scholarly journals Melatonin Ameliorates MI-Induced Cardiac Remodeling and Apoptosis through a JNK/p53-Dependent Mechanism in Diabetes Mellitus

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
Linhe Lu ◽  
Jipeng Ma ◽  
Mingming Sun ◽  
Xiaowu Wang ◽  
Erhe Gao ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Interstitial Fibrosis ◽  
Myocardial Dysfunction ◽  
Cardiac Injury ◽  
Diabetic Patients ◽  
High Fat ◽  
Adult Mice ◽  
Cardiac Geometry ◽  
And Function

Diabetes mellitus, a worldwide health threat, is considered an independent risk factor for cardiovascular diseases. The overall cardiovascular risk of diabetes is similar to the one having one myocardial infarction (MI) attack although the precise impact of diabetes on MI-induced myocardial anomalies remains elusive. Given that mortality following MI is much greater in diabetic patients compared to nondiabetic patients, this study was designed to examine the effect of melatonin on MI injury-induced myocardial dysfunction in diabetes. Adult mice were made diabetic using high-fat feeding and streptozotocin (100 mg/kg body weight) prior to MI and were treated with melatonin (50 mg/kg/d, p.o.) for 4 weeks prior to assessment of cardiac geometry and function. The MI procedure in diabetes displayed overt changes in cardiac geometry (chamber dilation and interstitial fibrosis) and functional anomalies (reduced fractional shortening and cardiomyocyte contractile capacity) in association with elevated c-Jun N-terminal kinase (JNK) phosphorylation and p53 level. Melatonin treatment markedly attenuated cardiac dysfunction and myocardial fibrosis in post-MI diabetic mice. Furthermore, melatonin decreased JNK phosphorylation, reduced p53 levels, and suppressed apoptosis in hearts from the post-MI diabetic group. In vitro findings revealed that melatonin effectively counteracted high-glucose/high fat-hypoxia-induced cardiomyocyte apoptosis and contractile dysfunction through a JNK-mediated mechanism, the effects of which were impaired by the JNK activator anisomycin. In summary, our study suggests that melatonin protects against myocardial injury in post-MI mice with diabetes, which offers a new therapeutic strategy for the management of MI-induced cardiac injury in diabetes.

scholarly journals The Functionality of Endothelial-Colony-Forming Cells from Patients with Diabetes Mellitus

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1731
Author(s):  
Caomhán J. Lyons ◽  
Timothy O'Brien
Keyword(s):  
Diabetes Mellitus ◽  
Cell Therapy ◽  
Diabetic Patients ◽  
Angiogenic Potential ◽  
Endothelial Colony Forming Cells ◽  
Allogeneic Cell Therapy ◽  
Patients With Diabetes ◽  
Pre Treatment

Endothelial-colony-forming cells (ECFCs) are a population of progenitor cells which have demonstrated promising angiogenic potential both in vitro and in vivo. However, ECFCs from diabetic patients have been shown to be dysfunctional compared to ECFCs from healthy donors. Diabetes mellitus itself presents with many vascular co-morbidities and it has been hypothesized that ECFCs may be a potential cell therapy option to promote revascularisation in these disorders. While an allogeneic cell therapy approach would offer the potential of an ‘off the shelf’ therapeutic product, to date little research has been carried out on umbilical cord-ECFCs in diabetic models. Alternatively, autologous cell therapy using peripheral blood-ECFCs allows the development of a personalised therapeutic approach to medicine; however, autologous diabetic ECFCs are dysfunctional and need to be repaired so they can effectively treat diabetic co-morbidities. Many different groups have modified autologous diabetic ECFCs to improve their function using a variety of methods including pre-treatment with different factors or with genetic modification. While the in vitro and in vivo data from the literature is promising, no ECFC therapy has proceeded to clinical trials to date, indicating that more research is needed for a potential ECFC therapy in the future to treat diabetic complications.

scholarly journals Ketogenic Diet Suppressed T-Regulatory Cells and Promoted Cardiac Fibrosis via Reducing Mitochondria-Associated Membranes and Inhibiting Mitochondrial Function

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Jun Tao ◽  
Hao Chen ◽  
Ya-Jing Wang ◽  
Jun-Xiong Qiu ◽  
Qing-Qi Meng ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Cardiac Function ◽  
Ketogenic Diet ◽  
Mitochondrial Respiration ◽  
Cardiac Fibrosis ◽  
Interstitial Fibrosis ◽  
Diabetic Patients ◽  
T Regulatory Cell ◽  
Metabolic Indices ◽  
And Function

Ketogenic diet (KD) is popular in diabetic patients but its cardiac safety and efficiency on the heart are unknown. The aim of the present study is to determine the effects and the underlined mechanisms of KD on cardiac function in diabetic cardiomyopathy (DCM). We used db/db mice to model DCM, and different diets (regular or KD) were used. Cardiac function and interstitial fibrosis were determined. T-regulatory cell (Treg) number and functions were evaluated. The effects of ketone body (KB) on fatty acid (FA) and glucose metabolism, mitochondria-associated endoplasmic reticulum membranes (MAMs), and mitochondrial respiration were assessed. The mechanisms via which KB regulated MAMs and Tregs were addressed. KD improved metabolic indices in db/db mice. However, KD impaired cardiac diastolic function and exacerbated ventricular fibrosis. Proportions of circulatory CD4+CD25+Foxp3+ cells in whole blood cells and serum levels of IL-4 and IL-10 were reduced in mice fed with KD. KB suppressed the differentiation to Tregs from naive CD4+ T cells. Cultured medium from KB-treated Tregs synergically activated cardiac fibroblasts. Meanwhile, KB inhibited Treg proliferation and productions of IL-4 and IL-10. Treg MAMs, mitochondrial respiration and respiratory complexes, and FA synthesis and oxidation were all suppressed by KB while glycolytic levels were increased. L-carnitine reversed Treg proliferation and function inhibited by KB. Proportions of ST2L+ cells in Tregs were reduced by KB, as well as the production of ST2L ligand, IL-33. Reinforcement expressions of ST2L in Tregs counteracted the reductions in MAMs, mitochondrial respiration, and Treg proliferations and productions of Treg cytokines IL-4 and IL-10. Therefore, despite the improvement of metabolic indices, KD impaired Treg expansion and function and promoted cardiac fibroblast activation and interstitial fibrosis. This could be mainly mediated by the suppression of MAMs and fatty acid metabolism inhibition via blunting IL-33/ST2L signaling.

scholarly journals LncRNA KCNQ1OT1 attenuates sepsis-induced myocardial injury via regulating miR-192-5p/XIAP axis

2020 ◽  
Vol 245 (7) ◽  
pp. 620-630 ◽  
Author(s):  
Fangyuan Sun ◽  
Weifang Yuan ◽  
Hao Wu ◽  
Gang Chen ◽  
Yuxia Sun ◽  
...  
Keyword(s):  
Myocardial Injury ◽  
Myocardial Dysfunction ◽  
Health Care Systems ◽  
Cardiac Injury ◽  
Convincing Evidence ◽  
Luciferase Reporter ◽  
H9c2 Cardiomyocytes ◽  
Care Systems

Myocardial dysfunction is a prime cause of death in sepsis. This study is to delve into the function of lncRNA KCNQ1OT1 in myocardial injury induced by sepsis. Sepsis-induced myocardial injury model in rat was initiated by intraperitoneally injecting of LPS (10 mg/kg) in vivo, and cardiomyocyte H9c2 was treated with LPS to mimic sepsis in vitro. KCNQ1OT1 and miR-192-5p expressions were detected by qRT-PCR. The cell viability was probed with CCK-8 experiment and the apoptosis of the cardiomyocytes was tested using flow cytometry analysis. Western blot was operated to determine apoptosis-related proteins expressions. ELISA was used to evaluate the levels of TNF-α, IL-6, and IL-1β. Bioinformatics analysis, RT-PCR, dual luciferase reporter assay, and RNA immunoprecipitation experiment were utilized to detect the interrelation of genes. Herein, we proved that KCNQ1OT1 was considerably down-regulated, whereas miR-192-5p was markedly increased in myocardial tissues of septic rats. KCNQ1OT1 interrelated with miR-192-5p, and negatively modulated its expression levels. Overexpression of KCNQ1OT1 or the transfection of miR-192-5p inhibitors greatly facilitated the viability and impeded the apoptosis of H9c2 cardiomyocytes. miR-192-5p paired with the 3ʹUTR of XIAP, and repressed its protein expression, and XIAP was modulated positively by KCNQ1OT1. In conclusion, our work indicates that down-regulation of KCNQ1OT1 advances cardiac injury through regulating miR-192-5p/XIAP axis during sepsis. Impact statement Sepsis-induced cardiomyopathy remains to be a major challenge to health care systems around the globe. There are no known therapies currently available that can cure the disease. This study provides convincing evidence that KCNQ1OT1 could attenuate sepsis-mediated myocardial injury. We further demonstrate that the beneficial function of KCNQ1OT1 was achieved by regulating the miR-192-5p/XIAP axis. We therefore found a new mechanism of cardioprotective effect of KCNQ1OT1, one which also offers a novel theoretical basis for the therapy of sepsis-induced cardiomyopathy.

scholarly journals ECM-enriched alginate hydrogels for bioartificial pancreas: an ideal niche to improve insulin secretion and diabetic glucose profile

2019 ◽  
Vol 17 (4) ◽  
pp. 228080001984892 ◽  
Author(s):  
Joana Crisóstomo ◽  
Ana M Pereira ◽  
Sílvia J Bidarra ◽  
Ana C Gonçalves ◽  
Pedro L Granja ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Beta Cells ◽  
Diabetic Patients ◽  
Bioartificial Pancreas ◽  
Multicellular Spheroids ◽  
Rgd Peptides ◽  
Alginate Hydrogels ◽  
And Function

Introduction: The success of a bioartificial pancreas crucially depends on ameliorating encapsulated beta cells survival and function. By mimicking the cellular in vivo niche, the aim of this study was to develop a novel model for beta cells encapsulation capable of establishing an appropriate microenvironment that supports interactions between cells and extracellular matrix (ECM) components. Methods: ECM components (Arg-Gly-Asp, abbreviated as RGD) were chemically incorporated in alginate hydrogels (alginate-RGD). After encapsulation, INS-1E beta cells outcome was analyzed in vitro and after their implantation in an animal model of diabetes. Results: Our alginate-RGD model demonstrated to be a good in vitro niche for supporting beta cells viability, proliferation, and activity, namely by improving the key feature of insulin secretion. RGD peptides promoted cell–matrix interactions, enhanced endogenous ECM components expression, and favored the assembly of individual cells into multicellular spheroids, an essential configuration for proper beta cell functioning. In vivo, our pivotal model for diabetes treatment exhibited an improved glycemic profile of type 2 diabetic rats, where insulin secreted from encapsulated cells was more efficiently used. Conclusions: We were able to successfully introduce a novel valuable function in an old ally in biomedical applications, the alginate. The proposed alginate-RGD model stands out as a promising approach to improve beta cells survival and function, increasing the success of this therapeutic strategy, which might greatly improve the quality of life of an increasing number of diabetic patients worldwide.

scholarly journals A role for Sfrp2 in cardiomyogenesis in vivo

2021 ◽  
Vol 118 (33) ◽  
pp. e2103676118
Author(s):  
José A. Gomez ◽  
Alan Payne ◽  
Richard E. Pratt ◽  
Conrad P. Hodgkinson ◽  
Victor J. Dzau
Keyword(s):  
Diphtheria Toxin ◽  
Cardiac Injury ◽  
The Body ◽  
Adult Mice ◽  
Physiological Properties ◽  
Diphtheria Toxin Receptor ◽  
Toxin Receptor ◽  
Control Adult

Cardiomyogenesis, the process by which the body generates cardiomyocytes, is poorly understood. We have recently shown that Sfrp2 promotes cardiomyogenesis in vitro. The objective of this study was to determine if Sfrp2 would similarly promote cardiomyogenesis in vivo. To test this hypothesis, we tracked multipotent cKit(+) cells in response to Sfrp2 treatment. In control adult mice, multipotent cKit(+) cells typically differentiated into endothelial cells but not cardiomyocytes. In contrast, Sfrp2 switched the fate of these cells. Following Sfrp2 injection, multipotent cKit(+) cells differentiated solely into cardiomyocytes. Sfrp2-derived cardiomyocytes integrated into the myocardium and exhibited identical physiological properties to preexisting native cardiomyocytes. The ability of Sfrp2 to promote cardiomyogenesis was further supported by tracking EdU-labeled cells. In addition, Sfrp2 did not promote the formation of new cardiomyocytes when the cKit(+) cell population was selectively ablated in vivo using a diphtheria toxin receptor–diphtheria toxin model. Notably, Sfrp2-induced cardiomyogenesis was associated with significant functional improvements in a cardiac injury model. In summary, our study further demonstrates the importance of Sfrp2 in cardiomyogenesis.

Skin disorders in patients with diabetes mellitus: a review

2021 ◽  
pp. 54-65
Author(s):  
C. Diehl
Keyword(s):  
Diabetes Mellitus ◽  
Extracellular Proteins ◽  
Diabetic Patients ◽  
World Population ◽  
Skin Disorders ◽  
Limited Joint Mobility ◽  
Systemic Complications ◽  
Cutaneous Infections ◽  
Dermal Collagen

Diabetes mellitus (DM) is a frequent metabolic disease whose prevalence is estimated to be around 9.3 % in the world population in the age group 20—79, corresponding to 463 million affected subjects. Moreover, this prevalence will probably increase in the course of the next years. It accounts for more than 90% of the diabetic patients. Besides systemic complications, those ay also be observed in dermatology. According to the region, the prevalence of skin disorders in patients suffering DM is ranging from 35.4 to 98.8 %. This makes these symptoms a frequent cause of consultation in dermatological practice. The most occurring disorders are skin infections, but yellow nails, candidiasis, acrochordons, limited joint mobility and idiopathic guttate hypomelanosis may also be frequently observed. Diabetic dermopathy and diabetic foot syndrome are also common, such as pigmentation disorders such as acanthosis nigricans and vitiligo. Differences between patterns of lesions remain unclear among types of DM (type 1 or type 2). Overall, cutaneous infection and xerosis showed to be highly prevalent and important skin disorders in several studies, regardless DM type. Among cutaneous infections, fungal aetiology appears to be the most common and those with bacterial origin are the less frequent.DM affects the skin through several mechanisms — High levels of glycaemia strongly affect skin homeostasis by impairing the normal functioning of keratinocytes in vitro, decreasing their proliferation and differentiation. They also lead to advanced glycation end products (AGEs) formation. The latter are formed from glycation of proteins, lipids and nucleic acids. They have various deleterious effects at skin levels: inducing reactive oxygen species (ROS) formation, impairing ROS clearance, as well as intra and extracellular proteins function, and inducing pro inflammatory cytokine through nuclear factor κβ (NF-κβ) pathway. AGE alters collagen properties, decreasing flexibility and solubility and increasing its rigidity, thickening dermal collagen, with increased cross linking from non-enzymatic glycosylation, participating in the development of fibrosis. In diabetic patients, the vascular changes found in the skin are similar to those caused by UV-exposure, i. e. thickening of the vessels walls, increasing from thigh to foot and most marked in the capillaries and leading to failure of vascular responsivenessThis paper is aimed to summarize all these pathologies, reporting their prevalence, giving a brief description of the symptoms, of their pathogenesis and guidelines for their management. Dermatologists have a key role in their treatment, but also in detecting new cases of DM when taking in charge these pathologies. They must also promote glycaemic control by these patients.

Cardiomyocyte-specific loss of RNA polymerase II subunit 5-mediating protein causes myocardial dysfunction and heart failure

2018 ◽  
Vol 115 (11) ◽  
pp. 1617-1628
Author(s):  
Jian Zhang ◽  
Jingyi Sheng ◽  
Liwei Dong ◽  
Yinli Xu ◽  
Liming Yu ◽  
...  
Keyword(s):  
Heart Failure ◽  
Rna Polymerase ◽  
Rna Polymerase Ii ◽  
Genome Stability ◽  
Transforming Growth Factor ◽  
Myocardial Dysfunction ◽  
Transforming Growth Factor Β ◽  
And Function ◽  
Deficient Mice

AbstractAimsMyocardial dysfunction is an important cause of heart failure (HF). RNA polymerase II subunit 5 (RPB5)-mediating protein (RMP) is a transcriptional mediating protein which co-ordinates cellular processes including gene expression, metabolism, proliferation, and genome stability. However, its role in cardiac disease remains unknown. We aimed to determine the role and regulatory mechanisms of RMP in cardiomyocyte function and the development of HF.Methods and resultsMyocardial RMP expression was examined in human heart tissues from healthy controls and patients with advanced HF. Compared to normal cardiac tissues, RMP levels were significantly decreased in the myocardium of patients with advanced HF. To investigate the role of RMP in cardiac function, Cre-loxP recombinase technology was used to generate tamoxifen-inducible cardiomyocyte-specific Rmp knockout mice. Unexpectedly, cardiomyocyte-specific deletion of Rmp in mice resulted in contractile dysfunction, cardiac dilatation, and fibrosis. Furthermore, the lifespan of cardiac-specific Rmp-deficient mice was significantly shortened when compared with littermates. Mechanistically, we found that chronic HF in Rmp-deficient mice was associated with impaired mitochondrial structure and function, which may be mediated via a transforming growth factor-β/Smad3-proliferator-activated receptor coactivator1α (PGC1α)-dependent mechanism. PGC1α overexpression partially rescued chronic HF in cardiomyocyte-specific Rmp-deficient mice, and Smad3 blockade protected against the loss of PGC1α and adenosine triphosphate content that was induced by silencing RMP in vitro.ConclusionsRMP plays a protective role in chronic HF. RMP may protect cardiomyocytes from injury by maintaining PGC1α-dependent mitochondrial biogenesis and function. The results from this study suggest that RMP may be a potential therapeutic agent for treating HF.

Accumulation of 5-oxoproline in myocardial dysfunction and the protective effects of OPLAH

2017 ◽  
Vol 9 (415) ◽  
pp. eaam8574 ◽  
Author(s):  
Atze van der Pol ◽  
Andres Gil ◽  
Herman H. W. Silljé ◽  
Jasper Tromp ◽  
Ekaterina S. Ovchinnikova ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Myocardial Dysfunction ◽  
Cardiac Injury ◽  
Transcriptional Analysis ◽  
Protective Effects ◽  
Elevated Plasma ◽  
Gene Profile ◽  
Adult Mice ◽  
And Oxidative Stress

In response to heart failure (HF), the heart reacts by repressing adult genes and expressing fetal genes, thereby returning to a more fetal-like gene profile. To identify genes involved in this process, we carried out transcriptional analysis on murine hearts at different stages of development and on hearts from adult mice with HF. Our screen identified Oplah, encoding for 5-oxoprolinase, a member of the γ-glutamyl cycle that functions by scavenging 5-oxoproline. OPLAH depletion occurred as a result of cardiac injury, leading to elevated 5-oxoproline and oxidative stress, whereas OPLAH overexpression improved cardiac function after ischemic injury. In HF patients, we observed elevated plasma 5-oxoproline, which was associated with a worse clinical outcome. Understanding and modulating fetal-like genes in the failing heart may lead to potential diagnostic, prognostic, and therapeutic options in HF.

scholarly journals Cardioprotective mechanism of SGLT2 inhibitor against myocardial infarction is through reduction of autosis

2021 ◽  
Author(s):  
Kai Jiang ◽  
Yue Xu ◽  
Dandan Wang ◽  
Feng Chen ◽  
Zizhuo Tu ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Myocardial Infarction ◽  
Ventricular Remodeling ◽  
Sglt2 Inhibitor ◽  
Glucose Deprivation ◽  
Protective Mechanism ◽  
Diabetic Patients ◽  
Autophagic Flux ◽  
Cardioprotective Effects

AbstractSodium-glucose cotransporter 2 (SGLT2) inhibitors reduce cardiovascular mortality in patients with diabetes mellitus but the protective mechanism remains elusive. Here we demonstrated that the SGLT2 inhibitor, Empagliflozin (EMPA), suppresses cardiomyocytes autosis (autophagic cell death) to confer cardioprotective effects. Using myocardial infarction (MI) mouse models with and without diabetes mellitus, EMPA treatment significantly reduced infarct size, and myocardial fibrosis, thereby leading to improved cardiac function and survival. In the context of ischemia and nutritional glucose deprivation where autosis is already highly stimulated, EMPA directly inhibits the activity of the Na+/H+ exchanger 1 (NHE1) in the cardiomyocytes to regulate excessive autophagy. Knockdown of NHE1 significantly rescued glucose deprivation-induced autosis. In contrast, overexpression of NHE1 aggravated the cardiomyocytes death in response to starvation, which was effectively rescued by EMPA treatment. Furthermore, in vitro and in vivo analysis of NHE1 and Beclin 1 knockout mice validated that EMPA’s cardioprotective effects are at least in part through downregulation of autophagic flux. These findings provide new insights for drug development, specifically targeting NHE1 and autosis for ventricular remodeling and heart failure after MI in both diabetic and non-diabetic patients.

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