Regulated cardiomyocyte death is a central contributor to myocardial infarction (MI)-associated injury. Mixed lineage kinase domain-like protein (MLKL), a key effector of necroptosis, has been implicated in cardiovascular disease; however, its role in MI remains incompletely defined. MLKL expression was evaluated in hypoxia-treated cardiomyocytes, infarcted murine hearts, and human cardiac tissue. MLKL function was investigated using siRNA-mediated knockdown in neonatal mouse cardiomyocytes and genetic deletion in mice subjected to left anterior descending (LAD) coronary artery ligation. Apoptosis- and pyroptosis-related signaling were assessed by immunoblotting and immunostaining. RIP3 expression and regulation were examined at both protein and mRNA levels, and the RIP3 inhibitor GSK'872 was used to assess pathway dependence. MLKL expression was increased in hypoxic cardiomyocytes, infarcted mouse hearts, and human failing cardiac tissue. Unexpectedly, MLKL deficiency was associated with aggravated myocardial injury, impaired cardiac function, and increased fibrosis following MI. Mechanistically, MLKL deficiency was associated with increased RIP3 protein abundance without a corresponding increase in RIP3 mRNA, consistent with post-transcriptional regulation. Further analyses indicated that MLKL deficiency reduced RIP3 ubiquitination and impaired proteasome-mediated degradation, resulting in RIP3 stabilization. Elevated RIP3 levels were accompanied by increased expression of apoptosis- and pyroptosis-related proteins, particularly at early time points after MI. Pharmacological inhibition of RIP3 with GSK'872 was associated with reduced apoptosis- and pyroptosis-related signaling and improved cardiac function. MLKL deficiency is associated with stabilization of RIP3 and enhanced activation of apoptosis- and pyroptosis-related signaling following MI, contributing to aggravated myocardial injury. These findings support a regulatory role for the MLKL-RIP3 axis in cardiomyocyte death and suggest that targeting RIP3 may represent a potential therapeutic strategy in myocardial infarction.
Obesity represents one of the most critical global public health challenges. Pancreatic lipase (PL) serves as a key therapeutic target for obesity control, whereas clinical synthetic PL inhibitors are greatly restricted by adverse reactions. Traditional Chinese medicines (TCMs) have a long-standing history in regulating lipid metabolism and ameliorating obesity-related disorders, and are characterized by remarkable structural diversity, low toxicity, and mild side effects, thus representing a promising source for developing safe and efficient PL inhibitors. In this work, an integrated strategy combining in silico screening and in vitro validation was employed to identify potential PL inhibitors from TCM components, including molecular docking, molecular dynamics simulation, MM/PBSA binding free energy computation, and in vitro enzymatic assay. Six compounds with docking scores ranging from -9.9 to -9.0 kcal/mol were selected for further investigation. Molecular dynamics simulations verified the favorable structural stability of the corresponding ligand-PL complexes, and MM/PBSA calculations demonstrated negative binding free energies from -21.24 ± 0.39 to -12.03 ± 0.40 kcal/mol. In vitro experiments indicated that three compounds (Hydroxygenkwanin, Atractylenolide I, and Peiminine) showed effective PL inhibitory activity, with IC50 values of 0.128 ± 0.009, 0.584 ± 0.031, and 0.748 ± 0.042 mM, respectively. These values are comparable to quercetin (0.231 ± 0.034 mM) but significantly higher than orlistat (0.481 ± 0.023 μM), which is attributed to their non-covalent binding pattern. Collectively, this study validated the reliability of the integrated in silico and in vitro screening strategy, identified three effective pancreatic lipase inhibitors derived from TCMs, established a robust paradigm for the discovery of natural PL inhibitors, and laid a solid foundation for subsequent research on natural anti-obesity agents.
Extracellular vesicles (EVs) mediate intercellular communication by delivering proteins and RNAs, with their molecular cargo often reflecting the biological context of their source. Perinatal tissues are promising sources of EV-related biomaterials with potential dermatologic applications. In this study, we compared EV-related molecular cargo from two umbilical cord-associated sources, umbilical cord mesenchymal stem cell (UCMSC)-derived EVs and cord blood plasma (CBP), to investigate whether these materials exhibit distinct functional effects on melanogenesis. UCMSC-derived EVs were isolated from conditioned culture medium and characterized using nanoparticle tracking analysis (NTA), cryo-electron microscopy (cryo-EM), and canonical EV marker detection, while cord blood samples were processed to obtain plasma following centrifugation and filtration, containing EVs together with soluble plasma components. Functional assays in the murine melanocyte cell line B16F10 demonstrated that UCMSC-derived EVs suppressed melanin production, whereas CBP treatment enhanced melanogenesis. Integrative omics analyses combining microRNAs (miRNAs) microarray profiling and proteomic characterization revealed distinct molecular signatures between UCMSC-derived EVs and CBP samples. Functional validation using miRNA mimic assays showed that selected miRNAs, including miR-6862-5p, miR-3622b-5p, miR-7847-3p, miR-6774-5p, and miR-4685-5p, reduced melanin production, whereas others, including miR-203a-3p, miR-126-3p, miR-139-5p, and miR-15b-5p, increased melanin levels. Pathway analysis using Ingenuity Pathway Analysis (IPA) (QIAGEN Inc.) associated these miRNA subsets with signaling pathways involved in melanogenesis. Together, these findings indicate that UCMSC-derived EVs and CBP exhibit opposite functional effects on melanogenesis and possess distinct miRNA and protein cargo profiles, providing potential molecular targets for modulating pigmentation and supporting the development of EV-related therapeutic strategies for pigmentation disorders.
Bartter syndrome (BS) represents a group of rare, autosomal recessive renal tubular disorders characterized by hypokalemic hypochloremic metabolic alkalosis, secondary hyperaldosteronism, and normal to low blood pressure. The underlying pathophysiology is primarily driven by defects in critical ion transport proteins or channels localized within the thick ascending limb of the loop of Henle, leading to impaired salt reabsorption. Recent advances in molecular genetics have refined the classification of Bartter syndrome. Current evidence supports SLC12A1, KCNJ1, CLCNKB, BSND, and MAGED2 as the core disease genes within the contemporary BS spectrum, with MAGED2 causing a distinct X-linked transient antenatal form. In contrast, gain-of-function CASR variants, historically labeled "type V Bartter syndrome", are now more appropriately described as CaSR-associated Bartter-like phenotypes within the broader spectrum of disorders of calcium homeostasis. Despite significant progress, two primary research limitations remain. First, fully elucidating genotype-phenotype correlations and overcoming diagnostic complexities continues to be highly challenging due to substantial phenotypic overlap and genetic heterogeneity. Compounding these diagnostic hurdles is the equally critical challenge of understanding mutation-driven pathogenic mechanisms to develop viable clinical interventions. This review systematically summarizes the current molecular genetic landscape of BS to address these gaps. We highlight the relationships between specific genetic variants and clinical manifestations, delve into molecular pathophysiology including protein misfolding and trafficking defects, and explore emerging therapeutic approaches such as molecular chaperones. By integrating genetic and clinical data, this work aims to provide a comprehensive framework to facilitate precise diagnosis and individualized treatment strategies, ultimately advancing precision medicine in the management of Bartter syndrome.
Inflammation can promote aggressive phenotypes in prostate cancer, including enhanced migration/EMT-like changes and inflammasome-associated cytokine release. Here, we examined whether curcumin modulates these inflammation-driven responses in androgen-independent prostate cancer cells. PC-3 and DU145 cells were treated with curcumin (10 or 25 μM) or N-acetylcysteine (NAC; 2 mM). Sub-cytotoxic dosing was defined by CCK-8 viability assays. LPS (0.5 μg/mL) was used to induce motility-, invasion-, and EMT-associated responses, assessed by wound-healing assay, Matrigel-coated Transwell invasion assay, and RT-qPCR of SNAI1, CDH1, and VIM. Intracellular ROS was quantified by CM-H2DCFDA flow cytometry. Inflammasome-associated and EMT-related protein changes were evaluated under LPS priming (24 h) followed by ATP triggering (5 mM, 1 h), with NLRP3, cleaved caspase-1, cleaved IL-1β, vimentin, and E-cadherin assessed by immunoblotting and IL-1β secretion measured by ELISA. Curcumin at 10-25 μM did not cause overt cytotoxicity and significantly reduced LPS-induced wound closure and invasive activity in both cell lines, accompanied by attenuation of EMT-associated transcriptional changes and a decrease in ROS-positive events. Under LPS priming/ATP triggering, inflammasome-associated protein signals and IL-1β secretion were robustly induced; curcumin suppressed IL-1β release and attenuated NLRP3, cleaved caspase-1, and cleaved IL-1β signals, while reversing vimentin/E-cadherin changes. NAC produced similar inhibitory patterns, supporting a redox-linked contribution to these responses. Collectively, curcumin dampens inflammation-driven motility/invasion, EMT-associated changes, and inflammasome-associated responses in androgen-independent prostate cancer cells.
Non-small cell lung cancer (NSCLC) accounts for nearly 85% of lung cancer cases and remains a leading cause of cancer-related mortality worldwide. Advances in molecular diagnostics and targeted therapies have transformed treatment paradigms, yet the integration of molecular testing into routine care for resected NSCLC specimens continues to face significant challenges. This review outlines the technical, clinical, and systemic barriers that limit the effectiveness of molecular testing. Key considerations include tissue quality, the limitations of formalin-fixed paraffin-embedded (FFPE) samples, and the comparative roles of conventional methods-such as immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and reverse transcription polymerase chain reaction (RT-PCR)-versus next-generation sequencing (NGS). We also discuss the prevalence and clinical relevance of common genomic alterations, including TP53, KRAS, EGFR, and ALK, as well as their impact on prognosis and treatment selection. Real-world obstacles such as accessibility, reimbursement, delays in testing, interdisciplinary coordination, and sample adequacy are critically examined. Emerging innovations-including multi-omics integration, spatial profiling, liquid biopsy, artificial intelligence, and novel targeted therapies-offer opportunities to overcome current limitations and improve patient outcomes. Finally, practical recommendations are proposed to optimize tissue handling, testing algorithms, and access to precision-guided therapies. By addressing these challenges, molecular testing in NSCLC can be more effectively leveraged to personalize treatment strategies and enhance survival outcomes.
Salmonella Enteritidis is a major threat to poultry health and food safety, underscoring the need for safe alternatives to conventional antibiotics. In this study, quercetin, a natural flavonoid with antibacterial and immunomodulatory properties, was evaluated using an integrated approach combining network pharmacology, molecular docking, in vitro antibacterial assays, and preliminary in vivo validation. Potential targets of quercetin and Salmonella Enteritidis were identified from the TCMSP and GeneCards databases, followed by protein-protein interaction analysis, topological screening, and GO/KEGG enrichment analyses. Five core targets, namely IL1B, IL6, STAT1, PTGS2, and IFNG, were identified and were mainly enriched in immune- and inflammation-related pathways. Molecular docking suggested favorable interactions between quercetin and these predicted targets. In vitro, quercetin showed moderate antibacterial activity against Salmonella Enteritidis, with a minimum inhibitory concentration of 256 μg/mL and a minimum bactericidal concentration of 512 μg/mL. In vivo, quercetin alleviated intestinal histopathological damage and reduced the transcriptional expression of the five target genes in infected chicks in a dose-dependent manner, with more evident effects at doses of 512 mg/kg or higher. These findings provide preliminary evidence that quercetin may exert both direct antibacterial and host-associated protective effects against Salmonella Enteritidis, although the underlying mechanisms require further validation.
Conventional hormonal and clinical models inadequately clarify the complex and diverse aspects of female infertility, resulting in poor reproductive outcomes and reduced egg viability. A growing body of research indicates that female reproductive failure is mostly due to disruptions in cellular homeostasis, especially concerning organelle quality control. Oxidative stress has emerged as a crucial mediator connecting metabolic, inflammatory, and ageing-related processes to ovarian failure, however its downstream impacts on intracellular organelle turnover remain insufficiently clarified. Our narrative review encapsulates the existing data for a unified pathogenic concept focused on the redox-regulated mitochondria-lysosome axis. We examine the interaction of oxidative stress, mitochondrial malfunction, compromised mitophagy, and lysosomal deficiency in granulosa cells and oocytes. Prolonged oxidative stress may disrupt this equilibrium, leading to defective mitochondria accumulation and impaired mitophagy. This self-perpetuating cycle may ultimately jeopardises reproductive viability and oocyte integrity. The integrated axis offers a shared molecular foundation for various infertility-related diseases, such as inadequate ovarian response, obesity-associated infertility, polycystic ovary syndrome, and ovarian ageing. Ultimately, we analyse new findings suggesting that specific antioxidant chemicals modify mitophagy and lysosomal function while also neutralising reactive oxygen species, highlighting their potential use in precision fertility treatments. Our research redefines female infertility as a condition of redox-dependent organelle quality control, thereby introducing novel avenues for identifying biomarkers, categorising patients, and targeting treatments in assisted reproduction.
Marine-derived bioactive peptides have attracted increasing attention as value-added functional ingredients. In this study, peptides (<3 kDa) were prepared from yellowfin tuna processing by-products and further fractionated by Sephadex G-25 gel filtration. The major fraction (TBP-MF) exhibited markedly improved compositional homogeneity compared with the unfractionated hydrolysate (TBP), providing a well-defined peptide system for subsequent characterization and biological evaluation. Physicochemical analyses demonstrated that TBP-MF possessed enhanced thermal stability and a more ordered secondary structure, characterized by pronounced β-sheet enrichment, as revealed by TGA/DSC, FTIR, and circular dichroism analyses. Morphological and colloidal characterization further showed that TBP-MF formed relatively uniform lamellar and fibrous assemblies with a narrower particle size distribution and reduced electrostatic stabilization, indicating a higher tendency toward ordered self-association. Peptidomic profiling combined with in silico analysis revealed that TBP-MF was enriched in short peptides with relatively higher PeptideRanker scores and a functional motif distribution containing relatively more neuro-related annotations, although angiotensin-converting enzyme (ACE)- and dipeptidyl peptidase IV (DPP-IV)-related motifs remained predominant in both groups. In differentiated PC12 cells, TBP-MF exhibited excellent cytocompatibility and induced a stable, concentration-dependent increase in the Cell Counting Kit-8 (CCK-8) readout (OD450), indicating enhanced cellular metabolic activity and/or increased cell number. In addition, TBP-MF significantly increased intracellular levels of key neurochemical factors associated with sleep-related regulation, including tetrahydrobiopterin (BH4), serotonin (5-HT), and γ-aminobutyric acid (GABA). Overall, this study highlights yellowfin tuna by-products as a promising marine resource for bioactive peptides and suggests that fractionation-driven structural refinement is associated with neuro-related biological activity in differentiated PC12 cells. These findings support the potential application of marine by-product-derived peptides as functional ingredients in health-related fields.
Cadmium exposure results in the impairment of pancreatic β-cells. The FTO protein, the product of the Fto gene, is a key regulator of diverse pathophysiological processes, including oxidative damage and cell death. However, it remains unclear whether Fto gene knockout affects cadmium-induced pancreatic β-cell damage, and the precise mechanisms involved are yet to be elucidated. Under conditions of cadmium exposure, Fto gene knockout was found to alleviate pancreatic β-cell damage significantly. Specifically, Fto gene knockout counteracted cadmium-induced cytotoxicity-manifested as reduced cell viability, increased apoptosis, and heightened lactate dehydrogenase (LDH) release-while simultaneously suppressing DNA damage and preserving cellular membrane integrity. On a molecular level, Fto gene knockout markedly mitigated cadmium-induced oxidative stress. This was achieved by curbing excessive reactive oxygen species (ROS) accumulation, lowering malondialdehyde (MDA) generation, and reducing 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels, alongside restoring superoxide dismutase (SOD) activity. Furthermore, ER-Tracker Red staining revealed that cadmium treatment induced clustered aggregation of the endoplasmic reticulum (ER) and increased fluorescence intensity, suggesting the activation of endoplasmic reticulum stress (ERS). Conversely, Fto knockout ameliorated ER morphological abnormalities, thereby effectively antagonizing the excessive activation of ERS. In summary, our study elucidates the impact and underlying molecular mechanisms of the Fto gene in cadmium-induced toxicity in pancreatic β-cells from the perspectives of oxidative damage, ERS, and apoptosis. These findings identify the Fto gene as a potential molecular target for mitigating cadmium-induced toxicity in pancreatic β-cells, thereby providing a new theoretical basis for the prevention and treatment of cadmium-induced pancreatic β-cell injury.
Inflammatory joint diseases, including osteoarthritis, are multifactorial disorders in which dysregulated innate immune signaling and non-coding RNA (ncRNA)-mediated regulation of gene expression play essential roles. MicroRNA-155 (miR-155), its host gene MIR155HG, and Toll-like receptor 4 (TLR4) form a tightly linked inflammatory signaling axis, yet their combined genetic variability in chronic joint inflammation remains insufficiently characterized. The aim of this study was to investigate genetic variants in MIR155HG exon 3, mature miR-155, and TLR4 exon 3 and assess their potential synergistic role in chronic inflammatory joint disease. A case-control study was conducted with 100 cases (50 osteoarthritis patients and 50 matched healthy controls). Genomic DNA was analysed using polymerase chain reaction (PCR) and Sanger sequencing. Variant alleles and genotypes were identified, and their allele frequencies and genotypes were calculated using Mutation Surveyor. Detected variants were compared with public databases, and in silico tools were used to estimate the structural impact of TLR4 missense mutations. Sixteen heterozygous variants were identified in MIR155HG exon 3, most of them novel and population-specific. Interestingly, the highest variant frequencies for MIR155HG exon 3 were observed at positions 12448G>GC and 12481T>TA (both 64.3%), followed by 12442T>TC (57.1%). Additionally, two novel variants were detected in the miR-155 gene (chr21:29,694,314 G>A and chr21:29,646,351 T>C), each present at an allele frequency of 7.1% and absent from current external variant databases. Moreover, two rare TLR4 exon-3 variants were identified; a synonymous variant, c.147C>A (Pro49Pro; rs375037549), and a missense mutation, c.148G>A (Asp50Asn; rs776561489). Notably, in silico analyses and molecular dynamic simulations indicated that the Asp50Asn (D50N) substitution destabilizes the TLR4 protein. Conclusion: Concurrent variants in MIR155HG, miR-155, and TLR4 suggest a convergent regulatory molecular axis that may contribute to disease susceptibility and inflammatory progression.
Breast cancer (BRCA) is the most common cancer worldwide, with an incidence exceeding that of lung cancer. Protein lactylation, a newly identified post-translational modification involving the binding of lactic acid to lysine residues, plays an important role in BRCA. However, its role in BRCA progression remains largely unexplored. This study aims to identify and characterize the lactylation-related genes involved in BRCA biology. Transcriptomic and clinical data of BRCA and normal breast tissues were obtained from TCGA and GEO. Lactylation-related genes were curated from literature and intersected with BRCA datasets to identify candidates. A prognostic risk model was constructed using LASSO and Cox regression. Functional enrichment was performed using KEGG, GSVA, and GSEA. Immune correlations were evaluated by ESTIMATE, CIBERSORT. Single-cell RNA-seq data were integrated to assess gene expression heterogeneity across tumor and immune compartments. In vitro, MDA-MB-231 cells were treated with sodium L-lactate and lactylation-inducing agents, and gene expression was validated by Western blot and RT-qPCR, while EdU and wound healing assays evaluated proliferation and migration. We identified six hub genes associated with the immune microenvironment. Notably, S100A4 is significantly underexpressed, suggesting their potential regulatory roles in BRCA. Further analysis demonstrated that lactylation-related genes are closely linked to immune regulation in BRCA, indicating a possible crosstalk between metabolic modification and tumor immunity. Additionally, we found that lactylation significantly influences gene expression patterns and immune infiltration in BRCA. Importantly, lactic acid ions were shown to upregulate lactylation levels in BRCA cells, underscoring the functional impact of metabolic signals on post-translational modifications in tumorigenesis. Our findings indicate a potential mechanism wherein lactylation affects BRCA progression via lactic acid-driven regulation of the immune microenvironment; they also highlight the possible involvement of S100A4 in this process and offer new insights that could contribute to the diagnosis and treatment of BRCA.
Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by cholinergic dysfunction, amyloid-β aggregation, mitochondrial stress, and aberrant kinase activity. Carotenoids, naturally occurring pigments with antioxidant and neuroprotective properties, have emerged as promising candidates for AD intervention. In this study, we performed a systematic stepwise computational screening of a large carotenoid library (n = 1191) to identify multitarget candidates against AD-related proteins. The workflow consisted of predefined ADMET filtering (oral absorption > 90%, Caco-2 > 0.9, logBB > -1, and absence of major CYP inhibition and toxicity alerts), reducing the dataset to 61 compounds, followed by multi-target molecular docking against AChE, BChE, BACE-1, MAO-B, and GSK3-β. Compounds were ranked using an aggregated mean docking score across all five targets, and the top-performing candidate was subjected to detailed mechanistic analyses. Hopkinsiaxanthin emerged as the highest-ranked multitarget carotenoid and was further evaluated using frontier molecular orbital (FMO) analysis, pharmacophore modeling, 100 ns molecular dynamics (MD) simulations, MM/PBSA binding free energy calculations, and per-residue decomposition. Docking predicted favorable estimated binding affinities toward all targets. MD simulations confirmed stable receptor-ligand complexes with low RMSD values (0.278-0.285 nm). MM/PBSA analysis indicated favorable binding free energies, particularly for GSK3-β (-22.73 kcal/mol) and AChE (-21.50 kcal/mol). Per-residue decomposition identified key hotspot residues driving stabilization. Overall, this structured computational framework identifies Hopkinsiaxanthin as a promising multitarget scaffold and supports its prioritization for experimental validation in AD models.
The insulin-like growth factor 1 (IGF-1) gene plays a key role in growth and production traits in livestock. Limited information is available regarding its genetic polymorphisms in Saudi camel breeds. This study aimed to investigate genetic variation in the IGF-1 gene among Saudi camel breeds to provide baseline genetic information for future association studies. A total of 176 camels representing six Saudi breeds were sampled. DNA was extracted and Polymerase chain reaction (PCR) amplification and Sanger sequencing were applied to detect IGF-1 polymorphisms. Genotype and allele frequencies were calculated across breeds, and statistical comparisons were performed based on proportional distributions to account for unequal sample sizes. Two single-nucleotide polymorphisms (SNPs) were identified: c.365G>A in exon 3 and c.435C>T in exon 5. The exon 3 variant resulted in a missense mutation (p. Arg122His) but was detected in heterozygous form in only one camel, and subsequent screening of 109 additional samples confirmed its rarity. The exon 5 variant was synonymous in isoform X1 and located in the 3' untranslated region of isoform X2. Sequencing of 176 camels revealed that c.435C>T was highly polymorphic across the examined breeds. Significant differences in genotype frequencies were observed within and among breeds (p < 0.001). The CT genotype predominated in Waddah (60%), Shageh (48%), and Sofor (60%), significantly exceeding CC and TT frequencies (p < 0.001). In Majaheem and Saheli, CT (47%) and TT (45%) were nearly equal and both significantly higher than CC (p < 0.001). Shaele exhibited a distinct pattern, with TT being most frequent (57%), significantly higher than CC (7%, p < 0.001) and CT (36%, p < 0.01). These findings indicate directional selection favoring the C allele in the Waddah and Shageh breeds, whereas the T allele is favored in the remaining breeds. This study provides the first baseline characterization of IGF-1 polymorphisms among Saudi camel breeds. Although no phenotypic associations were assessed, the results offer a foundation for future research examining relationships between IGF-1 variants and economically important traits.
Background: Cognitive and psychiatric disorders are caused by a complex interplay between genetic predisposition, environmental exposures, and dynamic molecular regulation in the brain. Animal models provide a controlled environment for examining these mechanisms, and advances in transcriptome and epigenomic technologies have greatly expanded our knowledge of disease-relevant pathways. Objective: This scoping review systematically maps and synthesizes the epigenetic and transcriptomic findings from the established animal models of four neuropsychiatric conditions-autism spectrum disorder (ASD), schizophrenia, depression, and Rett syndrome-drawing on a PRISMA-ScR-guided literature search. The review characterizes the breadth of evidence, identifies convergent and divergent molecular pathways, and highlights the translational gaps and therapeutic implications. Methods: Research employing chromatin accessibility testing, genome-wide DNA methylation mapping, single-cell and bulk RNA sequencing, histone modification profiling, and multi-omics integration in mouse and other validated animal models was thoroughly reviewed. A quality appraisal of the primary experimental studies (n = 63) was performed using a modified CAMARADES checklist. Results: Beyond generalized cellular stress responses, multi-omics analysis emphasizes the cell-type- and context-dependent nature of epigenetic changes in animal models, including isoform-specific histone modifications and model-dependent binding of HDAC/MeCP2 complexes to genes involved in synaptic plasticity. Single-cell RNA sequencing analyses have uniformly shown transcriptional changes in parvalbumin-positive (PV+) interneurons. Conclusions: The specific convergence of epigenetic disruptions in neural circuits involved in synaptic structure and inhibitory function could play a role in the generation of neuropsychiatric phenotypes in animal models, highlighting the importance of circuit- and cell-type-specific epigenetics while pointing to potential therapeutic avenues.
In an era marked by rising stress-related disorders and cardiovascular morbidity, understanding how the brain and heart adapt to environmental, physiological, and social stressors has become an urgent biomedical priority. This review advances an integrative framework centered on sociostasis, defined as the dynamic regulation of physiological state through social interaction, and its intersection with hormesis, a biphasic adaptive response to controlled stress that enhances resilience. We focus on four evolutionarily conserved neuropeptides, vasopressin, oxytocin, corticotropin-releasing hormone, and the urocortins, which serve as molecular bridges linking social behavior, neuroendocrine signaling, autonomic regulation, and cardiovascular function. Operating within an organized autonomic architecture, these systems calibrate responses to acute and chronic stress. Their context-dependent synergy enables adaptive flexibility under manageable challenge but may promote maladaptive cardiovascular remodeling when chronically dysregulated. Genetic vulnerability, developmental adversity, and persistent psychosocial stress can shift neuroendocrine-autonomic set points, increasing susceptibility to hypertension, endothelial dysfunction, and stress-induced cardiomyopathy. Conditioning and preconditioning paradigms illustrate how repeated exposure to subthreshold stressors primes cardiovascular tissues for future insults, enhancing ischemic tolerance and adaptive gene expression. We propose that cardiovascular hormesis depends not only on stimulus intensity but also on the integrity of neuroautonomic regulatory mechanisms that support recovery and flexibility. Vagal efficiency, a dynamic index of cardioinhibitory regulation, is discussed as a potential translational metric of adaptive capacity. By integrating molecular, physiological, and psychosocial perspectives, this framework conceptualizes cardiovascular resilience as an emergent property of coordinated hormetic signaling, neuropeptidergic modulation, autonomic regulation, and social buffering. Translational implications include peptide-based therapies, autonomic biofeedback, and behavioral interventions designed to enhance stress adaptability.
LncRNAs, defined as transcripts longer than 200 nucleotides with limited protein-coding potential, have emerged as important regulators of gene expression across multiple levels of cellular regulation. These molecules influence chromatin organization, transcriptional activity, and post-transcriptional processes through diverse interactions with DNA, RNA, and protein complexes. Although initially considered transcriptional byproducts, accumulating evidence now indicates that lncRNAs participate in a wide range of physiological processes and are implicated in numerous human diseases, including cancer, cardiovascular disorders, neurological diseases, and immune related conditions. However, the strength of mechanistic evidence varies substantially across the field, with robust functional validation currently limited to a relatively small number of well-characterized lncRNAs. In many cases, proposed regulatory roles remain supported primarily by expression correlations or limited perturbation studies, highlighting the need for careful evaluation of reproducibility, context dependence, and locus-specific effects. In addition, translating lncRNA discoveries into therapeutic strategies faces several practical challenges, including efficient tissue-specific delivery, subcellular localization constraints, isoform complexity, and potential off-target effects. This review provides an overview of current knowledge on lncRNA classification, biogenesis, and molecular mechanisms, evaluates their roles in human disease, and discusses emerging therapeutic approaches in the context of translational feasibility. By integrating mechanistic insights with current limitations and unresolved questions, we highlight priorities for future research aimed at harnessing lncRNAs for diagnostic and therapeutic applications in precision medicine.
Alzheimer's disease is a progressive neurodegenerative disorder marked by declining cognitive function. While early-stage treatment focuses on acetylcholinesterase (AChE) inhibition, butyrylcholinesterase (BChE) activity increases as the disease progresses, contributing to cholinergic deficits and neuroinflammation. This shift in enzyme dominance presents a compelling rationale for developing BChE-specific inhibitors as a potential therapeutic avenue. This study explores small, three-membered rings, scaffolds offering potential for interaction with the enzyme's active site, as building blocks for novel BChE inhibitors. Employing a computational approach based on quantum-chemical multiligand simultaneous molecular docking, we virtually fitted these compounds into the BChE active site to predict binding affinity and key interactions. Our calculations extend beyond simple shape matching by incorporating accurate electronic properties, leading to more reliable predictions of binding strength and stability. The goal was not immediate identification of potent inhibitors, but a systematic assessment of how these rings interact with BChE. This foundational knowledge will inform the design and synthesis of larger, more complex molecules with enhanced binding affinity and selectivity, ultimately aiming to develop compounds to inhibit BChE activity and potentially slow Alzheimer's progression.
Epimedium brevicornu is an important medicinal plant in China, whose main bioactive components are flavonoid glycosides. UDP-glycosyltransferases (UGTs) play key roles in flavonoid glycosylation and metabolic diversification. In this study, transcriptome data from four representative production regions in Gansu Province were used to systematically identify and analyze the UGT gene family in E. brevicornu. A total of 359 UGT members were identified, and 168 homologous genes with clear expression evidence were obtained from four geographical populations. Molecular evolutionary analysis showed that most UGT genes were under purifying selection, whereas UGT2, UGT52, UGT57, UGT241, UGT269, and UGT271 exhibited significant signals of positive selection in specific lineages (p < 0.05). Protein interaction analysis indicated that many UGT proteins were closely associated with key enzymes involved in flavonoid biosynthesis, including CHS (TT4), CHI (TT5), F3H, FLS, and DFR, suggesting their potential involvement in flavonoid metabolism. Promoter analysis further revealed a high enrichment of ERF (11,169 occurrences) and MYB (7673 occurrences) transcription factor binding sites in the upstream regions of UGT genes. In addition, UGT57 and UGT241 showed significantly higher expression levels in the QLH population. Molecular docking analysis indicated relatively strong binding affinities with quercetin, with binding energies of -7.23 kcal/mol and -4.62 kcal/mol, respectively. These results suggest that the sequence variation and differential expression of UGT genes may be associated with flavonoid glycosylation and ecological adaptation in Epimedium. This study provides a basis for understanding the evolutionary characteristics and expression patterns of the UGT gene family and offers candidate genes for future studies on flavonoid metabolism.
Endometrial cancer (EC) is the most common gynecologic malignancy in developed countries, with increasing incidence linked to obesity and metabolic dysfunction. While early-stage EC is often curable, advanced and recurrent disease remains difficult to treat due to resistance and limited therapeutic options. Natural products derived from traditional Chinese medicine have attracted attention as complementary strategies in EC management. These compounds exhibit multi-target effects, including modulation of estrogen signaling, inhibition of proliferation, induction of apoptosis, and regulation of immune and inflammatory pathways. This review summarizes current evidence on natural products in EC, integrating preclinical findings, emerging clinical data, and mechanistic insights from molecular and systems biology approaches. Key challenges, including variability, bioavailability, and insufficient clinical validation, are discussed. Future directions emphasize the integration of natural products into precision oncology frameworks.