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Regulated cell death (RCD) is a complex process that involves several cell types and plays a crucial role in vascular diseases. Vascular smooth muscle cells (VSMCs) are the predominant elements of the medial layer of blood vessels, and their regulated death contributes to the pathogenesis of vascular diseases. The types of regulated VSMC death include apoptosis, necroptosis, pyroptosis, ferroptosis, parthanatos, and autophagy‐dependent cell death (ADCD). In this review, we summarize the current evidence of regulated VSMC death pathways in major vascular diseases, such as atherosclerosis, vascular calcification, aortic aneurysm and dissection, hypertension, pulmonary arterial hypertension, neointimal hyperplasia, and inherited vascular diseases. All forms of RCD constitute a single, coordinated cell death system in which one pathway can compensate for another during disease progression. Pharmacologically targeting RCD pathways has potential for slowing and reversing disease progression, but challenges remain. A better understanding of the role of regulated VSMC death in vascular diseases and the underlying mechanisms may lead to novel pharmacological developments and help clinicians address the residual cardiovascular risk in patients with cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) are advancing cardiovascular development and disease modeling, drug testing, and regenerative therapies. However, hPSC-CM production is hindered by significant variability in the differentiation process. Establishment of early quality markers to monitor lineage progression and predict terminal differentiation outcomes would address this robustness and reproducibility roadblock in hPSC-CM production. An integrated transcriptomic and epigenomic analysis assesses how attributes of the cardiac progenitor cell (CPC) affect CM differentiation outcome. Resulting analysis identifies predictive markers of CPCs that give rise to high purity CM batches, including TTN , TRIM55 , DGKI, MEF2C, MAB21L2, MYL7 , LDB3 , SLC7A11, and CALD1. Predictive models developed from these genes provide high accuracy in determining terminal CM purities at the CPC stage. Further, insights into mechanisms of batch failure and dominant non-CM cell types generated in failed batches are elucidated. Namely EMT, MAPK, and WNT signaling emerge as significant drivers of batch divergence, giving rise to off-target populations of fibroblasts/mural cells, skeletal myocytes, epicardial cells, and a non-CPC SLC7A11+ subpopulation. This study demonstrates how integrated multi-omic analysis of progenitor cells can identify quality attributes of that progenitor and predict differentiation outcomes, thereby improving differentiation protocols and increasing process robustness. [Display omitted] • Genes that predict cardiac progenitor cell differentiation to cardiomyocytes. • Early epigenetic fate priming to cardiomyocyte fate in cardiac progenitor cells. • Progenitor-stage, gene-based predictive models for cardiomyocyte purity outcomes. [ABSTRACT FROM AUTHOR]

Human papillomavirus (HPV) is the most common sexually transmitted infection in the United States and worldwide, with more than 42 million Americans infected with types of HPV that are known to cause disease. Although the link between HPV and the development of a variety of cancers has been strongly established, recent literature has demonstrated a potential association between HPV and increased risk of cardiovascular disease. Nevertheless, despite plausible mechanisms for the development of cardiovascular disease with HPV infection, a causative relationship has yet to be firmly established, in part due to potential confounding risk factors between the two. In this 2-part series, we discuss the emerging relationship between HPV and cardiovascular disease. In part 1, we focus on the pathophysiology of HPV infection and potential mechanisms for the development of cardiovascular disease. [ABSTRACT FROM AUTHOR]

Introduction and objectives: Sri Lankans do not have a specific cardiovascular (CV) risk prediction model and therefore, World Health Organization(WHO) risk charts developed for the Southeast Asia Region are being used. We aimed to develop a CV risk prediction model specific for Sri Lankans using machine learning (ML) of data of a population-based, randomly selected cohort of Sri Lankans followed up for 10 years and to validate it in an external cohort. Material and methods: The cohort consisted of 2596 individuals between 40–65 years of age in 2007, who were followed up for 10 years. Of them, 179 developed hard CV diseases (CVD) by 2017. We developed three CV risk prediction models named model 1, 2 and 3 using ML. We compared predictive performances between models and the WHO risk charts using receiver operating characteristic curves (ROC). The most predictive and practical model for use in primary care, model 3 was named "SLCVD score" which used age, sex, smoking status, systolic blood pressure, history of diabetes, and total cholesterol level in the calculation. We developed an online platform to calculate the SLCVD score. Predictions of SLCVD score were validated in an external hospital-based cohort. Results: Model 1, 2, SLCVD score and the WHO risk charts predicted 173, 162, 169 and 10 of 179 observed events and the area under the ROC (AUC) were 0.98, 0.98, 0.98 and 0.52 respectively. During external validation, the SLCVD score and WHO risk charts predicted 56 and 18 respectively of 119 total events and AUCs were 0.64 and 0.54 respectively. Conclusions: SLCVD score is the first and only CV risk prediction model specific for Sri Lankans. It predicts the 10-year risk of developing a hard CVD in Sri Lankans. SLCVD score was more effective in predicting Sri Lankans at high CV risk than WHO risk charts. [ABSTRACT FROM AUTHOR]

PKD2 was first identified as the pathogenic protein for autosomal dominant polycystic kidney disease (ADPKD) and is widely recognized as an ion channel. Subsequent studies have shown that PKD2 is widely expressed in various animal tissues and plays a crucial role in tissue and organ development. Additionally, PKD2 is conserved from single-celled organisms to vertebrates. Here, we provide an overview of recent advances in the function of PKD2 in key model animals, focusing on the establishment of left–right organ asymmetry, renal homeostasis, cardiovascular development, and signal transduction in reproduction and mating. We specifically focus on the roles of PKD2 in development and highlight future prospects for PKD2 research. [ABSTRACT FROM AUTHOR]

Four new isoquinoline alkaloids, hypecotumines A-D (1–4), were isolated and identified from the whole herbs of Hypecoum erectum L. Their structures were determined by a combination of HRESIMS, NMR, and X-ray diffraction analysis methods. Compounds 1–4 were characterized by a terminal double bond at C-9 and their plausible biosynthetic pathway was hypothesized. Since PCSK9 plays a key role in the development of cardiovascular disease (CVD), exploration of PCSK inhibitors from natural products are beneficial for drug discovery of CVD treatment. SPR and Western blot assays showed compound 4 had PCSK9 inhibition activity with KD value of 59.9 µM and thus elevated the LDLR level. Further molecular docking studies demonstrated that 4 and PCSK9 could form stable interactions via key hydrogen bonds. [ABSTRACT FROM AUTHOR]

Lipoprotein (a), also known as Lp(a), is a type of lipoprotein that is structurally similar to low-density lipoprotein (LDL). It consists of an LDL-like particle with a specific protein called apolipoprotein (a) attached to it. Elevated levels of Lp(a) in the blood are significantly involved in the development of cardiovascular diseases, particularly atherosclerosis and aortic stenosis, by contributing to inflammation, oxidative stress, and calcification. Numerous epidemiological studies confirm the strong association between high Lp(a) levels and an increased risk of cardiovascular events such as myocardial infarction and stroke, highlighting the importance of including Lp(a) screening in comprehensive cardiovascular health evaluations. The positive correlation between high Lp(a) levels and increased cardiovascular risk underscores the need for developing appropriate and effective treatments to lower Lp(a) levels in patients. [ABSTRACT FROM AUTHOR]

Background: The ductus arteriosus (DA) is critical in maintaining postnatal circulation in neonates with obstructed systemic circulation (OSC) and pulmonary circulation (OPC). We hypothesized that the size of the DA and aortic isthmus (AoI) undergoes adaptive growth in utero to counteract the hemodynamic challenges in these congenital heart diseases (CHD). Methods: Postnatal echocardiograms of neonates diagnosed prenatally with ductal-dependent CHD who were started on prostaglandins within 24 h of birth were reviewed. We assessed the cross-sectional area of the aortic valve opening, pulmonary valve opening, AoI, and DA by calculating (diameter)2/body surface area. Neonates were classified into OSC or OPC then subgrouped depending upon the patency of semilunar valves: OSC with and without aortic atresia (OSC-AA and OSC-nAA, respectively) and OPC with and without pulmonary atresia (OPC-PA and OPC-nPA, respectively). Results: Ninety-four cases were studied. The DA in OSC was significantly larger than OPC, and the DA in OSC-AA was significantly larger than OSC-nAA. The size of the AoI was significantly larger in OPC than OSC and larger in OSC-AA than OSC-nAA. Within the OSC-nAA group, there was no significant difference in the size of the DA, AoI, or pulmonary valve opening between those with retrograde flow (RF) at the AoI and without (nRF) except the aortic valve opening was significantly larger in nRF. All groups had comparable cross-sectional areas of systemic output. Conclusions: Our findings suggest that DA and AoI show compensatory growth to maintain critical blood flow to vital organs against primary anatomical abnormalities in ductus-dependent CHD. (249 words) [ABSTRACT FROM AUTHOR]

Reduction of homocysteine-induced oxidative stress using two plant-derived compounds, amentoflavone (AMNT) and thymoquinone (TQ), is of therapeutic importance. Oxidative stress caused by homocysteine manifests as the development of cardiovascular and neurodegenerative diseases. An overview of the antioxidative properties of AMNT and TQ is provided, as well as the molecular mechanisms and therapeutic potential. Amentoflavone, a biflavonoid, and thymoquinone, a phytochemical from Nigella sativa, have shown notable antioxidant, anti-inflammatory and cytoprotective properties. The chemical structures and properties of these compounds, their natural sources and their traditional uses are also discussed. We examined the biochemical pathways involved in homocysteine metabolism and the induction of oxidative stress. Further, we explored the molecular pathways influenced by AMNT and TQ, highlighting their effects on cellular redox balance and their potential combined effects. Key findings include AMNT-mediated neutralization of free radicals and influence on mitochondrial function, TQ-mediated enhancement of antioxidant enzyme activities, and decreased lipid peroxidation. Bioavailability and pharmacokinetic limitations have been discussed, regardless of their therapeutic potential. Further research is necessary to optimize the efficacy of these compounds through the implementation of clinical trials and the development of novel delivery systems. Exploring the combined effects of other antioxidants is a future research direction for investigating their long-term safety and efficacy. This review aims to provide novel insights into the therapeutic potential of AMNT and TQ, emphasizing their roles in homocysteine-induced oxidative stress, and proposing avenues for future research. [ABSTRACT FROM AUTHOR]

The dorsal aorta (DA) is the first major blood vessel to develop in the embryonic cardiovascular system. Its formation is governed by a coordinated process involving the migration, specification, and arrangement of angioblasts into arterial and venous lineages, a process conserved across species. Although vascular endothelial growth factor a (VEGF-A) is known to drive DA specification and formation, the kinases involved in this process remain ambiguous. Thus, we investigated the role of protein kinase B (Akt) in zebrafish by generating a quadruple mutant (aktΔ/Δ), in which expression and activity of all Akt genes – akt1, -2, -3a and -3b – are strongly decreased. Live imaging of developing aktΔ/Δ DA uncovers early arteriovenous malformations. Single-cell RNA-sequencing analysis of aktΔ/Δ endothelial cells corroborates the impairment of arterial, yet not venous, cell specification. Notably, endothelial specific expression of ligand-independent activation of Notch or constitutively active Akt1 were sufficient to re-establish normal arterial specification in aktΔ/Δ. The Akt loss-of-function mutant unveils that Akt kinase can act upstream of Notch in arterial endothelial cells, and is involved in proper embryonic artery specification. This sheds light on cardiovascular development, revealing a mechanism behind congenital malformations. [ABSTRACT FROM AUTHOR]

Nicotinamide adenine dinucleotide (NAD+) is an essential metabolite that plays a crucial role in diverse biological processes, including energy metabolism, gene expression, DNA repair, and mitochondrial function. An aberrant NAD+ level mediates the development of cardiovascular dysfunction and diseases. Both in vivo and in vitro studies have demonstrated that nicotinamide mononucleotide (NMN), as a NAD+ precursor, alleviates the development of cardiovascular diseases such as heart failure, atherosclerosis, and myocardial ischemia/reperfusion injury. Importantly, NMN has suggested pharmacological activities mostly through its involvement in NAD+ biosynthesis. Several clinical studies have been conducted to investigate the efficacy and safety of NMN supplementation, indicating its potential role in cardiovascular protection without significant adverse effects. In this review, we systematically summarize the impact of NMN as a nutraceutical and potential therapeutic drug on cardiovascular diseases and emphasize the correlation between NMN supplementation and cardiovascular protection. [ABSTRACT FROM AUTHOR]

NAD+-dependent deacetylase sirtuin-1 (Sirt1) belongs to the sirtuins family, known to be longevity regulators, and exerts a key role in the prevention of vascular aging. By aging, the expression levels of Sirt1 decline with a severe impact on vascular function, such as the rise of endothelial dysfunction, which in turn promotes the development of cardiovascular diseases. In this context, the impact of Sirt1 activity in preventing endothelial senescence is particularly important. Given the key role of Sirt1 in counteracting endothelial senescence, great efforts have been made to deepen the knowledge about the intricate cross-talks and interactions of Sirt1 with other molecules, in order to set up possible strategies to boost Sirt1 activity to prevent or treat vascular aging. The aim of this review is to provide a proper background on the regulation and function of Sirt1 in the vascular endothelium and to discuss the recent advances regarding the therapeutic strategies of targeting Sirt1 to counteract vascular aging. [ABSTRACT FROM AUTHOR]

Mechanical force is the basis of cardiovascular development, homeostasis, and diseases. The perception and response of mechanical force by the cardiovascular system are crucial. However, the molecular mechanisms mediating mechanotransduction in the cardiovascular system are not yet understood. PIEZO1, a novel transmembrane mechanosensitive cation channel known for its regulation of touch sensation, has been found to be widely expressed in the mammalian cardiovascular system. In this review, we elucidate the role and mechanism of PIEZO1 as a mechanical sensor in cardiovascular development, homeostasis, and disease processes, including embryo survival, angiogenesis, cardiac development repair, vascular inflammation, lymphangiogenesis, blood pressure regulation, cardiac hypertrophy, cardiac fibrosis, ventricular remodeling, and heart failure. We further summarize chemical molecules targeting PIEZO1 for potential translational applications. Finally, we address the controversies surrounding emergent concepts and challenges in future applications. [ABSTRACT FROM AUTHOR]

Delta-9-tetrahydrocannabinol (THC), the psychoactive component of cannabis, remains a schedule I substance, thus safety data regarding the effects on the cardiovascular and prenatal health are limited. Importantly, there is evidence showing prenatal cannabis exposure can negatively impact fetal organ development, including the cardiovascular system. THC can cross the placenta and bind to cannabinoid receptors expressed in the developing fetus, including on endothelial cells. To understand the impact of prenatal THC exposure on the fetal cardiovascular system, we used our rhesus macaque model of prenatal daily edible THC consumption. Before conception, animals were acclimated to THC (2.5 mg/7 kg/day, equivalent to a heavy medical cannabis dose) and maintained on this dose daily throughout pregnancy. Fetal tissue samples were collected at gestational day 155 (full term is 168 days). Our model showed that in utero THC exposure was associated with a decreased heart weight-to-body weight ratio in offspring, warranting further mechanistic investigation. Histological examination of the fetal cardiac and vascular tissues did not reveal any significant effect of THC exposure on the maturity of collagen within the fetal heart or the aorta. Total collagen III expression and elastin production and organization were unchanged. However, bulk RNA-sequencing of vascular cells in the umbilical vein, umbilical artery, and fetal aorta demonstrated that THC alters the fetal vascular transcriptome and is associated with upregulated expression of genes involved in carbohydrate metabolism and inflammation. The long-term consequences of these findings are unknown but suggest that prenatal THC exposure may affect cardiovascular development in offspring. NEW & NOTEWORTHY: Prenatal cannabis use is increasing and despite the public health relevance, there is limited safety data regarding its impact on offspring cardiovascular health outcomes. We used a translational, nonhuman primate model of daily edible Δ-9-tetrahydrocannabinol (THC) consumption during pregnancy to assess its effects on the fetal cardiovascular system. THC-exposed fetal vascular tissues displayed upregulation of genes involved in cellular metabolism and inflammation, suggesting that prenatal THC exposure may impact fetal vascular tissues. [ABSTRACT FROM AUTHOR]

Human papillomavirus (HPV) is the most common sexually transmitted infection in the US and worldwide, with more than 42 million Americans infected with types of HPV that are known to cause disease. While the link between HPV and the development of a variety of cancers has been strongly established, recent literature has demonstrated a potential association between HPV and increased risk of cardiovascular disease. Nevertheless, despite plausible mechanisms for the development of cardiovascular disease with HPV infection, a causative relationship has yet to be firmly established, in part due to potential confounding risk factors between the two. In this 2-part series, we discuss the emerging relationship between HPV and cardiovascular disease. In part 2, we focus on novel risk factors for HPV infection and cardiovascular disease including adverse childhood events, socioeconomic status, and immunosuppression. We conclude with potential prevention and treatment strategies for HPV-related cardiovascular disease, as well as the future direction of the research. [ABSTRACT FROM AUTHOR]

Background: The congenital ventricular outflow tract malformations (CVOTMs) is a major congenital heart diseases (CHDs) subtype, and its pathogenesis is complex and unclear. Lipid metabolic plays a crucial role in embryonic cardiovascular development. However, due to the limited types of detectable metabolites in previous studies, findings on lipid metabolic and CHDs are still inconsistent, and the possible mechanism of CHDs remains unclear. Methods: The nest case-control study obtained subjects from the multicenter China Teratology Birth Cohort (CTBC), and maternal serum from the pregnant women enrolled during the first trimester was utilized. The subjects were divided into a discovery set and a validation set. The metabolomics of CVOTMs and normal fetuses were analyzed by targeted lipid metabolomics. Differential comparison, random forest and lasso regression were used to screen metabolic biomarkers. Results: The lipid metabolites were distributed differentially between the cases and controls. Setting the selection criteria of P value < 0.05, and fold change (FC) > 1.2 or < 0.833, we screened 70 differential metabolites. Within the prediction model by random forest and lasso regression, DG (14:0_18:0), DG (20:0_18:0), Cer (d18:2/20:0), Cer (d18:1/20:0) and LPC (0:0/18:1) showed good prediction effects in discovery and validation sets. Differential metabolites were mainly concentrated in glycerolipid and glycerophospholipids metabolism, insulin resistance and lipid & atherosclerosis pathways, which may be related to the occurrence and development of CVOTMs. Conclusion: Findings in this study provide a new metabolite data source for the research on CHDs. The differential metabolites and involved metabolic pathways may suggest new ideas for further mechanistic exploration of CHDs, and the selected biomarkers may provide some new clues for detection of COVTMs. [ABSTRACT FROM AUTHOR]

Psoriatic disease, encompassing both psoriasis (Pso) and psoriatic arthritis (PsA), is closely intertwined with a significantly elevated risk of developing cardiovascular diseases. This connection is further compounded by a higher prevalence of cardiometabolic comorbidities, including type 2 diabetes, obesity, insulin resistance, arterial hypertension, and dysregulated lipid profiles. These comorbidities exceed the rates seen in the general population and compound the potential for increased mortality among those living with this condition. Recognizing the heightened cardiometabolic risk inherent in psoriatic disease necessitates a fundamental shift in the treatment paradigm. It is no longer sufficient to focus solely on mitigating inflammation. Instead, there is an urgent need to address and effectively manage the metabolic parameters that have a substantial impact on cardiovascular health. Within this context, apremilast emerges as a pivotal treatment option for psoriatic disease. What sets apremilast apart is its dual-action potential, addressing not only inflammation but also the critical metabolic parameters. This comprehensive treatment approach opens up new opportunities to improve the well-being of people living with psoriatic disease. This review delves into the multifaceted aspects involved in the development of cardiovascular disease and its intricate association with psoriatic disease. We then provide an in-depth exploration of the pleiotropic effects of apremilast, highlighting its potential to simultaneously mitigate metabolic complications and inflammation in individuals affected by these conditions. [ABSTRACT FROM AUTHOR]

INTRODUCTION: We investigated the impact of metabolic dysfunction-associated steatotic liver disease (MASLD) on cardiovascular structure development in children. METHODS: We followed 1,356 children with the mean age of 6.6 years for 4.5 years in Beijing, China. We assessed the association of MASLD with cardiovascular structure (carotid intima-media thickness and left ventricular mass) outcomes at baseline and follow-up. RESULTS: Over follow-up, 59 children had persistent MASLD, 109 had incident MASLD (progression), and 35 had normalization of liver health. Children with MASLD normalization showed a significantly lower mean development in carotid intima-media thickness (0.161 vs 0.188 mm) and left ventricular mass (4.5 vs 12.4 g) than children with persistent MASLD. DISCUSSION: The control of MASLD was associated with improved cardiovascular structure development. [ABSTRACT FROM AUTHOR]

Serum amyloid P component (SAP) is a member the innate immune humoral arm and participated in various processes, including the innate immune responses, tissue remodeling, and the pathogenesis of inflammatory diseases. Remarkably, SAP is a highly versatile immunomodulatory factor that can serve as a drug target for treating amyloid diseases and reduce inflammation, fibrosis degree, and respiratory disease. In this review, we focus on the biological activities of SAP and its application in different systemic immune-associated diseases. First, we reviewed the regulatory effects of SAP on innate immune cells and possible mechanisms. Second, we emphasized SAP as a diagnostic marker and therapeutic target for immune-associated diseases, including the neuropsychiatric disorders. Third, we presented several recommendations for regulating SAP in immune cell function and potential areas for future research. Some authorities consider SAP to be a pattern recognition molecule that plays multiple roles in the innate immune system and inflammation. Developing therapeutics that target SAP or its associated signaling pathways may be a promising strategy for treating immune-associated diseases. • This review highlights the effects of SAP as a multifunctional immunomodulator on inflammation, pathogenic infections, and tissue remodeling. • This review summarizes the use of SAP as a diagnostic marker and therapeutic target in immune-related diseases such as amyloidosis, fibrosis, cardiovascular, respiratory, and neuropsychiatric disorders. • This review presents the potential of SAP in the study of the mechanism of action in the central nervous system and hopes to carry out targeted interventions based on SAP. [ABSTRACT FROM AUTHOR]

Background and Objectives: Atherosclerosis is one of the main reasons for cardiovascular disease development. This study aimed to analyze the association of mtDNA mutations and atherosclerotic plaques in carotid arteries of patients with atherosclerosis and conditionally healthy study participants from the Novosibirsk region. Methods: PCR fragments of DNA containing the regions of 10 investigated mtDNA mutations were pyrosequenced. The heteroplasmy levels of mtDNA mutations were analyzed using a quantitative method based on pyrosequencing technology developed by M. A. Sazonova and colleagues. Results: In the analysis of samples of patients with atherosclerotic plaques of the carotid arteries and conditionally healthy study participants from the Novosibirsk region, four proatherogenic mutations in the mitochondrial genome (m.5178C>A, m.652delG, m.12315G>A and m.3256C>T) and three antiatherogenic mutations in mtDNA (m.13513G>A, m.652insG, and m.14846G>A) were detected. A west–east gradient was found in the distribution of the mtDNA mutations m.5178C>A, m.3256C>T, m.652insG, and m.13513G>A. Conclusions: Therefore, four proatherogenic mutations in the mitochondrial genome (m.5178C>A, m.652delG, m.12315G>A, and m.3256C>T) and three antiatherogenic mutations in mtDNA (m.13513G>A, m.652insG, and m.14846G>A) were detected in patients with atherosclerotic plaques in their carotid arteries from the Novosibirsk region. [ABSTRACT FROM AUTHOR]

Stress exposure has been shown to modulate innate and adaptive immune responses. Indeed, stress favors myelopoiesis and monocyte generation and contributes to cardiovascular disease development. As sex hormones regulate innate and adaptive immune responses, we decided to investigate whether stress exposure leads to a different immune response in female and male mice. Our data demonstrated that psychosocial stressinduced neutrophilia in male, but not female mice. Importantly, we identified that B‐cell numbers were reduced in female, but not male mice upon exposure to stress. Thus, our study revealed that the stress‐induced immune alterations are sex‐dependent, and this is an important feature to consider for future investigations. [ABSTRACT FROM AUTHOR]

Due to the cancer therapy-related cardiovascular toxicity, heart failure following cancer therapy has a significant mortality rate. Gene-targeted therapy promotes the re-entry of existing cardiomyocytes into the cell cycle to achieve myocardial regeneration, which is a promising strategy for preventing and treating heart failure after myocardial infarction. Circular RNAs (circRNAs) are considered as potential targets for myocardial regeneration due to their strong stability, resistance to degradation, and potential role in heart development and cardiovascular diseases. By comparing the myocardial tissue of mice in the sham operation group and the Doxorubicin therapy group (DOX), we observed a significant decrease in Cirsorbs expression in the DOX group. Cirsorbs was predominantly localized in cardiomyocytes and exhibited high conservation. Subsequent investigations revealed that Cirsorbs could promote myocardial proliferation and inhibit myocardial apoptosis. Mechanistic studies further demonstrated that Cirsorbs could bind to miR99 and reduce its expression level. Meanwhile, miR99 was found to bind to GATA4 mRNA and decrease its expression level. The binding of Cirsorbs to miR99 alleviated the repression of miR99, thereby enhancing GATA4 expression and the transcription of downstream cyclin A2 and cyclin E1. This, in turn, increased cardiomyocyte proliferation and reduced apoptosis. In conclusion, Cirsorbs holds promise as an effective target for myocardial regeneration in reducing cancer therapy-related cardiovascular toxicity. [ABSTRACT FROM AUTHOR]

The arginyl-transferase ATE1 is a tRNA-dependent enzyme that covalently attaches an arginine molecule to a protein substrate. Conserved from yeast to humans, ATE1 deficiency in mice correlates with defects in cardiovascular development and angiogenesis and results in embryonic lethality, while conditional knockouts exhibit reproductive, developmental, and neurological deficiencies. Despite the recent revelation of the tRNA binding mechanism and the catalytic cycle of yeast ATE1, the structure-function relationship of ATE1 in higher organisms is not well understood. In this study, we present the three-dimensional structure of human ATE1 in an apo-state and in complex with its tRNA cofactor and a peptide substrate. In contrast to its yeast counterpart, human ATE1 forms a symmetric homodimer, which dissociates upon binding of a substrate. Furthermore, human ATE1 includes a unique and extended loop that wraps around tRNAArg, creating extensive contacts with the T-arm of the tRNA cofactor. Substituting key residues identified in the substrate binding site of ATE1 abolishes enzymatic activity and results in the accumulation of ATE1 substrates in cells. ATE1 is an essential gene in mammals and is recognized as a master regulator of cells. Here, the authors describe structural insights into human ATE1, revealing mechanisms that regulate arginylation activity in cells. [ABSTRACT FROM AUTHOR]

Polycyclic aromatic hydrocarbons (PAHs), pervasive organic compounds stemming from combustion processes and industrial activities, have raised significant concerns due to their ubiquitous presence in the environment and potential impact on human health. This review provides a comprehensive overview of the physiological effects of PAHs on diverse human body systems. Extensively studied for their respiratory toxicity, inhalation exposure to PAHs is associated with asthma, bronchitis, and impaired lung function. Moreover, certain PAHs are identified as carcinogens, heightening the risk of lung cancer. The cardiovascular system is also vulnerable to PAH exposure, as evidence suggests their contribution to oxidative stress, inflammation, and endothelial dysfunction, pivotal in cardiovascular disease development. PAHs exhibit endocrine-disrupting properties, influencing hormone levels and disrupting reproductive health, correlating with fertility issues, adverse birth outcomes, and developmental abnormalities. Understanding PAH-induced toxicity mechanisms is crucial for developing mitigation strategies. PAHs can directly interact with cellular components, modulate gene expression, induce oxidative stress, and cause DNA damage, leading to cellular dysfunction and apoptosis. This review underscores the ongoing need for research to fully elucidate the physiological effects of PAH exposure on human health. By synthesizing current knowledge, it aims to raise awareness of potential health risks associated with PAHs and stress the importance of preventive measures to reduce exposure. Ultimately, a comprehensive understanding of PAH-induced physiological impacts will inform the development of effective interventions and policies to safeguard human health in environments where PAH contamination is prevalent. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases (CVD) remain the leading cause of death worldwide and represent a major public health challenge. YiyiFuzi Powder (YYFZ), composed of Coicis semen and Fuzi, is a classical traditional Chinese medicine prescription from the Synopsis of Golden Chamber dating back to the Han Dynasty. Historically, YYFZ has been used to treat various CVD, rooted in Chinese therapeutic principles. Network pharmacology analysis indicated that YYFZ may exhibit direct or indirect effects on mitochondria-endoplasmic reticulum (ER) interactions. This review, focusing on the cardiovascular protective effects of Coicis semen and Fuzi, summarizes the potential mechanisms by which YYFZ acts on mitochondria and the ER. The underlying mechanisms are associated with regulating cardiovascular risk factors (such as blood lipids and glucose), impacting mitochondrial structure and function, modulating ER stress, inhibiting oxidative stress, suppressing inflammatory responses, regulating cellular apoptosis, and maintaining calcium ion balance. The involved pathways include, but were not limited to, upregulating the IGF-1/PI3K/AKT, cAMP/PKA, eNOS/NO/cGMP/SIRT1, SIRT1/PGC-1α, Klotho/SIRT1, OXPHOS/ATP, PPARα/PGC-1α/SIRT3, AMPK/JNK, PTEN/PI3K/AKT, β2-AR/PI3K/AKT, and modified Q cycle signaling pathways. Meanwhile, the MCU, NF-κB, and JAK/STAT signaling pathways were downregulated. The PERK/eIF2α/ATF4/CHOP, PERK/SREBP-1c/FAS, IRE1, PINK1-dependent mitophagy, and AMPK/mTOR signaling pathways were bidirectionally regulated. High-quality experimental studies are needed to further elucidate the underlying mechanisms of YYFZ in CVD treatment. [ABSTRACT FROM AUTHOR]

Background: According to the World Health Organisation's Health Report 2019, approximately 17.18 million people die from cardiovascular disease each year, accounting for more than 30% of all global deaths. Therefore, the occurrence of cardiovascular disease is still a global concern. The transcription factor 21 (TCF21) plays an important role in cardiovascular diseases. This article reviews the regulation mechanism of TCF21 expression and activity and focuses on its important role in atherosclerosis in order to contribute to the development of diagnosis and treatment of cardiovascular diseases. Summary: TCF21 is involved in the phenotypic regulation of vascular smooth muscle cells (VSMCs), promotes the proliferation and migration of VSMCs, and participates in the activation of inflammatory sequences. Increased proliferation and migration of VSMCs can lead to neointimal hyperplasia after vascular injury. Abnormal hyperplasia of neointima and inflammation are one of the main features of atherosclerosis. Therefore, targeting TCF21 may become a potential treatment for relieving atherosclerosis. Key Messages: TCF21 as a member of basic helix-loop-helix transcription factors regulates cell growth and differentiation by modulating gene expression during the development of different organs and plays an important role in cardiovascular development and disease. VSMCs and cells derived from VSMCs constitute the majority of plaques in atherosclerosis. TCF21 plays a key role in regulation of VSMCs' phenotype, thus accelerating atherogenesis in the early stage. However, TCF21 enhances plaque stability in late-stage atherosclerosis. The dual role of TCF21 should be considered in the translational medicine. [ABSTRACT FROM AUTHOR]

Adipose tissue is classically considered the primary site of lipid storage, but in recent years has garnered appreciation for its broad role as an endocrine organ, capable of remotely signaling to other tissues to alter their metabolic program. The adipose tissue is now recognized as a crucial regulator of cardiovascular health, mediated by the secretion of several bioactive products, with a wide range of endocrine and paracrine effects on the cardiovascular system. Thanks to the development and improvement of high‐throughput mass spectrometry, the size and components of the human secretome have been characterized. In this review, we summarized the recent advances in mass spectrometry‐based studies of the cell and tissue secretome for the understanding of adipose tissue biology, which may help to decipher the complex molecular mechanisms controlling the crosstalk between the adipose tissue and the cardiovascular system, and their possible clinical translation. [ABSTRACT FROM AUTHOR]

BACKGROUND Atherosclerosis (AS) stands as the primary contributor to cardiovascular disease, a pervasive global health concern. Extensive research has underscored the pivotal role of circular RNAs (circRNAs) in cardiovascular disease development. However, the specific functions of numerous circRNAs in AS remain poorly understood. METHODS Quantitative real-time PCR analysis revealed a significant upregulation of circ_0104652 in oxidized low-density lipoprotein (ox-LDL)-induced vascular smooth muscle cells (VSMCs). Loss-of-function experiments were subsequently employed to assess the impact of circ_0104652 on ox-LDL-induced VSMCs. RESULTS Silencing circ_0104652 was found to impede the proliferation and migration while promoting the apoptosis of ox-LDL-stimulated VSMCs. Mechanistic assays unveiled that circ_0104652 stabilized ADAM metallopeptidase with thrombospondin type 1 motif 7 (ADAMTS7) and high mobility group box 1 (HMGB1) by recruiting eukaryotic translation initiation factor 4A3 (EIF4A3) protein. Rescue assays further confirmed that circ_0104652 exerted its influence on ox-LDL-induced VSMC proliferation through modulation of ADAMTS7 and HMGB1. CONCLUSIONS This study elucidates the role of the circ_0104652/EIF4A3/ADAMTS7/HMGB1 axis in ox-LDL-stimulated VSMCs, providing valuable insights into the intricate mechanisms involved. [ABSTRACT FROM AUTHOR]

Placental insufficiency is one of the major causes of fetal growth restriction (FGR), a significant pregnancy disorder in which the fetus fails to achieve its full growth potential in utero. As well as the acute consequences of being born too small, affected offspring are at increased risk of cardiovascular disease, diabetes and other chronic diseases in later life. The placenta and heart develop concurrently, therefore placental maldevelopment and function in FGR may have profound effect on the growth and differentiation of many organ systems, including the heart. Hence, understanding the key molecular players that are synergistically linked in the development of the placenta and heart is critical. This review highlights the key growth factors, angiogenic molecules and transcription factors that are common causes of defective placental and cardiovascular development. [ABSTRACT FROM AUTHOR]

Elevated concentrations of palmitate in serum of obese individuals can impair endothelial function, contributing to development of cardiovascular disease. Although several molecular mechanisms of palmitate-induced endothelial dysfunction have been proposed, there is no consensus on what signaling event is the initial trigger of detrimental palmitate effects. Here we report that inhibitors of ER stress or ceramid synthesis can rescue palmitate-induced autophagy impairment in macro- and microvascular endothelial cells. Furthermore, palmitate-induced cholesterol synthesis was reverted using these inhibitors. Similar to cell culture data, autophagy markers were increased in serum of obese individuals. Subsequent lipidomic analysis revealed that palmitate changed the composition of membrane phospholipids in endothelial cells and that these effects were not reverted upon application of above-mentioned inhibitors. However, ER stress inhibition in palmitate-treated cells enhanced the synthesis of trilglycerides and restored ceramide levels to control condition. Our results suggest that palmitate induces ER-stress presumably by shift in membrane architecture, leading to impaired synthesis of triglycerides and enhanced production of ceramides and cholesterol, which altogether enhances lipotoxicity of palmitate in endothelial cells. [ABSTRACT FROM AUTHOR]

Visualization of protein dynamics is a crucial step in understanding cellular processes. Chromobodies, fluorescently labelled singledomain antibodies, have emerged as versatile probes for live cell imaging of endogenous proteins. However, how these chromobodies behave in vivo and how accurately they monitor tissue changes remain poorly explored. Here, we generated an endothelial-specific β-catenin chromobody-derived probe and analyzed its expression pattern during cardiovascular development in zebrafish. Using highresolution confocal imaging, we show that the chromobody signal correlates with the localization of β-catenin in the nucleus and at cell-cell junctions, and thereby can be used to assess endothelial maturation. Loss of Cadherin 5 strongly affects the localization of the chromobody at the cell membrane, confirming the cadherin-based adherens junction role of β-catenin. Furthermore, using a genetic model to block blood flow, we observed that cell junctions are compromised in most endothelial cells but not in the endocardium, highlighting the heterogeneous response of the endothelium to the lack of blood flow. Overall, our data further expand the use of chromobodies for in vivo applications and illustrate their potential to monitor tissue morphogenesis at high resolution. [ABSTRACT FROM AUTHOR]

Trimethylamine N‐oxide (TMAO) is a circulating microbiome‐derived metabolite implicated in the development of atherosclerosis and cardiovascular disease (CVD). We investigated whether plasma levels of TMAO, its precursors (betaine, carnitine, deoxycarnitine, choline), and TMAO‐to‐precursor ratios are associated with clinical outcomes, including CVD and mortality. This was followed by an in‐depth analysis of their genetic, gut microbial, and dietary determinants. The analyses were conducted in five Dutch prospective cohort studies including 7834 individuals. To further investigate association results, Mendelian Randomization (MR) was also explored. We found only plasma choline levels (hazard ratio [HR] 1.17, [95% CI 1.07; 1.28]) and not TMAO to be associated with CVD risk. Our association analyses uncovered 10 genome‐wide significant loci, including novel genomic regions for betaine (6p21.1, 6q25.3), choline (2q34, 5q31.1), and deoxycarnitine (10q21.2, 11p14.2) comprising several metabolic gene associations, for example, CPS1 or PEMT. Furthermore, our analyses uncovered 68 gut microbiota associations, mainly related to TMAO‐to‐precursors ratios and the Ruminococcaceae family, and 16 associations of food groups and metabolites including fish‐TMAO, meat‐carnitine, and plant‐based food‐betaine associations. No significant association was identified by the MR approach. Our analyses provide novel insights into the TMAO pathway, its determinants, and pathophysiological impact on the general population. Highlights: Exploration of microbiome‐related metabolites (trimethylamine N‐oxide [TMAO], choline, betaine, l‐carnitine, and deoxycarnitine) in 7834 participants from five population cohorts.Cardiovascular risk was associated with elevated choline concentrations, but not with TMAO concentrations.Characterization of the genetic architecture behind metabolite concentration variability.Identification of gut microbial taxonomic abundance associated with metabolite's plasma concentration levels.Fish intake is the major dietary driver of TMAO concentrations, and betaine is related to grains and vegetable intake. [ABSTRACT FROM AUTHOR]

Exposure to illumination from LED (light emitting diode) light may be an unsuspecting cause of human health problems, including cellular growth disruptions and cardiovascular issues. Vertebrate hearts comprise multiple chambers that create a rhythm resulting in continuous blood flow, which, if insufficient results in the heart retaining fluid. Here we report a preliminary study of the effect of exposing wild-type Danio rerio (zebrafish) embryos to 6500K, White, LED light on development of pericardial edema. Embryos were exposed to LED light from 12 hours post fertilization for 72 hours in one of the following conditions: (1) no exposure, (2) light/dark cycle of 12 hours/12 hours, and (3) 72 consecutive hours. Results indicated a significant relationship between exposure to LED lighting and pericardial edema; a significant relationship was seen between length of exposure and severity of pericardial edema. Pericardial edema became noticeable after 48 hours of light exposure. Further research should explore the effects of different wavelengths of LEDs on development of pericardial edema. Molecular studies might examine how LED exposure alters transcription factors involved in cardiac development. [ABSTRACT FROM AUTHOR]

Small nucleolar RNAs (snoRNAs) have extremely versatile functions. They regulate cardiac-relevant signaling pathways, oxidative and metabolic cellular stress, gene expression, and intercellular communication. Global downregulation of snoRNA expression was uncovered in patients with congenital heart disease and resembles the expression profiles of developing hearts. A broad snoRNA-tRNA-tRNA fragments (tRF) network regulates cellular transcriptome, translatome, and cardiovascular biology. Cardioprotective effects of cortical bone stem cell-derived exosomes on fibroblast activation are largely mediated by snoRNAs. An association between levels of circulating snoRNAs and myocardial infarction and heart failure has been found, indicating the potential of these snoRNAs as biomarkers. Small nucleolar RNAs (snoRNAs) are emerging as important regulators of cardiovascular (patho)biology. Several roles of snoRNAs have recently been identified in heart development and congenital heart diseases, as well as their dynamic regulation in hypertrophic and dilated cardiomyopathies, coronary heart disease (CHD), myocardial infarction (MI), cardiac fibrosis, and heart failure. Furthermore, reports of changes in vesicular snoRNA expression and altered levels of circulating snoRNAs in response to cardiac stress suggest that snoRNAs also function in cardiac signaling and intercellular communication. In this review, we summarize and discuss key findings and outline the clinical potential of snoRNAs considering current challenges and gaps in the field of cardiovascular diseases (CVDs). [ABSTRACT FROM AUTHOR]

Background: Patients with rheumatoid arthritis have significant cardiovascular mortality and morbidity. Objective: To investigate the effects of chronic inflammation in rheumatoid arthritis on cardiovascular morbidity association with cardiovascular risk factors risk factors. Mortality report is secondary just to show trends without sufficient statistical power as it is accidental endpoint. Methods: A total of 201 individuals without previous cardiovascular disease, 124 with rheumatoid arthritis (investigation group) and 77 with osteoarthritis (control group), were included in the study and followed up for an average of 8 years to assess the development of fatal or non-fatal cardiovascular diseases. The incidence and prevalence of cardiovascular risk factors were also investigated. Results: The total incidence of one or more fatal or nonfatal cardiovascular events was 43.9% in the investigation group and 37.5% in the control group. Of these patients, 31.7% and 30.9% survived cardiovascular events in the investigation and control groups, respectively. The most common cardiovascular disease among participants who completed the study and those who died during the study was chronic heart failure. The results of the subgroup analysis showed that strict inflammation control plays a central role in lowering cardiovascular risk. Conclusion: A multidisciplinary approach to these patients is of paramount importance, especially with the cooperation of immunologists and cardiologists for early detection, prevention, and management of cardiovascular risks and diseases. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases (CVDs) can be described as a global health emergency imploring possible prevention strategies. Although the pathogenesis of CVDs has been extensively studied, the role of mitochondrial dysfunction in CVD development has yet to be investigated. Diabetic cardiomyopathy, ischemic-reperfusion injury, and heart failure are some of the CVDs resulting from mitochondrial dysfunction Recent evidence from the research states that any dysfunction of mitochondria has an impact on metabolic alteration, eventually causes the death of a healthy cell and therefore, progressively directing to the predisposition of disease. Cardiovascular research investigating the targets that both protect and treat mitochondrial damage will help reduce the risk and increase the quality of life of patients suffering from various CVDs. One such target, i.e., nuclear sirtuin SIRT6 is strongly associated with cardiac function. However, the link between mitochondrial dysfunction and SIRT6 concerning cardiovascular pathologies remains poorly understood. Although the Role of SIRT6 in skeletal muscles and cardiomyocytes through mitochondrial regulation has been well understood, its specific role in mitochondrial maintenance in cardiomyocytes is poorly determined. The review aims to explore the domain-specific function of SIRT6 in cardiomyocytes and is an effort to know how SIRT6, mitochondria, and CVDs are related. [ABSTRACT FROM AUTHOR]

Plasminogen activator inhibitor-1 (PAI-1) has a significant role in fibrinolysis, atherogenesis, cellular senescence, and chronic inflammation. OSA (obstructive sleep apnea) leads to increased PAI-1 levels and the development of cardiovascular disease (CVD). The aim of this study was to determine the effects of CPAP therapy on coagulation parameters and PAI-1 in patients with severe OSA. This prospective, controlled study enrolled 57 patients who were newly diagnosed with severe OSA, 37 of whom had had good CPAP adherence after 6 months of therapy (usage of the device for at least 4 h per night), and their data were analyzed. The analysis showed a statistically significant increase in D-dimer values before CPAP therapy (415 (316.5–537.5)) vs. after therapy (499 (327–652)), p = 0.0282, and a decrease in fibrinogen values (3.665 ± 0.752 before CPAP therapy vs. 3.365 ± 0.771 after therapy, p = 0.0075)). PAI-1 concentration values before and after CPAP therapy did not differ significantly (17.35 ± 7.01 ng/mL before CPAP therapy vs. 17.42 ± 6.99 ng/mL after therapy, p = 0.9367). This study shows a tendency for fibrinolytic capacity to improve in patients with OSA after CPAP therapy, although PAI-1 levels did not differ significantly. [ABSTRACT FROM AUTHOR]

The development of the cardiovascular system is a highly intricate process that encompasses various types of cells and communication pathways. During embryonic development, specific cells differentiate and organize to form complex structures of the heart and blood vessels. An important group of cells involved in this process is called cardiac neural crest cells. These cells originate from the dorsal neural tube and migrate to the circumpharyngeal ridge, pharyngeal arches 3–6, and invade the developing heart through the cardiac outflow tract. Once they reach their destination, cardiac neural crest cells contribute to the formation of important structures in the cardiovascular system. These structures include the aortic arch arteries, the aorticopulmonary septum, cardiac valves, the heart conduction system, cardiomyocytes, and smooth muscle cells found in the middle layers of the aortic arch arteries. Disruptions in the migration, proliferation, or differentiation of cardiac neural crest cells during embryonic development, as seen in conditions such as DiGeorge syndrome, can lead to a variety of congenital heart defects. These defects encompass a wide range of abnormalities, including Tetralogy of Fallot, outflow tract abnormalities, persistent truncus arteriosus, double outlet right ventricle, interrupted aortic arch, ventricular septal defects, abnormalities of the aortic arch, as well as abnormalities in the function of semilunar valves, myocardium, and cardiac conduction system.

This article provides a comprehensive overview of the aging process and its impact on human health. It explores the physical effects of aging, such as the deterioration of hearing, vision, muscles, bones, and joints, as well as the increased susceptibility to diseases. The article also discusses the differences in aging among animal species and the potential for humans to achieve extreme longevity and regeneration. It highlights recent breakthroughs in aging research, including the understanding of cellular mechanisms and the potential for therapeutic strategies. The article also examines the commonalities between degenerative diseases and the role of physical exercise in preventing and treating age-related diseases. It further explores the mechanisms of aging, such as genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, and mitochondrial dysfunction. The article emphasizes the importance of endothelial function in cardiovascular health and the potential of lifestyle changes and exercise in promoting healthy vascular aging. It concludes by discussing recent advances in aging research, including genetic and molecular breakthroughs, and the potential for translating these findings into clinical applications to improve the quality of life for the aging population. [Extracted from the article]

As a traditional Chinesemedicinal herb with a long history, Codonopsis pilosula (CP) has attracted much attention from the medical community in recent years. This review summarizes the research progress of CP in the medical field in the past 5 years. By searching and analyzing the literature, and combining with Cytoscape software, we comprehensively examined the role and mechanism of action of CP in individual application, combination drug application, and the role andmechanism of action of codonopsis pilosula's active ingredients in a variety of diseases. It also analyzes the medicinal use of CP and its application value in medicine. This review found that CP mainly manifests important roles in several diseases, such as cardiovascular system, nervous system, digestive system, immune system, etc., and regulates the development of many diseases mainly through the mechanisms of inflammation regulation, oxidative stress, immunomodulation and apoptosis. Its rich pharmacological activities and diverse medicinal effects endow CP with broad prospects and application values. This review provides valuable reference and guidance for the further development of CP in traditional Chinese medicine. [ABSTRACT FROM AUTHOR]

In recent years, there has been a growing interest in the concept of the "gut–brain axis". In addition to well-studied diseases associated with an imbalance in gut microbiota, such as cancer, chronic inflammation, and cardiovascular diseases, research is now exploring the potential role of gut microbial dysbiosis in the onset and development of brain-related diseases. When the function of the intestinal barrier is altered by dysbiosis, the aberrant immune system response interacts with the nervous system, leading to a state of "neuroinflammation". The gut microbiota–brain axis is mediated by inflammatory and immunological mechanisms, neurotransmitters, and neuroendocrine pathways. This narrative review aims to illustrate the molecular basis of neuroinflammation and elaborate on the concept of the gut–brain axis by virtue of analyzing the various metabolites produced by the gut microbiome and how they might impact the nervous system. Additionally, the current review will highlight how sex influences these molecular mechanisms. In fact, sex hormones impact the brain–gut microbiota axis at different levels, such as the central nervous system, the enteric nervous one, and enteroendocrine cells. A deeper understanding of the gut–brain axis in human health and disease is crucial to guide diagnoses, treatments, and preventive interventions. [ABSTRACT FROM AUTHOR]

• HFPO-TA exposure causes linearized heart, affects gene expression related to heart looping. • HFPO-TA induces sprouting angiogenesis, and disturbs gene expression of VEGF signaling pathway in vascular development. • HFPO-TA reduces erythropoiesis, resulting in heme metabolism disruption. • HFPO-TA induces oxidative stress, inhibits cell proliferation, and causes apoptosis. As an increasingly used alternative to perfluorooctanoic acid (PFOA), hexafluoropropylene oxide trimer acid (HFPO-TA) has been widely detected in global water environments. However, little is known regarding its toxic effects on cardiovascular development. Here, zebrafish embryos were treated with egg water containing 0, 60, 120, or 240 mg/L HFPO-TA. Results showed that HFPO-TA treatment led to a significant reduction in both larval survival percentage and heart rate. Furthermore, HFPO-TA exposure caused severe pericardial edema and elongation of the sinus venous to bulbus arteriosus distance (SV-BA) in Tg (myl7: GFP) transgenic larvae, disrupting the expression of genes involved in heart development and thus causing abnormal heart looping. Obvious sprouting angiogenesis was observed in the 120 and 240 mg/L exposed Tg (fli: GFP) transgenic larvae. HFPO-TA treatment also impacted the mRNA levels of genes involved in the vascular endothelial growth factor (VEGF) pathway and embryonic vascular development. HFPO-TA exposure significantly decreased erythrocyte number in Tg (gata1: DsRed) transgenic embryos and influenced gene expression associated with the heme metabolism pathway. HFPO-TA also induced oxidative stress and altered the transcriptional levels of genes related to cell cycle and apoptosis, inhibiting cell proliferation while promoting apoptosis. Therefore, HFPO-TA exposure may induce abnormal development of the cardiovascular and hematopoietic systems in zebrafish embryos, suggesting it may not be a suitable or safe alternative for PFOA. [Display omitted] [ABSTRACT FROM AUTHOR]

Cardiovascular diseases pose a serious threat to human health. The onset of cardiovascular diseases involves the comprehensive effects of multiple genes and environmental factors, and multiple signaling pathways are involved in regulating the occurrence and development of cardiovascular diseases. The Hippo pathway is a highly conserved signaling pathway involved in the regulation of cell proliferation, apoptosis, and differentiation. Recently, it has been widely studied in the fields of cardiovascular disease, cancer, and cell regeneration. Non-coding RNA (ncRNAs), which are important small molecules for the regulation of gene expression in cells, can directly target genes and have diverse regulatory functions. Recent studies have found that ncRNAs interact with Hippo pathway components to regulate myocardial fibrosis, cardiomyocyte proliferation, apoptosis, and hypertrophy and play an important role in cardiovascular disease. In this review, we describe the mode of action of ncRNAs in regulating the Hippo pathway, provide new ideas for further research, and identify molecules involved in the mechanism of action of ncRNAs and the Hippo pathway as potential therapeutic targets, with the aim of finding new modes of action for the treatment and prevention of cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Arachidonic acid (AA) has three main metabolic pathways: the cycloxygenases (COXs) pathway, the lipoxygenases (LOXs) pathway, and the cytochrome P450s (CYPs) pathway. AA produces epoxyeicosatrienoic acids (EETs) through the CYPs pathway. EETs are very unstable in vivo and can be degraded in seconds to minutes. EETs have multiple degradation pathways, but are mainly degraded in the presence of soluble epoxide hydrolase (sEH). sEH is an enzyme of bifunctional nature, and current research focuses on the activity of its C-terminal epoxide hydrolase (sEH-H), which hydrolyzes the EETs to the corresponding inactive or low activity diol. Previous studies have reported that EETs have cardiovascular protective effects, and the activity of sEH-H plays a role by degrading EETs and inhibiting their protective effects. The activity of sEH-H plays a different role in different cells, such as inhibiting endothelial cell proliferation and migration, but promoting vascular smooth muscle cell proliferation and migration. Therefore, it is of interest whether the activity of sEH-H is involved in the initiation and progression of cardiovascular diseases by affecting the function of different cells through EETs. [ABSTRACT FROM AUTHOR]

Exosomes are membrane-bound micro-vesicles that possess endless therapeutic potential for treatment of numerous pathologies including autoimmune, cardiovascular, ocular, and nervous disorders. Despite considerable knowledge about exosome biogenesis and secretion, still, there is a lack of information regarding exosome uptake by cell types and internal signaling pathways through which these exosomes process cellular response. Exosomes are key components of cell signaling and intercellular communication. In central nervous system (CNS), exosomes can penetrate BBB and maintain homeostasis by myelin sheath regulation and the waste products elimination. Therefore, the current review summarizes role of exosomes and their use as biomarkers in cardiovascular, nervous and ocular disorders. This aspect of exosomes provides positive hope to monitor disease development and enable early diagnosis and treatment optimization. In this review, we have summarized recent findings on physiological and therapeutic effects of exosomes and also attempt to provide insights about stress-preconditioned exosomes and stem cell-derived exosomes. [ABSTRACT FROM AUTHOR]

In 1992, a transcendental report suggested that the receptor of advanced glycation end-products (RAGE) functions as a cell surface receptor for a wide and diverse group of compounds, commonly referred to as advanced glycation end-products (AGEs), resulting from the non-enzymatic glycation of lipids and proteins in response to hyperglycemia. The interaction of these compounds with RAGE represents an essential element in triggering the cellular response to proteins or lipids that become glycated. Although initially demonstrated for diabetes complications, a growing body of evidence clearly supports RAGE's role in human diseases. Moreover, the recognizing capacities of this receptor have been extended to a plethora of structurally diverse ligands. As a result, it has been acknowledged as a pattern recognition receptor (PRR) and functionally categorized as the RAGE axis. The ligation to RAGE leads the initiation of a complex signaling cascade and thus triggering crucial cellular events in the pathophysiology of many human diseases. In the present review, we intend to summarize basic features of the RAGE axis biology as well as its contribution to some relevant human diseases such as metabolic diseases, neurodegenerative, cardiovascular, autoimmune, and chronic airways diseases, and cancer as a result of exposure to AGEs, as well as many other ligands. [ABSTRACT FROM AUTHOR]

The CACCC-box motif emerges as a pivotal cis-regulatory element implicated in diverse developmental processes and diseases, particularly cardiovascular diseases (CVDs). This study centers on the intricate interplay between the CACCC-box and its binding proteins such as: the Krüppel-Like Family (KLF) of transcription factors as primary effectors in the context of CVDs. Our analysis was through a bioinformatics approach, which revealed significant transcriptional activity among KLF subgroup 2, exhibiting the highest number of interactions focusing on the established roles: pluripotency, cancer, and cardiovascular development and diseases. Our analysis reveals KLF's interactions with GATA4, MEF2C, NKX2.5 and other ~90 potential genes that participate in the regulation of the hypertrophic environment (or CVDs' Environment). Also, the GO analysis showed that genes containing the motif CACCC were enriched for multiple CVDs; in combination with STRING analysis, these results pointed to a link between KLFs and these diseases. The analysis further identifies other potential CACCC-box binding factors, such as SP family members, WT1, VEZF1, and -SALL4, which are implicated in cardiac contraction, remodeling, and inflammation processes. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction-associated steatotic liver disease (MASLD) is not only related to traditional cardiovascular risk factors like type 2 diabetes mellitus and obesity, but it is also an independent risk factor for the development of cardiovascular disease. MASLD has been shown to be independently related to endothelial dysfunction and atherosclerosis. MASLD is characterized by a chronic proinflammatory response that, in turn, may induce a prothrombotic state. Several mechanisms such as endothelial and platelet dysfunction, changes in the coagulative factors, lower fibrinolytic activity can contribute to induce the prothrombotic state. Platelets are players and addresses of metabolic dysregulation; obesity and insulin resistance are related to platelet hyperactivation. Furthermore, platelets can exert a direct effect on liver cells, particularly through the release of mediators from granules. Growing data in literature support the use of antiplatelet agent as a treatment for MASLD. The use of antiplatelets drugs seems to exert beneficial effects on hepatocellular carcinoma prevention in patients with MASLD, since platelets contribute to fibrosis progression and cancer development. This review aims to summarize the main data on the role of platelets in the pathogenesis of MASLD and its main complications such as cardiovascular events and the development of liver fibrosis. Furthermore, we will examine the role of antiplatelet therapy not only in the prevention and treatment of cardiovascular events but also as a possible anti-fibrotic and anti-tumor agent. [ABSTRACT FROM AUTHOR]

Particulate matter of size ≤ 2.5 μm (PM2.5) is a critical environmental threat that considerably contributes to the global disease burden. However, accompanied by the rapid research progress in this field, the existing research on developmental toxicity is still constrained by limited data sources, varying quality, and insufficient in-depth mechanistic analysis. This review includes the currently available epidemiological and laboratory evidence and comprehensively characterizes the adverse effects of PM2.5 on developing individuals in different regions and various pollution sources. In addition, this review explores the effect of PM2.5 exposure to individuals of different ethnicities, genders, and socioeconomic levels on adverse birth outcomes and cardiopulmonary and neurological development. Furthermore, the molecular mechanisms involved in the adverse health effects of PM2.5 primarily encompass transcriptional and translational regulation, oxidative stress, inflammatory response, and epigenetic modulation. The primary findings and novel perspectives regarding the association between public health and PM2.5 were examined, highlighting the need for future studies to explore its sources, composition, and sex-specific effects. Additionally, further research is required to delve deeper into the more intricate underlying mechanisms to effectively prevent or mitigate the harmful effects of air pollution on human health. [ABSTRACT FROM AUTHOR]