Transcriptome wide changes in long noncoding RNAs in diabetic ischemic heart disease.

More than 10% of adults in the United States have type 2 diabetes mellitus (DM) with a 2-4 times higher prevalence of ischemic heart disease than the non-diabetics. Despite extensive research approaches to limit this life-threatening condition have proven unsuccessful, highlighting the need for understanding underlying molecular mechanisms. Long noncoding RNAs (lncRNAs), which regulate gene expression by acting as signals, decoys, guides, or scaffolds have been implicated in diverse cardiovascular conditions. However, their role in ischemic heart disease in DM remains poorly understood. We provide new insights into the lncRNA expression profile after ischemic heart disease in DM mice. We performed unbiased RNA sequencing of well-characterized type 2 DM model db/db mice or its control db/+ subjected to sham or MI surgery. Computational analysis of the RNA sequencing of these LV tissues identified several differentially expressed lncRNAs between (db/db sham vs. db/db MI) including Gm19522 and Gm8075. lncRNA Gm-19522 may regulate DNA replication via DNA protein kinases, while lncRNA Gm-8075 is associated with cancer gene dysregulation and PI3K/Akt pathways. Thus, the downregulation of lncRNAs Gm19522 and Gm8075 post-MI may serve as potential biomarkers or novel therapeutic targets to improve cardiac repair/recovery in diabetic ischemic heart disease.

Mini Review: the non-neuronal cardiac cholinergic system in type-2 diabetes mellitus.

Diabetic heart disease remains the leading cause of death in individuals with type-2 diabetes mellitus (T2DM). Both insulin resistance and metabolic derangement, hallmark features of T2DM, develop early and progressively impair cardiovascular function. These factors result in altered cardiac metabolism and energetics, as well as coronary vascular dysfunction, among other consequences. Therefore, gaining a deeper understanding of the mechanisms underlying the pathophysiology of diabetic heart disease is crucial for developing novel therapies for T2DM-associated cardiovascular disease. Cardiomyocytes are equipped with the cholinergic machinery, known as the non-neuronal cardiac cholinergic system (NNCCS), for synthesizing and secreting acetylcholine (ACh) as well as possessing muscarinic ACh receptor for ACh binding and initiating signaling cascade. ACh from cardiomyocytes regulates glucose metabolism and energetics, endothelial function, and among others, in an auto/paracrine manner. Presently, there is only one preclinical animal model - diabetic db/db mice with cardiac-specific overexpression of choline transferase (Chat) gene - to study the effect of activated NNCCS in the diabetic heart. In this mini-review, we discuss the physiological role of NNCCS, the connection between NNCCS activation and cardiovascular function in T2DM and summarize the current knowledge of S-Nitroso-NPivaloyl-D-Penicillamine (SNPiP), a novel inducer of NNCCS, as a potential therapeutic strategy to modulate NNCCS activity for diabetic heart disease.

Role of mitochondrial ribosomal protein L7/L12 (MRPL12) in diabetic ischemic heart disease.

BACKGROUND: Myocardial infarction (MI) is a significant cause of death in diabetic patients. Growing evidence suggests that mitochondrial dysfunction contributes to heart failure in diabetes. However, the molecular mechanisms of mitochondrial dysfunction mediating heart failure in diabetes are still poorly understood. METHODS: We examined MRPL12 levels in right atrial appendage tissues from diabetic patients undergoing coronary artery bypass graft (CABG) surgery. Using AC-16 cells overexpressing MRPL12 under normal and hyperglycemic conditions we performed mitochondrial functional assays OXPHOS, bioenergetics, mitochondrial membrane potential, ATP production and cell death. RESULTS: We observed elevated MRPL12 levels in heart tissue samples from diabetic patients with ischemic heart disease compared to non-diabetic patients. Overexpression of MRPL12 under hyperglycemic conditions did not affect oxidative phosphorylation (OXPHOS) levels, cellular ATP levels, or cardiomyocyte cell death. However, notable impairment in mitochondrial membrane potential (MMP) was observed under hyperglycemic conditions, along with alterations in both basal respiration oxygen consumption rate (OCR) and maximal respiratory capacity OCR. CONCLUSIONS: Overall, our results suggest that MRPL12 may have a compensatory role in the diabetic myocardium with ischemic heart disease, suggesting that MRPL12 may implicate in the pathophysiology of MI in diabetes.

Autonomic nervous system and endocrine system response to upper or lower cervical spine mobilization in males with persistent post-concussion symptoms: a proof-of-concept trial.

INTRODUCTION: The peripheral stress response, consisting of the autonomic nervous system (ANS) and hypothalamic pituitary adrenal-axis (HPA-axis), functions to maintain homeostasis in response to stressors. Cervical spine manual therapy has been shown to differentially modulate the stress response in healthy populations. No study has investigated whether cervical spine mobilizations can differentially modulate the stress response in individuals with persistent post-concussion symptoms (PPCS), a population characterized by a dysfunctional stress response. METHODS: A randomized, controlled, parallel design trial was performed to investigate whether upper or lower cervical spine mobilization can differentially modulate components of the stress response in individuals with PPCS. The outcomes were salivary cortisol (sCOR) concentration (primary) and the HRV metric, rMSSD, measured with a smartphone application (secondary). Nineteen males diagnosed with PPCS, aged 19-35, were included. Participants were randomly assigned into either intervention group, upper (n = 10) or lower (n = 9) cervical spine mobilization. Each outcome was collected at different time points, pre- and post-intervention. Statistical analyses were performed using the Friedman's Two-Way ANOVA, Mann-Whitney U test, and Wilcoxon Signed Rank Test. RESULTS: There was a statistically significant within-group reduction in sCOR concentration 30 minutes following lower cervical spine mobilizations and statistically significant within-group increase in rMSSD 30 minutes following upper cervical spine mobilizations. CONCLUSION: The results of this trial provide preliminary evidence for cervical spine mobilizations to differentially modulate components of the stress response at specific time points. Understanding the mechanisms of the effect of cervical spine mobilizations on the stress response provides a novel rationale for selecting cervical spine mobilizations to rehabilitate individuals with PPCS.

Retraction notice to "Non-neuronal cholinergic system delays cardiac remodelling in type 1 diabetes" [Heliyon 9 (2023) e17434].

[This retracts the article DOI: 10.1016/j.heliyon.2023.e17434.].

Myocardial glycophagy flux dysregulation and glycogen accumulation characterize diabetic cardiomyopathy.

Diabetic heart disease morbidity and mortality is escalating. No specific therapeutics exist and mechanistic understanding of diabetic cardiomyopathy etiology is lacking. While lipid accumulation is a recognized cardiomyocyte phenotype of diabetes, less is known about glycolytic fuel handling and storage. Based on in vitro studies, we postulated the operation of an autophagy pathway in the myocardium specific for glycogen homeostasis - glycophagy. Here we visualize occurrence of cardiac glycophagy and show that the diabetic myocardium is characterized by marked glycogen elevation and altered cardiomyocyte glycogen localization. We establish that cardiac glycophagy flux is disturbed in diabetes. Glycophagy may represent a potential therapeutic target for alleviating the myocardial impacts of metabolic disruption in diabetic heart disease.

Non-coding RNAs as therapeutic targets and biomarkers in ischaemic heart disease.

The adult heart is a complex, multicellular organ that is subjected to a series of regulatory stimuli and circuits and has poor reparative potential. Despite progress in our understanding of disease mechanisms and in the quality of health care, ischaemic heart disease remains the leading cause of death globally, owing to adverse cardiac remodelling, leading to ischaemic cardiomyopathy and heart failure. Therapeutic targets are urgently required for the protection and repair of the ischaemic heart. Moreover, personalized clinical biomarkers are necessary for clinical diagnosis, medical management and to inform the individual response to treatment. Non-coding RNAs (ncRNAs) deeply influence cardiovascular functions and contribute to communication between cells in the cardiac microenvironment and between the heart and other organs. As such, ncRNAs are candidates for translation into clinical practice. However, ncRNA biology has not yet been completely deciphered, given that classes and modes of action have emerged only in the past 5 years. In this Review, we discuss the latest discoveries from basic research on ncRNAs and highlight both the clinical value and the challenges underscoring the translation of these molecules as biomarkers and therapeutic regulators of the processes contributing to the initiation, progression and potentially the prevention or resolution of ischaemic heart disease and heart failure.

The role of cardiac pericytes in health and disease: therapeutic targets for myocardial infarction.

Millions of cardiomyocytes die immediately after myocardial infarction, regardless of whether the culprit coronary artery undergoes prompt revascularization. Residual ischaemia in the peri-infarct border zone causes further cardiomyocyte damage, resulting in a progressive decline in contractile function. To date, no treatment has succeeded in increasing the vascularization of the infarcted heart. In the past decade, new approaches that can target the heart's highly plastic perivascular niche have been proposed. The perivascular environment is populated by mesenchymal progenitor cells, fibroblasts, myofibroblasts and pericytes, which can together mount a healing response to the ischaemic damage. In the infarcted heart, pericytes have crucial roles in angiogenesis, scar formation and stabilization, and control of the inflammatory response. Persistent ischaemia and accrual of age-related risk factors can lead to pericyte depletion and dysfunction. In this Review, we describe the phenotypic changes that characterize the response of cardiac pericytes to ischaemia and the potential of pericyte-based therapy for restoring the perivascular niche after myocardial infarction. Pericyte-related therapies that can salvage the area at risk of an ischaemic injury include exogenously administered pericytes, pericyte-derived exosomes, pericyte-engineered biomaterials, and pharmacological approaches that can stimulate the differentiation of constitutively resident pericytes towards an arteriogenic phenotype. Promising preclinical results from in vitro and in vivo studies indicate that pericytes have crucial roles in the treatment of coronary artery disease and the prevention of post-ischaemic heart failure.

Healthy grocery delivery in the usual care for adults recovering from an acute coronary event: protocol for a three-arm randomised controlled trial.

INTRODUCTION: Coronary heart disease is a major contributor to the global burden of disease. Appropriate nutrition is a cornerstone of the prevention and treatment of coronary heart disease; however, barriers including cost and access to recommended foods limits long-term adherence for many. We are conducting, in adults with coronary heart disease, a randomised controlled trial comparing usual care with two dietary interventions in which usual care is augmented by 12 weeks free delivered groceries. METHODS AND ANALYSIS: Three hundred adults recovering from an acute coronary event will be recruited from outpatient cardiovascular services in three regions of Aotearoa New Zealand. Participants will be randomly allocated to three arms: usual care (control group), usual care and the free delivery of foods high in dietary fibre or usual care and the free delivery of foods high in unsaturated fats. Interventions duration is 12 weeks, with a further 12 months follow-up. The primary outcome measures are change in low-density lipoprotein (LDL) cholesterol concentration following the intervention, and a cost-effectiveness analysis of healthcare access and social costs in the year after the intervention. A broad range of secondary outcome measures include other blood lipids, anthropometry, glycaemia, inflammatory markers, gut microbiome, dietary biomarkers, food acceptability, dietary change and the facilitators and barriers to dietary change. The trial will determine whether the free provision of groceries known to reduce cardiovascular risk within usual care will be clinically beneficial and justify the cost of doing so. Results may also provide an indication of the relative benefit of foods rich in dietary fibre or unsaturated fats in coronary heart disease management. ETHICS AND DISSEMINATION: This trial, The Healthy Heart Study, has Health and Disability Ethics Committee approval (20/NTB/121), underwent Maori consultation, and has locality authority to be conducted in Canterbury, Otago and Southland. TRIAL REGISTRATION NUMBER: ACTRN12620000689976, U1111-1250-1499.

The role of micro-RNAs in neuropathic pain-a scoping review.

Neuropathic pain can be caused by a lesion or disease of the somatosensory system characterised by pathological neuro-immune alterations. At a molecular level, microRNAs (miRNAs) act as regulators of gene expression orchestrating both immune and neuronal processes. Thus, miRNAs may act as essential modulators of processes for the establishment and maintenance of neuropathic pain. The objective/aims of this scoping review was to explore and chart the literature to identify miRNAs that are dysregulated in neuropathic pain. The following databases were searched from inception to March 2023: PubMed, EBSCO, CINAHL, Cochrane Library, and SCOPUS. Two independent reviewers screened, extracted data, and independently assessed the risk of bias in included studies. The JBI critical appraisal checklist was used for critical appraisal. A narrative synthesis was used to summarise the evidence. Seven studies (total of 384 participants) that met our eligibility criteria were included in this scoping review. Our review has identified different miRNAs that are commonly involved in the chronic neuropathic pain conditions including miR-132, miR-101, and miR-199a. Our review findings further suggest that expression of miRNAs to be significantly associated with increased diabetic disease duration, HbA1C levels, and fibrinogen levels. Our review findings suggest that there is clear association between miRNA expression and chronic neuropathic pain conditions. Therefore, increasing the specificity by selecting a candidate miRNA and identifying its target mRNA is an area of future research.

Non-neuronal cholinergic system delays cardiac remodelling in type 1 diabetes.

Aims: Type 1 diabetes mellitus (T1DM) is associated with increased risk of cardiovascular disease (CVD) and mortality. The underlying mechanisms for T1DM-induced heart disease still remains unclear. In this study, we aimed to investigate the effects of cardiac non-neuronal cholinergic system (cNNCS) activation on T1DM-induced cardiac remodelling. Methods: T1DM was induced in C57Bl6 mice using low-dose streptozotocin. Western blot analysis was used to measure the expression of cNNCS components at different time points (4, 8, 12, and 16 weeks after T1DM induction). To assess the potential benefits of cNNCS activation, T1DM was induced in mice with cardiomyocyte-specific overexpression of choline acetyltransferase (ChAT), the enzyme required for acetylcholine (Ac) synthesis. We evaluated the effects of ChAT overexpression on cNNCS components, vascular and cardiac remodelling, and cardiac function. Key findings: Western blot analysis revealed dysregulation of cNNCS components in hearts of T1DM mice. Intracardiac ACh levels were also reduced in T1DM. Activation of ChAT significantly increased intracardiac ACh levels and prevented diabetes-induced dysregulation of cNNCS components. This was associated with preserved microvessel density, reduced apoptosis and fibrosis, and improved cardiac function. Significance: Our study suggests that cNNCS dysregulation may contribute to T1DM-induced cardiac remodelling, and that increasing ACh levels may be a potential therapeutic strategy to prevent or delay T1DM-induced heart disease.

Combination of precipitation and size exclusion chromatography as an effective method for exosome like extracellular vesicle isolation from pericardial fluids.

Extracellular vesicles (EVs), such as exosomes, are nanovesicles that have received significant attention due to their ability to contain various molecular cargos. EVs found in biological fluids have been demonstrated to have therapeutic potential, including as biomarkers. Despite being extensively studied, a significant downfall in EV research is the lack of standardised protocol for its isolation from human biological fluids, where EVs usually exist at low densities. In this study, we tested two well-established EV isolation protocols, precipitation, and size exclusion chromatography (SEC), to determine their efficiency in isolating EVs from the pericardial fluid. Precipitation alone resulted in high yields of low-purity exosomes as tested by DLS analysis, transmission electron microscopy, immunogold labelling and western blotting for the exosomal surface proteins. While EVs isolated by SEC were pure, the concentration was low. Interestingly, the combination of precipitation followed by SEC resulted in high EV yields with good purity. Our results suggest that the combination method can be adapted to isolate EVs from body fluids which have low densities of EV.

Role of noncoding RNAs in cardiac ageing.

The global population is estimated to reach 9.8 billion by 2050, of which 2.1 billion will comprise individuals above 60 years of age. As the number of elderly is estimated to double from 2017, it is a victory of the modern healthcare system but also worrisome as ageing, and the onset of chronic disease are correlated. Among other chronic conditions, cardiovascular diseases (CVDs) are the leading cause of death in the aged population. While the underlying cause of the age-associated development of CVDs is not fully understood, studies indicate the role of non-coding RNAs such as microRNAs (miRNAs) and long noncoding RNAs (lnc-RNAs) in the development of age-associated CVDs. miRNAs and lnc-RNAs are non-coding RNAs which control gene expression at the post-transcriptional level. The expression of specific miRNAs and lnc-RNAs are reportedly dysregulated with age, leading to cardiovascular system changes and ultimately causing CVDs. Since miRNAs and lnc-RNAs play several vital roles in maintaining the normal functioning of the cardiovascular system, they are also being explored for their therapeutic potential as a treatment for CVDs. This review will first explore the pathophysiological changes associated with ageing. Next, we will review the known mechanisms underlying the development of CVD in ageing with a specific focus on miRNA and lnc-RNAs. Finally, we will discuss the therapeutic options and future challenges towards healthy cardiac ageing. With the global ageing population on the rise, this review will provide a fundamental understanding of some of the underlying molecular mechanisms of cardiac ageing.

Autonomic nervous system and endocrine system response to upper and lower cervical spine mobilization in healthy male adults: a randomized crossover trial.

BACKGROUND: Cervical spine mobilizations may differentially modulate both components of the stress response, consisting of the autonomic nervous system and hypothalamic pituitary adrenal-axis, depending on whether the target location is the upper or lower cervical spine. To date, no study has investigated this. METHODS: A randomized, crossover trial investigated the effects of upper versus lower cervical mobilization on both components of the stress response simultaneously. The primary outcome was salivary cortisol (sCOR) concentration. The secondary outcome was heart rate variability measured with a smartphone application. Twenty healthy males, aged 21-35, were included. Participants were randomly assigned to block-AB (upper then lower cervical mobilization, n = 10) or block-BA (lower than upper cervical mobilization, n = 10), separated by a one-week washout period. All interventions were performed in the same room (University clinic) under controlled conditions. Statistical analyses were performed with a Friedman's Two-Way ANOVA and Wilcoxon Signed Rank Test. RESULTS: Within groups, sCOR concentration reduced thirty-minutes following lower cervical mobilization (p = 0.049). Between groups, sCOR concentration was different at thirty-minutes following the intervention (p = 0.018). CONCLUSION: There was a statistically significant reduction in sCOR concentration following lower cervical spine mobilization, and between-group difference, 30 min following the intervention. This indicates that mobilizations applied to separate target locations within the cervical spine can differentially modulate the stress response.

A review of formulations and preclinical studies of inhaled rifampicin for its clinical translation.

Inhaled drug delivery is a promising approach to achieving high lung drug concentrations to facilitate efficient treatment of tuberculosis (TB) and to reduce the overall duration of treatment. Rifampicin is a good candidate for delivery via the pulmonary route. There have been no clinical studies yet at relevant inhaled doses despite the numerous studies investigating its formulation and preclinical properties for pulmonary delivery. This review discusses the clinical implications of pulmonary drug delivery in TB treatment, the drug delivery systems reported for pulmonary delivery of rifampicin, animal models, and the animal studies on inhaled rifampicin formulations, and the research gaps hindering the transition from preclinical development to clinical investigation. A review of reports in the literature suggested there have been minimal attempts to test inhaled formulations of rifampicin in laboratory animals at relevant high doses and there is a lack of appropriate studies in animal models. Published studies have reported testing only low doses (≤ 20 mg/kg) of rifampicin, and none of the studies has investigated the safety of inhaled rifampicin after repeated administration. Preclinical evaluations of inhaled anti-TB drugs, such as rifampicin, should include high-dose formulations in preclinical models, determined based on allometric conversions, for relevant high-dose anti-TB therapy in humans.

Healing the Ischaemic Heart: A Critical Review of Stem Cell Therapies.

Ischaemic heart disease (IHD) remains the leading cause of mortality worldwide. Current pharmaceutical treatments focus on delaying, rather than preventing disease progression. The only curative treatment available is orthotopic heart transplantation, which is greatly limited by a lack of available donors and the possibility for immune rejection. As a result, novel therapies are consistently being sought to improve the quality and duration of life of those suffering from IHD. Stem cell therapies have garnered attention globally owing to their potential to replace lost cardiac cells, regenerate the ischaemic myocardium and to release protective paracrine factors. Despite recent advances in regenerative cardiology, one of the biggest challenges in the clinical translation of cell-based therapies is determining the most efficacious cell type for repair. Multiple cell types have been investigated in clinical trials; with inconsistent methodologies and isolation protocols making it difficult to draw strong conclusions. This review provides an overview of IHD focusing on pathogenesis and complications, followed by a summary of different stem cells which have been trialled for use in the treatment of IHD, and ends by exploring the known mechanisms by which stem cells mediate their beneficial effects on ischaemic myocardium.