Search Results (251)

Background/Objectives: Management of bipolar disorder is marked by variability in lithium response, with responders constituting a distinct clinical subgroup. Although pharmacogenetic studies implicate polymorphisms in neuroplasticity-related genes (BDNF) and hypothalamic–pituitary–adrenal (HPA) axis regulators (NR3C1), the underlying biophysical mechanisms remain poorly characterized. This study aims to bridge this structural–mechanistic gap by quantifying the atomic-level effects of key lithium-response polymorphisms on protein–protein interaction stability and conformational dynamics. Methods: Variant sequences for BDNF rs6265 and NR3C1 rs56149945 were generated and structurally modeled with SWISS-MODEL. Protein–protein interaction analyses focused on the BDNF–TrkB and NR3C1–FKBP5 systems. Structural alignment and conformational comparisons were performed with ChimeraX and US-align, while interaction energetics were evaluated with PRODIGY and HawkDock. Conformational flexibility was assessed using CABS-flex through RMSF analysis. Results: Structural validation showed acceptable model quality. Binding analyses indicated stronger interactions in the variant complexes. In the BDNF–TrkB complex, binding affinity shifted from −13.8 to −15.1 kcal/mol with an ~8.5-fold lower dissociation constant, while the NR3C1–FKBP5 variant complex shifted from −16.3 to −18.8 kcal/mol with an ~65-fold lower dissociation constant. MM/GBSA calculations supported increased stability, with binding energies changing from −61.98 to −83.91 kcal/mol (BDNF–TrkB) and from −18.88 to −31.25 kcal/mol (NR3C1–FKBP5). Structural superposition showed high conservation of global folds (pruned RMSD 0.779 Å and 0.310 Å; TM-scores 0.753 and 0.967). RMSF profiles were largely overlapping, indicating localized interface adjustments rather than global conformational changes. Conclusions: These findings suggest that lithium-response polymorphisms may modulate protein–protein interaction stability while preserving overall structure, providing a structural framework for exploring genetic influences on lithium treatment response. Full article

Background/Objectives: Adaptogens are plant-derived substances that enhance the body’s nonspecific resistance to physical, chemical, biological, and psychological stressors by normalizing physiological functions. This article discusses the molecular mechanisms of action of seven key plant adaptogens—Rhodiola rosea, Schisandra chinensis, Withania somnifera, Eleutherococcus senticosus, Panax ginseng, Ocimum tenuiflorum, and Bacopa monnieri—in the context of chronic stress and lifestyle-related diseases. Methods: A review of the scientific literature is performed, including preclinical in vitro and in vivo studies, randomized placebo-controlled clinical trials, and studies employing network pharmacology analyses, molecular docking, and genomic techniques such as gene expression profiling. The interactions of active constituents with signaling pathways, molecular targets, and synergistic mechanisms were analyzed based on publications from the years 2010–2025. Results: Adaptogens exhibit pleiotropic activity: they regulate the HPA axis (Hypothalamic–Pituitary–Adrenal axis); induce Hsp70/Hsp16 expression; modulate SAPK/JNK, FOXO, and NF-κB pathways; and demonstrate antioxidant and mitoprotective effects. Specific mechanisms include: salidroside from R. rosea activating PI3K/Akt; schizandrin B from S. chinensis stimulating Hsp70; withanolides from W. somnifera inhibiting PDE4D; ginsenosides from P. ginseng suppressing FKBP51; and bacosides from B. monnieri enhancing acetylcholine synthesis. Clinical studies confirm reductions in cortisol levels (14–30%), decreased fatigue, and improved cognitive function without adverse effects. Conclusions: Understanding the molecular mechanisms of adaptogens supports their application in integrative medicine for the treatment of stress-related disorders, depression, anxiety, and neurodegenerative diseases. Further clinical studies are needed to optimize dosages and standardize extracts. Full article

Cardiac Ca²⁺ handling is critical for excitation–contraction coupling (ECC), with the ryanodine receptor type 2 (RyR2) serving as the key sarcoplasmic reticulum (SR) Ca²⁺ release channel in cardiomyocytes. The dysfunction of RyR2 is linked to fatal cardiac arrhythmias, including heart failure (HF) and catecholaminergic polymorphic ventricular tachycardia (CPVT). This review aims to elucidate the structural basis of RyR2, its core role in cardiac ECC and Ca²⁺ homeostasis, and the regulatory mechanisms of key modulators on its activity. By integrating recent high-resolution cryo-EM structural analyses with molecular and cellular studies on RyR2 regulation, as well as clinical evidence of RyR2 mutations in arrhythmogenic heart diseases, we provide a comprehensive overview of the field. Cryo-EM has unraveled RyR2’s gating mechanisms, ligand-binding sites, and structural features. Functionally, RyR2 mediates calcium-induced calcium release (CICR) and maintains Ca²⁺ homeostasis through coordination with SERCA2a and NCX. Key modulators (CaM, FKBP12.6, and PKA/CaMKII) and disease-linked mutations regulate RyR2 activity through distinct pathways, with defective RyR2 leading to store-overload-induced Ca²⁺ release (SOICR) and arrhythmias. Furthermore, reactive oxygen species (ROS) can induce RyR2 oxidation, establishing a pathological Ca²⁺ leak-ROS cycle in heart disease. In conclusion, RyR2 is a pivotal sensor of myocardial function, with its structural and regulatory mechanisms now well-characterized by recent studies. However, the effects of numerous RyR2 mutations remain unclear, and deeper mechanistic insights will lay a key foundation for developing novel therapies against RyR2-related cardiac diseases. Full article

Bighead carp (Hypophthalmichthys nobilis) is a key aquaculture species, with the head and its orbital fat being a commercially valuable product. To elucidate the molecular basis of growth variation, we performed comparative transcriptome analysis of orbital fat from extreme growth phenotypes at juvenile (6 months) and market-size (18 months) stages. In juveniles, slow growth was linked to upregulation of stress-responsive genes (sgk1, fkbp5, lipg), while fast growth correlated with higher expression of stress-buffering (crhbp) and nutrient-signaling (rbp2, mgea5) genes. At 18 months, divergent growth aligned with opposing lipid metabolic states: a pro-anabolic profile (dgat2, fads2) supported fast growth, whereas a catabolic profile (cpt1b, ppargc1a) was associated with slow growth. These results demonstrate stage-specific transcriptional reprogramming in orbital fat underlying growth variation. This study provides a molecular framework for orbital fat-mediated growth regulation and highlights potential candidate genes for molecular breeding in bighead carp. Full article

Suicidal behavior is a multifactorial and highly heritable phenotype; however, data concerning its genetic determinants in disparate ethnic groups remain limited. Genes implicated in serotonergic neurotransmission and stress response regulation are regarded as primary candidates for elucidating biological vulnerability to suicide. The objective of this study is to investigate the relationship between suicide attempts and candidate gene polymorphisms in an ethnically homogeneous Kazakh population from Astana, Kazakhstan. The study’s sample population comprised 126 patients with a documented history of suicide attempts and 120 age- and gender-matched controls without a history of suicidal behavior. A comprehensive genotyping analysis was conducted, encompassing polymorphisms in genes associated with serotonergic signaling, stress response, and neuroplasticity (TPH1, TPH2, HTR2A, MAOA, SLC6A4, ANKK1, BDNF, COMT, CXCL8, SKA2, and FKBP5). The associations were assessed across several genetic models, using odds ratios with 95% confidence intervals. A substantial correlation was identified between the HTR2A rs6311 polymorphism and suicide attempts. The CC genotype exhibited a protective effect (p = 1.36 × 10⁻⁵), while the TT genotype was associated with an elevated risk (OR = 3.16; 95% CI: 1.72–5.81). The association remained robust after stratification by sex, with an even stronger effect observed in women (OR = 4.70; 95% CI: 2.08–10.64). A nominal sex-specific association was observed for the SKA2 rs7208505 variant, suggesting a potential role in stress-response mechanisms in women; however, this association was no longer statistically significant after adjustment for multiple comparisons. These results identify HTR2A rs6311 as a potential genetic marker of suicide risk in the Kazakh population and support the involvement of serotonergic receptor regulation in the biological mechanisms underlying suicidal behavior. The results underscore the significance of sex-specific genetic influences, thereby enhancing our understanding of the polygenic underpinnings of suicidality. Full article

Accumulating evidence indicates that epigenetic and post-transcriptional mechanisms interact to shape stress vulnerability and the adaptive capacity of the central nervous system (CNS). This review aimed to identify molecular markers with potential prognostic value for stress-induced CNS disorders. We analyzed 93 publications (2008–2025) identified in PubMed, Scopus, Web of Science Core Collection, and the Cochrane Library, including 80 original experimental and clinical studies, as well as 13 reviews and meta-analyses addressing epigenetic regulation, hypothalamic–pituitary–adrenal (HPA) axis function, CNS remodeling, and therapeutic or environmental modulation in stress-exposed models and clinical cohorts with stress-related disorders. Across studies, altered methylation of NR3C1, FKBP5, and BDNF, reduced hippocampal histone acetylation, and shifts in microRNA profiles (miR-16, miR-124, miR-132, miR-135a, miR-34c) were repeatedly associated with HPA axis dysregulation, limbic system remodeling, and phenotypes relevant to PTSD and depression. Evidence further suggests that at least some of these signatures show partial reversibility, with modulation reported after pharmacological interventions (e.g., SSRIs, histone deacetylase inhibitors, FKBP51 inhibitors, ketamine) and non-pharmacological approaches (e.g., physical activity, social support) in animal models and, to a lesser extent, in clinical and observational studies. We conclude that targeted modulation of specific epigenetic and post-transcriptional pathways supports the development of candidate biomarkers and may inform stratified prevention and treatment strategies for stress-induced CNS disorders, while acknowledging that further validation in large, well-characterized cohorts is required. Full article

The origins of major depressive disorder (MDD) are complex, involving both environmental influences and a substantial genetic contribution. Genetic polymorphisms have been implicated in modulating susceptibility, disease course, and treatment response, yet findings are often modest, population-dependent, and sometimes inconsistent. This narrative review synthesizes current evidence on genetic variants associated with MDD, highlighting well-replicated results while distinguishing exploratory or emerging findings. Key systems reviewed include serotonergic (SLC6A4), neurotrophic (BDNF rs6265 and rs962369), dopaminergic and stress-response pathways (COMT, FKBP5, CRHR1), as well as additional emerging genes such as MAOA, TPH2, and FTO. We evaluate these variants in the context of their biological relevance, including neuroplasticity, neurotransmission, and hypothalamic–pituitary–adrenal (HPA) axis regulation, and discuss how polygenic and epigenetic interactions may shape clinical heterogeneity. This framework not only integrates current genetic knowledge but also outlines potential translational applications, offering perspectives for personalized approaches to diagnosis, prognosis, and treatment in MDD. Full article

Burnout syndrome is increasingly recognized as a significant occupational health issue, characterized by emotional exhaustion, depersonalization, and a reduced sense of personal accomplishment. It predominantly arises from chronic work-related stress, but recent research has highlighted the role of genetic and epigenetic factors in determining individual vulnerability to burnout. This review aims to synthesize findings regarding the genetic footprints of burnout, focusing on genes related to stress regulation, including the 5-HTT (serotonin transporter) gene, BDNF (brain-derived neurotrophic factor) gene, and NR3C1 (glucocorticoid receptor) gene. Twin studies reveal that burnout is moderately heritable, with genetic factors accounting for 33–36% of the variability in burnout-related traits, such as emotional exhaustion and performance-based self-esteem. However, burnout risk seems highly driven by non-shared environmental factors, such as work stress, lack of social support, and personal coping mechanisms. Specific genetic polymorphisms in the serotonergic system (5-HTT) and HPA axis genes (NR3C1, FKBP5) have been linked to increased burnout susceptibility, particularly in individuals exposed to chronic job strain or early-life stressful situations. Variations in 5-HTT rs6354 and HTR2A rs6313 are associated with altered stress reactivity, while polymorphisms in NR3C1 and FKBP5 contribute to dysregulation of the HPA axis, which influences cortisol secretion patterns in response to stress. Increased methylation in genes like BDNF and SLC6A4 has been observed in individuals with burnout, suggesting that environmental stressors may lead to lasting changes in gene expression, contributing to the syndrome’s development. Studies on telomere length have shown that burnout is associated with accelerated cellular aging, with individuals exhibiting shorter telomeres, particularly during high-stress periods. These findings hold particular relevance for professionals within the forensic and justice systems, including law enforcement, the judiciary, and forensic experts, who operate under chronic, high-stakes stress. We examine how understanding the biological basis of burnout can inform more objective ‘fitness-for-duty’ evaluations and provide a scientific framework for distinguishing physiological exhaustion from professional negligence in legal contexts. Full article

With the aim of identifying key proteins that play a role in the disorder tinnitus, interactions between proteins involved in thalamo-amygdala signaling under conditions of normal hearing (NH), acoustic stimulation (AS), and tinnitus (Tin) were studied. Three gene lists compiled from the GeneCards database using keywords were characterized by analyses of overlap, protein–protein interaction (PPI) networks, and by protein-enrichment analysis. Key proteins were selected on the basis of the degree and combined score value of the corresponding PPI network. In the NH process, BDNF, CASP3, and PVALB were identified as high-degree proteins (HDPs). In the AS process, BDNF, PVALB, and DLG4 are the top three HDPs; in the Tin process, these are BDNF, APP, and TNF. In the Tin process, key proteins appear that differ pre- and postsynaptically from those detectable in NH or AS. The glucocorticoid receptor NR3C1 and its interaction with FKBP5, a glucocorticoid receptor-induced co-chaperone, appear to be of particular importance for the emotional aspects of tinnitus. In tinnitus, the HDPs, together with their high-score interaction proteins, indicate processes of chronic neurodegeneration and of changes in transcription, intercellular communication, and in the survival and growth of neurons. Full article

Background/Objectives: Synovial sarcoma (SS) is a rare and aggressive soft-tissue malignancy characterized by complex molecular alterations and poor prognosis, highlighting the need for targeted immunotherapeutic strategies. This study aimed to design a rational multi-epitope vaccine targeting the FKBP10 oncoprotein to elicit effective immune responses against SS. Methods: Transcriptomic data from the GEO dataset GSE144190, comprising 10 tumor and 9 normal tissue samples, were analyzed to identify differentially expressed genes (DEGs). Results: Our findings revealed significantly upregulated FKBP10 with a log2 fold change of 3.55, baseMean expression of 1521.84, and adjusted p-value of 8.37 × 10⁻²⁶. Mutational analysis across 7782 sarcoma samples indicated a low alteration frequency of ~1.5%, primarily missense variants. Functional mapping showed FKBP10 as a hub interacting with multiple collagen chains and chaperone proteins, implicating its role in extracellular matrix organization and protein folding. Linear B-cell epitope prediction identified 17 epitopes (6–21 amino acids), while T-cell mapping yielded 10 MHC class I and 9 MHC class II high-affinity epitopes, all antigenic (VaxiJen > 0.5) and non-allergenic. A multi-epitope vaccine was constructed incorporating a 50S ribosomal protein L22 adjuvant, linkers, and a 6× histidine tag. Physicochemical analysis showed a molecular weight of 36.43 kDa, pI 6.97, instability index 31.79, aliphatic index 64.88, and GRAVY −0.509, indicating stability and hydrophilicity. Structural modeling validated 82.5% residues in favored regions. Molecular docking revealed strong binding with TLR4 (−9.7 kcal/mol) and TLR9 (−9.4 kcal/mol), and 200 ns molecular dynamics simulations confirmed stable RMSD trajectories, low RMSF at binding residues (<4 Å), persistent hydrogen bonding, compact radius of gyration (38–42 Å for TLR4; ~20 Å for TLR9), favorable total energy (−1400 to −1500 kcal/mol for TLR4; −650 to −720 kcal/mol for TLR9), and stable SASA (~52,000–54,000 Ų). Conclusions: These findings demonstrate that the FKBP10 multi-epitope vaccine is structurally stable, immunogenic, and capable of engaging key innate immune receptors, supporting its potential as a promising immunotherapeutic candidate for synovial sarcoma. Full article

Sheep’s meat production and quality are influenced by genetic and physiological factors that affect muscle development, growth, and fat deposition metabolism. However, the breed-specific transcriptional landscapes driving these traits in Indian sheep breeds, especially in Nellore (meat-type) and Deccani (wool-meat type) breeds are remain unexplored. Therefore, this study aimed to investigate the differences in muscle growth and fat deposition between Nellore and Deccani breeds by integrating transcriptomic profiling, carcass characteristics, and histological analysis of longissimus dorsi muscle and liver tissues. Carcass assessment revealed higher Hot Carcass Weight (HCW), Cold Carcass Weight (CCW), Hot Carcass Yield (HCY) and Cold Carcass Yield (CCY), and larger myofibrillar cross-sectional area (p < 0.05), indicating enhanced musculature, which was observed in Nellore. Deccani showed elevated Intramuscular Fat (IMF) deposition (p < 0.05), indicating improved meat flavour/juiciness. Transcriptomic profiling revealed several Differentially Expressed Genes (DEGs) associated with meat quality and quantity traits. In Nellore, the genes WFIKKN2, FGFRL1, FKBP4, and IRF1 were upregulated, while the gene TAS1R2 was downregulated, leading to enhanced muscle development, superior carcass traits, thermotolerance, and immunity. While Deccani showed higher expression of lipid metabolism genes PLA2G4F, ACSL1, ACOX1, CPT1A, and PLIN1, which are linked to higher IMF content. Functional enrichment analysis revealed 46 significantly enriched GO terms for the DEGs (p < 0.05), including oxidoreductase activity, muscle development, etc. These outcomes demonstrate novel genetic markers and key biological insights into the regulation of muscle development, thermotolerance, immunity, and IMF for future validation in Indian sheep breeds. Full article

Chronic stress and sustained hypothalamic–pituitary–adrenal (HPA) axis activation are major contributors to metabolic bone diseases, including osteoporosis. However, the precise molecular mechanisms by which chronic stress-induced HPA axis dysregulation drives bone deterioration remain unclear. A Chronic Unpredictable Mild Stress (CUMS) model was established in male rats to simulate prolonged stress exposure. Animals were randomly allocated into three groups: control, 10-week CUMS, and 20-week CUMS (n = 10/group). Model validity was confirmed via behavioral assessments. Bone mineral density (BMD) and trabecular microarchitecture were quantified using micro-computed tomography (micro-CT). Serum corticosterone (CORT) levels, HPA axis negative feedback function, and the expression of pro-inflammatory cytokines (IL-1β, TNF-α) in HPA-regulatory brain regions (hippocampus, prefrontal cortex, hypothalamus) were assessed. Critically, glucocorticoid receptor (GR) expression and nuclear translocation in these brain regions and bone tissue were examined by immunofluorescence and Western blot analysis. CUMS exposure induced progressive, time-dependent bone loss, with the 20-week group exhibiting significantly greater reductions in BMD and trabecular quality compared to the 10-week and control groups. While the HPA axis showed initial hyperactivation, the 20-week group displayed adrenal exhaustion (reduced serum CORT) alongside elevated ACTH, indicating feedback failure. Mechanistically, stress significantly impaired GR nuclear translocation in both brain and bone tissues, coinciding with the upregulation of FKBP5 and pro-inflammatory cytokines. Notably, despite low systemic CORT at late stages, skeletal 11β-HSD1 expression was significantly upregulated, creating a local microenvironment of glucocorticoid toxicity that aggravated osteoblast apoptosis. Our findings demonstrate that chronic stress induces progressive, time-dependent bone loss through a cascade of HPA axis dysregulation and impaired GR signaling. The FKBP5-mediated impairment of GR nuclear translocation in both central and peripheral tissues fosters glucocorticoid resistance, perpetuating hypercortisolemia and a pro-inflammatory milieu that directly accelerates osteoblast apoptosis and bone deterioration. These findings identify the HPA-GR axis as a critical pathway linking chronic stress to osteoporosis and suggest that restoring GR signaling offers a potential therapeutic strategy. Full article

Hydroxyprogesterone (HP) is a synthetic progestogen widely used in obstetric care, and its potential influence on breast cancer biology has become an emerging area of interest. Despite its clinical use, the molecular mechanisms by which HP affects tumor tissue remain insufficiently explored. In this study, transcriptomic profiling was performed to investigate gene expression changes associated with HP in operable breast cancer. Pre-operative 17α-HP caproate (17-OHPC) exposure was associated, in normal adjacent tissue (NAT), with activation of steroid-hormone and lipid/xenobiotic-metabolism programs and crosstalk to phosphoinositide 3-kinase (PI3K)–Akt and nuclear factor kappa B (NF-κB). In NAT, these pathways showed the largest absolute log₂ fold-change (|log₂FC|); significance is reported as false discovery rate (FDR) throughout (e.g., FKBP5↑ with HP). In tumor tissue, the dominant signal reflected tight-junction/apical-junction and extracellular matrix (ECM)-receptor remodeling (e.g., CLDN4↑). We prioritized FKBP5 (HP pharmacodynamics) and CLDN4 (tumor baseline) as the main candidates; TSPO and SGK1 are reported as exploratory. This discovery-level, hypothesis-generating analysis nominates candidate biomarkers and pathway signals for prioritization and evaluation in independent datasets and future studies. These findings provide mechanistic insight into HP’s molecular effects in breast cancer and suggest potential applications in biomarker perioperative management. Full article

Rice (Oryza sativa L.) is a major global staple crop, yet its productivity is severely constrained by rice blast disease caused by Magnaporthe oryzae. FK506-binding proteins (FKBPs) are peptidyl-prolyl cis-trans isomerases involved in protein folding, stress response, and signaling regulation, but their roles in rice blast resistance remain unclear. In this study, we performed a comprehensive identification and characterization of FKBP gene family members in two rice cultivars, Nipponbare (NIP) and Zhonghua 11 (ZH11), based on the latest T2T (telomere-to-telomere) genome assembly of ZH11 and the reference genome of NIP. A total of 24 and 29 FKBP genes were detected in NIP and ZH11, respectively, indicating a slight expansion in ZH11. Phylogenetic and collinearity analyses revealed strong conservation of FKBP family members between the two cultivars, while several ZH11-specific genes likely resulted from recent duplication events. Promoter analysis showed that FKBP genes are enriched in stress and hormone responsive cis-elements, particularly those related to ABA, MeJA, and SA signaling. Transcriptomic and RT-qPCR analyses demonstrated that multiple FKBP genes were significantly regulated during M. oryzae infection, suggesting their potential involvement in defense signaling pathways. This study provides a comprehensive overview of FKBP gene family evolution and expression in rice, identifies candidate genes potentially associated with blast resistance, and offers valuable insights for molecular breeding aimed at improving disease resistance in rice. Full article

Autism spectrum disorder (ASD) arises from complex genetic and environmental influences. Despite its prevalence and being the focus of study for several decades, its causes and their underlying mechanisms are still not fully understood. However, one consistent causal mechanism of interest is epigenetic modification. While some risk factors, such as maternal stress, nutrition, and environmental toxins, have a more established epigenetic connection, early-life stress (ELS) in the postnatal years is less studied but may be just as impactful in terms of phenotypic outcomes. A major intermediary between ELS and ASD is likely the hypothalamic–pituitary–adrenal axis (HPA axis), which has been shown to be epigenetically modified by ELS and whose genes and dysfunction overlap with ASD genes and symptoms. In this narrative review, we synthesize human and animal evidence to examine the relationships between ELS and ASD through epigenetic regulation of a non-exhaustive list of autism candidate genes involved in the HPA axis, including NR3C1, FKBP5, MECP2, GAD1, RELN, SHANK3, OXTR, and BDNF. We discuss how ELS-induced epigenetics may modulate HPA axis negative feedback, and how epigenetic alterations in this pathway and associated genes could affect ASD phenotypes. Full article