Search

Background and Objective: Many studies have showed malformation of low frequency of electromagnetic fields (EMF) on different tissues. This study was carried out to evaluate the effect of low frequency electromagnetic fields on the heart of white-leghorn chicken embryo. Materials and Methods: In this experimental study, 90 healthy, fresh and fertilized eggs were allocated into 6 groups including control, sham, and four preincubated experimental groups. Experimental groups I, II, III and IV (1.33, 2.66, 5.52 and 7.32 mT) were located in the electromagnetic device, sham group was located into the same coil with no exposure for 24h before incubation. Control, sham and experimental groups incubated (37±0.5 ºC, 60% humidity) for 14 days. Results: Disassembling cell regulation in experimental group I, dense nucleus of myocytes and increase of intercellular spaces in experimental group II, necrosis and bleeding in the heart tissue in experimental groups III and IV were seen in compare to control and sham groups. There was a significant increase in the level of activity of alkaline phosphatase in the heart of experimental groups in compare to control and sham groups. Conclusion: Low frequency of electromagnetic fields caused alternations in cardiac tissue and elevation of Alkaline phosphatase activity in chicken embryos.

In patients with type II diabetes, the development of diabetic cardiomyopathy (DC) is associated with a high risk of mortality. Left ventricular hypertrophy, diastolic dysfunction, and exercise intolerance are the first signs of DC. The underlying mechanisms are not fully elucidated, and there is an urgent need for specific biomarkers and molecular targets for early diagnosis and treatment. Mitochondrial alterations play a key role in the development of DC, and microRNAs regulating mitochondrial function are emerging as potential biomarkers of metabolic stress in DC. L-Arginine (Arg) supplementation has been shown to be an effective strategy for improving mitochondrial function and energetics, with a significant impact on physical performance. The aim of the current study was to evaluate the effects of Arg supplementation on cardiac mitochondrial function, DC development, and relative phenotypes including exercise intolerance. We used db/db mice as a model of type II diabetes, chronically treated with Arg (1 mg/kg/day) for 12 weeks. Arg-treated db/db mice showed preserved diastolic function and left ventricular morphology compared with untreated diabetic mice. Arg supplementation also improved exercise tolerance and the propensity to physical activity. Mitochondrial respiration was significantly increased in cardiomyocytes isolated from treated db/db mice, as well as in diabetic cardiomyocytes treated with Arg in vitro. The improvement of cardiac mitochondrial function in db/db + Arg mice was associated with an increase in PGC-1-alpha levels, mitochondrial biogenesis, recycling, and antioxidant capacity. Arg treatment prevented the accumulation of circulating and cardiac miR-143 in db/db mice, which is an index of metabolic stress and activation of mitochondrial damage mechanisms. In conclusion, Arg supplementation is effective in preventing the development of DC, preserving diastolic function and exercise tolerance by improving mitochondrial fitness and homeostasis. Additionally, miR-143 could potentially be employed to monitor cardiac metabolic stress and the effects of Arg treatment in diabetes., Competing Interests: Declarations. Competing interests: Gaetano Santulli declares that he is Associate Editor of Cardiovascular Diabetology and that the article was assigned to another Editor to assume responsibility for overseeing peer review. This submissions was subject to the exact same review process as any other manuscript submitted to the journal. Licenses: Figure 1 was created in BioRender. License was granted to Iaccarino, G. (2024- BioRender.com/c38b746)., (© 2024. The Author(s).)

Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a protein crucial for cellular stress response and survival, particularly in the nervous and cardiovascular systems. Unlike traditional neurotrophic factors, MANF primarily regulates endoplasmic reticulum (ER) stress and protects cells by reducing ER stress-induced apoptosis. MANF operates both inside and outside cells, influencing key pathways like JAK/STAT and NF-κB to enhance cell survival during stress. Beyond its neuroprotective role, MANF is also vital in cardiovascular protection, mitigating damage by reducing inflammation and maintaining cellular function. Elevated MANF levels have been observed in patients experiencing myocardial infarction and murine models of ischemia-reperfusion (I/R) injury, highlighting its importance in these conditions. Overexpression of MANF in cardiomyocytes reduces ER-stress-induced cell death, while its depletion worsens this effect. Treatment with recombinant MANF (rMANF) has been shown to improve cardiac function in mice with I/R injury by decreasing infarct size and inflammation. Research also indicates that alterations in the α1-helix region of MANF can impact its structure, expression, secretion, and overall function. Given its protective effects and involvement in critical signaling pathways, MANF is being explored as a potential therapeutic target for ER stress-related diseases, including neurodegenerative disorders and cardiovascular conditions like myocardial I/R injury., (© 2024. The Author(s).)

BACKGROUNDRecent studies conducted in individuals who survived COVID-19 suggest that SARS-CoV-2 infection is associated with an increased risk of dyslipidemia. However, it remains unclear whether this augmented risk is confirmed in the general population and how this phenomenon is affecting the overall burden of cardiometabolic diseases.METHODSTo address these aspects, we conducted a 6-year longitudinal study to examine the broader effects of COVID-19 on dyslipidemia incidence in a real-world population (228,266 individuals) residing in Naples in southern Italy. The pre-COVID-19 and COVID-19 groups were balanced for demographic and clinical factors using propensity score matching.RESULTSOur analysis spans a period of 3 years during the COVID-19 pandemic (2020-2022), comparing dyslipidemia incidence with pre-pandemic data (2017-2019), with a follow-up of at least 1,095 days corresponding to 21,349,215 person-years. During the COVID-19 period, we detected an increased risk of developing any dyslipidemia when compared with the pre-COVID-19 triennium (OR = 1.29; 95% CI, 1.19-1.39). Importantly, these estimates were adjusted for comorbidities by a multivariate analysis.CONCLUSIONSTaken together, our data reveal a notable rise in dyslipidemia incidence during the COVID-19 pandemic, suggesting the utility of establishing specialized clinical monitoring protocols for patients who survive COVID-19 to mitigate the risk of developing dyslipidemia.

The Golgi compartment performs a number of crucial roles in the cell. However, the exact molecular mechanisms underlying these actions are not fully defined. Pathogenic mutations in genes encoding Golgi proteins may serve as an important source for expanding our knowledge. For instance, mutations in the gene encoding Transmembrane protein 165 (TMEM165) were discovered as a cause of a new type of congenital disorder of glycosylation (CDG). Comprehensive studies of TMEM165 in different model systems, including mammals, yeast, and fish uncovered the new realm of Mn 2+ homeostasis regulation. TMEM165 was shown to act as a Ca 2+ /Mn 2+ :H + antiporter in the medial- and trans-Golgi network, pumping the metal ions into the Golgi lumen and protons outside. Disruption of TMEM165 antiporter activity results in defects in N- and O-glycosylation of proteins and glycosylation of lipids. Impaired glycosylation of TMEM165-CDG arises from a lack of Mn 2+ within the Golgi. Nevertheless, Mn 2+ insufficiency in the Golgi is compensated by the activity of the ATPase SERCA2. TMEM165 turnover has also been found to be regulated by Mn 2+ cytosolic concentration. Besides causing CDG, recent investigations have demonstrated the functional involvement of TMEM165 in several other pathologies including cancer and mental health disorders. This systematic review summarizes the available information on TMEM165 molecular structure, cellular function, and its roles in health and disease., Competing Interests: Conflict of interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr Santulli is an Editorial Board Member for JBC and was not involved in the editorial review or the decision to publish this article. The other authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Ischemia with non-obstructive coronary artery (INOCA) is a common cause of hospital admissions, leading to negative outcomes and reduced quality of life. Central to its pathophysiology is endothelial dysfunction, which contributes to myocardial ischemia despite the absence of significant coronary artery blockage. Addressing endothelial dysfunction is essential in managing INOCA to alleviate symptoms and prevent cardiovascular events. Recent studies have identified diabetes mellitus (DM) as a significant factor exacerbating INOCA complications by promoting endothelial impairment and coronary microvascular dysfunction. MicroRNAs (miRNAs) have emerged as potential biomarkers and therapeutic targets in various biological processes, including endothelial dysfunction and cardiovascular diseases. However, research on miRNA biomarkers in INOCA patients is sparse. In this study, we examined a panel of circulating miRNAs involved in the regulation of endothelial function in INOCA patients with and without DM. We analyzed miRNA expression using RT-qPCR in a cohort of consecutive INOCA patients undergoing percutaneous coronary intervention. We detected a significant dysregulation of miR-363-5p and miR-92a-3p in INOCA patients with DM compared to those without DM, indicating their role as biomarkers for predicting and monitoring endothelial dysfunction in INOCA patients with DM., (© 2024. The Author(s).)

Background: Prediabetes has garnered increasing attention due to its association with cardiovascular conditions, especially hypertension, which heightens the risk of prefrailty and frailty among older individuals., Methods: We screened elders with prefrail hypertension from March 2021 to January 2023. We assessed the correlation linking cognitive dysfunction (Montreal Cognitive Assessment score), insulin resistance (triglyceride-to-glucose index), and physical impairment (5-meter gait speed). Then, we measured the risk of developing frailty after a 1-year follow-up period, adjusting the outcome using multivariable Cox regression analysis. We also investigated the impact of administering 500 mg of metformin once daily to a subset of frail subjects for an additional 6 months., Results: We assessed the relationship between the triglyceride-to-glucose index and the Montreal Cognitive Assessment score, observing a significant correlation (r, 0.880; P <0.0001). Similarly, we analyzed the association between the triglyceride-to-glucose index and 5-meter gait speed, uncovering a significant link between insulin resistance and physical impairment (r, 0.809; P <0.0001). Prediabetes was found to significantly ( P <0.0001) elevate the risk of frailty development compared with individuals without prediabetes by the end of the 1-year follow-up, a finding confirmed via multivariable analysis with Cox regression. Furthermore, among the subgroup of subjects who developed frailty, those who received metformin exhibited a significant decrease in frailty levels ( P <0.0001)., Conclusions: Insulin resistance and prediabetes play substantial roles in the development of cognitive and physical impairments, highlighting their importance in managing hypertension, even before the onset of frank diabetes. Metformin, a well-established drug for the treatment of diabetes, has shown favorable effects in mitigating frailty., Competing Interests: Disclosures None.

Aging represents a complex biological progression affecting the entire body, marked by a gradual decline in tissue function, rendering organs more susceptible to stress and diseases. The human heart holds significant importance in this context, as its aging process poses life-threatening risks. It entails macroscopic morphological shifts and biochemical changes that collectively contribute to diminished cardiac function. Among the numerous pivotal factors in aging, mitochondria play a critical role, intersecting with various molecular pathways and housing several aging-related agents. In this comprehensive review, we provide an updated overview of the functional role of mitochondria in cardiac aging., Competing Interests: Conflicts of interest All authors declared that there are no conflicts of interest.

Emerging evidence indicates that the relationship between coronavirus disease 2019 (COVID-19) and diabetes is 2-fold: 1) it is known that the presence of diabetes and other metabolic alterations poses a considerably high risk to develop a severe COVID-19; 2) patients who survived a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have an increased risk of developing new-onset diabetes. However, the mechanisms underlying this association are mostly unknown, and there are no reliable biomarkers to predict the development of new-onset diabetes. In the present study, we demonstrate that a specific microRNA (miR-34a) contained in circulating extracellular vesicles released by endothelial cells reliably predicts the risk of developing new-onset diabetes in COVID-19. This association was independent of age, sex, body mass index (BMI), hypertension, dyslipidemia, smoking status, and D-dimer. SIGNIFICANCE STATEMENT: We demonstrate for the first time that a specific microRNA (miR-34a) contained in circulating extracellular vesicles released by endothelial cells is able to reliably predict the risk of developing diabetes after having contracted coronavirus disease 2019 (COVID-19). This association was independent of age, sex, body mass index (BMI), hypertension, dyslipidemia, smoking status, and D-dimer. Our findings are also relevant when considering the emerging importance of post-acute sequelae of COVID-19, with systemic manifestations observed even months after viral negativization (long COVID)., (Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.)

Taurine, a naturally occurring sulfur-containing amino acid, has attracted significant attention in recent years due to its potential health benefits. Found in various foods and often used in energy drinks and supplements, taurine has been studied extensively to understand its impact on human physiology. Determining its exact functional roles represents a complex and multifaceted topic. We provide an overview of the scientific literature and present an analysis of the effects of taurine on various aspects of human health, focusing on aging and cardiovascular pathophysiology, but also including athletic performance, metabolic regulation, and neurological function. Additionally, our report summarizes the current recommendations for taurine intake and addresses potential safety concerns. Evidence from both human and animal studies indicates that taurine may have beneficial cardiovascular effects, including blood pressure regulation, improved cardiac fitness, and enhanced vascular health. Its mechanisms of action and antioxidant properties make it also an intriguing candidate for potential anti-aging strategies.

SGLT2 (sodium-glucose cotransporter 2) enables glucose and sodium reabsorption in the kidney. SGLT2-inhibitors (also known as gliflozins, which include canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin) act by increasing glycosuria, thereby reducing glycemia. These drugs are critical to reach and keep glycemic control, a crucial feature, especially in patients with comorbidities, like frail individuals. Several studies evaluated the effects of SGLT2-inhibitors in different settings beyond diabetes, revealing that they are actually pleiotropic drugs. We recently evidenced the favorable effects of SGLT2-inhibition on physical and cognitive impairment in frail older adults with diabetes and hypertension. In the present overview, we summarize the latest clinical and preclinical studies exploring the main effects of SGLT2-inhibitors on kidney and heart, emphasizing their potential beneficial actions in frailty., Competing Interests: Disclosures None.

Ischemic cardiac disease is a major cause of mortality worldwide. However, the exact molecular processes underlying this disorder are not fully known. This study includes a comprehensive and coordinated set of in vivo and in vitro experiments using human cardiac specimens from patients with postischemic heart failure (HF) and healthy control subjects, a murine model of HF, and cellular systems. These approaches identified for the first time a specific pattern of maladaptive chromatin remodeling, namely a double methylation of histone 3 at lysine 27 and a single methylation at lysine 36 (H3&#95;K27me2K36me1) consistently induced by ischemic injury in all these settings: human HF; murine HF; and in vitro models. Mechanistically, this work demonstrates that this histone modification mediates the ischemia-induced transcriptional repression of PPARG coactivator 1α (PGC1α), master regulator of mitochondrial function and biogenesis. Intriguingly, both the augmented H3&#95;K27me2K36me1 and the mitochondrial dysfunction ensued by PGC1α down-regulation were significantly attenuated by the treatment with β-hydroxybutyrate, the most abundant ketone body in humans, revealing a novel pathway coupling metabolism to gene expression. Taken together, these findings establish maladaptive chromatin remodeling as a key mechanism in postischemic heart injury, functionally modulated by ketone bodies., Competing Interests: Prof Santulli has received support in part from the National Institutes of Health (NIH): National Heart, Lung, and Blood Institute (NHLBI: R01-HL164772, R01-HL159062, R01-HL146691, T32-HL144456), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK: R01-DK123259, R01-DK033823), National Center for Advancing Translational Sciences (NCATS: UL1-TR002556-06, UM1-TR004400) to Dr Santulli, from the Diabetes Action Research and Education Foundation (to Dr Santulli), and from the Monique Weill-Caulier and Irma T. Hirschl Trusts (to Dr Santulli). Dr Gambardella has received support from a postdoctoral fellowship of the American Heart Association (AHA-20POST35211151). Dr Jankauskas has received support from a postdoctoral fellowship of the American Heart Association (AHA-21POST836407). Dr Kansakar has received support from a postdoctoral fellowship of the American Heart Association (AHA-23POST1026190). Dr Varzideh has received support from a postdoctoral fellowship of the American Heart Association (AHA-22POST915561). Dr Sidoli has received support from the Leukemia Research Foundation (Hollis Brownstein New Investigator Research Grant), Relay Therapeutics, Deerfield (Xseed award), Merck, AFAR (Sagol Network GerOmics award), and the NIH Office of the Director (1S10-OD030286-01). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2023 The Authors.)

Introduction: Sodium Glucose co-Transporter 2 (SGLT2) inhibitors (also known as 'gliflozins') represent a cornerstone to treat diabetes mellitus. Moreover, recent randomized clinical trials have demonstrated important cardioprotective effects of gliflozins, independent of the presence of diabetes. Herein, we summarize the recent therapeutic progress in the cardiovascular field obtained with SGLT2 inhibitors., Area Covered: We critically examine the rationale and results of recent clinical studies examining the effects of SGLT2 inhibitors on cardiovascular outcomes, along with a brief overview of the main ongoing trials that have been designed in order to answer the many pending questions in the field of gliflozins and cardiovascular disease., Expert Opinion: The favorable results of several clinical trials have broadened the therapeutic scenario for SGLT2 inhibitors, opening, at the same time, new challenges. Additionally, recent preclinical findings have evidenced off-target effects of SGLT2 inhibitors.

Background: Cardiac fibrosis represents a key element in the pathophysiology of heart failure with preserved ejection fraction (HFpEF), a condition highly prevalent amongst geriatric patients, especially if diabetic. The microRNA 181c (miR-181c) has been shown to be associated with the response to exercise training in HFpEF patients and has been also linked to diabetic cardiovascular complications. However, the underlying mechanisms have not been fully elucidated., Objective: To measure circulating miR-181c in elderly patients with HFpEF and diabetes mellitus (DM) and identify gene targets pathophysiologically relevant in HFpEF., Methods: We quantified circulating miR-181c in frail older adults with a confirmed diagnosis of HFpEF and DM, and, as control, we enrolled age-matched subjects without HFpEF and without DM. We validated in human cardiac fibroblasts the molecular mechanisms linking miR-181c to a pro-fibrotic response., Results: 51 frail patients were included :34 patients with DM and HFpEF and 17 age-matched controls. We observed that miR-181c was significantly upregulated (p < 0.0001) in HFpEF patients vs controls. We confirmed in vitro that miR-181c is targeting PRKN and SMAD7., Conclusions: We demonstrate that miR-181c levels are significantly increased in frail elderly adults with DM and HFpEF and that miR-181c targets PRKN and SMAD7 in human cardiac fibroblasts., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Embryonic stem cells (ESCs) are derived from the inner cell mass (ICM) of the blastocyst. ESCs have two distinctive properties: ability to proliferate indefinitely, a feature referred as "self-renewal", and to differentiate into different cell types, a peculiar characteristic known as "pluripotency". Self-renewal and pluripotency of ESCs are finely orchestrated by precise external and internal networks including epigenetic modifications, transcription factors, signaling pathways, and histone modifications. In this systematic review, we examine the main molecular mechanisms that sustain self-renewal and pluripotency in both murine and human ESCs. Moreover, we discuss the latest literature on human naïve pluripotency.

L-Arginine (L-Arg), is a semi-essential amino acid involved in the formation of nitric oxide. The functional relevance of L-Arg in diabetes mellitus has been evaluated both in animal models and in human subjects. In the literature there are several lines of evidence indicating that L-Arg has beneficial effects in diabetes and numerous studies advocate its administration to attenuate glucose intolerance in diabetic patients. Here we present a comprehensive overview of the main studies exploring the effects of L-Arg in diabetes, including preclinical and clinical reports on this topic., (© 2023. The Author(s).)

MicroRNAs (miRs) are small non-coding RNAs that modulate the expression of several target genes. Fibroblast growth factor binding protein 1 (FGFBP1) has been associated with endothelial dysfunction at the level of the blood-brain barrier (BBB). However, the underlying mechanisms are mostly unknown and there are no studies investigating the relationship between miRs and FGFBP1. Thus, the overarching aim of the present study was to identify and validate which miR can specifically target FGFBP1 in human brain microvascular endothelial cells, which represent the best in vitro model of the BBB. We were able to identify and validate miR-4432 as a fundamental modulator of FGFBP1 and we demonstrated that miR-4432 significantly reduces mitochondrial oxidative stress, a well-established pathophysiological hallmark of hypertension.

In this comprehensive review, we examine the main preclinical and clinical investigations assessing the effects of different forms of choline supplementation currently available, including choline alfoscerate (C 8 H 20 NO 6 P), also known as alpha-glycerophosphocholine (α-GPC, or GPC), choline bitartrate, lecithin, and citicoline, which are cholinergic compounds and precursors of acetylcholine. Extensively used as food supplements, they have been shown to represent an effective strategy for boosting memory and enhancing cognitive function., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Kansakar, Trimarco, Mone, Varzideh, Lombardi and Santulli.)

Purpose of Review: The current review aims to present the latest scientific updates on the role of Sortilin in the pathophysiology of hypertension., Recent Findings: The main focus of this systematic overview is on the functional contribution of Sortilin to the pathogenesis of hypertension. Sortilin is a glycoprotein mostly known for its actions as a trafficking molecule directing proteins to specific secretory or endocytic compartments of the cell. Emerging evidence indicates that Sortilin is associated with pathological conditions, including inflammation, arteriosclerosis, dyslipidemia, insulin resistance, and vascular calcification. Most recently, Sortilin has been shown to finely control endothelial function and to drive hypertension by modulating sphingolipid/ceramide homeostasis and by triggering oxidative stress., Summary: The latest findings linking Sortilin and hypertension that are herein discussed can inspire novel areas of research which could eventually lead to the discovery of new therapeutic strategies in cardiovascular medicine., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Ischemia with nonobstructive coronary arteries (INOCA) is a prevailing finding in patients with angina. However, the main factors underlying the risk of being rehospitalized for chest pain in patients with INOCA remain mostly unknown., Research Design and Methods: We evaluated INOCA patients referred to the "Casa di Cura Montevergine" in Mercogliano (Avellino), Italy, from January 2016 to January 2021 for percutaneous coronary intervention (PCI). In these subjects, we assessed the impact of the stress hyperglycemia ratio (SHR), defined as the ratio of mmol/L blood glucose and % HbA1c, on the risk of rehospitalization for chest pain., Results: A total of 2,874 patients with INOCA successfully completed the study. At the 1-year follow-up, the risk of rehospitalization for chest pain was significantly higher (P < 0.001) in INOCA patients with SHR >1 compared to patients with SHR ≤1. These findings were confirmed by multivariable analyses (adjusting for potential confounders, including age, BMI, blood pressure, heart rate, chronic kidney disease, and cholesterol), propensity score matching, and inverse probability of treatment weighting., Conclusions: Our data indicate, to our knowledge for the first time, that SHR on hospital admission significantly and independently increases the risk of rehospitalization for chest pain in INOCA patients., (© 2023 by the American Diabetes Association.)

Oxidative stress and endothelial dysfunction have been shown to play crucial roles in the pathophysiology of COVID-19 (coronavirus disease 2019). On these grounds, we sought to investigate the impact of COVID-19 on lipid peroxidation and ferroptosis in human endothelial cells. We hypothesized that oxidative stress and lipid peroxidation induced by COVID-19 in endothelial cells could be linked to the disease outcome. Thus, we collected serum from COVID-19 patients on hospital admission, and we incubated these sera with human endothelial cells, comparing the effects on the generation of reactive oxygen species (ROS) and lipid peroxidation between patients who survived and patients who did not survive. We found that the serum from non-survivors significantly increased lipid peroxidation. Moreover, serum from non-survivors markedly regulated the expression levels of the main markers of ferroptosis, including GPX4, SLC7A11, FTH1, and SAT1, a response that was rescued by silencing TNFR1 on endothelial cells. Taken together, our data indicate that serum from patients who did not survive COVID-19 triggers lipid peroxidation in human endothelial cells.