Cardioprotective effects of early versus late initiated antiretroviral treatment in adolescents with perinatal HIV-1 infection.

Whether, and how, cardioprotective effects of antiretroviral treatment (ART) in adolescents with perinatal HIV infection (APHIV) vary with age at treatment initiation is unknown. We used magnetic resonance imaging to compare cardiac status between APHIV initiated on ART at < 5 years of age (early ART, n = 37) and ≥ 5 years of age (delayed ART, n = 34) versus HIV-uninfected peers (n = 21), reporting z-score mean differences adjusted for confounders. Relative to HIV-uninfected adolescents, APHIV with early ART had higher left ventricular (LV) global circumferential strain (GCS) [adjusted mean (95%CI) z-score: 0.53 (0.13, 0.92)] and maximum indexed left atrium volume (LAVi) [adjusted z-score: 0.55 (0.08, 1.02)]. In contrast, APHIV with delayed ART had greater indexed LV end-diastolic volume (LVEDVi) [adjusted z-score: 0.47 (0.09, 0.86)] and extracellular volume fraction [adjusted z-score: 0.79 (0.20, 1.37)], but lower GCS [adjusted z-score: -0.51 (-0.91, -0.10)] than HIV-uninfected peers. APHIV had distinct albeit subclinical cardiac phenotypes depending on ART initiation age. Changes in early ART suggested comparatively worse diastology with preserved systolic function while delayed ART was associated with comparatively increased diffuse fibrosis and LV dilatation with reduced systolic function. The long-term clinical significance of these changes remains to be determined.

Optimizing myocardial cell protection with xanthine derivative KMUP-3 potentiates autophagy through the PI3K/Akt/eNOS axis.

BACKGROUND: Autophagy can have either beneficial or detrimental effects on various heart diseases. Pharmacological interventions improve cardiac function, which is correlated with enhanced autophagy. To assess whether a xanthine derivative (KMUP-3) treatment coincides with enhanced autophagy while also providing cardio-protection, we investigated the hypothesis that KMUP-3 treatment activation of autophagy through PI3K/Akt/eNOS signalling offered cardioprotective properties. METHODS: The pro-autophagic effect of KMUP-3 was performed in a neonatal rat model targeting cardiac fibroblasts and cardiomyocytes, and by assessing the impact of KMUP-3 treatment on cardiotoxicity, we used antimycin A-induced cardiomyocytes. RESULTS: As determined by transmission electron microscopy observation, KMUP-3 enhanced autophagosome formation in cardiac fibroblasts. Furthermore, KMUP-3 significantly increased the expressions of autophagy-related proteins, LC3 and Beclin-1, both in a time- and dose-dependent manner; moreover, the pro-autophagy and nitric oxide enhancement effects of KMUP-3 were abolished by inhibitors targeting eNOS and PI3K in cardiac fibroblasts and cardiomyocytes. Notably, KMUP-3 ameliorated cytotoxic effects induced by antimycin A, demonstrating its protective autophagic response. CONCLUSION: These findings enable the core pathway of PI3K/Akt/eNOS axis in KMUP-3-enhanced autophagy activation and suggest its principal role in safeguarding against cardiotoxicity.

Cardioprotective Effect of Eugenol Against Cd-Induced Inflammation, Oxidative Stress, and Dyslipidemia in Male Rats: An In Vivo and Molecular Docking Study.

Cadmium, a highly toxic heavy metal, can cause severe damage to several vital organs including the kidney, liver, and brain. Many of the natural compounds found in aromatic plants have beneficial pharmacological properties. Eugenol is one such compound reported to have anti-inflammatory and antioxidant properties. The aim of this study is to investigate whether eugenol, a natural compound found in aromatic plants known for its anti-inflammatory and antioxidant properties, can mitigate the detrimental effects of cadmium exposure on cardiac inflammation, oxidative stress, and dyslipidemia. Male albino rats were subjected to randomization into four groups, each comprising six animals, to investigate the potential of eugenol in mitigating cadmium-induced toxicity. All groups received oral gavage treatment for 21 days. Following the treatment regimen, cardiac tissue specimens were collected for analysis. The assessment of cardiac antioxidant status entailed the determination of enzymatic activities including catalase, SOD, GST, and GPx. Additionally, levels of lipid peroxidation, reduced glutathione, protein carbonyl oxidation, and thiol levels were quantified in the cardiac tissue samples. To evaluate cardiac damage, marker enzymes such as LDH and CK-MB were measured. Furthermore, the inflammatory response in the cardiac tissue induced by cadmium exposure was assessed through the quantification of NO, TNF-α, and IL-6 levels. Additionally, molecular docking and dynamics studies were conducted utilizing autodock and GLIDE methodologies. Cadmium administration markedly enhanced the activities of LDH and CK-MB, prominent cardiac markers. Furthermore, cadmium treatment also demonstrated a significant decrease in the reduced glutathione levels and antioxidant enzyme activities. Significant elevation of the inflammatory markers was also observed in the cadmium-treated group. Eugenol treatment effectively ameliorates cadmium-induced biochemical changes. This study underscores the potent anti-inflammatory and antioxidant attributes of eugenol. Co-administration of eugenol alongside cadmium exhibited remarkable protective efficacy against cadmium-induced cardio-toxicity. Eugenol demonstrated the capability to reinstate the cellular redox equilibrium of rats subjected to cadmium treatment to levels akin to those of the normal control group.

Recent Advances in Serum Biomarkers for Cardiological Risk Stratification and Insight into the Cardiac Management of the Patients With Hematological Malignancies Treated With Targeted Therapy.

Cardiovascular diseases (CVD) have emerged as a common and serious complication of cancer treatment, particularly in patients undergoing cardiotoxic therapies. Over the last few years, the medical community has become increasingly aware of the potential for cardiotoxicity resulting from cancer treatments involving chemotherapy, targeted therapies, and radiation therapy. This recognition is due to the significant risk of morbidity and mortality in cancer patients and survivors resulting from such treatment-induced cardiovascular damage. While the cardiotoxic effects of chemotherapy and targeted therapy have been discussed in medical literature, only a limited number of studies have explored the role of serum biomarkers in cardiological risk stratification. In recent years, serum biomarkers have emerged as a valuable tool for assessing and managing cardiotoxicity in patients with hematological malignancies. This review article provides a summary of the current state of knowledge on the usefulness of biomarkers in managing cardiotoxicity resulting from different targeted therapies throughout the cancer care continuum. Although cardiac biomarkers have demonstrated potential in identifying subclinical cardiotoxicity and tracking the response to cardioprotective treatments, further research is necessary to determine optimal biomarkers and surveillance strategies. The incorporation of cardiac biomarkers into clinical practice in patients undergoing targeted therapies could potentially lead to improved long-term cardiovascular outcomes in cancer patients and survivors.

What do we know about platelets in myocardial ischemia-reperfusion injury and why is it important?

Myocardial ischemia-reperfusion injury (MIRI), the joint result of ischemic injury and reperfusion injury, is associated with poor outcomes in patients with acute myocardial infarction undergoing primary percutaneous coronary intervention. Accumulating evidence demonstrates that activated platelets directly contribute to the pathogenesis of MIRI through participating in the formation of microthrombi, interaction with leukocytes, secretion of active substances, constriction of microvasculature, and activation of spinal afferent nerves. The molecular mechanisms underlying the above detrimental effects of activated platelets include the homotypic and heterotypic interactions through surface receptors, transduction of intracellular signals, and secretion of active substances. Revealing the roles of platelet activation in MIRI and the associated mechanisms would provide potential targets/strategies for the clinical evaluation and treatment of MIRI. Further studies are needed to characterize the temporal (ischemia phase vs. reperfusion phase) and spatial (systemic vs. local) distributions of platelet activation in MIRI by multi-omics strategies. To improve the likelihood of translating novel cardioprotective interventions into clinical practice, basic researches maximally replicating the complexity of clinical scenarios would be necessary.

Alpha-lipoic acid enhances ischemic postconditioning-mediated improvement of myocardial infarction and apoptosis in diabetic rats with ischemia/reperfusion injury.

This work evaluated the combined effects of alpha-lipoic acid (ALA) and ischemic postconditioning (Post) on myocardial infarction and cell death in rats with chronic type-II diabetes following ischemia/reperfusion injury. The rats received a high-fat diet and were given one intraperitoneal injection of 35 mg/kg streptozotocin to induce chronic diabetes. They were then pretreated with ALA (100 mg/kg/day, orally) for 5 weeks before undergoing ischemia/reperfusion (I/R) insult. The hearts experienced 35 min regional ischemia through ligating the left anterior descending coronary artery, followed by 60 min reperfusion. The Post protocol involved 6 cycles of a 10/10 s algorithm, applied during the early stage of reperfusion. The use of Post alone did not significantly alter lactate dehydrogenase and infarct size levels, while ALA showed positive effects. Similar findings were observed for apoptotic changes with single treatments. However, the concurrent administration of ALA and Post significantly reduced the protein expressions of Bax, Bax/Bcl2, and cleaved caspase-3 while increasing Bcl2 expression. Additionally, the histopathological findings of the combined therapy were superior to those of single treatments. The concomitant use of ALA and Post effectively inhibited apoptosis, leading to cardiac recovery after I/R injury in diabetic conditions. This strategy could improve outcomes for preserving diabetic hearts following I/R insults.

Cardioprotective properties of quercetin in fescue toxicosis-induced cardiotoxicity via heart-gut axis in lambs (Ovis Aries).

The present study investigated whether quercetin mitigated fescue toxicosis-induced cardiovascular injury via the heart-gut axis. Twenty-four commercial Dorper lambs were stratified by body weight and assigned randomly to diets in one of four groups: endophyte-free without quercetin (E-,Q-), endophyte-positive without quercetin (E+,Q-), endophyte-positive plus 4 g/kg quercetin (E+,Q+) or endophyte-free plus 4 g/kg quercetin (E-,Q+) for 42 days. Body weight and average daily feed intake (ADFI) of lambs fed the endophyte-positive diets showed significant decreases. However, in the groups treated with quercetin, there were significant alterations of cardiac enzymes. Furthermore, reduced fescue toxicosis-induced histopathological lesions of heart and aorta were demonstrated in the E+,Q+ lambs. Results also suggested quercetin eased cardiovascular oxidative injury by inhibiting the increase of oxidative metabolites, and enhancing the levels of antioxidases. Quercetin reduced the inflammation response through suppressing NF-κB signaling pathway activation. Additionally, quercetin ameliorated fescue toxicosis-induced mitochondria dysfunction and improved mitochondrial quality control through enhancing PGC-1α-mediated mitochondrial biogenesis, maintaining the mitochondrial dynamics, and relieving aberrant Parkin/PINK-mediated mitophagy. Quercetin enhanced gastrointestinal microbial alpha and beta diversity, alleviated gut microbiota and microbiome derived metabolites-SCFAs dysbiosis by fescue toxicosis. These findings signified that quercetin may play a cardio-protective role via regulating the heart-gut microbiome axis.

Renin-Angiotensin System: Updated Understanding and Role in Physiological and Pathophysiological States.

The classical view of the renin-angiotensin system (RAS) is that of the circulating hormone pathway involved in salt and water homeostasis and blood pressure regulation. It is also involved in the pathogenesis of cardiac and renal disorders. This led to the creation of drugs blocking the actions of this classical pathway, which improved cardiac and renal outcomes. Our understanding of the RAS has significantly expanded with the discovery of new peptides involved in this complex pathway. Over the last two decades, a counter-regulatory or protective pathway has been discovered that opposes the effects of the classical pathway. Components of RAS are also implicated in the pathogenesis of obesity and its metabolic diseases. The continued discovery of newer molecules also provides novel therapeutic targets to improve disease outcomes. This article aims to provide an overview of an updated understanding of the RAS, its role in physiological and pathological processes, and potential novel therapeutic options from RAS for managing cardiorenal disorders, obesity, and related metabolic disorders.

Keeping the Heart Healthy: The Role of Exercise in Cardiac Repair and Regeneration.

Significance: Heart failure is often accompanied by a decrease in the number of cardiomyocytes. Although the adult mammalian hearts have limited regenerative capacity, the rate of regeneration is extremely low and decreases with age. Exercise is an effective means to improve cardiovascular function and prevent cardiovascular diseases. However, the molecular mechanisms of how exercise acts on cardiomyocytes are still not fully elucidated. Therefore, it is important to explore the role of exercise in cardiomyocytes and cardiac regeneration. Recent Advances: Recent advances have shown that the effects of exercise on cardiomyocytes are critical for cardiac repair and regeneration. Exercise can induce cardiomyocyte growth by increasing the size and number. It can induce physiological cardiomyocyte hypertrophy, inhibit cardiomyocyte apoptosis, and promote cardiomyocyte proliferation. In this review, we have discussed the molecular mechanisms and recent studies of exercise-induced cardiac regeneration, with a focus on its effects on cardiomyocytes. Critical Issues: There is no effective way to promote cardiac regeneration. Moderate exercise can keep the heart healthy by encouraging adult cardiomyocytes to survive and regenerate. Therefore, exercise could be a promising tool for stimulating the regenerative capability of the heart and keeping the heart healthy. Future Directions: Although exercise is an important measure to promote cardiomyocyte growth and subsequent cardiac regeneration, more studies are needed on how to do beneficial exercise and what factors are involved in cardiac repair and regeneration. Thus, it is important to clarify the mechanisms, pathways, and other critical factors involved in the exercise-mediated cardiac repair and regeneration. Antioxid. Redox Signal. 39, 1088-1107.

Exercise training and experimental myocardial ischemia and reperfusion: A systematic review and meta-analysis.

Background: Despite the success of interventional coronary reperfusion strategies, morbidity and mortality from acute myocardial infarction are still substantial. Physical exercise is a well-recognized effective non-pharmacological therapy for cardiovascular diseases. Therefore, the objective of this systematic review was to analyze studies in animal models of ischemia-reperfusion in association with physical exercise protocols. Search strategy: Articles published on the topic over a 13-year period (2010-2022) were searched in two databases (PubMed and Google Scholar) using the keywords exercise training, ischemia/reperfusion or ischemia reperfusion injury. Meta-analysis and quality assessment of the studies were performed using the Review Manager 5.3 program. Results: From the 238 articles retrieved from PubMed and 200 from Google Scholar, after screening and eligibility assessment, 26 articles were included in the systematic review and meta-analysis. For meta-analysis comparing the group of previously exercised animals with the non-exercised animals and then submitted to ischemia-reperfusion, the infarct size was significantly decreased by exercise (p < 0.00001). In addition, the group exercised had increased heart-to-body weight ratio (p < 0.00001) and improved ejection fraction as measured by echocardiography (p < 0.0004) in comparison to non-exercised animals. Conclusion: We concluded that the animal models of ischemia-reperfusion indicates that exercise reduce infarct size and preserve ejection fraction, associated with beneficial myocardial remodeling.

Cardio-Protective Role of a Gut Hormone Obestatin: A Narrative Review.

Obestatin is a gut hormone composed of 23 amino acids that play a role in protecting the heart. It is synthesized from the same preproghrelin gut hormone gene as another gut hormone. The function and receptor of obestatin remain controversial, despite being present in various organs such as the liver, heart, mammary gland, pancreas, and more. The activity of obestatin is opposite to that of ghrelin, another hormone. The GPR-39 receptor is used by obestatin to exert its effects. Obestatin's cardioprotective role can be attributed to its ability to affect various factors, including adipose tissue, blood pressure regulation, heart, ischemia-reperfusion injury, endothelial cells, and diabetes. Because these factors are related to the cardiovascular system, modifying them via obestatin can provide cardioprotection. Furthermore, ghrelin, its antagonist hormone, regulates cardiovascular health. Diabetes mellitus, hypertension, and ischemia-reperfusion injury can all alter ghrelin/obestatin levels. Obestatin has also been shown to impact other organs, reducing weight and appetite, inhibiting food intake, and increasing adipogenesis. Obestatin has a brief half-life and is quickly degraded by proteases in the blood, liver, and kidneys after entering circulation. This article offers insights into the cardiac function of obestatin.

Purification, Structural Analysis and Cardio-Protective Activity of Polysaccharides from Radix Astragali.

Two polysaccharides, named APS2-I and APS3-I, were purified from the water extract of Radix Astragali. The average molecular weight of APS2-I was 1.96 × 106 Da and composed of Man, Rha, GlcA, GalA, Glc, Gal, Xyl, and Ara in a molar ratio of 2.3:4.8:1.7:14.0:5.8:11.7:2.8:12.6, while the average molecular weight of APS3-I was 3.91 × 106 Da and composed of Rha, GalA, Glc, Gal, and Ara in a molar ratio of 0.8:2.3:0.8:2.3:4.1. Biological evaluation showed APS2-I and APS3-I had significant antioxidant activity and myocardial protection activity. Furthermore, total polysaccharide treatment could significantly enhance hemodynamic parameters and improve cardiac function in rat ischemia and reperfusion isolated heart models. These results provided important information for the clinical application of APS in the field of cardiovascular disease and implied that Astragalus polysaccharides (APS) could be considered as a reference for the quality control of Radix Astragali.

Effect of phosphodiesterase type 5 inhibitors on major adverse cardiovascular events and overall mortality in a large nationwide cohort of men with erectile dysfunction and cardiovascular risk factors: A retrospective, observational study based on healthcare claims and national death index data.

BACKGROUND: Treatment with phosphodiesterase type 5 inhibitors (PDE-5is) is effective in treating erectile dysfunction (ED). AIM: The objective of this study was to determine the effect of PDE-5is on the incidence of major adverse cardiovascular (CV) events (MACE; composite outcome of CV death, hospitalization for myocardial infarction, coronary revascularization, stroke, heart failure, and unstable angina pectoris) and overall mortality. METHODS: A retrospective observational cohort study was conducted in a large US claims database in men with ≥1 diagnosis of ED without prior MACE within 1 year, from January 1, 2006, to October 31, 2020. The exposed group had ≥1 claim for PDE-5i and the unexposed group had no claims for PDE-5i, and the groups were matched up to 1:4 on baseline risk variables. OUTCOME: The primary outcome was MACE and the secondary outcomes were overall mortality and individual components of MACE, determined by multivariable Cox proportional hazard modeling. RESULTS: Matched plus multivariable analyses showed that MACE was lower by 13% in men exposed (n = 23 816) to PDE-5is (hazard ratio [HR] 0.87; 95% CI 0.79-0.95; P = .001) vs nonexposure (n = 48 682) over mean follow-up periods of 37 and 29 months, respectively, with lower incidence of coronary revascularization (HR 0.85; 95% CI 0.73-0.98; P = .029), heart failure (HR 0.83; 95% CI 0.72-0.97; P = .016), unstable angina (HR 0.78; 95% CI 0.64-0.96; P = .021), and CV death (HR 0.61; 95% CI 0.41-0.90; P = .014) with PDE-5i exposure. Phosphodiesterase type 5 inhibitor-exposed men had a 25% lower incidence of overall mortality (HR 0.75; 95% CI 0.65-0.87; P < .001). Men without coronary artery disease (CAD) but with CV risk factors at baseline showed a similar pattern. In the main study cohort, men in the highest quartile of PDE-5i exposure had the lowest incidence of MACE (HR 0.45; 95% CI 0.37-0.54; P < .001) and overall mortality (HR 0.51; 95% CI 0.37-0.71; P < .001) vs the lowest exposure quartile. In a subgroup with baseline type 2 diabetes (n = 6503), PDE-5i exposure was associated with a lower MACE risk (HR 0.79; 95% CI 0.64-0.97; P = .022). CLINICAL IMPLICATIONS: PDE-5is may have cardioprotective effects. STRENGTHS AND LIMITATIONS: Strengths are the large numbers of participants and consistency of the data; limitations include the retrospective nature of the study and unknown confounders. CONCLUSIONS: In a large population of US men with ED, PDE-5i exposure was associated with lower incidence of MACE, CV death, and overall mortality risk compared to non-exposure. Risk reduction correlated with PDE-5i exposure level.

Chrysin: A polyedric flavone as a tool to explore new phytotherapeutic applications and drug design.

In the field of pharmaceutical research, a branch that has become more and more interesting is phytochemistry. Among phytochemicals, flavonoids have been studied a lot over the past 30 years. This review summarizes the chemical characteristics, metabolism, applications, and toxicity of a particular flavonoid, chrysin, recorded in the last 10 years and supported by solid biological assays. Furthermore, this review highlights some derivatives of chrysin investigated to obtain more bioavailable molecules that maintain or improve chrysin's bioactivities, enclosing a chrysin patent section, as well.

Spinal cord astrocytes regulate myocardial ischemia-reperfusion injury.

Astrocytes play a key role in the response to injury and noxious stimuli, but its role in myocardial ischemia-reperfusion (I/R) injury remains largely unknown. Here we determined whether manipulation of spinal astrocyte activity affected myocardial I/R injury and the underlying mechanisms. By ligating the left coronary artery to establish an in vivo I/R rat model, we observed a 1.7-fold rise in glial fibrillary acidic protein (GFAP) protein level in spinal cord following myocardial I/R injury. Inhibition of spinal astrocytes by intrathecal injection of fluoro-citrate, an astrocyte inhibitor, decreased GFAP immunostaining and reduced infarct size by 29% relative to the I/R group. Using a Designer Receptor Exclusively Activated by Designer Drugs (DREADD) chemogenetic approach, we bi-directionally manipulated astrocyte activity employing GFAP promoter-driven Gq- or Gi-coupled signaling. The Gq-DREADD-mediated activation of spinal astrocytes caused transient receptor potential vanilloid 1 (TRPV1) activation and neuropeptide release leading to a 1.3-fold increase in infarct size, 1.2-fold rise in serum norepinephrine level and higher arrhythmia score relative to I/R group. In contrast, Gi-DREADD-mediated inhibition of spinal astrocytes suppressed TRPV1-mediated nociceptive signaling, resulting in 35% reduction of infarct size and 51% reduction of arrhythmia score from I/R group, as well as lowering serum norepinephrine level from 3158 ± 108 to 2047 ± 95 pg/mL. Further, intrathecal administration of TRPV1 or neuropeptide antagonists reduced infarct size and serum norepinephrine level. These findings demonstrate a functional role of spinal astrocytes in myocardial I/R injury and provide a novel potential therapeutic approach targeting spinal cord astrocytes for the prevention of cardiac injury.

Glucose control independent mechanisms involved in the cardiovascular benefits of glucagon-like peptide-1 receptor agonists.

Patients with type 2 diabetes mellitus (T2DM) face a high risk of developing cardiovascular diseases. However, traditional hypoglycemic drugs have limited effects on macrovascular complications of the disease. Clinical trials have confirmed that glucagon-like peptide-1 receptor agonists (GLP-1RAs), in addition to their capability of controlling blood glucose, can also decrease the risk of cardiovascular events in T2DM. The protective influence of GLP-1RAs on coronary heart disease and heart failure has been proven in recent clinical studies. Therefore, the international guidelines recommend GLP-1 RAs as the first-line therapy for patients with T2DM having cardiovascular disease. Notwithstanding the widespread clinical application of GLP-1RAs, the underlying mechanisms through which GLP-1RAs exert cardiovascular benefits in patients with DM remain unclear. In this review, we systematically summarize the mechanisms of action of GLP-1RAs responsible for producing favorable effects on the cardiovascular system, beyond their capability of blood glucose regulation. GLP-1RA-mediated cardiovascular protection is manifested through multiple mechanisms, including oxidative stress, inflammation, endoplasmic reticulum stress, apoptosis, and vascular/cardiac remodeling. The understanding of these mechanisms will facilitate the development of new and promising therapeutic modalities for T2DM. Furthermore, we have identified several promising targets for future research in this area.

Management and treatment of cardiotoxicity due to anticancer drugs: 10 questions and answers.

Since the introduction of anthracyclines into clinical practice in the 1960s, chemotherapy has always been associated with cardiotoxicity. Patients on cardiotoxic drugs can develop a wide range of cardiovascular diseases, including left ventricular (LV) systolic dysfunction and heart failure (HF), arrhythmias, hypertension, and coronary artery disease (CAD). The rising number of cancer patients, population ageing, and the frequent overlap of cardiovascular and oncological diseases have highlighted the importance of close collaboration between cardiologists and oncologists. As a result, in 1995, cardiologists at the IEO (European Institute of Oncology) coined the term cardioncology, a new discipline focused on the dynamics of cardiovascular disease in cancer patients. Given the complex scenario characterized by a constant dialogue between the oncological condition and cardiovascular comorbidity, it is essential for the clinician to get the knowledge to properly fulfill the needs of the oncological patient under cardiotoxic treatment. Through the answer to 10 questions, we aim to describe the complex issue of cardiotoxicity by addressing the main critical points and current evidence related to the assessment, management, treatment, and surveillance of cancer patients under chemotherapy.

Notoginsenoside R1 Regulates Ischemic Myocardial Lipid Metabolism by Activating the AKT/mTOR Signaling Pathway.

Ischemic heart diseases are responsible for more than one-third of all deaths worldwide. Radix notoginseng is widely used to treat ischemic heart disease in China and other Asian countries, and notoginsenoside R1 (NGR1) is its characteristic and large-amount ingredient. However, the potential molecular mechanisms of NGR1 in improving ischemic heart diseases are unclear. In this study, we combined pharmacological evaluation with network pharmacology, myocardial proteomics, and conventional molecular dynamics (MD) simulation to explore the cardio-protection mechanisms of NGR1. Our results revealed that NGR1 improved the echocardiographic, tissue pathological, and serum biochemical perturbations in myocardial ischemic rats. The network pharmacology studies indicated that NGR1 mainly regulated smooth muscle cell proliferation, vasculature development, and lipid metabolism signaling, especially in the PI3K/AKT pathway. Myocardial proteomics revealed that the function of NGR1 was focused on regulating metabolic and energy supply processes. The research combined reverse-docked targets with differential proteins and demonstrated that NGR1 modulated lipid metabolism in ischemic myocardia by interacting with mTOR and AKT. Conventional MD simulation was applied to investigate the influence of NGR1 on the structural stabilization of the mTOR and AKT complex. The results suggested that NGR1 can strengthen the affinity stabilization of mTOR and AKT. Our study first revealed that NGR1 enhanced the affinity stabilization of mTOR and AKT, thus promoting the activation of the AKT/mTOR pathway and improving lipid metabolic abnormity in myocardial ischemic rats.

Long-term effectiveness of empiric cardio-protection in patients receiving cardiotoxic chemotherapies: A systematic review & bayesian network meta-analysis.

BACKGROUND: Cardioprotective therapies represent an important avenue to reduce treatment-limiting cardiotoxicities in patients receiving chemotherapy. However, the optimal duration, strategy and long-term efficacy of empiric cardio-protection remains unknown. METHODS: Leveraging the MEDLINE/Pubmed, CENTRAL and clinicaltrials.gov databases, we identified all randomised controlled trials investigating cardioprotective therapies from inception to November 2021 (PROSPERO-ID:CRD42021265006). Cardioprotective classes included ACEIs, ARBs, Beta-blockers, dexrazoxane (DEX), statins and mineralocorticoid receptor antagonists. The primary end-point was new-onset heart failure (HF). Secondary outcomes were the mean difference in left ventricular ejection fraction (LVEF) change, hypotension and all-cause mortality. Network meta-analyses were used to assess the cardioprotective effects of each therapy to deduce the most effective therapies. Both analyses were performed using a Bayesian random effects model to estimate risk ratios (RR) and 95% credible intervals (95% CrI). RESULTS: Overall, from 726 articles, 39 trials evaluating 5931 participants (38.0 ± 19.1 years, 72.0% females) were identified. The use of any cardioprotective strategy associated with reduction in new-onset HF (RR:0.32; 95% CrI:0.19-0.55), improved LVEF (mean difference: 3.92%; 95% CrI:2.81-5.07), increased hypotension (RR:3.27; 95% CrI:1.38-9.87) and no difference in mortality. Based on control arms, the number-needed-to-treat for 'any' cardioprotective therapy to prevent one incident HF event was 45, including a number-needed-to-treat of 21 with ≥1 year of therapy. Dexrazoxane was most effective at HF prevention (Surface Under the Cumulative Ranking curve: 81.47%), and mineralocorticoid receptor antagonists were most effective at preserving LVEF (Surface Under the Cumulative Ranking curve: 99.22%). CONCLUSION: Cardiotoxicity remains a challenge for patients requiring anticancer therapies. The initiation of extended duration cardioprotection reduces incident HF. Additional head-to-head trials are needed.

Poly(I:C) attenuates myocardial ischemia/reperfusion injury by restoring autophagic function.

Polyinosinic-polycytidylic acid (poly(I:C)) is the agonist of Toll-like receptor 3 (TLR3), which participates in innate immune responses under the condition of myocardial ischemia/reperfusion injury (MIRI). It has been shown that poly(I:C) exhibited cardioprotective activities through the PI3K/Akt pathway, which is the main signal transduction pathway during autophagy. However, the precise mechanism by whether poly(I:C) regulates autophagy remains poorly understood. Thus, this study was designed to investigate the therapeutic effect of poly(I:C) against MIRI and the underlying pathway connection with autophagy. We demonstrated that 1.25 and 5 mg/kg poly(I:C) preconditioning significantly reduced myocardial infarct size and cardiac dysfunction. Moreover, poly(I:C) significantly promoted cell survival by restoring autophagy flux and then regulating it to an adequate level Increased autophagy protein Beclin1 and LC3II together with p62 degradation after additional chloroquine. In addition, mRFP-GFP-LC3 adenoviruses exhibited autophagy activity in neonatal rat cardiac myocytes (NRCMs). Mechanistically, poly(I:C) activated the PI3K/AKT/mTOR pathway to induce autophagy, which was abolished by LY294002 (PI3K antagonist), rapamycin (autophagy activator and mTOR inhibitor), or 3-methyladenine (autophagy inhibitor), suggesting either inhibition of the PI3K/Akt/mTOR pathway or autophagy activity interrupt the beneficial effect of poly(I:C) preconditioning. In conclusion, poly(I:C) promotes cardiomyocyte survival from ischemia/reperfusion injury by regulating autophagy via the PI3K/Akt/mTOR pathway.