Treatment Of Cardiovascular Diseases Research Articles

Detecting and managing the patient with chronic kidney disease in primary care: A review of the latest guidelines.

Chronic kidney disease (CKD) is a major global health problem, affecting about 9.5% of the population and 850 million people worldwide. In primary care, most CKD is caused by diabetes and/or hypertension, but a substantial proportion of cases may have alternative causes. During the early stages, CKD is asymptomatic, and many people are unaware that they are living with the disease. Despite the lack of symptoms, CKD is associated with elevated risks of cardiovascular disease, progressive kidney disease, kidney failure and premature mortality. Risk reduction strategies are effective and cost-effective but require early diagnosis through testing of the estimated glomerular filtration rate and albuminuria in high-risk populations. Once diagnosed, the treatment of CKD centres around lifestyle interventions, blood pressure and glycaemic control, and preventative treatments for cardiovascular disease and kidney disease progression. Most patients with CKD should be managed with statins, renin-angiotensin-aldosterone system inhibitors and sodium-glucose cotransporter-2 inhibitors. Additional treatment options to reduce cardiorenal risk are available in patients with diabetes, including glucagon-like peptide-1 receptor agonists and non-steroidal mineralocorticoid receptor antagonists. The Kidney Failure Risk Equation is a new tool that can support the identification of patients at high risk of progressive kidney disease and kidney failure and can be used to guide referrals to nephrology. This review summarizes the latest guidance relevant to managing adults with, or at risk of, CKD and provides practical advice for managing patients with CKD in primary care.

Research Progress in Pharmacological Effects and Mechanisms of Angelica sinensis against Cardiovascular and Cerebrovascular Diseases.

Angelica sinensis (Oliv.) Diels (A. sinensis) is a medicinal and edible values substance, which could promote blood circulation and enrich blood. It possesses rich chemical components and nutrients, which have significant therapeutic effects on cardiovascular and cerebrovascular diseases. It is commonly used for the prevention and treatment of cardiovascular and cerebrovascular diseases in the elderly, especially in improving ischemic damage to the heart and brain, protecting vascular cells, and regulating inflammatory reactions. This article reviews the main pharmacological effects and clinical research of A. sinensis on cardiovascular and cerebrovascular diseases in recent years, explores the effect of its chemical components on cardiovascular and cerebrovascular diseases by regulating the expression of functional proteins and inhibiting inflammation, anti-apoptosis, and antioxidant mechanisms. It provides a reference for further research on A. sinensis and the development of related drugs. It provides a new reference direction for the in-depth research and application of A. sinensis in the prevention, improvement, and treatment of cardiovascular and cerebrovascular diseases.

A mathematical model to design pillar-shaped bioinspired mechanical sensors

Soft robots and sensor/actuator systems are often based on bioinspired designs to leverage nature patterns. Specifically, pillar-shaped sensors are useful for human activity monitoring, locomotion of soft robots or treatment of cardiovascular diseases. If electric or magnetic particles are added in the manufacturing process, these structures can be tuned through remote fields to attain a specific mechanical behaviour. This promising technique has direct applications in high-impact fields such as bioengineering, soft robots or sensor designing. Filament-shaped smart sensors can send electrical signals when subjected to an external mechanical stimulus or provide a mechanical response when a remote and controllable field is applied broadening their possibilities of action. As the efficient design of these structures is highly challenging, developing a technical tool with a low computational cost to help throughout layout processes (i.e. inverse engineering) is pivotal. Theoretical modelling of the kinematics and dynamics of a wire-shaped structure under an external action is the first step to provide a methodology to help designing mechanical sensors in an efficient, understandable and low time-consuming way. The event of mechanical deformation after receiving the external stimulus and before sending the corresponding output signal is key in the conceptualisation process of smart sensors. This work intends to give insight into the dynamics of a deformable pillar-shaped sensor component under an external action without addressing or coupling its causes and, hence, provide the general mechanical framework to serve as basis for multiphysics formulations for pillar-shaped sensor design.

Camera-Based Seismocardiogram for Heart Rate Variability Monitoring.

Heart rate variability (HRV) is a crucial metric that quantifies the variation between consecutive heartbeats, serving as a significant indicator of autonomic nervous system (ANS) activity. It has found widespread applications in clinical diagnosis, treatment, and prevention of cardiovascular diseases. In this study, we proposed an optical model for defocused speckle imaging, to simultaneously incorporate out-of-plane translation and rotation-induced motion for highly-sensitive non-contact seismocardiogram (SCG) measurement. Using electrocardiogram (ECG) signals as the gold standard, we evaluated the performance of photoplethysmogram (PPG) signals and speckle-based SCG signals in assessing HRV. The results indicated that the HRV parameters measured from SCG signals extracted from laser speckle videos showed higher consistency with the results obtained from the ECG signals compared to PPG signals. Additionally, we confirmed that even when clothing obstructed the measurement site, the efficacy of SCG signals extracted from the motion of laser speckle patterns persisted in assessing the HRV levels. This demonstrates the robustness of camera-based non-contact SCG in monitoring HRV, highlighting its potential as a reliable, non-contact alternative to traditional contact-PPG sensors.

Recent developments in the diagnosis, treatment, and management of cardiovascular diseases through artificial intelligence and other innovative approaches

Recent developments in the diagnosis, treatment, and management of cardiovascular diseases through artificial intelligence and other innovative approaches

Examination of Cardiac Activity with ECG Monitoring Using Heart Rate Variability Methods.

The paper presents a system for analyzing cardiac activity with the possibility of continuous and remote monitoring. The created sensor mobile device monitors heart activity by means of the convenient and imperceptible registration of cardiac signals. At the same time, the behavior of the human body is also monitored through the accelerometer and gyroscope built into the device, thanks to which it is possible to signal in the event of loss of consciousness or fall (in patients with syncope). Conducting real-time cardio monitoring and the analysis of recordings using various mathematical methods (linear, non-linear, and graphical) enables the research, accurate diagnosis, timely assistance, and correct treatment of cardiovascular diseases. The paper examines the recordings of patients diagnosed with arrhythmia and syncope recorded by electrocardiography (ECG) sensors in real conditions. The obtained results are subjected to statistical analysis to determine the accuracy and significance of the obtained results. The studies show significant deviations in the patients with arrhythmia and syncope regarding the obtained values of the studied parameters of heart rate variability (HRV) from the accepted normal values (for example, the root mean square of successive differences between normal heartbeats (RMSSD) in healthy individuals is 24.02 ms, while, in patients with arrhythmia (6.09 ms) and syncope (5.21 ms), it is much lower). The obtained quantitative and graphic results identify some possible abnormalities and demonstrate disorders regarding the activity of the autonomic nervous system, which is directly related to the work of the heart.

Naoxintong capsule remodels gut microbiota and ameliorates early-stage atherosclerosis in apolipoprotein E-deficient mice

BackgroundNaoxintong capsule (NXT) is a compound traditional Chinese medicine prescription with demonstrated effect for the treatment of cardiovascular and cerebrovascular diseases including atherosclerosis (AS). However, the pharmacological mechanisms of NXT in ameliorating early-stage AS are still unclear, especially regarding the role of gut microbiota. PurposeThis study is aiming to evaluate the therapeutic effect of NXT against early-stage AS, and further illustrate the potential correlations among AS, gut microbiota, and NXT. MethodsThirty-two male ApoE knockout mice (C57BL/6 background) were fed with a high cholesterol diet (HCD) for 4 weeks to establish an early-stage AS model. NXT in two different dosages and simvastatin (Simv) were than administrated for another 8 weeks. Lipid metabolism indicators and inflammation levels were measured with corresponding assay kits. Changes in blood vessels, liver lesions, and intestinal barrier proteins were evaluated with different staining methods. Furthermore, the gut microbiota structure was analyzed using 16S rRNA sequencing technology, while GC–MS was utilized to determine the fecal contents of short-chain fatty acids (SCFAs). ResultsAdministration of NXT significantly ameliorated obesity, hyperlipidemia, systemic inflammation, vasculopathy, liver injury, and intestinal barrier disorder in AS mice. Administration of NXT also significantly regulated the gut microbiota disturbance and increased the total contents of fecal SCFAs in AS mice. Furthermore, acetic acid content and the relative abundance of Faecalibacterium in feces were proposed as potential therapeutic biomarkers of NXT for AS treatment as indicated via the correlation analysis. ConclusionThis study demonstrated that NXT could effectively treat early-stage AS induced by HCD in mice. NXT regulated the gut microbiota and metabolites, maintained intestinal homeostasis, and improved the systemic inflammatory response. These findings may provide robust experimental support for the clinical use of NXT for AS treatment.

An Updated Review on the Therapeutic Potential of Stem Cells for Treating Cardiovascular Disorders

Despite significant progress in the field of medicine, cardiovascular illnesses continue to be the primary cause of mortality on a global scale. The increasing prevalence of cardiovascular illnesses necessitates the exploration of novel and potential therapeutic strategies to address the escalating risk associated with CVDs. Stem cell therapy has emerged as the central focus of regenerative cardiovascular medicine, surpassing all other treatments and therapies. Multiple clinical trials and studies have demonstrated that stem cell therapy, particularly mesenchymal stem cells, is the most appealing approach for treating cardiac disorders due to their significant therapeutic potential. Recent research have shown that mesenchymal stem cells have a positive impact on several cardiac muscle diseases, such as heart failure, problems with blood vessel lining, damage caused by lack of blood flow, and high blood pressure in the lungs. This study specifically examines the potential, preconditioning techniques, methods of administration, and mechanisms of mesenchymal stem cell (MSC) therapy for the treatment of cardiovascular diseases (CVDs).

In Vitro Stability and Pharmacokinetic Study of Pedunculoside and Its Beta-CD Polymer Inclusion Complex

Pedunculoside, a triterpene saponin derived from various Ilex species, holds potential as a treatment for cardiovascular diseases. However, its clinical application is hindered by poor bioavailability, rapid elimination, and extensive intestinal metabolism to rotundic acid. To address these issues, a water-soluble inclusion complex of pedunculoside, namely, the beta-CD polymer inclusion complex of pedunculoside (pedunculoside–βCDP), was prepared in this study, and a comparative in vitro stability and pharmacokinetic behavior study was performed between pedunculoside and pedunculoside–βCDP. Both pedunculoside and pedunculoside–βCDP exhibited the highest stability in simulated gastric fluid and simulated intestinal fluid but were readily metabolized when co-incubated with Bifidobacterium adolescentis and Bifidobacterium breve. An LC-MS/MS analytical method for the simultaneous determination of pedunculoside and rotundic acid in rat plasma was successfully established, validated, and applied to investigate the pharmacokinetic behavior after rats were intravenously administered with pedunculoside or pedunculoside–βCDP. The results indicated that pedunculoside–βCDP could significantly improve the pharmacokinetic profile of pedunculoside by increasing plasma exposure, retarding elimination, and reducing intestinal metabolism. This study enhances our understanding of pedunculoside–βCDP’s metabolic fate and pharmacokinetic properties and potentially advances its further research, development, and clinical application.

The Essence of Lipoproteins in Cardiovascular Health and Diseases Treated by Photodynamic Therapy

Lipids, together with lipoprotein particles, are the cause of atherosclerosis, which is a pathology of the cardiovascular system. In addition, it affects inflammatory processes and affects the vessels and heart. In pharmaceutical answer to this, statins are considered a first-stage treatment method to block cholesterol synthesis. Many times, additional drugs are also used with this method to lower lipid concentrations in order to achieve certain values of low-density lipoprotein (LDL) cholesterol. Recent advances in photodynamic therapy (PDT) as a new cancer treatment have gained the therapy much attention as a minimally invasive and highly selective method. Photodynamic therapy has been proven more effective than chemotherapy, radiotherapy, and immunotherapy alone in numerous studies. Consequently, photodynamic therapy research has expanded in many fields of medicine due to its increased therapeutic effects and reduced side effects. Currently, PDT is the most commonly used therapy for treating age-related macular degeneration, as well as inflammatory diseases, and skin infections. The effectiveness of photodynamic therapy against a number of pathogens has also been demonstrated in various studies. Also, PDT has been used in the treatment of cardiovascular diseases, such as atherosclerosis and hyperplasia of the arterial intima. This review evaluates the effectiveness and usefulness of photodynamic therapy in cardiovascular diseases. According to the analysis, photodynamic therapy is a promising approach for treating cardiovascular diseases and may lead to new clinical trials and management standards. Our review addresses the used therapeutic strategies and also describes new therapeutic strategies to reduce the cardiovascular burden that is induced by lipids.

Ginkgo biloba and Its Chemical Components in the Management of Alzheimer's Disease.

The pathogenesis of Alzheimer's disease (AD), a degenerative disease of the central nervous system, remains unclear. The main manifestations of AD include cognitive and behavioral disorders, neuropsychiatric symptoms, neuroinflammation, amyloid plaques, and neurofibrillary tangles. However, current drugs for AD once the dementia stage has been reached only treat symptoms and do not delay progression, and the research and development of targeted drugs for AD have reached a bottleneck. Thus, other treatment options are needed. Bioactive ingredients derived from plants are promising therapeutic agents. Specifically, Ginkgo biloba (Gb) extracts exert anti-oxidant, anticancer, neuroplastic, neurotransmitter-modulating, blood fluidity, and anti-inflammatory effects, offering alternative options in the treatment of cardiovascular, metabolic, and neurodegenerative diseases. The main chemical components of Gb include flavonoids, terpene lactones, proanthocyanidins, organic acids, polysaccharides, and amino acids. Gb and its extracts have shown remarkable therapeutic effects on various neurodegenerative diseases, including AD, with few adverse reactions. Thus, high-quality Gb extracts are a well-established treatment option for AD. In this review, we summarize the insights derived from traditional Chinese medicine, experimental models, and emerging clinical trials on the role of Gb and its chemical components in the treatment of the main clinical manifestations of AD.

Research Progress on Multiple Effects and Clinical Application of Proprotein Convertase Subtilisin-kexin9 Inhibitors

PCSK9 inhibitors (Proprotein convertase subtilisin-kexin9 inhibitors) not only have a good lipid-lowering effect but also have the effects of improving cardiovascular outcome, anti-inflammation, reducing oxidative stress and improving vascular endothelium. In recent years, the continuous research and development of PCSK9 inhibitors have provided new ideas for the treatment of cardiovascular diseases. This article reviews the multiple action mechanisms of PCSK9 inhibitors and their research in kidney disease and cerebrovascular diseases.

The effect of obesity phenotype changes on cardiovascular outcomes in adults older than 40 years in the prospective cohort of the Tehran lipids and glucose study (TLGS): joint model of longitudinal and time-to-event data

BackgroundObesity is a worldwide health concern with serious clinical effects, including myocardial infarction (MI), stroke, cardiovascular diseases (CVDs), and all-cause mortality. The present study aimed to assess the association of obesity phenotypes and different CVDs and mortality in males and females by simultaneously considering the longitudinal and survival time data.MethodsIn the Tehran Lipid and Glucose Study (TLGS), participants older than three years were selected by a multi-stage random cluster sampling method and followed for about 19 years. In the current study, individuals aged over 40 years without a medical history of CVD, stroke, MI, and coronary heart disease were included. Exclusions comprised those undergoing treatment for CVD and those with more than 30% missing information or incomplete data. Joint modeling of longitudinal binary outcome and survival time data was applied to assess the dependency and the association between the changes in obesity phenotypes and time to occurrence of CVD, MI, stroke, and CVD mortality. To account for any potential sex-related confounding effect on the association between the obesity phenotypes and CVD outcomes, sex-specific analysis was carried out. The analysis was performed using packages (JMbayes2) of R software (version 4.2.1).ResultsOverall, 6350 adults above 40 years were included. In the joint modeling of CVD outcome among males, literates and participants with a family history of diabetes were at lower risk of CVD compared to illiterates and those with no family history of diabetes in the Bayesian Cox model. Current smokers were at higher risk of CVD compared to non-smokers. In a logistic mixed effects model, odds of obesity phenotype was higher among participants with low physical activity, family history of diabetes and older age compared to males with high physical activity, no family history of diabetes and younger age. In females, based on the results of the Bayesian Cox model, participants with family history of diabetes, family history of CVD, abnormal obesity phenotype and past smokers had a higher risk of CVD compared to those with no history of diabetes, CVD and nonsmokers. In the obesity varying model, odds of obesity phenotype was higher among females with history of diabetes and older age compared to those with no history of diabetes and who were younger. There was no significant variable associated with MI among males in the Bayesian Cox model. Odds of obesity phenotype was higher in males with low physical activity compared to those with high physical activity in the obesity varying model, whereas current smokers were at lower odds of obesity phenotype than nonsmokers. In females, risk of MI was higher among those with family history of diabetes compared to those with no history of diabetes in the Bayesian Cox model. In the logistic mixed effects model, a direct and significant association was found between age and obesity phenotype. In males, participants with history of diabetes, abnormal obesity phenotype and older age were at higher risk of stroke in the Bayesian Cox model compared to males with no history of diabetes, normal obesity phenotype and younger persons. In the obesity varying model, odds of obesity phenotype was higher in males with low physical activity, family history of diabetes and older age compared to those with high physical activity, no family history of diabetes and who were younger. Smokers had a lower odds of obesity phenotype than nonsmokers. In females, past smokers and those with family history of diabetes were at higher risk of stroke compared to nonsmokers and females with no history of diabetes in the Bayesian Cox model. In the obesity varying model, females with family history of diabetes and older ages had a higher odds of obesity phenotype compared to those with no family history of diabetes and who were younger. Among males, risk of CVD mortality was lower in past smokers compared to nonsmokers in the survival model. A direct and significant association was found between age and CVD mortality. Odds of obesity phenotype was higher in males with a history of diabetes than in those with no family history of diabetes in the logistic mixed effects model.ConclusionsIt seems that modifications to metabolic disorders may have an impact on the heightened incidence of CVDs. Based on this, males with obesity and any type of metabolic disorder had a higher risk of CVD, stroke and CVD mortality (excluding MI) compared to those with a normal body mass index (BMI) and no metabolic disorders. Females with obesity and any type of metabolic disorder were at higher risk of CVD(, MI and stroke compared to those with a normal BMI and no metabolic disorders suggesting that obesity and metabolic disorders are related. Due to its synergistic effect on high blood pressure, metabolic disorders raise the risk of CVD.

Decoding the enigmatic last gasotransmitter. The intriguing journey of HNO: From hidden origins to clues on reactivity and detection

This review focuses on HNO, a molecule of immense chemical and biological importance that has intrigued scientists for decades. Despite its elusive and transient nature, HNO may play an important role in various physiological processes, particularly in cardiovascular regulation. This review thoroughly examines the formation, chemical properties, and biological significance of HNO and highlights ongoing research efforts to unravel its mysteries. Challenges in studying HNO arise from its high reactivity, short half-life, and complex interactions with other nitrogen oxides, particularly nitric oxide. Detection and quantification of HNO in biological systems pose difficulties, prompting the development of advanced techniques. Active research into endogenous HNO formation is revealing intricate pathways within biological systems, the elucidation of which is crucial for exploiting its therapeutic potential. The multifaceted role of HNO in cardiovascular regulation, influencing vasorelaxation, blood pressure reduction, and enhanced cardiac contractility, underscores its profound impact on the circulatory system. Ongoing research holds promise for treating conditions such as hypertension and heart failure. As clinical applications expand, HNO research may unlock treatments for cardiovascular disease, inflammatory disorders, and cancer. The recent discovery of endogenous HNO production in plants adds a new dimension. While numerous clues have emerged, the scientific saga underscores that mysteries persist, evolve, and beckon to perpetual exploration in the realm of science.

Gut Microbiome and Its Role in Valvular Heart Disease: Not a "Gutted" Relationship.

The role of the gut microbiome (GM) and oral microbiome (OM) in cardiovascular disease (CVD) has been increasingly being understood in recent years. It is well known that GM is a risk factor for various CVD phenotypes, including hypertension, dyslipidemia, heart failure and atrial fibrillation. However, its role in valvular heart disease (VHD) is less well understood. Research shows that, direct, microbe-mediated and indirect, metabolite-mediated damage as a result of gut dysbiosis and environmental factors results in a subclinical, chronic, systemic inflammatory state, which promotes inflammatory cell infiltration in heart valves and subsequently, via pro-inflammatory molecules, initiates a cascade of reaction, resulting in valve calcification, fibrosis and dysfunction. This relationship between GM and VHD adds a pathophysiological link to the pathogenesis of VHD, which can be aimed therapeutically, in order to prevent or regress any risk for valvular pathologies. Therapeutic interventions include dietary modifications and lifestyle interventions, in order to influence environmental factors that can promote gut dysbiosis. Furthermore, the combination of probiotics and prebiotics, as well as fecal m transplantation and targeted treatment with inducers or inhibitors of microbial enzymes have showed promising results in animal and/or clinical studies, with the potential to reduce the inflammatory state and restore the normal gut flora in patients. This review, thus, is going to discuss the pathophysiological links behind the relationship of GM, CVD and VHD, as well as explore the recent data regarding the effect of GM-altering treatment in CVD, cardiac function and systemic inflammation.

The Therapeutic Potential of Four Main Compounds of Zanthoxylum nitidum (Roxb.) DC: A Comprehensive Study on Biological Processes, Anti-Inflammatory Effects, and Myocardial Toxicity.

Zanthoxylum nitidum (Roxb.) DC. (Z. nitidum) is a traditional Chinese medicinal plant that is indigenous to the southern regions of China. Previous research has provided evidence of the significant anti-inflammatory, antibacterial, and anticancer properties exhibited by Z. nitidum. The potential therapeutic effects and cardiac toxicity of Z. nitidum remain uncertain. The aim of this research was to investigate the potential therapeutic properties of the four main compounds of Z. nitidum in cardiovascular diseases, their impact on the electrical activity of cardiomyocytes, and the underlying mechanism of their anti-inflammatory effects. We selected the four compounds from Z. nitidum with a high concentration and specific biological activity: nitidine chloride (NC), chelerythrine chloride (CHE), magnoflorine chloride (MAG), and hesperidin (HE). A proteomic analysis was conducted on the myocardial tissues of beagle dogs following the administration of NC to investigate the role of NC in vivo and the associated biological processes. A bioinformatic analysis was used to predict the in vivo biological processes that MAG, CHE, and HE were involved in. Molecular docking was used to simulate the binding between compounds and their targets. The effect of the compounds on ion channels in cardiomyocytes was evaluated through a patch clamp experiment. Organ-on-a-chip (OOC) technology was developed to mimic the physiological conditions of the heart in vivo. Proteomic and bioinformatic analyses demonstrated that the four compounds of Z. nitidum are extensively involved in various cardiovascular-related biological pathways. The findings from the patch clamp experiments indicate that NC, CHE, MAG, and HE elicit a distinct activation or inhibition of the IK1 and ICa-L in cardiomyocytes. Finally, the anti-inflammatory effects of the compounds on cardiomyocytes were verified using OOC technology. NC, CHE, MAG, and HE demonstrate anti-inflammatory effects through their specific interactions with prostaglandin-endoperoxide synthase 2 (PTGS2) and significantly influence ion channels in cardiomyocytes. Our study provides a foundation for utilizing NC, CHE, MAG, and HE in the treatment of cardiovascular diseases.

Device regulation and surveillance in vascular care: Challenges and opportunities.

Cardiovascular devices are essential for the treatment of cardiovascular diseases including cerebrovascular, coronary, valvular, congenital, peripheral vascular and arrhythmic diseases. The regulation and surveillance of vascular devices in real-world practice, however, presents challenges during each individual product's life cycle. Four examples illustrate recent challenges and questions regarding safety, appropriate use and efficacy arising from FDA approved devices used in real-world practice. We outline potential pathways wherein providers, regulators and payors could potentially provide high-quality cardiovascular care, identify safety signals, ensure equitable device access, and study potential issues with devices in real-world practice.

Salvia miltiorrhiza suppresses cardiomyocyte ferroptosis after myocardial infarction by activating Nrf2 signaling

Ethnopharmacological relevanceFerroptosis, a recently identified non-apoptotic form of cell death reliant on iron, is distinguished by an escalation in lipid reactive oxygen species (ROS) that are iron-dependent. This phenomenon has a strong correlation with irregularities in iron metabolism and lipid peroxidation. Salvia miltiorrhiza Bunge (DS), a medicinal herb frequently utilized in China, is highly esteemed for its therapeutic effectiveness in enhancing blood circulation and ameliorating blood stasis, particularly during the treatment of cardiovascular diseases (CVDs). Numerous pharmacological studies have identified that DS manifests antioxidative stress effects as well as inhibits lipid peroxidation. However, ambiguity persists regarding the potential of DS to impede ferroptosis in cardiomyocytes and subsequently improve myocardial damage post-myocardial infarction (MI). Aim of the studyThe present work focused on investigating whether DS could be used to prevent the ferroptosis of cardiomyocytes and improve post-MI myocardial damage. Materials and methodsIn vivo experiments: Through ligation of the left anterior descending coronary artery, we constructed both a wild-type (WT) and NF-E2 p45-related factor 2 knockout (Nrf2−/−) mouse model of MI. Effects of DS and ferrostatin-1 (Fer-1) on post-MI cardiomyocyte ferroptosis were examined through detecting ferroptosis and myocardial damage-related indicators as well as Nrf2 signaling-associated protein levels. In vitro experiments: Erastin was used for stimulating H9C2 cardiomyocytes to construct an in vitro ferroptosis cardiomyocyte model. Effects of DS and Fer-1 on cardiomyocyte ferroptosis were determined based on ferroptosis-related indicators and Nrf2 signaling-associated protein levels. Additionally, inhibitor and activator of Nrf2 were used for confirming the impact of Nrf2 signaling on DS's effect on cardiomyocyte ferroptosis. ResultsIn vivo: In comparison to the model group, DS suppressed ferroptosis in cardiomyocytes post-MI and ameliorated myocardial damage by inducing Nrf2 signaling-related proteins (Nrf2, xCT, GPX4), diminishing tissue ferrous iron and malondialdehyde (MDA) content. Additionally, it enhanced glutathione (GSH) levels and total superoxide dismutase (SOD) activity, effects that are aligned with those of Fer-1. Moreover, the effect of DS on alleviating cardiomyocyte ferroptosis after MI could be partly inhibited through Nrf2 knockdown. In vitro: Compared with the erastin group, DS inhibited cardiomyocyte ferroptosis by promoting the expression of Nrf2 signaling-related proteins, reducing ferrous iron, ROS, and MDA levels, but increasing GSH content and SOD activity, consistent with the effect of Fer-1. Additionally, Nrf2 inhibition increased erastin-mediated ferroptosis of cardiomyocytes through decreasing Nrf2 signaling-related protein expressions. Co-treatment with DS and Nrf2 activator failed to further enhance the anti-ferroptosis effect of DS. ConclusionMI is accompanied by cardiomyocyte ferroptosis, whose underlying mechanism is probably associated with Nrf2 signaling inhibition. DS possibly suppresses ferroptosis of cardiomyocytes and improves myocardial damage after MI through activating Nrf2 signaling.

Identification of Riluzole derivatives as novel calmodulin inhibitors with neuroprotective activity by a joint synthesis, biosensor, and computational guided strategy

The development of new molecules for the treatment of calmodulin related cardiovascular or neurodegenerative diseases is an interesting goal. In this work, we introduce a novel strategy with four main steps: (1) chemical synthesis of target molecules, (2) Förster Resonance Energy Transfer (FRET) biosensor development and in vitro biological assay of new derivatives, (3) Cheminformatics models development and in vivo activity prediction, and (4) Docking studies. This strategy is illustrated with a case study. Firstly, a series of 4-substituted Riluzole derivatives 1–3 were synthetized through a strategy that involves the construction of the 4-bromoriluzole framework and its further functionalization via palladium catalysis or organolithium chemistry. Next, a FRET biosensor for monitoring Ca2+-dependent CaM-ligands interactions has been developed and used for the in vitro assay of Riluzole derivatives. In particular, the best inhibition (80%) was observed for 4-methoxyphenylriluzole 2b. Besides, we trained and validated a new Networks Invariant, Information Fusion, Perturbation Theory, and Machine Learning (NIFPTML) model for predicting probability profiles of in vivo biological activity parameters in different regions of the brain. Next, we used this model to predict the in vivo activity of the compounds experimentally studied in vitro. Last, docking study conducted on Riluzole and its derivatives has provided valuable insights into their binding conformations with the target protein, involving calmodulin and the SK4 channel. This new combined strategy may be useful to reduce assay costs (animals, materials, time, and human resources) in the drug discovery process of calmodulin inhibitors.

Genetically identified mediators associated with increased risk of stroke and cardiovascular disease in individuals with autism spectrum disorder

Growing evidence suggested that individuals with autism spectrum disorder (ASD) associated with stroke and cardiovascular disease (CVD). However, the causal association between ASD and the risk of stroke and CVD remains unclear. To validate this, we performed two-sample Mendelian randomization (MR) and two-step mediation MR analyses, using relevant genetic variants sourced from the largest genome-wide association studies (GWASs). Two-sample MR evidence indicated causal relationships between ASD and any stroke (OR = 1.1184, 95% CI: 1.0302–1.2142, P < 0.01), ischemic stroke (IS) (OR = 1.1157, 95% CI: 1.0237–1.2160, P = 0.01), large-artery atherosclerotic stroke (LAS) (OR = 1.2902, 95% CI: 1.0395–1.6013, P = 0.02), atrial fibrillation (AF) (OR = 1.0820, 95% CI: 1.0019–1.1684, P = 0.04), and heart failure (HF) (OR = 1.1018, 95% CI: 1.0007–1.2132, P = 0.05). Additionally, two-step mediation MR suggested that type 2 diabetes mellitus (T2DM) partially mediated this effect (OR = 1.14, 95%CI: 1.02–1.28, P = 0.03). The mediated proportion were 10.96% (95% CI: 0.58%–12.10%) for any stroke, 11.77% (95% CI: 10.58%–12.97%) for IS, 10.62% (95% CI: 8.04%–13.20%) for LAS, and 7.57% (95% CI: 6.79%–8.36%) for HF. However, no mediated effect was observed between ASD and AF risk. These findings have implications for the development of prevention strategies and interventions for stroke and CVD in patients with ASD.