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      Chinese herbal medicine and active ingredients for diabetic cardiomyopathy: molecular mechanisms regulating endoplasmic reticulum stress

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          Abstract

          Abstract Background: Diabetic cardiomyopathy (DCM) is one of the serious microvascular complications of diabetes mellitus. It is often associated with clinical manifestations such as arrhythmias and heart failure, and significantly reduces the quality of life and years of survival of patients. Endoplasmic reticulum stress (ERS) is the removal of unfolded and misfolded proteins and is an important mechanism for the maintenance of cellular homeostasis. ERS plays an important role in the pathogenesis of DCM by causing cardiomyocyte apoptosis, insulin resistance, calcium imbalance, myocardial hypertrophy and fibrosis. Targeting ERS is a new direction in the treatment of DCM. A large number of studies have shown that Chinese herbal medicine and active ingredients can significantly improve the clinical outcome of DCM patients through intervention in ERS and effects on myocardial structure and function, which has become one of the hot research directions.

          Purpose: The aim of this review is to elucidate and summarize the roles and mechanisms of Chinese herbal medicine and active ingredients that have the potential to modulate endoplasmic reticulum stress, thereby contributing to better management of DCM.

          Methods: Databases such as PubMed, Web of Science, China National Knowledge Internet, and Wanfang Data Knowledge Service Platform were used to search, analyze, and collect literature, in order to review the mechanisms by which phytochemicals inhibit the progression of DCM by targeting the ERS and its key signaling pathways. Keywords used included “diabetic cardiomyopathy” and “endoplasmic reticulum stress.”

          Results: This review found that Chinese herbs and their active ingredients can regulate ERS through IRE1, ATF6, and PERK pathways to reduce cardiomyocyte apoptosis, ameliorate myocardial fibrosis, and attenuate myocardial hypertrophy for the treatment of DCM.

          Conclusion: A comprehensive source of information on potential ERS inhibitors is provided in this review. The analysis of the literature suggests that Chinese herbal medicine and its active ingredients can be used as potential drug candidates for the treatment of DCM. In short, we cannot ignore the role of traditional Chinese medicine in regulating ERS and treating DCM, and look forward to more research and new drugs to come.

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          Most cited references148

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          Diabetic Cardiomyopathy

          James Sowers, Guanghong Jia, Michael A. Hill (2018)
          Heart failure and related morbidity and mortality are increasing at an alarming rate, in large part, because of increases in aging, obesity, and diabetes mellitus. The clinical outcomes associated with heart failure are considerably worse for patients with diabetes mellitus than for those without diabetes mellitus. In people with diabetes mellitus, the presence of myocardial dysfunction in the absence of overt clinical coronary artery disease, valvular disease, and other conventional cardiovascular risk factors, such as hypertension and dyslipidemia, has led to the descriptive terminology, diabetic cardiomyopathy. The prevalence of diabetic cardiomyopathy is increasing in parallel with the increase in diabetes mellitus. Diabetic cardiomyopathy is initially characterized by myocardial fibrosis, dysfunctional remodeling, and associated diastolic dysfunction, later by systolic dysfunction, and eventually by clinical heart failure. Impaired cardiac insulin metabolic signaling, mitochondrial dysfunction, increases in oxidative stress, reduced nitric oxide bioavailability, elevations in advanced glycation end products and collagen-based cardiomyocyte and extracellular matrix stiffness, impaired mitochondrial and cardiomyocyte calcium handling, inflammation, renin-angiotensin-aldosterone system activation, cardiac autonomic neuropathy, endoplasmic reticulum stress, microvascular dysfunction, and a myriad of cardiac metabolic abnormalities have all been implicated in the development and progression of diabetic cardiomyopathy. Molecular mechanisms linked to the underlying pathophysiological changes include abnormalities in AMP-activated protein kinase, peroxisome proliferator-activated receptors, O-linked N-acetylglucosamine, protein kinase C, microRNA, and exosome pathways. The aim of this review is to provide a contemporary view of these instigators of diabetic cardiomyopathy, as well as mechanistically based strategies for the prevention and treatment of diabetic cardiomyopathy.
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            The role of endoplasmic reticulum stress in human pathology.

            Scott A Oakes, Feroz Papa (2015)
            Numerous genetic and environmental insults impede the ability of cells to properly fold and posttranslationally modify secretory and transmembrane proteins in the endoplasmic reticulum (ER), leading to a buildup of misfolded proteins in this organelle--a condition called ER stress. ER-stressed cells must rapidly restore protein-folding capacity to match protein-folding demand if they are to survive. In the presence of high levels of misfolded proteins in the ER, an intracellular signaling pathway called the unfolded protein response (UPR) induces a set of transcriptional and translational events that restore ER homeostasis. However, if ER stress persists chronically at high levels, a terminal UPR program ensures that cells commit to self-destruction. Chronic ER stress and defects in UPR signaling are emerging as key contributors to a growing list of human diseases, including diabetes, neurodegeneration, and cancer. Hence, there is much interest in targeting components of the UPR as a therapeutic strategy to combat these ER stress-associated pathologies.
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              Insulin resistance and hyperinsulinaemia in diabetic cardiomyopathy.

              Guanghong Jia, Vincent DeMarco, James Sowers (2016)
              Insulin resistance, type 2 diabetes mellitus and associated hyperinsulinaemia can promote the development of a specific form of cardiomyopathy that is independent of coronary artery disease and hypertension. Termed diabetic cardiomyopathy, this form of cardiomyopathy is a major cause of morbidity and mortality in developed nations, and the prevalence of this condition is rising in parallel with increases in the incidence of obesity and type 2 diabetes mellitus. Of note, female patients seem to be particularly susceptible to the development of this complication of metabolic disease. The diabetic cardiomyopathy observed in insulin- resistant or hyperinsulinaemic states is characterized by impaired myocardial insulin signalling, mitochondrial dysfunction, endoplasmic reticulum stress, impaired calcium homeostasis, abnormal coronary microcirculation, activation of the sympathetic nervous system, activation of the renin-angiotensin-aldosterone system and maladaptive immune responses. These pathophysiological changes result in oxidative stress, fibrosis, hypertrophy, cardiac diastolic dysfunction and eventually systolic heart failure. This Review highlights a surge in diabetic cardiomyopathy research, summarizes current understanding of the molecular mechanisms underpinning this condition and explores potential preventive and therapeutic strategies.
              Article 0 comments Cited 349 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Lianjun Ao: URI : https://loop.frontiersin.org/people/2432056/overviewRole:
                Zhengtao Chen: URI : https://loop.frontiersin.org/people/1520286/overviewRole: Role: Role:
                Jiacheng Yin: Role:
                Yulin Leng: Role: Role: Role:
                Yue Luo: Role:
                Xiaoxu Fu: Role: Role:
                Hanyu Liu: URI : https://loop.frontiersin.org/people/2253104/overviewRole:
                Xiaoke Liu: URI : https://loop.frontiersin.org/people/1333254/overviewRole:
                Hong Gao: Role:
                Chunguang Xie: URI : https://loop.frontiersin.org/people/1710819/overviewRole: Role: Role: Role:
                Journal
                Journal ID (nlm-ta): Front Pharmacol
                Journal ID (iso-abbrev): Front Pharmacol
                Journal ID (publisher-id): Front. Pharmacol.
                Title: Frontiers in Pharmacology
                Publisher: Frontiers Media S.A.
                ISSN (Electronic): 1663-9812
                Publication date (Electronic): 07 November 2023
                Publication date Collection: 2023
                Volume: 14
                Electronic Location Identifier: 1290023
                Affiliations
                [1] 1 Hospital of Chengdu University of Traditional Chinese Medicine , Chengdu, Sichuan, China
                [2] 2 Affiliated Hospital of Jiangxi University of Chinese Medicine , Nanchang, Jiangxi, China
                [3] 3 TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province , Chengdu, Sichuan, China
                [4] 4 Department of Endocrinology , Hospital of Chengdu University of Traditional Chinese Medicine , Chengdu, China
                Author notes

                Edited by: Zhihao Liu, University of Maryland, College Park, United States

                Reviewed by: Syed Anees Ahmed, East Carolina University, United States

                Priyanka Choudhury, Medical College of Wisconsin, United States

                *Correspondence: Chunguang Xie, xiecg@ 123456cdutcm.edu.cn
                Article
                Publisher ID: 1290023
                DOI: 10.3389/fphar.2023.1290023
                PMC ID: 10661377
                SO-VID: 2616e289-90cd-44bf-a5a2-578aca661c76
                Copyright © Copyright © 2023 Ao, Chen, Yin, Leng, Luo, Fu, Liu, Liu, Gao and Xie.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                Date received : 06 September 2023
                Date accepted : 23 October 2023
                Funding
                The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by grants from National Administration of Traditional Chinese Medicine Qi Huang Scholars support project, National Administration of Traditional Chinese Medicine (ZYYCXTD-C-202209), Major Science and Technology Projects of Science and Technology Department of Sichuan Province (2022ZDZX0022).
                Categories
                Subject: Pharmacology
                Subject: Review
                Custom metadata
                section-at-acceptance Ethnopharmacology

                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine
                Keywords: diabetic cardiomyopathy,endoplasmic reticulum stress,chinese herbal medicine,active ingredients,mechanism of action
                Data availability:
                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine
                Keywords: diabetic cardiomyopathy, endoplasmic reticulum stress, chinese herbal medicine, active ingredients, mechanism of action

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