibit multifaceted roles in disease progression by manipulating pyroptosis. This review focuses on new findings concerning how EVs shape disease progression in infectious and non-infectious diseases by regulating pyroptosis. Understanding the characteristics and activity of EVs-mediated pyroptotic death may conducive to the discovery of novel mechanisms and more efficient therapeutic targets in infectious and non-infectious diseases.
Collapse
Affiliation(s)
- Cai-Hua Zhang
- School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei 434023, China; Department of Oncology, People's Hospital Affiliated to Chongqing Three Gorges Medical College, Chongqing 404100, China
| | - Ding-Ci Lu
- School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei 434023, China
| | - Ying Liu
- School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei 434023, China
| | - Lingzhi Wang
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117600 Singapore; Cancer Science Institute of Singapore, National University of Singapore, 117599 Singapore; NUS Centre for Cancer Research (N2CR), National University of Singapore, 117599 Singapore.
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117600 Singapore; NUS Centre for Cancer Research (N2CR), National University of Singapore, 117599 Singapore.
| | - Zhaowu Ma
- School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei 434023, China.
| |
Collapse
|
|
33
|
Shi Y, Liu J, Hou M, Tan Z, Chen F, Zhang J, Liu Y, Leng Y. Ursolic acid improves necroptosis via STAT3 signaling in intestinal ischemia/reperfusion injury. Int Immunopharmacol 2024; 138:112463. [PMID: 38971110 DOI: 10.1016/j.intimp.2024.112463] [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: 09/26/2023] [Revised: 04/29/2024] [Accepted: 06/07/2024] [Indexed: 07/08/2024]
Abstract
Intestinal ischemia/reperfusion injury (IRI) poses a serious threat to human survival and quality of life with high mortality and morbidity rates. The current absence of effective treatments for intestinal IRI highlights the urgent need to identify new therapeutic targets. Ursolic acid (UA), a pentacyclic triterpene natural compound, has been shown to possess various pharmacological properties including intestinal protection. However, its potential protective efficacy on intestinal IRI remains elusive. This study aimed to investigate the effect of UA on intestinal IRI and explore the underlying mechanisms. To achieve this, we utilized network pharmacology to analyze the mechanism of UA in intestinal IRI and assessed UA's effects on intestinal IRI using a mouse model of superior mesenteric artery occlusion/reperfusion and an in vitro model of oxygen-glucose deprivation and reperfusion-induced IEC-6 cells. Our results demonstrated that UA improved necroptosis through the RIP1/RIP3/MLKL pathway, reduced necroinflammation via the HMGB1/TLR4/NF-κB pathway, attenuated morphological damage, and enhanced intestinal barrier function. Furthermore, UA pretreatment downregulated the phosphorylation level of signal transducer and activator of transcription 3 (STAT3). The effects of UA were attenuated by the STAT3 agonist Colivelin. In conclusion, our study suggests that UA can improve intestinal IRI by inhibiting necroptosis in enterocytes via the suppression of STAT3 activation. These results provide a theoretical basis for UA treatment of intestinal IRI and related clinical diseases.
Collapse
Affiliation(s)
- Yajing Shi
- The First School of Clinical Medicine of Lanzhou University, Lanzhou, 730000, PR China; Department of Anesthesiology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710000, PR China
| | - Jie Liu
- The First School of Clinical Medicine of Lanzhou University, Lanzhou, 730000, PR China
| | - Min Hou
- The First School of Clinical Medicine of Lanzhou University, Lanzhou, 730000, PR China
| | - Zhiguo Tan
- The First School of Clinical Medicine of Lanzhou University, Lanzhou, 730000, PR China
| | - Feng Chen
- The First School of Clinical Medicine of Lanzhou University, Lanzhou, 730000, PR China
| | - Jianmin Zhang
- The First School of Clinical Medicine of Lanzhou University, Lanzhou, 730000, PR China
| | - Yongqiang Liu
- The First School of Clinical Medicine of Lanzhou University, Lanzhou, 730000, PR China; Department of Anesthesiology, the First Hospital of Lanzhou University, Lanzhou, 730000, PR China
| | - Yufang Leng
- The First School of Clinical Medicine of Lanzhou University, Lanzhou, 730000, PR China; Department of Anesthesiology, the First Hospital of Lanzhou University, Lanzhou, 730000, PR China.
| |
Collapse
|
|
34
|
Pang B, Dong G, Pang T, Sun X, Liu X, Nie Y, Chang X. Advances in pathogenesis and treatment of vascular endothelial injury-related diseases mediated by mitochondrial abnormality. Front Pharmacol 2024; 15:1422686. [PMID: 39281286 PMCID: PMC11394189 DOI: 10.3389/fphar.2024.1422686] [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: 04/24/2024] [Accepted: 08/13/2024] [Indexed: 09/18/2024] Open
Abstract
Vascular endothelial cells, serving as a barrier between blood and the arterial wall, play a crucial role in the early stages of the development of atherosclerosis, cardiovascular diseases (CVDs), and Alzheimer's disease (AD). Mitochondria, known as the powerhouses of the cell, are not only involved in energy production but also regulate key biological processes in vascular endothelial cells, including redox signaling, cellular aging, calcium homeostasis, angiogenesis, apoptosis, and inflammatory responses. The mitochondrial quality control (MQC) system is essential for maintaining mitochondrial homeostasis. Current research indicates that mitochondrial dysfunction is a significant driver of endothelial injury and CVDs. This article provides a comprehensive overview of the causes of endothelial injury in CVDs, ischemic stroke in cerebrovascular diseases, and AD, elucidating the roles and mechanisms of mitochondria in these conditions, and aims to develop more effective therapeutic strategies. Additionally, the article offers treatment strategies for cardiovascular and cerebrovascular diseases, including the use of clinical drugs, antioxidants, stem cell therapy, and specific polyphenols, providing new insights and methods for the clinical diagnosis and treatment of related vascular injuries to improve patient prognosis and quality of life. Future research should delve deeper into the molecular and mechanistic links between mitochondrial abnormalities and endothelial injury, and explore how to regulate mitochondrial function to prevent and treat CVDs.
Collapse
Affiliation(s)
- Boxian Pang
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
- CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, China
| | - Guangtong Dong
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
| | - Tieliang Pang
- Beijing Anding Hospital, Capital Medical University, Beijing, China
| | - Xinyao Sun
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
| | - Xin Liu
- Bioscience Department, University of Nottingham, Nottingham, United Kingdom
| | - Yifeng Nie
- CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, China
| | - Xing Chang
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| |
Collapse
|
|
35
|
Ma S, Song Y, Xu Y, Wang C, Yang Y, Zheng Y, Lu Q, Chen Q, Wu J, Wang B, Chen M. Mild Therapeutic Hypothermia Alleviated Myocardial Ischemia/Reperfusion Injury via Targeting SLC25A10 to Suppress Mitochondrial Apoptosis. J Cardiovasc Transl Res 2024; 17:946-958. [PMID: 38568407 PMCID: PMC11371862 DOI: 10.1007/s12265-024-10503-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Accepted: 02/19/2024] [Indexed: 09/04/2024]
Abstract
Myocardial ischemia/reperfusion injury (MI/RI) is identified as a severe vascular emergency, and the treatment strategy of MI/RI still needs further improvement. The present study aimed to investigate the potential effects of mild therapeutic hypothermia (MTH) on MI/RI and underlying mechanisms. In ischemia/reperfusion (I/R) rats, MTH treatment significantly improved myocardial injury, attenuated myocardial infarction, and inhibited the mitochondrial apoptosis pathway. The results of proteomics identified SLC25A10 as the main target of MTH treatment. Consistently, SLC25A10 expressions in I/R rat myocardium and hypoxia and reoxygenation (H/R) cardiomyocytes were significantly suppressed, which was effectively reversed by MTH treatment. In H/R cardiomyocytes, MTH treatment significantly improved cell injury, mitochondrial dysfunction, and inhibited the mitochondrial apoptosis pathway, which were partially reversed by SLC25A10 deletion. These findings suggested that MTH treatment could protect against MI/RI by modulating SLC25A10 expression to suppress mitochondrial apoptosis pathway, providing new theoretical basis for clinical application of MTH treatment for MI/RI.
Collapse
MESH Headings
- Animals
- Myocardial Reperfusion Injury/prevention & control
- Myocardial Reperfusion Injury/metabolism
- Myocardial Reperfusion Injury/pathology
- Myocardial Reperfusion Injury/genetics
- Apoptosis
- Mitochondria, Heart/metabolism
- Mitochondria, Heart/pathology
- Mitochondria, Heart/drug effects
- Myocytes, Cardiac/metabolism
- Myocytes, Cardiac/pathology
- Myocytes, Cardiac/drug effects
- Male
- Disease Models, Animal
- Hypothermia, Induced
- Rats, Sprague-Dawley
- Signal Transduction
- Myocardial Infarction/metabolism
- Myocardial Infarction/pathology
- Myocardial Infarction/genetics
- Myocardial Infarction/therapy
- Cells, Cultured
- Apoptosis Regulatory Proteins/metabolism
- Apoptosis Regulatory Proteins/genetics
- Rats
Collapse
Affiliation(s)
- Senlin Ma
- Department of Emergency, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Yun Song
- Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Yanxin Xu
- Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Chao Wang
- Department of Emergency, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Yifan Yang
- Department of Emergency, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Yanchao Zheng
- Department of Emergency, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Qiuxin Lu
- Department of Emergency, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Qingjiang Chen
- Department of Emergency, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Jian Wu
- Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Bin Wang
- Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, 200040, China.
| | - Mingquan Chen
- Department of Emergency, Huashan Hospital, Fudan University, Shanghai, 200040, China.
| |
Collapse
|
|
36
|
Zhang J, Zhao Y, Gong N. Endoplasmic reticulum stress signaling modulates ischemia/reperfusion injury in the aged heart by regulating mitochondrial maintenance. Mol Med 2024; 30:107. [PMID: 39044180 PMCID: PMC11265325 DOI: 10.1186/s10020-024-00869-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Accepted: 06/27/2024] [Indexed: 07/25/2024] Open
Abstract
Aging is associated with an increased risk of myocardial ischemia/reperfusion injury (IRI). With an increasing prevalence of cardiovascular diseases such as coronary arteriosclerosis in older people, there has been increasing interest in understanding the mechanisms of myocardial IRI to develop therapeutics that can attenuate its damaging effects. Previous studies identified that abnormal mitochondria, involved in cellar senescence and oxidative stress, are the master subcellular organelle that induces IRI. In addition, endoplasmic reticulum (ER) stress is also associated with IRI. Cellular adaptation to ER stress is achieved by the activation of ER molecular chaperones and folding enzymes, which provide an important link between ER stress and oxidative stress gene programs. In this review, we outline how these ER stress-related molecules affect myocardial IRI via the crosstalk of ER stress and mitochondrial homeostasis and discuss how these may offer promising novel therapeutic targets and strategies against age-related cardiovascular diseases.
Collapse
Affiliation(s)
- Ji Zhang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation of Ministry of Education, National Health Commission and Chinese Academy of Medical Sciences, Wuhan, Hubei, 430030, P.R. China
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Institute of Urology & Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, Anhui, 230022, P.R. China
| | - Yuanyuan Zhao
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation of Ministry of Education, National Health Commission and Chinese Academy of Medical Sciences, Wuhan, Hubei, 430030, P.R. China
| | - Nianqiao Gong
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation of Ministry of Education, National Health Commission and Chinese Academy of Medical Sciences, Wuhan, Hubei, 430030, P.R. China.
| |
Collapse
|
|
37
|
Ni L, Yang L, Lin Y. Recent progress of endoplasmic reticulum stress in the mechanism of atherosclerosis. Front Cardiovasc Med 2024; 11:1413441. [PMID: 39070554 PMCID: PMC11282489 DOI: 10.3389/fcvm.2024.1413441] [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: 05/01/2024] [Accepted: 06/26/2024] [Indexed: 07/30/2024] Open
Abstract
The research progress of endoplasmic reticulum (ER) stress in atherosclerosis (AS) is of great concern. The ER, a critical cellular organelle, plays a role in important biological processes including protein synthesis, folding, and modification. Various pathological factors may cause ER stress, and sustained or excessive ER stress triggers the unfolded protein response, ultimately resulting in apoptosis and disease. Recently, researchers have discovered the importance of ER stress in the onset and advancement of AS. ER stress contributes to the occurrence of AS through different pathways such as apoptosis, inflammatory response, oxidative stress, and autophagy. Therefore, this review focuses on the mechanisms of ER stress in the development of AS and related therapeutic targets, which will contribute to a deeper understanding of the disease's pathogenesis and provide novel strategies for preventing and treating AS.
Collapse
Affiliation(s)
| | | | - Yuanyuan Lin
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
| |
Collapse
|
|
38
|
Dou B, Zhu Y, Sun M, Wang L, Tang Y, Tian S, Wang F. Mechanisms of Flavonoids and Their Derivatives in Endothelial Dysfunction Induced by Oxidative Stress in Diabetes. Molecules 2024; 29:3265. [PMID: 39064844 PMCID: PMC11279171 DOI: 10.3390/molecules29143265] [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: 06/07/2024] [Revised: 07/02/2024] [Accepted: 07/05/2024] [Indexed: 07/28/2024] Open
Abstract
Diabetic complications pose a significant threat to life and have a negative impact on quality of life in individuals with diabetes. Among the various factors contributing to the development of these complications, endothelial dysfunction plays a key role. The main mechanism underlying endothelial dysfunction in diabetes is oxidative stress, which adversely affects the production and availability of nitric oxide (NO). Flavonoids, a group of phenolic compounds found in vegetables, fruits, and fungi, exhibit strong antioxidant and anti-inflammatory properties. Several studies have provided evidence to suggest that flavonoids have a protective effect on diabetic complications. This review focuses on the imbalance between reactive oxygen species and the antioxidant system, as well as the changes in endothelial factors in diabetes. Furthermore, we summarize the protective mechanisms of flavonoids and their derivatives on endothelial dysfunction in diabetes by alleviating oxidative stress and modulating other signaling pathways. Although several studies underline the positive influence of flavonoids and their derivatives on endothelial dysfunction induced by oxidative stress in diabetes, numerous aspects still require clarification, such as optimal consumption levels, bioavailability, and side effects. Consequently, further investigations are necessary to enhance our understanding of the therapeutic potential of flavonoids and their derivatives in the treatment of diabetic complications.
Collapse
Affiliation(s)
| | | | | | | | | | | | - Furong Wang
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250300, China
| |
Collapse
|
|
39
|
Pan X, Hao E, Zhang F, Wei W, Du Z, Yan G, Wang X, Deng J, Hou X. Diabetes cardiomyopathy: targeted regulation of mitochondrial dysfunction and therapeutic potential of plant secondary metabolites. Front Pharmacol 2024; 15:1401961. [PMID: 39045049 PMCID: PMC11263127 DOI: 10.3389/fphar.2024.1401961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2024] [Accepted: 06/11/2024] [Indexed: 07/25/2024] Open
Abstract
Diabetic cardiomyopathy (DCM) is a specific heart condition in diabetic patients, which is a major cause of heart failure and significantly affects quality of life. DCM is manifested as abnormal cardiac structure and function in the absence of ischaemic or hypertensive heart disease in individuals with diabetes. Although the development of DCM involves multiple pathological mechanisms, mitochondrial dysfunction is considered to play a crucial role. The regulatory mechanisms of mitochondrial dysfunction mainly include mitochondrial dynamics, oxidative stress, calcium handling, uncoupling, biogenesis, mitophagy, and insulin signaling. Targeting mitochondrial function in the treatment of DCM has attracted increasing attention. Studies have shown that plant secondary metabolites contribute to improving mitochondrial function and alleviating the development of DCM. This review outlines the role of mitochondrial dysfunction in the pathogenesis of DCM and discusses the regulatory mechanism for mitochondrial dysfunction. In addition, it also summarizes treatment strategies based on plant secondary metabolites. These strategies targeting the treatment of mitochondrial dysfunction may help prevent and treat DCM.
Collapse
Affiliation(s)
- Xianglong Pan
- Department of Pharmaceutical, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang, China
| | - Erwei Hao
- Guangxi Key Laboratory of Efficacy Study on Chinese Materia Medica, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
- Guangxi Collaborative Innovation Center for Research on Functional Ingredients of Agricultural Residues, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
- Guangxi Key Laboratory of TCM Formulas Theory and Transformation for Damp Diseases, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Fan Zhang
- Guangxi Key Laboratory of Efficacy Study on Chinese Materia Medica, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
- Guangxi Collaborative Innovation Center for Research on Functional Ingredients of Agricultural Residues, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
- Guangxi Key Laboratory of TCM Formulas Theory and Transformation for Damp Diseases, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Wei Wei
- Guangxi Key Laboratory of Efficacy Study on Chinese Materia Medica, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
- Guangxi Collaborative Innovation Center for Research on Functional Ingredients of Agricultural Residues, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
- Guangxi Key Laboratory of TCM Formulas Theory and Transformation for Damp Diseases, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Zhengcai Du
- Guangxi Key Laboratory of Efficacy Study on Chinese Materia Medica, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
- Guangxi Collaborative Innovation Center for Research on Functional Ingredients of Agricultural Residues, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
- Guangxi Key Laboratory of TCM Formulas Theory and Transformation for Damp Diseases, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Guangli Yan
- Department of Pharmaceutical, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang, China
| | - Xijun Wang
- Department of Pharmaceutical, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang, China
| | - Jiagang Deng
- Guangxi Key Laboratory of Efficacy Study on Chinese Materia Medica, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
- Guangxi Collaborative Innovation Center for Research on Functional Ingredients of Agricultural Residues, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
- Guangxi Key Laboratory of TCM Formulas Theory and Transformation for Damp Diseases, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Xiaotao Hou
- Department of Pharmaceutical, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang, China
- Guangxi Key Laboratory of Efficacy Study on Chinese Materia Medica, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
- Guangxi Collaborative Innovation Center for Research on Functional Ingredients of Agricultural Residues, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
- Guangxi Key Laboratory of TCM Formulas Theory and Transformation for Damp Diseases, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| |
Collapse
|
|
40
|
Somasundaram I, Jain SM, Blot-Chabaud M, Pathak S, Banerjee A, Rawat S, Sharma NR, Duttaroy AK. Mitochondrial dysfunction and its association with age-related disorders. Front Physiol 2024; 15:1384966. [PMID: 39015222 PMCID: PMC11250148 DOI: 10.3389/fphys.2024.1384966] [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: 02/12/2024] [Accepted: 06/10/2024] [Indexed: 07/18/2024] Open
Abstract
Aging is a complex process that features a functional decline in many organelles. Various factors influence the aging process, such as chromosomal abnormalities, epigenetic changes, telomere shortening, oxidative stress, and mitochondrial dysfunction. Mitochondrial dysfunction significantly impacts aging because mitochondria regulate cellular energy, oxidative balance, and calcium levels. Mitochondrial integrity is maintained by mitophagy, which helps maintain cellular homeostasis, prevents ROS production, and protects against mtDNA damage. However, increased calcium uptake and oxidative stress can disrupt mitochondrial membrane potential and permeability, leading to the apoptotic cascade. This disruption causes increased production of free radicals, leading to oxidative modification and accumulation of mitochondrial DNA mutations, which contribute to cellular dysfunction and aging. Mitochondrial dysfunction, resulting from structural and functional changes, is linked to age-related degenerative diseases. This review focuses on mitochondrial dysfunction, its implications in aging and age-related disorders, and potential anti-aging strategies through targeting mitochondrial dysfunction.
Collapse
Affiliation(s)
- Indumathi Somasundaram
- Biotechnology Engineering, Kolhapur Institute of Technology’s College of Engineering, Kolhapur, India
| | - Samatha M. Jain
- Department of Biotechnology, Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Chennai, India
| | | | - Surajit Pathak
- Department of Biotechnology, Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Chennai, India
| | - Antara Banerjee
- Department of Biotechnology, Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Chennai, India
| | - Sonali Rawat
- Stem Cell Facility, DBT-Centre of Excellence for Stem Cell Research, All India Institute of Medical Sciences, New Delhi, India
| | - Neeta Raj Sharma
- School of Bioengineering and Biosciences, Lovely Professional University, Phagwara, India
| | - Asim K. Duttaroy
- Department of Nutrition, Faculty of Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
| |
Collapse
|
|
41
|
Yan Y, Zhao C, Niu J, Yan P, Li J, Wang D, Li G. Rationale and Design of the IMPROVE Trial: A Multicenter, Randomized, Controlled, Open-label, Blinded-endpoint Trial Assessing the Efficacy of Remote Ischemic Conditioning in Patients Undergoing Off-Pump Coronary Artery Bypass Grafting. Adv Ther 2024; 41:3003-3012. [PMID: 38616242 DOI: 10.1007/s12325-024-02836-7] [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: 12/02/2023] [Accepted: 03/07/2024] [Indexed: 04/16/2024]
Abstract
INTRODUCTION Despite the appearance of off-pump coronary artery bypass grafting (CABG), ischemia-reperfusion injury (IRI) in the perioperative period still arouses concerns of clinicians. Remote ischemic conditioning (RIC) is the process of repeated ischemia and reperfusion in the peripheral vessels, which is proven to reduce IRI in vital organs. However, the effect of RIC in patients undergoing off-pump CABG is still unclear. METHODS This IMPROVE trial is a national, multicenter, randomized, controlled, open-label, blinded-endpoint clinical trial designed to assess whether RIC intervention can improve short-term prognosis of patients undergoing off-pump CABG. It plans to enroll 648 patients who will be randomly assigned into a RIC group or control group. Patients in the RIC group will receive four cycles of 5 min of pressurization (about 200 mmHg) and 5 min of rest in the 3 days before and 7 days after the surgery. PLANNED OUTCOMES The primary outcome is the occurrence of major adverse cardiovascular and cerebrovascular events (MACCE) within the 3-month follow-up. MACCE is defined as all-cause death, myocardial infarction, stroke, and coronary revascularization surgery. CLINICAL TRIAL REGISTRATION NCT06141525 (ClinicalTrials.gov).
Collapse
Affiliation(s)
- Yang Yan
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
| | - Changying Zhao
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Jialan Niu
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Pengyun Yan
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Jing Li
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Department of Cardiovascular Surgery, People's Hospital of Qinghai Province, Xining, China
| | - Duolao Wang
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Department of Clinical Sciences, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, UK
- Department of Neurology, Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Guoliang Li
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
| |
Collapse
|
|
42
|
Chen C, Ou W, Yang C, Liu H, Yang T, Mo H, Lu W, Yan J, Chen A. Queen bee acid pretreatment attenuates myocardial ischemia/reperfusion injury by enhancing autophagic flux. Heliyon 2024; 10:e33371. [PMID: 39021954 PMCID: PMC11253658 DOI: 10.1016/j.heliyon.2024.e33371] [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: 01/20/2024] [Revised: 06/19/2024] [Accepted: 06/20/2024] [Indexed: 07/20/2024] Open
Abstract
Queen bee acid (QBA), which is exclusively found in royal jelly, has anti-inflammatory, antihypercholesterolemic, and antiangiogenic effects. A recent study demonstrated that QBA enhances autophagic flux in the heart. Considering the significant role of autophagy in the development of myocardial ischemia/reperfusion (I/R) injury, we investigated the effect of pretreatment with QBA on myocardial damage. In an in vivo model, left coronary artery blockage for 30 min and reperfusion for 2 h were used to induce myocardial I/R. In an in vitro model, neonatal rat cardiomyocytes (NRCs) were exposed to 3 h of hypoxia and 3 h of reoxygenation (H/R). Our results showed that pretreatment with QBA increased the cell viability of cardiomyocytes exposed to H/R in a dose-dependent manner, and the best protective concentration of QBA was 100 μM. Next, we noted that QBA pretreatment (24h before H/R) enhanced autophagic flux and attenuated mitochondrial damage, cardiac oxidative stress and apoptosis in NRCs exposed to H/R injury, and these effects were weakened by cotreatment with the autophagy inhibitor bafilomycin A1 (Baf). In addition, similar results were observed when QBA (10 mg/kg) was injected intraperitoneally into I/R mice 30 min before ischemia. Compared to mice subjected to I/R alone, those treated with QBA had decreased myocardial infarct area and increased cardiac function, whereas, these effects were partly reversed by Baf. Notably, in NRCs exposed to H/R, tandem fluorescent mRFP-GFP-LC3 assays indicated increased autophagosome degradation due to the increase in autophagic flux upon QBA treatment, but coinjection of Baf blocked autophagic flux. In this investigation, no notable adverse effects of QBA were detected in either cellular or animal models. Our findings suggest that QBA pretreatment mitigates myocardial I/R injury by eliminating dysfunctional mitochondria and reducing reactive oxygen species via promoting autophagic flux.
Collapse
Affiliation(s)
- Changhai Chen
- Department of Cardiology, Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
- Department of Cardiology, The Affiliated Suqian First People's Hospital of Nanjing Medical University, Suqian, Jiangsu, People's Republic of China
- Laboratory of Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
- Guangdong Provincial Key Laboratory of Shock and Microcirculation, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
| | - Wen Ou
- Department of Cardiology, Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
- Laboratory of Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
- Guangdong Provincial Key Laboratory of Shock and Microcirculation, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
| | - Chaobo Yang
- Department of Cardiology, Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
- Laboratory of Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
- Guangdong Provincial Key Laboratory of Shock and Microcirculation, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
| | - Haiqiong Liu
- Department of Health Management, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
- Laboratory of Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
- Guangdong Provincial Key Laboratory of Shock and Microcirculation, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
| | - Tao Yang
- Department of Cardiology, Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
- Laboratory of Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
- Guangdong Provincial Key Laboratory of Shock and Microcirculation, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
- Department of Cardiovascular Medicine, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, People's Republic of China
| | - Huaqiang Mo
- Department of Cardiology, Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
- Laboratory of Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
- Guangdong Provincial Key Laboratory of Shock and Microcirculation, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
| | - Weizhe Lu
- Department of Cardiology, Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
- Laboratory of Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
- Guangdong Provincial Key Laboratory of Shock and Microcirculation, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
| | - Jing Yan
- Department of Cardiology, Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
- Laboratory of Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
- Guangdong Provincial Key Laboratory of Shock and Microcirculation, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
| | - Aihua Chen
- Department of Health Management, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
- Laboratory of Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
- Guangdong Provincial Key Laboratory of Shock and Microcirculation, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
| |
Collapse
|
|
43
|
Du Y, Li J, Dai Z, Chen Y, Zhao Y, Liu X, Xia T, Zhu P, Wang Y. Pyruvate kinase M2 sustains cardiac mitochondrial quality surveillance in septic cardiomyopathy by regulating prohibitin 2 abundance via S91 phosphorylation. Cell Mol Life Sci 2024; 81:254. [PMID: 38856931 PMCID: PMC11335292 DOI: 10.1007/s00018-024-05253-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 04/11/2024] [Accepted: 04/20/2024] [Indexed: 06/11/2024]
Abstract
The endogenous mitochondrial quality control (MQC) system serves to protect mitochondria against cellular stressors. Although mitochondrial dysfunction contributes to cardiac damage during many pathological conditions, the regulatory signals influencing MQC disruption during septic cardiomyopathy (SC) remain unclear. This study aimed to investigate the involvement of pyruvate kinase M2 (PKM2) and prohibitin 2 (PHB2) interaction followed by MQC impairment in the pathogenesis of SC. We utilized LPS-induced SC models in PKM2 transgenic (PKM2TG) mice, PHB2S91D-knockin mice, and PKM2-overexpressing HL-1 cardiomyocytes. After LPS-induced SC, cardiac PKM2 expression was significantly downregulated in wild-type mice, whereas PKM2 overexpression in vivo sustained heart function, suppressed myocardial inflammation, and attenuated cardiomyocyte death. PKM2 overexpression relieved sepsis-related mitochondrial damage via MQC normalization, evidenced by balanced mitochondrial fission/fusion, activated mitophagy, restored mitochondrial biogenesis, and inhibited mitochondrial unfolded protein response. Docking simulations, co-IP, and domain deletion mutant protein transfection experiments showed that PKM2 phosphorylates PHB2 at Ser91, preventing LPS-mediated PHB2 degradation. Additionally, the A domain of PKM2 and the PHB domain of PHB2 are required for PKM2-PHB2 binding and PHB2 phosphorylation. After LPS exposure, expression of a phosphorylation-defective PHB2S91A mutant negated the protective effects of PKM2 overexpression. Moreover, knockin mice expressing a phosphorylation-mimetic PHB2S91D mutant showed improved heart function, reduced inflammation, and preserved mitochondrial function following sepsis induction. Abundant PKM2 expression is a prerequisite to sustain PKM2-PHB2 interaction which is a key element for preservation of PHB2 phosphorylation and MQC, presenting novel interventive targets for the treatment of septic cardiomyopathy.
Collapse
Affiliation(s)
- Yingzhen Du
- The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Medical School of Chinese PLA, Beijing, China
| | - Jialei Li
- School of Medicine, Southern Medical University, Guangzhou, Guangdong, China
| | - Zhe Dai
- School of Medicine, Southern Medical University, Guangzhou, Guangdong, China
| | - Yuxin Chen
- School of Medicine, Southern Medical University, Guangzhou, Guangdong, China
| | - Yao Zhao
- School of Medicine, Southern Medical University, Guangzhou, Guangdong, China
| | - Xiaoman Liu
- School of Medicine, Southern Medical University, Guangzhou, Guangdong, China
| | - Tian Xia
- Department of Clinical Laboratory Medicine, The First Medical Centre, Medical School of Chinese People's Liberation Army, Beijing, China
- Xianning Medical College, Hubei University of Science & Technology, Xianning, China
| | - Pingjun Zhu
- The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Medical School of Chinese PLA, Beijing, China.
| | - Yijin Wang
- The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Medical School of Chinese PLA, Beijing, China.
| |
Collapse
|
|
44
|
Xia J, Chen C, Sun Y, Li S, Li Y, Cheng BR, Pang Y, Li Y, Li D, Lin Q. Panax quinquefolius saponins and panax notoginseng saponins attenuate myocardial hypoxia-reoxygenation injury by reducing excessive mitophagy. Cell Biochem Biophys 2024; 82:1179-1191. [PMID: 38713401 DOI: 10.1007/s12013-024-01267-z] [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] [Accepted: 03/29/2024] [Indexed: 05/08/2024]
Abstract
OBJECTIVE Panax quinquefolius saponins (PQS) and Panax notoginseng saponins (PNS) are key bioactive compounds in Panax quinquefolius L. and Panax notoginseng, commonly used in the treatment of clinical ischemic heart disease. However, their potential in mitigating myocardial ischemia-reperfusion injury remains uncertain. This study aims to evaluate the protective effects of combined PQS and PNS administration in myocardial hypoxia/reoxygenation (H/R) injury and explore the underlying mechanisms. METHODS To investigate the involvement of HIF-1α/BNIP3 mitophagy pathway in the myocardial protection conferred by PNS and PQS, we employed small interfering BNIP3 (siBNIP3) to silence key proteins of the pathway. H9C2 cells were categorized into four groups: control, H/R, H/R + PQS + PNS, and H/R + PQS + PNS+siBNIP3. Cell viability was assessed by Cell Counting Kit-8, apoptosis rates determined via flow cytometry, mitochondrial membrane potential assessed with the JC-1 fluorescent probes, intracellular reactive oxygen species detected with 2',7'-dichlorodihydrofluorescein diacetate, mitochondrial superoxide production quantified with MitoSOX Red, and autophagic flux monitored with mRFP-GFP-LC3 adenoviral vectors. Autophagosomes and their ultrastructure were visualized through transmission electron microscopy. Moreover, mRNA and protein levels were analyzed via real-time PCR and Western blotting. RESULTS PQS + PNS administration significantly increased cell viability, reduced apoptosis, lowered reactive oxygen species levels and mitochondrial superoxide production, mitigated mitochondrial dysfunction, and induced autophagic flux. Notably, siBNIP3 intervention did not counteract the cardioprotective effect of PQS + PNS. The PQS + PNS group showed downregulated mRNA expression of HIF-1α and BNIP3, along with reduced HIF-1α protein expression compared to the H/R group. CONCLUSIONS PQS + PNS protects against myocardial H/R injury, potentially by downregulating mitophagy through the HIF-1α/BNIP3 pathway.
Collapse
Affiliation(s)
- Junyan Xia
- Department of Cardiology, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, 100700, Beijing, China
| | - Cong Chen
- Department of Cardiology, Guanganmen Hospital, China Academy of Chinese Medical Sciences, 100053, Beijing, China
| | - Yanan Sun
- Experimental Research Center, China Academy of Chinese Medical Sciences, 100700, Beijing, China
| | - Sinai Li
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Institute of Traditional Chinese Medicine, 100010, Beijing, China
| | - Yuxuan Li
- Department of Cardiology, Dongfang Hospital Affiliated to Beijing University of Chinese Medicine, 100078, Beijing, China
| | - Bai-Ru Cheng
- Department of Cardiology, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, 100700, Beijing, China
| | - Yanting Pang
- Department of Cardiology, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, 100700, Beijing, China
| | - Yan Li
- Department of Cardiology, Dongfang Hospital Affiliated to Beijing University of Chinese Medicine, 100078, Beijing, China
| | - Dong Li
- Department of Cardiology, Dongfang Hospital Affiliated to Beijing University of Chinese Medicine, 100078, Beijing, China.
| | - Qian Lin
- Department of Cardiology, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, 100700, Beijing, China.
| |
Collapse
|
|
45
|
Yin J, Zheng X, Zhao Y, Shen X, Cheng T, Shao X, Jing X, Huang S, Lin W. Investigating the Therapeutic Effects of Ferroptosis on Myocardial Ischemia-Reperfusion Injury Using a Dual-Locking Mitochondrial Targeting Strategy. Angew Chem Int Ed Engl 2024; 63:e202402537. [PMID: 38509827 DOI: 10.1002/anie.202402537] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2024] [Revised: 03/17/2024] [Accepted: 03/19/2024] [Indexed: 03/22/2024]
Abstract
Research on ferroptosis in myocardial ischemia/reperfusion injury (MIRI) using mitochondrial viscosity as a nexus holds great promise for MIRI therapy. However, high-precision visualisation of mitochondrial viscosity remains a formidable task owing to the debilitating electrostatic interactions caused by damaged mitochondrial membrane potential. Herein, we propose a dual-locking mitochondria-targeting strategy that incorporates electrostatic forces and probe-protein molecular docking. Even in damaged mitochondria, stable and precise visualisation of mitochondrial viscosity in triggered and medicated MIRI was achieved owing to the sustained driving forces (e.g., pi-cation, pi-alkyl interactions, etc.) between the developed probe, CBS, and the mitochondrial membrane protein. Moreover, complemented by a western blot, we confirmed that ferrostatin-1 exerts its therapeutic effect on MIRI by improving the system xc-/GSH/GPX4 antioxidant system, confirming the therapeutic value of ferroptosis in MIRI. This study presents a novel strategy for developing robust mitochondrial probes, thereby advancing MIRI treatment.
Collapse
Affiliation(s)
- Junling Yin
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, 250117, Shandong, People's Republic of China
| | - Xueying Zheng
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, 250117, Shandong, People's Republic of China
| | - Yuxi Zhao
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, 250117, Shandong, People's Republic of China
| | - Xiaotong Shen
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, 250117, Shandong, People's Republic of China
| | - Tian Cheng
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, 250117, Shandong, People's Republic of China
| | - Xinyu Shao
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, 250117, Shandong, People's Republic of China
| | - Xinying Jing
- Institute of Optical Materials and Chemical Biology, Guangxi Key Laboratory of Electrochemical Energy Materials, School of Chemistry and Chemical Engineering, Guangxi University, Nanning, Guangxi, 530004, People's Republic of China
| | - Shuhong Huang
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, 250117, Shandong, People's Republic of China
| | - Weiying Lin
- Institute of Optical Materials and Chemical Biology, Guangxi Key Laboratory of Electrochemical Energy Materials, School of Chemistry and Chemical Engineering, Guangxi University, Nanning, Guangxi, 530004, People's Republic of China
| |
Collapse
|
|
46
|
Xu M, Wang W, Cheng J, Qu H, Xu M, Wang L. Effects of mitochondrial dysfunction on cellular function: Role in atherosclerosis. Biomed Pharmacother 2024; 174:116587. [PMID: 38636397 DOI: 10.1016/j.biopha.2024.116587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 04/02/2024] [Accepted: 04/10/2024] [Indexed: 04/20/2024] Open
Abstract
Atherosclerosis, an immunoinflammatory disease of medium and large arteries, is associated with life-threatening clinical events, such as acute coronary syndromes and stroke. Chronic inflammation and impaired lipoprotein metabolism are considered to be among the leading causes of atherosclerosis, while numerous risk factors, including arterial hypertension, diabetes mellitus, obesity, and aging, can contribute to the development of the disease. In recent years, emerging evidence has underlined the key role of mitochondrial dysfunction in the pathogenesis of atherosclerosis. Mitochondrial dysfunction is believed to result in an increase in reactive oxygen species, leading to oxidative stress, chronic inflammation, and intracellular lipid deposition, all of which can contribute to the pathogenesis of atherosclerosis. Critical cells, including endothelial cells, vascular smooth muscle cells, and macrophages, play an important role in atherosclerosis. Mitochondrial function is also involved in maintaining the normal function of these cells. To better understand the relationship between mitochondrial dysfunction and atherosclerosis, this review summarizes the findings of recent studies and discusses the role of mitochondrial dysfunction in the risk factors and critical cells of atherosclerosis. FACTS: OPEN QUESTIONS.
Collapse
Affiliation(s)
- Minwen Xu
- Clinical Skills Center, First Affiliated Hospital of Gannan Medical University, Ganzhou 341000, China
| | - Wenjun Wang
- Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Jingpei Cheng
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou 341000, China; Basic Medical College, Gannan Medical University, Ganzhou 341000, China
| | - Hongen Qu
- Gannan Normal University, Ganzhou 341000, China.
| | - Minjuan Xu
- Department of Obstetrics and Gynecology, Ganzhou People's Hospital, Ganzhou 341000, China.
| | - Liefeng Wang
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou 341000, China; Basic Medical College, Gannan Medical University, Ganzhou 341000, China.
| |
Collapse
|
|
47
|
Xu F, He Y, Xu A, Ren L, Xu J, Shao Y, Wang M, Zhao W, Zhang Y, Lu P, Zhang L. Triphenyl phosphate induces cardiotoxicity through myocardial fibrosis mediated by apoptosis and mitophagy of cardiomyocyte in mice. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2024; 346:123651. [PMID: 38408505 DOI: 10.1016/j.envpol.2024.123651] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 02/05/2024] [Accepted: 02/23/2024] [Indexed: 02/28/2024]
Abstract
Triphenyl phosphate (TPHP) is an organophosphorus flame retardant, but its cardiac toxicity has not been adequately investigated. Therefore, in the current study, the effect of TPHP on the heart and the underlying mechanism involved was evaluated. C57BL/6 J mice were administered TPHP (0, 5, and 50 mg/kg/day) for 30 days. In addition, H9c2 cells were treated with three various concentrations (0, 50, and 150 μM) of TPHP, with and without the reactive oxygen species (ROS) scavenger N-acetyl-L-cysteine or the mitochondrial fusion promoter M1. TPHP caused cardiac fibrosis and increased the levels of CK-MB and LDH in the serum. TPHP increased the levels of ROS, malondialdehyde (MDA), and decreased the level of superoxide dismutase (SOD) and Glutathione peroxidase (GSH-Px). Furthermore, TPHP caused mitochondrial damage, and induced fusion and fission disorders that contributed to mitophagy in both the heart of C57BL/6 J mice and H9c2 cells. Transcriptome analysis showed that TPHP induced up- or down-regulated expression of various genes in myocardial tissue and revealed enriched apoptosis pathways. It was also found that TPHP could remarkably increase the expression levels of Bax, cleaved Caspase-9, cleaved Caspase-3, and decreased Bcl-2, thereby causing apoptosis in H9c2 cells. Taken together, the results suggested that TPHP promoted mitophagy through mitochondria fusion dysfunction resulting from oxidative stress, leading to fibrosis by inducing myocardial apoptosis.
Collapse
Affiliation(s)
- Feibo Xu
- School of Basic Medical Sciences, Binzhou Medical University, Yantai, 264003, China
| | - Yu He
- School of Basic Medical Sciences, Binzhou Medical University, Yantai, 264003, China
| | - Aili Xu
- School of Basic Medical Sciences, Binzhou Medical University, Yantai, 264003, China
| | - Lihua Ren
- School of Nursing, Peking University, Beijing, 100191, China
| | - Jinyu Xu
- School of Basic Medical Sciences, Binzhou Medical University, Yantai, 264003, China
| | - Yali Shao
- School of Basic Medical Sciences, Binzhou Medical University, Yantai, 264003, China
| | - Minxin Wang
- School of Basic Medical Sciences, Binzhou Medical University, Yantai, 264003, China
| | - Wei Zhao
- School of Basic Medical Sciences, Binzhou Medical University, Yantai, 264003, China
| | - Ying Zhang
- School of Basic Medical Sciences, Binzhou Medical University, Yantai, 264003, China
| | - Peng Lu
- School of Public Health and Management, Binzhou Medical University, Yantai, 264003, China
| | - Lianshuang Zhang
- School of Basic Medical Sciences, Binzhou Medical University, Yantai, 264003, China.
| |
Collapse
|
|
48
|
Wu H, Li H, Zhang Q, Song J, Chen Y, Wang ZM, Jiang W. CircBCL2L13 attenuates cardiomyocyte oxidative stress and apoptosis in cardiac ischemia‒reperfusion injury via miR-1246/PEG3 signaling. J Biochem Mol Toxicol 2024; 38:e23711. [PMID: 38605443 DOI: 10.1002/jbt.23711] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2023] [Revised: 02/16/2024] [Accepted: 03/29/2024] [Indexed: 04/13/2024]
Abstract
Ischemia‒reperfusion (I/R) is a common complication in the clinical treatment of acute myocardial infarction (MI), in which cardiomyocytes play a pivotal role in the recovery of cardiac function after reperfusion injury. The expression of numerous circular ribonucleic acids (circRNAs) is disrupted in I/R-induced cardiac damage, but the potential role of circRNAs in I/R damage has not been fully elucidated. The purpose of the present study was to clarify the biological action and molecular mechanism of circRNA 002166 (also termed circCL2L13) in postmyocardial I/R. Oxygen-glucose deprivation/reoxygenation (OGD/R) in an in vivo model was performed to simulate I/R damage. real-time polymerase chain reaction analysis was also conducted to evaluate the relationships of the SOD1, SOD2, NRF2, HO1 and GPX4 indicators with oxidative stress injury. TUNEL immunofluorescence was used to evaluate the degree of cardiomyocyte apoptosis in the different treatment groups. The circBCL2L13 level was markedly upregulated in myocardial tissues from a mouse I/R model. Overexpression of circBCL2L13 markedly attenuated the expression of oxidative stress-related genes and apoptosis in OGD/R-induced cardiomyocytes. A mechanistic study revealed that circBCL2L13 functions as a ceRNA for miR-1246 and modulates paternally expressed gene 3 (PEG3). Eventually, circBCL2L13 was proven to regulate PEG3 by targeting miR-1246, thereby protecting against OGD/R-induced cardiomyocyte oxidative damage and apoptosis. In conclusion, our study confirmed that the circBCL2L13/miR-1246/PEG3 axis suppressed the progression of OGD/R injury in cardiomyocytes, which might lead to new therapeutic strategies for cardiac I/R injury.
Collapse
Affiliation(s)
- Hua Wu
- Department of Radiology, First People's Hospital of Jingdezhen, Jingdezhen, Jiangxi, China
| | - Hairui Li
- Cardiology Division, Department of Medicine, The University of Hong Kong Shen Zhen Hospital, Shenzhen, Guangdong, China
| | - Qian Zhang
- Cardiology Division, Department of Medicine, The University of Hong Kong Shen Zhen Hospital, Shenzhen, Guangdong, China
| | - Jia Song
- Department of Medicine (Section of Cardiovascular Research), Baylor College of Medicine, Houston, Texas, USA
| | - Yongbin Chen
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA
| | - Ze-Mu Wang
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Weipeng Jiang
- Department of Cardiology, South China Hospital of Shenzhen University, Shenzhen, Guangdong, China
| |
Collapse
|
|
49
|
Wang H, Slotabec L, Didik S, Li Z, Leng L, Zhao B, Bucala R, Li J. A small molecule macrophage migration inhibitory factor agonist ameliorates age-related myocardial intolerance to ischemia-reperfusion insults via metabolic regulation. Metabolism 2024; 153:155792. [PMID: 38232801 PMCID: PMC10932879 DOI: 10.1016/j.metabol.2024.155792] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 12/27/2023] [Accepted: 01/09/2024] [Indexed: 01/19/2024]
Abstract
Macrophage migration inhibitory factor (MIF) is an innate cytokine that regulates both inflammatory and homeostatic responses. MIF is expressed by cardiomyocytes, where it exerts a protective action against ischemia-reperfusion (I/R) injury by activating AMP-activated protein kinase (AMPK). This effect is attenuated in the senescent heart due to an intrinsic, age-related reduction in MIF expression. We hypothesized that treating the aged heart with the small molecule MIF agonist (MIF20) can reinforce protective MIF signaling in cardiomyocytes, leading to a beneficial effect against I/R stress. The administration of MIF20 at the onset of reperfusion was found to not only decrease myocardial infarct size but also preserves systolic function in the aged heart. Protection from I/R injury was reduced in mice with cardiomyocyte-specific Mif deletion, consistent with the mechanism of action of MIF20 to allosterically increase MIF affinity for its cognate receptor CD74. We further found MIF20 to contribute to the maintenance of mitochondrial fitness and to preserve the contractile properties of aged cardiomyocytes under hypoxia/reoxygenation. MIF20 augments protective metabolic responses by reducing the NADH/NAD ratio, leading to a decrease in the accumulation of reactive oxygen species (ROS) in the aged myocardium under I/R stress. We also identify alterations in the expression levels of the downstream effectors PDK4 and LCAD, which participate in the remodeling of the cardiac metabolic profile. Data from this study demonstrates that pharmacologic augmentation of MIF signaling provides beneficial homeostatic actions on senescent myocardium under I/R stress.
Collapse
Affiliation(s)
- Hao Wang
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, United States of America
| | - Lily Slotabec
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, United States of America
| | - Steven Didik
- Department of Surgery, University of South Florida, FL 33612, United States of America
| | - Zehui Li
- Department of Surgery, University of South Florida, FL 33612, United States of America
| | - Lin Leng
- Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, United States of America
| | - Bi Zhao
- Genomics Program, College of Public Health, University of South Florida, Tampa, FL 33612, United States of America.
| | - Richard Bucala
- Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, United States of America
| | - Ji Li
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, United States of America; G.V. (Sonny) Montgomery VA Medical Center, Jackson, MS 39216, United States of America.
| |
Collapse
|
|
50
|
Chen Z, Liu T, Yuan H, Sun H, Liu S, Zhang S, Liu L, Jiang S, Tang Y, Liu Z. Bioinformatics integration reveals key genes associated with mitophagy in myocardial ischemia-reperfusion injury. BMC Cardiovasc Disord 2024; 24:183. [PMID: 38539069 PMCID: PMC10967080 DOI: 10.1186/s12872-024-03834-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Accepted: 03/09/2024] [Indexed: 11/14/2024] Open
Abstract
BACKGROUND Myocardial ischemia is a prevalent cardiovascular disorder associated with significant morbidity and mortality. While prompt restoration of blood flow is essential for improving patient outcomes, the subsequent reperfusion process can result in myocardial ischemia-reperfusion injury (MIRI). Mitophagy, a specialized autophagic mechanism, has consistently been implicated in various cardiovascular disorders. However, the specific connection between ischemia-reperfusion and mitophagy remains elusive. This study aims to elucidate and validate central mitophagy-related genes associated with MIRI through comprehensive bioinformatics analysis. METHODS We acquired the microarray expression profile dataset (GSE108940) from the Gene Expression Omnibus (GEO) and identified differentially expressed genes (DEGs) using GEO2R. Subsequently, these DEGs were cross-referenced with the mitophagy database, and differential nucleotide sequence analysis was performed through enrichment analysis. Protein-protein interaction (PPI) network analysis was employed to identify hub genes, followed by clustering of these hub genes using cytoHubba and MCODE within Cytoscape software. Gene set enrichment analysis (GSEA) was conducted on central genes. Additionally, Western blotting, immunofluorescence, and quantitative polymerase chain reaction (qPCR) analyses were conducted to validate the expression patterns of pivotal genes in MIRI rat model and H9C2 cardiomyocytes. RESULTS A total of 2719 DEGs and 61 mitophagy-DEGs were identified, followed by enrichment analyses and the construction of a PPI network. HSP90AA1, RPS27A, EEF2, EIF4A1, EIF2S1, HIF-1α, and BNIP3 emerged as the seven hub genes identified by cytoHubba and MCODE of Cytoscape software. Functional clustering analysis of HIF-1α and BNIP3 yielded a score of 9.647, as determined by Cytoscape (MCODE). In our MIRI rat model, Western blot and immunofluorescence analyses confirmed a significant elevation in the expression of HIF-1α and BNIP3, accompanied by a notable increase in the ratio of LC3II to LC3I. Subsequently, qPCR confirmed a significant upregulation of HIF-1α, BNIP3, and LC3 mRNA in the MIRI group. Activation of the HIF-1α/BNIP3 pathway mediates the regulation of the degree of Mitophagy, thereby effectively reducing apoptosis in rat H9C2 cardiomyocytes. CONCLUSIONS This study has identified seven central genes among mitophagy-related DEGs that may play a pivotal role in MIRI, suggesting a correlation between the HIF-1α/BNIP3 pathway of mitophagy and the pathogenesis of MIRI. The findings highlight the potential importance of mitophagy in MIRI and provide valuable insights into underlying mechanisms and potential therapeutic targets for further exploration in future studies.
Collapse
Affiliation(s)
- Zhian Chen
- Department of Clinical Medicine, Changchun University of Chinese Medicine, No. 1035, Boshuo Road, Nanguan District, Changchun, 130,117, Jilin Province, China
| | - Tianying Liu
- Department of Clinical Medicine, Changchun University of Chinese Medicine, No. 1035, Boshuo Road, Nanguan District, Changchun, 130,117, Jilin Province, China
| | - Hao Yuan
- Department of Clinical Medicine, Changchun University of Chinese Medicine, No. 1035, Boshuo Road, Nanguan District, Changchun, 130,117, Jilin Province, China
| | - Han Sun
- Department of Clinical Medicine, Changchun University of Chinese Medicine, No. 1035, Boshuo Road, Nanguan District, Changchun, 130,117, Jilin Province, China
| | - Sitong Liu
- Department of Clinical Medicine, Changchun University of Chinese Medicine, No. 1035, Boshuo Road, Nanguan District, Changchun, 130,117, Jilin Province, China
| | - Shuai Zhang
- Department of Clinical Medicine, Changchun University of Chinese Medicine, No. 1035, Boshuo Road, Nanguan District, Changchun, 130,117, Jilin Province, China
| | - Li Liu
- Department of Clinical Medicine, Changchun University of Chinese Medicine, No. 1035, Boshuo Road, Nanguan District, Changchun, 130,117, Jilin Province, China
| | - Shuang Jiang
- Department of Clinical Medicine, Changchun University of Chinese Medicine, No. 1035, Boshuo Road, Nanguan District, Changchun, 130,117, Jilin Province, China
| | - Yong Tang
- Department of Clinical Medicine, Changchun University of Chinese Medicine, No. 1035, Boshuo Road, Nanguan District, Changchun, 130,117, Jilin Province, China.
| | - Zhi Liu
- Department of Clinical Medicine, Changchun University of Chinese Medicine, No. 1035, Boshuo Road, Nanguan District, Changchun, 130,117, Jilin Province, China.
| |
Collapse
|