Search Results (500)

Vascular smooth muscle cells (VSMCs) are central to the maintenance of vascular homeostasis and the progression of cardiovascular diseases (CVDs), owing to their remarkable phenotypic plasticity. This editorial introduces a Special Issue of Cells that compiles recent advances in our understanding of the molecular, epigenetic, metabolic, and mechanical mechanisms that govern VSMC behavior. Highlighted contributions explore the roles of RNA modifications, chromatin remodeling, lipid metabolism, and mechanotransduction in VSMC phenotypic switching, revealing new therapeutic targets and diagnostic opportunities. Together, these studies emphasize the multifactorial regulation of VSMC plasticity and its dual role in vascular repair and disease pathogenesis. Full article

Benign prostatic hyperplasia (BPH) is a multifactorial condition that is highly prevalent and affects aging males. It frequently results in lower urinary tract symptoms (LUTS) and a reduced quality of life. While hormonal dysregulation and chronic inflammation have long been implicated in BPH pathogenesis, recent evidence highlights the role of physical activity in modulating prostate health. In this narrative review, evidence from quantitative studies examining the effect of exercise on BPH risk and symptom severity was first synthesized. Collectively, these studies suggest that regular physical activity is associated with a lower incidence and reduced progression of BPH. The potential mechanisms through which exercise may exert protective effects on the prostate were then explored. These include modulation of sympathetic nervous system activity, alterations in hormonal profiles (e.g., testosterone and insulin), suppression of chronic inflammation and oxidative stress, and the promotion of autophagy within prostatic tissue. Central to these mechanisms is the role of myokines—signaling molecules secreted by skeletal muscle during exercise. Key myokines, such as irisin, interleukin-6 (IL-6), brain-derived neurotrophic factor (BDNF), and myostatin, are reviewed in the context of prostate health. These molecules regulate inflammatory pathways, metabolic processes, and tissue remodeling. For instance, exercise-induced reductions in myostatin are linked to improved insulin sensitivity and decreased fat accumulation, while elevated irisin and BDNF levels may exert anti-inflammatory and metabolic benefits relevant to BPH pathophysiology. Although direct causal evidence linking myokines to BPH is still emerging, their biological plausibility and observed systemic effects suggest a promising avenue for non-pharmacological intervention. Future research should focus on identifying the specific myokines involved, elucidating their molecular mechanisms within the prostate, and evaluating their therapeutic potential in clinical trials. Full article

Background/Objectives: Maternal exposures are known to influence the risk of isolated cleft lip with or without cleft palate (CL/P)—a common and highly heritable birth defect with a multifactorial etiology. Methods: To identify new risk loci, we conducted a genome-wide gene–environment interaction (GEI) analysis of CL/P with maternal smoking and vitamin use in Filipinos (N_cases = 540, N_controls = 260). Since GEI analyses are typically low in power and the results can be difficult to interpret, we applied multiple testing frameworks to evaluate potential GEI effects: a one degree-of-freedom (1df) GxE test, the 3df joint test, and the two-step EDGE approach. Results: While no genome-wide significant interactions were detected, we identified 11 suggestive GEIs with smoking and 24 with vitamin use. Several implicated loci contain biologically plausible genes. Notable interactions with smoking include loci near FEZF1, TWIST2, and NET1. While FEZF1 is involved in early neuronal development, TWIST2 and NET1 regulate epithelial–mesenchymal transition, which is required for proper lip and palate fusion. Interactions with vitamins encompass CECR2—a chromatin remodeling protein required for neural tube closure—and FURIN, a critical protease during early embryogenesis that activates various growth factors and extracellular matrix proteins. The activity of both proteins is influenced by folic acid. Conclusions: Our findings highlight the critical role of maternal exposures in identifying genes associated with structural birth defects such as CL/P and provide new paths to explore for CL/P genetics. Full article

Acute lung injury (ALI), a life-threatening clinical syndrome with multifactorial origins, is characterized by uncontrolled pulmonary inflammation and disrupted alveolar–capillary barrier integrity, leading to progressive hypoxemia and respiratory failure. In this hypoxic setting, hypoxia-inducible factor (HIF)-1 is activated, acting as a central regulator of the inflammatory response and reparative processes in injured lung tissue during ALI. The role of HIF-1 is distinctly dualistic; it promotes both anti-inflammatory and reparative mechanisms to a certain extent, while potentially exacerbating inflammation, thus having a complex impact on disease progression. We explore the latest understanding of the role of hypoxia/HIF-mediated inflammatory and reparative pathways in ALI and consider the potential therapeutic applications of drugs targeting these pathways for the development of innovative treatment strategies. Therefore, this review aims to guide future research and clinical applications by emphasizing HIF-1 as a key therapeutic target for ALI. Full article

Arginine vasopressin (AVP) and oxytocin (OXT) are neuropeptides traditionally recognized for their roles in the control of osmoregulation, blood pressure, lactation, and parturition in mammals. However, growing evidence suggests that AVPand OXT also regulate gonadal functions in teleost fish. Their expression in both male and female gonads, the presence of their receptors in ovaries and testes, and their interactions with steroids and other gonadal factors indicate a role in modulating gametogenesis and steroidogenesis via autocrine and paracrine mechanisms. Here, we review the current findings on AVP and OXT in teleost gonads, compared to the observed functions in mammals, emphasizing their systemic interactions within the hypothalamic–pituitary–gonadal (HPG) axis. While highlighting the roles of gonadal AVP and OXT in fish reproduction, we underscore the need for further research to unravel their complex multifactorial regulatory networks. Insights into the vasopressinergic system could enhance aquaculture practices by improving spawning success and reproductive efficiency. Full article

Cardiovascular diseases (CVDs) are the leading causes of death worldwide, and most of them are connected with atherosclerosis (AS). Hypertension (HT), hyperlipidemia (HPL), and hyperglycaemia (HG) are the main risk factors responsible for CVD and have become a significant public health issue. AS might be a prime causative factor in CVD, and it originates from endothelial cell dysfunction. On the other hand, the factors mentioned above might cause endothelial cell damage as a consequence of endothelial dysfunction (ED) or might be regarded as a consequence of ED. Thus, endothelial cells are critical for maintaining vascular health and homeostasis, and their function is a key contributor to the initiation and progression of AS. The autoregulation of microcirculation, which is functionally present in the brain and kidneys, and from the physiological and pathophysiological point of view, is of high importance to preserve the proper function of the endothelium of blood vessels. The key factor responsible for cardiovascular system regulation and proper action is nitric oxide (NO). Disturbances in NO synthesis and/or bioavailability, caused by oxidative stress and/or inflammation, accompany or even precede diseases such as HT, angiogenesis-associated disorders, HPL, and HG, which are on the pathway of AS development. In the present review, we attempted to synthesize recent advances in understanding the pathophysiology of multifactorial-related AS. Full article

Chronic pain is a multifactorial and complex condition that significantly affects individuals’ quality of life. The underlying mechanisms of chronic pain involve complex alterations in neural circuits, gene expression, and cellular signaling pathways. Recently, ncRNAs, such as miRNAs, lncRNAs, circRNAs, and siRNAs, have been identified as crucial regulators in the pathophysiology of chronic pain. These ncRNAs modulate gene expression at both the transcriptional and post-transcriptional levels, affecting pain-related pathways like inflammation, neuronal plasticity, and sensory processing. miRNAs have been shown to control genes involved in pain perception and nociceptive signaling, while lncRNAs interact with chromatin remodeling factors and transcription factors to modify pain-related gene expression. CircRNAs act as sponges for miRNAs, thereby influencing pain mechanisms. siRNAs, recognized for their gene-silencing capabilities, also participate in regulating the expression of pain-related genes. This review examines the diverse roles of ncRNAs in chronic pain, emphasizing their potential as biomarkers for pain assessment and as targets for novel therapeutic strategies. A profound understanding of the ncRNA-mediated regulatory networks involved in chronic pain could result in more effective and personalized pain management solutions. Full article

Background/Objectives: Reproductive efficiency in breeding boars critically impacts swine industry productivity, with sperm quality being multifactorially regulated by gut microbiota. This study aimed to elucidate the microbiota–metabolite interactions underlying sperm quality differences in Tibetan boars. Methods: Integrated 16S rRNA sequencing and untargeted metabolomics were performed on fecal and semen samples from eight healthy Tibetan boars (31–33 months old), stratified into low-semen (CJ) and high-semen utilization (HJ) groups. Analyses included sperm quality assessment, microbial profiling, and metabolic pathway enrichment. Results: The HJ group exhibited significantly enhanced sperm motility and semen utilization rates (p < 0.05). Gut microbiota composition differed markedly, with Firmicutes and Proteobacteria enriched in HJ boars. Metabolomics identified key metabolites positively correlated with sperm quality (e.g., butyrate, phenyllactic acid), while lithocholic acid showed negative associations. KEGG analysis revealed predominant involvement in butanoate metabolism and bile acid biosynthesis. Core microbiota (e.g., Ruminococcus) modulated sperm quality through short-chain fatty acid networks and bile acid homeostasis. Conclusions: Gut microbiota regulated the sperm microenvironment via a “metabolic-immune” dual pathway mediated by the gut–testis axis. These findings establish a theoretical basis for probiotic or metabolite-targeted strategies to improve boar reproductive performance. Full article

Background/Objectives: The INK4 locus at chromosome 9p21.3, encoding CDKN2A, CDKN2B and the long non-coding RNA CDKN2B-AS1 (ANRIL), has been implicated in multiple diseases, including glaucoma and cardiovascular disease. ANRIL plays a critical role in gene regulation, inflammation and cell proliferation, contributing to disease susceptibility through shared molecular mechanisms. This study aims to identify SNPs within the INK4 locus associated with both glaucoma and CVD using the Open Targets Genetics platform and assess their pleiotropic effects. Methods: We utilised the Open Targets Genetics platform to identify SNPs at the INK4 locus associated with glaucoma and CVD. For each SNP, we recorded its genomic location, statistical significance and associated phenotypes. We further analysed the SNPs using the Genome Aggregation Database (gnomAD) to confirm their genomic position. Phenotypic associations were assessed using PheWAS data. Results: We identified 20 GWAS SNPs significantly associated with both glaucoma and CVD. All SNPs were located within intronic regions of the long non-coding RNA ANRIL. Certain SNPs such as rs4977756, rs1333037 and rs1063192 have known pleiotropic effects, influencing retinal ganglion cell survival in glaucoma and vascular smooth muscle cell proliferation in CVD. These SNPs influence shared biological pathways, including inflammation, oxidative stress and epigenetic regulation, and may exert either protective or pathogenic effects. Certain SNPs such as rs7853090 and rs1434537531 remain underexplored, emphasising the need for further research. Conclusions: This study highlights the pleiotropic role of ANRIL in glaucoma and CVD, driven by shared genetic and molecular pathways. While SNPs within ANRIL provide valuable insights into disease mechanisms, these conditions remain complex, influenced by multiple genetic and environmental factors. Targeting ANRIL therapeutically poses challenges due to its non-coding nature, but emerging RNA-based therapies, including antisense oligonucleotides and small-molecule modulators, hold promise. Further research into underexplored SNPs and ANRIL’s regulatory mechanisms is essential for advancing therapeutic development and understanding these multifactorial diseases. Full article

Alzheimer’s disease (AD) is the leading cause of dementia, with a prevalence expected to escalate with the aging of the world population as life expectancy increases. In spite of significant progress made in the investigation of the etiology and pathogenesis of the disease, many mechanistic aspects that could support the implementation of novel therapeutic avenues remain unresolved. Research during the last decade has revealed a crucial role for mitochondria-mediated pathways dysregulation as significant contributors to the disease, highlighting the relevance of changes in brain metabolism and bioenergetics as well as the induction of oxidative stress conditions for neurodegeneration. This review summarizes mitochondrial functional changes associated with AD with emphasis in the dysregulation of redox homeostasis and the role of nuclear factor erythroid 2-related factor 2 (Nrf2), not only as a central regulator of the antioxidant response but also as a more recently described modulator of cellular metabolic pathways. Potential therapeutic strategies targeting oxidative stress and mitochondrial dysfunction are also discussed, with particular emphasis on the use of small molecules Nrf2 activators. Exploiting the multifactorial properties of the transcription factor in either novel or combination-based pharmacological approaches targeting multiple genes and pathways may contribute to providing more definitive and precise therapeutic perspectives. Full article

Background/Objectives: Patients with chronic kidney disease (CKD) are associated with a significantly elevated cardiovascular risk. The incidence and prevalence of mediated cardiac disorders and major adverse cardiac events (MACEs), such as heart failure, arrhythmias, acute coronary syndrome (ACS) based on coronary artery disease (CAD), stroke, venous thromboembolism, and peripheral artery disease, are significantly higher in CKD patients as compared with the general population. Methods: This narrative review summarizes the current clinical understanding, the pathophysiological mechanisms, and the clinical consequences in the context of cardiovascular risk and disease in CKD. Results: The impact of CKD on mediated cardiovascular disorders and elevated MACE prevalence is complex and multifactorial. The underlying mechanisms involve various traditional cardiovascular risk factors, such as arterial hypertension, smoking, dyslipidemia, and diabetes. Furthermore, CKD-specific molecular and pathophysiological factors, such as chronic inflammation and associated oxidative stress and endothelial cell dysfunction, pro-coagulatory status, uremic toxins and uremic lipids, progressive vascular calcification, and alterations in the regulation of the renin–angiotensin–aldosterone system (RAAS) and sympathetic activation cause an increased cardiovascular risk. Conclusions: Understanding the complex disease mechanisms between CKD and elevated cardiovascular risk might contribute to optimizing individual patients’ risk stratification and result in individualized diagnostic and treatment strategies via appropriate clinical biomarker application and individualized anti-inflammatory approaches. Full article

Background/Objectives: Obesity is a chronic and multifactorial disease that affects billions of people, and among the factors responsible for obesity are a sedentary lifestyle, a high-calorie diet, and genetic factors. Excessive caloric intake causes adipocyte hypertrophy and hyperplasia, contributing to the secretion of metabolically active molecules, known as adipokines, by adipose tissue. Individuals living with obesity have increased pro-inflammatory adipokines and a reduction in anti-inflammatory adipokines. Nuts contain bioactive compounds associated with potential health benefits, although these effects may vary depending on individual and dietary factors. Thus, this work aimed to critically review the impact of consuming almonds, walnuts, and mixed nuts on the production of adipokines associated with obesity and overweight. Methods: A comprehensive search was carried out using the terms associated with the theme of the work. The inclusion criteria for manuscripts used were the following: (1) in vivo studies; (2) intervention with oilseeds (nuts); (3) results related to adipokines and/or obesity; and (4) publications in English. Results: Studies show that regular intake of nuts reduces total cholesterol levels, LDL-c, and triglycerides and increases HDL-c in individuals with obesity. However, few studies demonstrate changes in adipokine levels related to the intake of nuts. A larger amount of 30 g of mixed nuts appears to be more beneficial for regulating adipokines in overweight or obese individuals than using nuts in larger amounts or isolated form. Of all the adipokines reported, only the results for IL-6 appear consistent, while the others remain unclear. Conclusions: Furthermore, more studies focusing specifically on this topic and humans are needed to draw greater conclusions, including the amount that results in a beneficial effect on health. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD), the leading chronic liver condition globally, constitutes a major etiological contributor to hepatocellular carcinoma (HCC). Its transition from steatosis to non-alcoholic steatohepatitis (NASH) involves progressive fibrosis, ultimately predisposing to HCC. The pathogenesis involves multifactorial interactions among genetic susceptibility, environmental triggers, and obesity-associated metabolic dysregulation. Crucially, the gut–liver axis serves as a pivotal regulatory mechanism in MASLD development. Current therapeutic strategies prioritize lifestyle interventions for metabolic syndrome management, while pharmacological options remain limited, underscoring the need for new therapies. Emerging evidence highlights phenolic acids—bioactive phytochemicals from medicinal plants—as multi-target agents against MASLD. These compounds demonstrate therapeutic efficacy via antioxidative modulation of stress, anti-inflammatory activity, and gut–liver axis regulation. This review synthesizes recent advances in natural phenolic acids for MASLD intervention, emphasizing their potential as preventive and therapeutic candidates. Their multimodal mechanisms may inform innovative drug development paradigms targeting MASLD pathogenesis. Full article

Salicornia brachiata Roxb., an economically and ecologically significant halophytic species native to Sri Lanka, produces dimorphic seeds. Despite their importance for commercial cultivation and conservation, germination studies of these dimorphic seeds remain limited. This study investigated the effects of temperature (25 °C, 30 °C, 35 °C), gibberellic acid (GA₃) treatment, geographic location of seed source (Jaffna vs. Puttalam coastal regions), seed type (central vs. lateral), and perianth presence/absence on germination under controlled conditions. Our results show that temperature, GA₃, and geographic location of the seed source significantly influenced seed germination. This study presents the first documented evidence of physiological dormancy (PD) in S. brachiata seeds, with successful dormancy breaking achieved using GA₃ treatment at 25 °C. Although perianth and seed type alone had no significant direct effects on germination, they were involved in multiple significant interactions—two-, three-, and four-way—with other factors. These findings highlight the multifactorial regulation of S. brachiata seed germination, suggesting that tailored propagation strategies, incorporating environmental and physiological variables, can optimize germination. These findings offer practical solutions for enhancing germination in saline agriculture and habitat restoration efforts of S. brachiata. Full article

This study explores the genetic regulators of microRNAs (miRNAs) using a set of machine learning models to predict miRNA expression levels from gene expression data. Employing machine learning, we accurately predicted the expression of 353 human miRNAs (R² > 0.5), revealing robust miRNA–gene regulatory relationships. By analyzing the coefficients of these predictive models, we identified genetic regulators for each miRNA and highlighted the multifactorial nature of miRNA regulation. Further network analysis uncovered that miRNAs with higher predictive accuracy are more densely connected to their top predictive genes, reflecting strong regulatory control within miRNA–gene networks. To refine these insights, we filtered the miRNA–gene interaction networks to identify miRNAs specifically associated with enriched pathways, such as synaptic function and cardiovascular processes. From this pathway-centric analysis, we present a curated list of miRNAs and their genetic regulators, pinpointing their activity within distinct biological contexts. Additionally, our study provides a comprehensive set of metrics and coefficients for the genes most predictive of miRNA expression, along with a filtered subnetwork of miRNAs linked to specific pathways and phenotypes. By integrating miRNA expression predictors with network analysis and pathway enrichment, this work advances our understanding of miRNA regulatory mechanisms and their roles across distinct biological systems. Our approach enables researchers to train custom models using TCGA data and predict miRNA expression from gene expression inputs. Full article