Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome that accounts for more than half of heart failure cases and disproportionately affects older women. Biological sex is a key determinant of HFpEF, influencing epidemiology, comorbidity profiles, cardiac structure, clinical outcomes, and therapeutic responses. Women more commonly exhibit concentric left ventricular remodeling and diastolic dysfunction, frequently in association with obesity, hypertension, diabetes, and anemia, whereas men more often present with ischemic heart disease, renal dysfunction, and right ventricular involvement. These sex differences extend to prognosis, quality of life, and responses to therapies such as spironolactone and sacubitril/valsartan. At the mechanistic level, women exhibit greater metabolic dysregulation, heightened inflammatory responses, and more pronounced ventricular–arterial stiffening, whereas men show more prominent ischemic and cardiorenal perturbations. Emerging evidence indicates that these sex-specific features arise from distinct but interconnected pathophysiological pathways, including mitochondrial dysfunction, renin–angiotensin–aldosterone system (RAAS) imbalance, microvascular inflammation, impaired NO–cGMP–PKG signaling, and extracellular matrix remodeling. These pathways are differentially regulated by gonadal hormones, sex chromosome dosage, and X-linked gene escape from inactivation, which together shape cardiac stiffness, fibrosis, oxidative stress, and immune activation. Overall, these findings highlight the complex interplay between hormonal, chromosomal, and molecular mechanisms underlying sex differences in HFpEF. A better understanding of these processes may help explain disease heterogeneity, guide the rational identification of sex-dependent therapeutic targets, and support the development of sex-informed prevention and therapeutic strategies.
Tooth wear is a common, multifactorial non-carious dental hard tissue disease, and it may lead to a range of problems such as hypersensitivity, occlusal dysfunction, and aesthetic defects, significantly impacting patients’ oral health and quality of life. This article aims to systematically review the clinical assessment, diagnostic methods, pathophysiology, and etiological classification of tooth wear, with a focus on discussing evidence-based restorative and pharmacological management strategies, thereby providing a theoretical basis and practical guidance for clinical practice. This review provides an overview of the fundamental concepts and classification of tooth wear, encompassing both mechanical and chemical forms. With regard to clinical assessment, it outlines fundamental examination methods such as visual inspection and history taking, and reviews the application and development of standardized indices, including the Basic Erosive Wear Examination (BEWE) and the Tooth Wear Index (TWI), as well as adjunctive tools like intraoral photographs. In terms of etiology, it analyzes the interaction mechanisms of mechanical wear (attrition and abrasion), chemical wear (erosion), and biomechanical fatigue, and further classifies etiological factors according to typical location and morphological characteristics. Regarding treatment, this review emphasizes etiological intervention and risk factor management, and evaluates the performance and indications of restorative materials such as composite resin, ceramic, and CAD/CAM resin matrix composites. It also discusses key techniques for achieving durable long-term bonding, as well as the value and future prospects of integrating digital workflows, such as intraoral scanning and digital smile design (DSD), into diagnosis, treatment planning, and clinical management. In addition, it reviews pharmacological strategies for tooth wear, especially topical remineralizing agents, from the perspective of therapeutic targets and mechanisms of action. The modern management of tooth wear depends on early identification and accurate etiological diagnosis, appropriate selection of restorative materials based on long-term performance, and the synergistic application of minimally invasive adhesive techniques, digital technologies, adjuvant pharmacological therapies, and individualized risk control throughout the treatment process.
Right heart failure (RHF) represents a multifactorial and clinically challenging syndrome characterized by complex pathophysiology and a persistent unmet therapeutic need. Despite an extensive body of literature delineating diverse putative determinants capable of modulating disease susceptibility and progression, the precise molecular mechanisms continue to be inadequately elucidated. The purpose of this study was to identify mechanisms underlying higenamine (HIG)-mediated therapy for RHF by combining network pharmacology with molecular dynamics (MD) techniques. Based on drug-likeness properties, HIG was identified as a promising phytoconstituent against RHF. It is predicted to exert its effects by modulating pathways related to pro-growth, angiogenesis and inflammation, all of which are associated with ESR1, PPARG and TGFBR1. Molecular docking and MD were subsequently employed to further confirm the binding of HIG to ESR1. Finally, HIG is considered to hold potential in modulating key pathological pathways of RHF, offering a promising experimental basis for the future development of novel therapeutics against RHF.
The progression of cardiovascular disease shows significant sexual dimorphism: although females generally develop the disease later in life, they exhibit a higher age-related incidence than males. While current studies have separately reported sex differences in atherosclerotic development in Apoe−/− and Ldlr−/−, a comparative assessment of these sex-specific characteristics across both models is lacking. This study therefore aimed to assess the influence of sex on atherosclerosis using both Apoe−/− and Ldlr−/− mice. Eight-week-old mice were fed an atherogenic ALMN diet for 20 weeks to promote plaque development. We performed comprehensive analyses of: (1) systemic metabolic parameters (lipid profile, glucose metabolism); (2) atherosclerotic burden (whole aorta and aortic sinus plaque area); and (3) plaque composition (necrotic core size, collagen content, macrophage infiltration) in mice of both sexes. As a result, male mice showed higher lipid levels, worse glucose tolerance, and reduced insulin sensitivity compared to females in both models. Apoe−/− mice showed minimal sex differences in atherosclerosis with a trend toward increased plaque size in females. Plaque composition did not differ significantly between sexes in Apoe−/− mice. In contrast, Ldlr−/− males exhibited greater whole aortic plaque burden than females, yet plaque stability also remained similar across sexes. This comparative analysis of two widely used murine atherosclerosis models reveals genotype-dependent sexual dimorphism. This study underscores the importance of considering the distinct sex-specific characteristics of Apoe−/− and Ldlr−/− mice when selecting animal models for exploring atherosclerosis pathomechanisms as well as effective pharmacotherapies, and further supports the necessity of developing sex-specific therapies.
Autophagy is integral in the protection and survival of cardiomyocytes in heart disease. If impaired, it can lead to apoptosis of healthy cardiac tissue. This review discusses the role of autophagy in heart disease. Primary mechanisms and their benefits for cellular homeostasis in cardiomyocytes will be explored as well as the effects of dysregulated autophagy on aggravating conditions and the potential therapeutic approaches to modulate autophagy to improve outcomes in heart disease. Autophagy degrades damaged cellular components during myocardial infarction, increasing energy levels to reduce Ischemic/Reperfusion injury. However, over-activation of autophagy can contribute to this injury by forming excessive autophagosomes, which destabilize mitochondria, consequently accelerating cell apoptosis and cardiac injury. In atherosclerosis, disrupted autophagy promotes cell apoptosis, exacerbating inflammation and worsening atherogenesis. In contrast, tightly regulated autophagy promotes cell survival in vascular smooth muscle cells. Autophagy helps adaptively remodel the heart and compensate for cardiac overload. Abnormal levels of autophagy can increase the progression of cardiac hypertrophy to heart failure by degrading crucial cellular components. Autophagy plays various roles in many heart diseases, making it a promising target in developing new therapies to recover and minimize heart disease damage. When exploring pharmacological treatments for diabetic cardiomyopathy, a large percentage are autophagy modulators, which have the potential to be utilized to promote cardiac repair in cardiovascular disease.
Myocardial lipotoxicity is a fundamental pathological mechanism responsible for myocardial injury associated with various metabolic disorders such as obesity and type 2 diabetes. This condition arises from an imbalance in lipid metabolic homeostasis, leading to the excessive accumulation of toxic lipid intermediates in cardiomyocytes, which ultimately results in structural and functional impairments of the myocardium. This review provides a comprehensive overview of the mechanisms by which myocardial lipotoxicity occurs and its significant involvement in cardiovascular diseases, including heart failure, arrhythmias, and atherosclerosis. The myocardium primarily acquires exogenous fatty acids through albumin-bound free fatty acids and lipoprotein lipase-mediated lipolysis, facilitated by transporter proteins like CD36 and FATP. When the uptake of fatty acids surpasses oxidative capacity, toxic lipids such as ceramides and DAG accumulate, disrupting essential signaling pathways—including AMPK, PPAR, PKC, and NF-κB. This disruption triggers mitochondrial dysfunction, endoplasmic reticulum stress, oxidative stress, inflammatory responses, and various forms of cell death. Together, these mechanisms lead to myocardial remodeling, abnormalities in electrical activity, and the onset and progression of vascular pathologies. The article also reviews current therapeutic strategies aimed at mitigating myocardial lipotoxicity, including lifestyle modifications and pharmacological interventions such as SGLT2 inhibitors and trimetazidine. Furthermore, it explores future research directions, focusing on ceramide synthesis, inflammatory pathways, and personalized medicine, with the goal of providing a theoretical foundation and innovative insights for the clinical prevention and treatment of lipotoxicity-related cardiovascular diseases.
Single-cell RNA sequencing (scRNA-seq) has transformed precision oncology by allowing for high-resolution transcriptome investigation at the individual cell level. Unlike bulk RNA sequencing, which yields averaged gene expression data, scRNA-seq exposes cellular heterogeneity inside tumors, detecting rare cancer subpopulations, stem-like cells, and drug-resistant clones. This skill has major implications for tumor drug discovery, enabling researchers to identify new therapeutic targets, anticipate patient-specific medication responses, and devise more accurate treatment plans. Furthermore, scRNA-seq allows for a better knowledge of tumor microenvironment interactions, revealing information on the roles of immune and stromal cells in cancer growth and therapeutic resistance. Recent advances in scRNA-seq technologies, including as droplet-based sequencing systems and spatial transcriptomics, have increased their usefulness in oncology research. Droplet-based technologies allow scientists to study tumor differences in much greater detail than ever before, utilizing platforms created by 10× Genomics and Drop-seq, which allow the high-throughput collection and barcoding of thousands of individual cells. These systems enable researchers to find rare cell groups that are frequently undetectable with bulk RNA-seq, specifically, cancer stem cells or drug-resistant clones. Spatial transcriptomics, on the other hand, maps different cellular subpopulations directly within the tumor microenvironment by fusing tissue architecture and gene expression profiling. Understanding cancer growth and treatment resistance requires knowledge of immune infiltration patterns, cell-cell interactions, and tumor evolution dynamics, all of which are crucially revealed by this technique. All of these developments have combined to make scRNA-seq an effective tool for identifying new biomarkers, predicting treatment outcomes, and directing the creation of precision oncology plans. Furthermore, the combination of artificial intelligence (AI) and machine learning has improved the interpretation of scRNA-seq datasets, allowing for the discovery of major oncogenic pathways and possible therapeutic candidates. Despite its transformative promise, scRNA-seq faces significant barriers to widespread use in clinical cancer, including high sequencing costs, technical constraints in single-cell isolation, and the complexity of bioinformatics analysis. This study investigates the present applications of scRNA-seq in tumor drug discovery, focusing on recent advances in discovering druggable targets, tracking tumor progression, and overcoming therapeutic resistance. We also highlight new tactics for overcoming current difficulties, including as advancements in multi-omics integration and computational modeling. As scRNA-seq advances, it is predicted to play a critical role in bringing precision oncology into clinical practice, ultimately improving cancer treatment outcomes through more effective and tailored therapeutic interventions.
G protein-coupled receptors (GPCRs) are key mediators of cellular signaling, governing fundamental physiological and pathophysiological processes. This central role establishes them as prominent drug targets for a wide range of diseases. The concept of GPCR biased signaling was initially defined by the receptor’s ability to differentially engage G proteins versus β-arrestins. Research has since broadened this paradigm to reveal diverse mechanisms, including preferential coupling to specific Gα subtypes, spatially segregated signaling, regulation by post-translational modifications (e.g., phosphorylation), and distinct outputs from receptor oligomers. Together, these findings illuminate the complex signaling repertoire of GPCRs. Leveraging biased signaling to activate beneficial pathways, therefore offers a compelling path toward therapeutics with enhanced efficacy and reduced adverse effects. This review explores the evolution of GPCR biased signaling concepts and evaluates the current pipeline of investigational and approved drugs emerging from this paradigm.
Using network pharmacology, we identified the active ingredients and potential targets of the “Danshen & Hawthorn” herb pair for treating NAFLD. Disease targets for NAFLD were retrieved from relevant databases, and a “herb-ingredient-target” network was constructed. KEGG pathway analysis revealed that the therapeutic mechanism was associated with the IL-17, TNF, and PPAR signaling pathways, among others. Experimental validation in both in vitro (cellular model of steatosis) and in vivo (zebrafish model of NAFLD) models demonstrated that the herbal extract alleviated high-fat-induced damage. Virtual molecular docking of the top-ranked compound-target pairs identified potential key binding residues: PHE 207, TYR 134, HIS 25, GLY 143, and SER 53 for Pparg-Quercetin; ILE 317, MET 355, and PHE 273 for Ppara-Eburicoic acid; and ILE 354, PHE 351, TYR 314, SER 280, and HIS 440 for Hmox1-Dehydroeburicoic acid. In conclusion, the “Danshen & Hawthorn” herb pair ameliorates NAFLD by modulating the expression of PPARα, TNF-α, and IL-17, thereby reducing inflammation and lipid accumulation. This study provides molecular-level insights by identifying critical amino acid residues for target engagement.
The nucleolus is recognized as the largest and most architecturally complex membrane-less organelle within the mammalian nucleus, exhibiting pronounced structural dynamics. Notably, this compartment demonstrates exceptional sensitivity to cellular stress; such perturbations frequently culminate in nucleolar stress, a condition characterized by structural disintegration, functional compromise, and organellar destabilization. Nucleolar stress has emerged as a critical paradigm, positing the nucleolus as both a stress sensor and a signaling hub under pathological conditions. Mechanistically, nucleolar stress responses have been demonstrated to exert pleiotropic regulatory effects on cell cycle progression, differentiation and cell fate determination, thereby triggering apoptosis, senescence, or autophagy in stressed cells. The nucleolus, being the principal site of ribosomal biogenesis and cell cycle control, has been implicated in the pathogenesis of cardiovascular disorders. Clinical and experimental evidence consistently reveals distinct nucleolar morphological aberrations and ribosomal dysfunction during cardiovascular stress events, particularly in myocardial infarction and cardiomyopathy. These disruptions have been shown to impair cardiac proteostasis and metabolic homeostasis, consequently exacerbating myocardial dysfunction. Therefore, elucidating the molecular mechanisms underlying stress-induced nucleolar signaling pathways may provide two key translational benefits: the identification of novel diagnostic biomarkers for early cardiovascular disease detection, and the discovery of precision therapeutic targets. Such advancements could substantially refine clinical management strategies and improve patients’ prognoses.
The rising global prevalence of Type 2 Diabetes Mellitus (T2DM) and obesity has intensified the search for novel therapeutic agents, with Glucagon-like peptide-1 (GLP-1) emerging as a key regulator of glucose homeostasis and insulin secretion. While synthetic GLP-1 receptor agonists (RAs) like semaglutide and tirzepatide dominate clinical use, plant-derived GLP-1 modulators present a promising alternative due to their natural origin, diverse mechanisms, and potential for reduced side effects. This review systematically evaluates 34 medicinal plants—including Agave tequilana (fructans), Berberis vulgaris (berberine), Momordica charantia (bitter melon), and Panax ginseng (ginsenosides)—that exhibit GLP-1 agonist activity through pathways such as DPP-4 inhibition, bitter taste receptor activation, and SCFA-mediated GLP-1 secretion. Comparative analysis reveals that while synthetic agonists offer superior HbA1c reduction (1–2%) and weight loss (5–22.5%), natural compounds provide multimodal benefits, including anti-inflammatory, antioxidant, and beta-cell protective effects. However, clinical evidence remains limited, with most studies confined to preclinical models. Future research should prioritize human trials, bioavailability optimization, and synergistic formulations to harness the full therapeutic potential of plant-derived GLP-1 agonists in metabolic disorders.
Aging is a multifactorial biological process that leads to the gradual decline of physiological functions, contributing to the onset of age-related diseases. Nitazoxanide (NTZ) is an FDA-approved antiparasitic drug with anti-senescence effects. However, its anti-aging effects and the underlying molecular mechanisms remain incompletely understood. This study investigated the anti-aging effects of NTZ in Caenorhabditis elegans and in a D-galactose (D-Gal)-induced accelerated aging mouse model. In C. elegans, NTZ treatment significantly extended both lifespan and healthspan, as demonstrated by reduced lipofuscin accumulation, decreased reactive oxygen species (ROS) levels, and improved locomotor activity. In the D-Gal mouse model, NTZ treatment ameliorated cognitive and physical decline, improved skin tissue integrity, and protected hippocampal neurons from degeneration. Computational target prediction and pathway analysis identified 122 potential anti-aging targets of NTZ. Network pharmacology analysis revealed that NTZ targets the PI3K signaling pathway, a key regulator of aging, and identifies PI3K p110 catalytic isoform as a central hub in this cascade, confirming its pivotal role in NTZ-mediated anti-aging effects. Molecular docking and dynamics simulations further validated the stable binding of NTZ to PI3K p110 catalytic isoforms, demonstrating a high-affinity interaction that disrupts PI3K signaling. Together, these findings provide molecular evidence supporting NTZ as a promising candidate for anti-aging therapy, with potential applications in age-related diseases.
Stroke is a leading cause of morbidity and mortality worldwide, characterized by complex pathological processes including ionic imbalance, oxidative stress, neuroinflammation, and apoptosis. Carvacrol, a naturally occurring monoterpenoid phenol, has gained attention in drug development for its potent antioxidant, anti-inflammatory, anti-apoptotic, and transient receptor potential melastatin 7 (TRPM7)-inhibitory properties. This review summarizes current evidence regarding the neuroprotective effects of carvacrol in various in vitro and in vivo models of cerebral ischemia and hypoxia. Mechanistic insights reveal that carvacrol modulates multiple molecular pathways, mitigates oxidative damage, suppresses neuroinflammation, alleviates neuronal apoptosis, and inhibits TRPM7 channel activity in cerebral ischemia and hypoxia. Finally, the broader applications of carvacrol in various diseases and its translational prospects are discussed, emphasizing the need for further preclinical and clinical studies to facilitate its development into a novel neuroprotective agent and adjunctive drug for stroke therapy.
Background: Shengmai San (SMS), a classical traditional Chinese medicine (TCM) formulation, has been clinically used for centuries in the treatment of ischemic stroke (IS). However, the complexity of SMS leads to ambiguous bioactive components and poorly understood mechanisms of action. Therefore, the development of optimized active component combinations from SMS represents a promising strategy for novel therapeutic agents against IS. Methods: In this study, we developed an active component combination (ACCS) from SMS and evaluated the neuroprotective effect of ACCS in a rat middle cerebral artery occlusion (MCAO) model. An integrated multi-omics approach, combining 16S rRNA gut microbiota sequencing with serum untargeted metabolomics, was employed to elucidate the underlying neuroprotective mechanisms. Results: ACCS treatment significantly reduced cerebral infarct volume, improved neurobehavioral function, and restored cerebral blood flow in the ischemic region. Furthermore, ACCS modulated gut microbial structure, restored microbial diversity and increased the abundance of beneficial bacterial populations. Meanwhile, ACCS ameliorated serum metabolic disturbances induced by MCAO. Conclusion: This study rationally designed a bioactive combination derived from a TCM formulae, establishing a polypharmacological strategy for the treatment of ischemic stroke.
Background: Caloric restriction (CR) is a powerful non-pharmacologic intervention known to extend lifespan and improve cardiovascular health. Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) exert antihypertrophic and antifibrotic effects through natriuretic peptide receptor 1 (NPR1), a guanylyl cyclase receptor that generates cyclic GMP (cGMP). Whether intact NPR1 signaling is required for the cardioprotective effects of CR remains unknown. Methods: NPR1 knockout (KO), heterozygous KO (+/−), and wild-type (WT) littermate mice were subjected to a CR regimen (20% caloric reduction for 2 weeks, then 40% for 2 weeks). WT mice were subjected to transverse aortic constriction (TAC) to model acute pressure overload, whereas NPR1-deficient mice were studied in the setting of established genetic cardiomyopathy. Cardiac structure, function, fibrosis, apoptosis, ATP levels, oxidative and ER stress, and signaling pathways (cGMP, eNOS/NO/sGC) were assessed by echocardiography, histology, biochemical assays, and Western blotting. Results: In WT mice, CR significantly attenuated TAC-induced hypertrophy, preserved cardiac function, reduced fibrosis, and decreased oxidative and ER stress. In contrast, CR did not attenuate or reverse established NPR1-deficiency-induced hypertrophy, fibrosis, or dysfunction, despite reducing oxidative stress and ER stress. CR preserved ATP content in NPR1 KO hearts, but cGMP levels remained profoundly depressed (~90% reduction). Compensatory activation of NO-sGC signaling was observed in NPR1 KO hearts, but this response was insufficient to restore myocardial cGMP levels or limit structural remodeling. Conclusions: These findings indicate that intact NPR1-cGMP signaling is required for CR-mediated protection against pressure-overload–induced cardiac remodeling, whereas CR alone is insufficient to reverse established, genetically programmed cardiomyopathy in the absence of NPR1. Although CR reduces oxidative stress, ER stress, and preserves myocardial ATP, these adaptations are insufficient to compensate for the loss of NPR1-cGMP signaling in reversing established pathological cardiac remodeling. Thus, the cardioprotective efficacy of CR appears to be context-dependent and may require intact natriuretic peptide signaling.
Cardiovascular disease remains the leading global cause of death, with rising prevalence and mortality, underscoring the need for regenerative strategies. This review synthesizes evidence on mesenchymal stromal/stem cells and their exosomes in cardiac repair. Preclinical studies show paracrine-driven benefits such as pro-angiogenic, anti-apoptotic, anti-fibrotic, and immunomodulatory effects, which may be driven in part by exosomal cargo such as microRNAs. Early clinical trials establish safety and signal improvements in remodeling and function, however, Phase III trial results have been mixed, and no MSC-based product has yet been approved for routine clinical use. We also discuss next-generation induced pluripotent stem cells-derived mesenchymal stromal/stem cells, which offer scalability and consistency but require rigorous control of residual pluripotency and tumorigenicity risk. Future priorities include standardized GMP manufacturing, source and payload optimization, targeted delivery (including cell-free exosomes and biomaterials), and biomarker-guided patient selection to enable effective clinical translation.
Erectile dysfunction (ED) is a prevalent male sexual dysfunction that can be categorized into organic and psychological forms. The organic type is further subdivided into neurogenic, vasogenic, drug-induced, and endocrine subtypes, among others. Risk factors for ED include smoking, obesity, diabetes, cardiovascular disease, and various psychological influences. Treatment strategies for managing the symptoms encompass lifestyle modifications, pharmacotherapy, physical therapy, stem cell therapy, and surgical interventions. Pharmacological options consist of phosphodiesterase inhibitors, testosterone, and α-adrenoceptor antagonists, while physical modalities include vacuum erection devices, prostaglandin E1 injection, and low-intensity extracorporeal shock wave therapy (LI-ESWT). Surgical procedures such as penile prosthesis implantation, are typically reserved for patients unsuited to non-surgical approaches or those experiencing adverse effects or unresponsiveness to medical therapy. This review elaborates on key aspects of ED, investigates diverse pathological mechanisms associated with the disorder, and outlines current treatment modalities.
Qifuyin (QFY) has been used for the treatment of senile dementia in traditional Chinese medicine. Polysaccharides are the main components in QFY, but they have not been sufficiently studied. Here, we extracted QFY polysaccharides (QFYP) with 29.9 ± 0.81% yield and 70.1 ± 0.10% purity using hydrothermal extraction and alcohol precipitation. The QFYP-1 and QFYP-2 were separated through DEAE-52 cellulose column chromatography. The 207.1 mg QFYP-1 was obtained with 20.71% yield and 92.8% purity. The 108.0 mg QFYP-2 was extracted with 10.80% yield and 84.5% purity. The in vitro anti-oxidant assay showed that QFYP could scavenge DPPH, ABTS+, O2- radicals and chelate Fe2+, with IC50 of 0.43 mg/mL, 0.92 mg/mL, 3.4 mg/mL and 6.5 mg/mL respectively. In vivo animal experiments showed that QFYP increased the head regeneration score of the decapitated planaria after 72 h. The free-swimming behavior test of the post-regenerated planaria showed that QFYP increased the total motion distance and movement angle of planaria. This indicated that QFYP was successfully prepared, and exerted anti-oxidant effects and promoted regenerative activities.
