Search Results (358)

Connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) is a severe form of pulmonary hypertension with poor prognosis. It most commonly arises in systemic sclerosis (SSc), followed by systemic lupus erythematosus (SLE) and mixed connective tissue disease (MCTD). Its pathogenesis involves a complex interplay of immune dysregulation, chronic inflammation, endothelial injury, vascular remodeling, and fibrosis. Although vasodilators targeting the endothelin, nitric oxide, and prostacyclin pathways remain the therapeutic backbone, newer agents—including the activin signal inhibitor sotatercept and inhaled treprostinil—have expanded treatment options. Immune-targeted therapies such as glucocorticoids, cyclophosphamide, mycophenolate mofetil, rituximab, and IL-6 receptor inhibitors may benefit inflammation-dominant PAH phenotypes, while fibrotic phenotypes continue to demonstrate limited responsiveness. In addition to brain natriuretic peptide (BNP), N-terminal (NT)-proBNP and disease-specific autoantibodies, emerging biomarkers show promise for early detection, risk stratification, and personalized treatment, though validation in CTD-PAH is lacking. Advances in animal models replicating immune-mediated vascular injury and fibrosis have further improved mechanistic understanding. Despite these developments, substantial unmet needs remain, including the absence of disease-specific therapeutic strategies, limited biomarker integration into clinical practice, and a scarcity of large, well-designed trials targeting individual CTD subtypes. Addressing these gaps will be essential for improving prognosis in patients with CTD-PAH. Full article

This systematic review investigates the impact of chronic stress on treatment outcomes among cancer patients with divergent survival rates, focusing on breast, prostate, pancreatic, and ovarian cancers. The analysis explores how chronic stress influences molecular pathways and tumor progression while comparing cancers with five-year survival rates above and below 50%. A comprehensive literature search was conducted in PubMed and Scopus for studies published between 2014 and 2025 using combinations of keywords related to “chronic stress,” “psychological stress,” “psychotherapy,” and selected cancer types. All studies met the inclusion criteria according to the PRISMA 2020 guidelines. Evidence suggests that chronic stress is associated with the activation of neuroendocrine and immune mechanisms, including β-adrenergic and glucocorticoid signaling. These multifactorial processes are associated with disease progression and survival, particularly in pancreatic and ovarian cancers; however, these links remain primarily associative rather than causative. Conversely, psychotherapeutic interventions alleviate stress-related biological responses, improve quality of life, and may indirectly enhance therapeutic efficacy. By structuring the evidence around cancers with higher versus lower five-year survival, our review provides a survival informed synthesis of cancer type specific stress biology and stress-mitigating interventions, highlighting potentially targetable pathways and clear evidence gaps for future trials. The findings underscore the need to integrate psychological care into oncological practice to improve overall outcomes. Full article

Osteoporosis is a prevalent skeletal disorder characterized by reduced bone mass and microarchitectural deterioration, leading to increased fracture risk, particularly in aging populations. Postmenopausal osteoporosis (PMOP) remains the most common primary form and results from abrupt estrogen deficiency after menopause, which disrupts bone remodeling by accelerating the receptor activator of nuclear factor-κB ligand (RANKL)-mediated osteoclastogenesis, suppressing Wnt/β-catenin signaling, and promoting inflammatory cytokine production. In contrast, drug-induced osteoporosis (DIOP) encompasses a heterogeneous group of secondary bone disorders arising from pharmacologic exposures. Glucocorticoids suppress osteoblastogenesis, enhance osteoclast activity, and increase reactive oxygen species; long-term bisphosphonate therapy may oversuppress bone turnover, resulting in microdamage accumulation; denosumab withdrawal triggers a unique rebound surge in RANKL activity, often leading to rapid bone loss and multiple vertebral fractures. Medications including aromatase inhibitors, SSRIs, proton pump inhibitors, heparin, and antiepileptic drugs impair bone quality through diverse mechanisms. Standard antiresorptive agents remain first-line therapies, while anabolic agents such as teriparatide, abaloparatide, and romosozumab provide enhanced benefits in high-risk or drug-suppressed bone states. Transitional bisphosphonate therapy is essential when discontinuing denosumab, and individualized treatment plans—including drug holidays, lifestyle interventions, and monitoring vulnerable patients—are critical for optimizing outcomes. Emerging approaches such as small interfering RNA (siRNA)-based therapeutics, anti-sclerostin agents, digital monitoring technologies, and regenerative strategies show promise for future precision medicine management. Understanding the distinct and overlapping molecular mechanisms of osteoporosis is essential for improving fracture prevention and long-term skeletal health. Full article

Social isolation and loneliness represent critical psychosocial stressors associated with profound hormonal dysregulation and adverse behavioral outcomes. This review synthesizes current evidence on neuroendocrine mechanisms linking perceived and objective social disconnection to health consequences, emphasizing hypothalamic–pituitary–adrenal axis dysfunction, altered glucocorticoid signaling, and inflammatory pathways. Loneliness activates conserved transcriptional responses with upregulated proinflammatory gene expression and downregulated antiviral responses, mediated through sustained cortisol elevation and glucocorticoid resistance. Neural circuit alterations in reward processing, particularly the ventral tegmental area-nucleus accumbens pathway, contribute to anhedonia, social withdrawal, and cognitive decline. Sex differences in neuroendocrine responses reveal distinct hormonal profiles and circuit-specific adaptations. Emerging interventions targeting oxytocin and arginine vasopressin systems, alongside behavioral approaches addressing loneliness-induced cognitive biases, show promise. Critical research gaps include a mechanistic understanding of epigenetic modifications, sex-specific therapeutic responses, and translational applications across diverse populations. Understanding the endocrine–behavior interface in social disconnection offers opportunities for targeted interventions addressing this growing public health challenge. Full article

Genotypic characteristics may determine the body’s response to stressful conditions as well as its susceptibility to cardiovascular diseases and stroke. Old age worsens the course of these diseases, and often concomitant hypertension can negatively affect brain function, especially in cases of social isolation. In this work, we studied how social isolation and hypertension affect the transcription activity of genes associated with glucocorticoid signaling in the rat brain. The study was performed on 10-month-old rats of the outbred Wistar stock (n = 48) and the inbred spontaneously hypertensive (SHR) strain (n = 28). The animals of each genotype were divided into groups, one of which was kept in home cages in groups of 3–4 individuals, and the other in single cages for 3 months. Physiological parameters and plasma corticosterone were controlled before the start and after 3 months of isolation. Each group was additionally divided into two subgroups: one subjected to 1 h of restraint stress, and changes in blood glucose and corticosterone levels were assessed. At the end, the levels of Nr3c1, Nr3c2, Hsd11b1, and Fkbp5 mRNAs were measured in the hippocampus and frontal cortex using the Q-PCR technique. After isolation, weight gain stopped in SHRs, although blood pressure did not change, and heart rate increased in rats of both genotypes. In response to restraint, there was practically no increase in corticosterone in isolated Wistar rats, whereas in SHRs, there were significant glucose and corticosterone responses. Significant disruptions in the system responsible for corticosterone-activated signaling cascades were found in the brains of SHR rats. The transcriptional activity of genes encoding corticosterone receptors and proteins regulating their action was reduced in the hippocampus and frontal cortex in SHRs compared to Wistar rats. However, neither isolation nor acute stress significantly affected the contents of transcripts studied. Meanwhile, after isolation, the relationships between the expression of these genes changed significantly, in different directions, in rats of the studied genotypes, both within and between brain structures. Thus, the SHR genotype is associated with persistent changes in the brain that affect the expression of glucocorticoid-associated genes. This indicates a more complex regulation of the stress response, not limited only by the feedback system within the hypothalamic–pituitary–adrenocortical or sympatho-adrenomedullary systems, but operated at the level of the limbic system and the cerebral cortex. Full article

Depression is a multifactorial disorder shaped by genetic, psychosocial, and biological influences, with hypotheses ranging from monoamine deficiency and neuroplasticity deficits to inflammation and stress-induced dysregulation. St. John’s wort (Hypericum perforatum L.) has long been used as an herbal antidepressant and is supported by clinical evidence for efficacy and safety in mild-to-moderate depression. While its multimodal mechanisms have been linked to neurotransmitter reuptake inhibition, neuroendocrine regulation, and modulation of neuroplasticity, recent findings suggest an additional role at the membrane level. Emerging lipidomic studies highlight that Ze 117, a low-hyperforin H. perforatum extract, counteracts stress- and glucocorticoid-induced increases in membrane fluidity by modulating lipid composition and cholesterol metabolism. These effects normalize receptor mobility and signal transduction, particularly of β1-adrenoceptors, and modulate glycerophospholipid metabolism in both cellular and animal models. Such membrane-stabilizing properties may represent a novel mechanistic pathway complementing classical neurochemical actions. This review revisits the mechanisms of St. John’s wort with a special focus on its impact on membrane lipids, positioning lipidomics as a promising tool for elucidating antidepressant activity. These insights may open avenues toward personalized therapeutic strategies in depression. Full article

Sarcopenia, characterized by the progressive loss of skeletal muscle mass and function, is exacerbated by glucocorticoid exposure. Although there is growing interest in natural therapies for muscle atrophy, the effects of Quercus acuta Thunb. fruit extract (QA) on sarcopenia or glucocorticoid-induced muscle loss had not been previously investigated. QA is an evergreen oak known for its antioxidant and anti-inflammatory properties, with polyphenolic components reported to enhance oxidative and metabolic homeostasis in various tissues. Based on these properties, we hypothesized that QA could counteract muscle atrophy by modulating anabolic and catabolic signaling pathways. The research utilized both in vitro (C2C12 myotubes) and in vivo (ICR mice) models to assess QA’s effects. Daily oral administration of QA (100–200 mg/kg) was given to mice with dexamethasone (Dex)-induced muscle atrophy. Techniques included H&E staining to assess muscle mass and fiber cross-sectional area (CSA), Western blot, and ELISA analyses to investigate signaling pathways. Confocal imaging was also used to confirm cellular changes. In vitro QA treatment improved myotube integrity by increasing myogenic differentiation markers (MyoD, MyoG) and suppressing atrophy-related E3 ligases, specifically MuRF-1 and FBX32/Atrogin-1. Confocal imaging showed that QA inhibited the nuclear localization of FOXO1 and reduced FBX32 expression. In vivo, daily oral administration of QA significantly preserved gastrocnemius muscle mass and fiber cross-sectional area in Dex-treated mice. QA restored the IGF-1/PI3K/Akt signaling pathway and attenuated FOXO1-dependent proteolytic activation. Collectively, these findings demonstrate that QA possesses potent anti-atrophic and myoprotective effects mediated through the modulation of the IGF-1/Akt-FOXO axis. QA has potential as a novel natural therapeutic for preventing glucocorticoid-induced sarcopenia. Full article

Major depressive disorder (MDD) is a complex and heterogeneous psychiatric condition with high global prevalence and significant personal and societal burdens. While traditionally focused on neuronal dysfunction, emerging research highlights a critical role for astrocytes—glial cells essential for maintaining brain homeostasis in the pathogenesis of depression. This review explores how chronic stress, a major risk factor for MDD, disrupts astrocyte function through multiple converging mechanisms. We detail the normal physiological roles of astrocytes in synaptic regulation, neurotransmitter cycling, metabolic support, and neurovascular integrity, and examine how these functions are compromised under chronic stress. Key molecular pathways implicated include glucocorticoid receptor (GR) signaling dysregulation, neuroinflammatory responses, glutamate excitotoxicity, oxidative stress, and epigenetic alterations. Evidence from histological and transcriptomic studies in both human postmortem tissue and rodent models reveals consistent changes in astrocyte-specific genes, such as GFAP, SLC1A2, SLC1A3, BDNF, and AQP4, supporting their involvement in depressive pathology. Finally, we discuss therapeutic strategies targeting astrocyte dysfunction—including EAAT2 upregulation, neuromodulation, anti-inflammatory approaches, GR modulation, and glial-focused epigenetic therapies. Understanding astrocyte pathology in the context of chronic stress not only refines our understanding of MDD but also opens novel avenues for treatment development. Full article

Glucocorticoids are key regulators of vertebrate physiology, orchestrating metabolic, immune, and developmental processes that enable adaptation to stress. In teleosts, cortisol is the primary glucocorticoid, acting through classical genomic pathways and rapid non-genomic mechanisms. Although genomic signaling has been widely characterized, non-genomic actions remain poorly understood in skeletal muscle, a tissue of both biological and economic importance. In this study, we examined the effects of cortisol and its membrane-impermeable analog, cortisol-BSA, on rainbow trout (Oncorhynchus mykiss) skeletal muscle under in vivo and in vitro conditions. Transcript analysis demonstrated that cortisol and cortisol-BSA rapidly induced pax3 (2.28 ± 0.22- and 2.48 ± 0.45-fold change, respectively) and myf5 expression (3.03 ± 0.47- and 2.31 ± 0.29-fold change, respectively) at 1 h, whereas prolonged cortisol and cortisol-BSA exposure resulted in their downregulation (0.34 ± 0.07- and 0.38 ± 0.14-fold change, respectively). In cultured myotubes, cortisol-BSA activated protein kinase A (PKA) (2.24 ± 0.25-fold change) and enhanced phosphorylation of its downstream target CREB (3.2 ± 0.21-fold change) in a time-dependent manner; these effects were abolished by the PKA inhibitor H89. Moreover, inhibition of PKA signaling suppressed cortisol-BSA–induced pax3 and myf5 expression (1.31 ± 0.28-fold change and 1.89 ± 0.28-fold change, respectively). Together, these findings provide the first mechanistic evidence that non-genomic cortisol signaling regulates the PKA–CREB axis in fish skeletal muscle, promoting the early transcriptional activation of promyogenic factors. This work underscores the complementary role of rapid cortisol actions in fine-tuning myogenic responses under acute stress, offering new perspectives on muscle plasticity in teleosts. Full article

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare systemic vasculitis characterized by asthma, eosinophilia, and necrotizing inflammation of small- to medium-sized vessels. Accumulating evidence indicates that EGPA is a polygenic and heterogeneous disorder comprising distinct antineutrophil cytoplasmic antibody (ANCA)–defined endotypes with divergent genetic backgrounds, immune pathways, and clinical phenotypes. Its pathogenesis reflects the convergence of epithelial–alarmin signaling, type 2 inflammation, eosinophil effector mechanisms, and B-cell/autoantibody responses, with myeloperoxidase (MPO)-ANCA serving as a hallmark of the vasculitic subset. Recent advances in genomics, immunology, and multi-omics profiling have uncovered biomarkers and molecular circuits sustaining disease activity and guiding therapeutic stratification. The identification of the interleukin (IL)-5–eosinophil axis, epithelial-derived alarmins, and B-cell/IgG4 networks as central pathogenic nodes has enabled the development of targeted biologic therapies that are redefining treatment paradigms. Benralizumab (anti-IL-5Rα) has recently been approved for EGPA following the phase 3 head-to-head MANDARA trial, which demonstrated non-inferiority to mepolizumab in achieving remission (BVAS = 0 with ≤4 mg/day prednisone equivalent) at weeks 36 and 48. These results, together with the established efficacy of mepolizumab, inform practical selection between IL-5 and IL-5Rα blockade and support glucocorticoid-sparing approaches. A structured literature search (2015–2025) was conducted in PubMed, Scopus, and Web of Science to identify recent advances in epidemiology, genetics, biomarkers, and targeted therapies for EGPA. This updated review integrates molecular insights, clinical endotypes, and therapeutic innovations to outline current evidence and future precision-medicine strategies aimed at improving long-term patient outcomes. Full article

Canine atopic dermatitis (cAD) is a chronic, pruritic, inflammatory skin disease with complex immunopathogenesis involving dysregulated cytokine networks. In recent years, targeted therapies have transformed the management of cAD by directly or indirectly modulating cytokine activity. Lokivetmab, a monoclonal antibody neutralizing interleukin-31, represents a breakthrough in veterinary dermatology, providing rapid and sustained reduction in pruritus with a favorable safety profile. Janus kinase inhibitors, including oclacitinib and the newer ilunocitinib, act downstream by blocking cytokine signal transduction, offering effective control of both acute and chronic phases of disease. Ciclosporin, a calcineurin inhibitor, remains a valuable immunosuppressant for long-term cAD management, while topical tacrolimus provides localized benefits. Together, these therapies mark a paradigm shift from non-specific immunosuppressants to precision medicine. In this context, precision medicine refers to therapeutic strategies that selectively target key cytokines or intracellular signaling pathways central to the pathogenesis of cAD, such as IL-31 or the JAK/STAT axis. Unlike traditional immunosuppressants such as glucocorticoids, which exert broad and non-selective immune suppression, these agents modulate defined molecular mechanisms, thereby improving efficacy and minimizing adverse effects. Consequently, they enable improved quality of life for affected dogs and their owners. Future strategies will likely focus on patient stratification and personalized approaches based on immunological endotypes. Full article

Glucocorticoid therapy, using agents like dexamethasone (Dexa), often leads to muscle atrophy by increasing protein degradation via the ubiquitin–proteasome system while suppressing protein synthesis. Stigmasterol, a phytosterol with known bioactivities, has an unexplored role in muscle atrophy. This study investigated stigmasterol’s protective effects against Dexa-induced muscle atrophy and its impact on the FoxO3 and mTORC1 signaling pathways. Differentiated C2C12 myotubes were treated with Dexa (50 µM) ± stigmasterol (10 µM), and the morphology, viability, and protein levels in the FoxO3/MuRF1/MAFbx catabolic and mTOR/p70S6K/4E-BP1 anabolic signaling pathways were assessed. C57BL/6 mice received Dexa (20 mg/kg/day i.p.) ± stigmasterol (3 mg/kg/day oral) for 21 days, and the body/muscle mass, bone mineral density (BMD), fiber cross-sectional area (CSA), and muscle protein expression were measured. Stigmasterol (10 µM) was non-toxic and attenuated Dexa-induced reductions in myotube diameter and fusion in vitro, concurrent with suppressing Dexa-induced upregulation of FoxO3/MuRF1/MAFbx proteins and preventing the Dexa-induced dephosphorylation of mTOR/p70S6K/4E-BP1 proteins. In vivo, stigmasterol mitigated Dexa-induced losses in body weight, muscle mass, BMD, and fiber CSA. This protection was associated with attenuated upregulation of FoxO3 and MAFbx proteins in muscle tissue. Stigmasterol protected against Dexa-induced muscle atrophy in vitro and in vivo via modulation of the FoxO3–MAFbx catabolic pathway. These findings suggest stigmasterol inhibits excessive glucocorticoid-induced muscle protein breakdown. It therefore warrants further investigation as a potential therapeutic agent for glucocorticoid myopathy. Full article

Background/Objectives: Long non-coding RNAs (lncRNAs) are increasingly recognized as key regulators of immune pathways and may hold diagnostic and therapeutic relevance in autoimmune diseases such as Multiple Sclerosis (MS). However, research on lncRNAs in MS remains fragmented and geographically clustered. This systematic review aimed to collate and critically evaluate studies of lncRNA expression in MS, assess consistency of findings across studies, and synthesize proposed functional implications of the most frequently studied lncRNAs. Methods: This PROSPERO-registered review (CRD420250575938), conducted in accordance with PRISMA, searched PubMed, Scopus, Embase, and Web of Science (2010–2024) for studies evaluating lncRNA expression in adult MS (≥18 years of age). Eligible studies included ≥20 participants and assessed lncRNAs in blood, PBMCs, serum, plasma, or CSF using qRT-PCR, RNA-seq, or microarrays. Pediatric, review, animal, and in vitro studies were excluded. Two reviewers independently screened and extracted data, with risk of bias evaluated using QUADAS-2. Results: Narrative synthesis of 51 studies identified 77 unique lncRNAs. A limited set (MALAT1, GAS5, MEG3, H19) demonstrated consistent dysregulation in MS, whereas others (THRIL, IFNG-AS1, HOTAIR, TUG1) exhibited context-dependent expression influenced by treatment, relapse status, or demographics. Functional annotations converged on immune pathways, including NF-κB, STAT3, IFN-γ/Th1, and glucocorticoid signaling. Conclusions: This review identifies reproducible and context-specific lncRNA dysregulation in MS, emphasizing the need for transcriptome-wide approaches, standardized methods, and multi-center validation. Current evidence is constrained by geographic clustering, preselection bias, and methodological heterogeneity. Full article

Background and Objectives: People living with HIV (PLWH) have excess fragility fractures not fully explained by areal DXA. We reviewed bone “quality” in PLWH—microarchitecture, estimated strength, tissue-level properties—and vertebral fractures (VFs). Methods: PRISMA-conform systematic review (2000–2025) of randomized, cohort, and cross-sectional studies assessing HR-pQCT (±finite-element analysis), trabecular bone score (TBS), impact microindentation (BMSi), femoral QCT/MRI, and VF imaging (DXA-VFA or radiography). Risk of bias used ROBINS-I (non-randomized) and RoB 2 (randomized/switch). No meta-analysis was performed due to clinical/methodological heterogeneity; evidence was synthesized narratively per SWiM. Results: Fourteen studies met criteria. HR-pQCT showed cortical/trabecular deficits with lower finite-element–estimated strength in PLWH. BMSi was 3–4 units lower; it declined after ART initiation but improved after TDF→TAF switch. TBS was modestly lower and reclassified risk when BMD was non-osteoporotic. VF prevalence was 12–25% and frequently occurred at non-osteoporotic BMD. Signals aligned with modifiable risks (smoking, glucocorticoids) and specific ART exposures. Conclusions: Beyond DXA, PLWH exhibit quantifiable decrements in microarchitecture, estimated strength, and tissue-level properties alongside a meaningful VF burden. TBS and VFA are pragmatic, scalable adjuncts to refine risk; HR-pQCT/BMSi add mechanistic value in research/tertiary settings. Prospective studies linking these metrics to incident fractures are warranted. Full article

Sarcopenia, characterized by progressive skeletal muscle mass, strength, and functional loss, imposes a substantial global health burden. Irisin, a myokine derived from fibronectin type III domain-containing protein 5 (FNDC5), is critical for muscle health. Here, we investigate its role in mitigating glucocorticoid-induced sarcopenia using a mouse and C2C12 myotubes model. We quantified FNDC5/irisin levels in skeletal muscle and plasma and assessed muscle function (body weight, grip strength, wire-hanging, and locomotor activity), histology, and mitochondrial features following irisin administration to dexamethasone-treated mice. Western blot analyzed synthesis/hydrolysis regulators, apoptosis markers, and mitochondrial regulators in mouse muscle tissues and C2C12 myotubes. The results show that FNDC5/irisin was significantly downregulated in sarcopenic mice and atrophic C2C12 myotubes; exogenous irisin rescued muscle mass loss and functional impairment, improving body weight, muscle mass, grip strength, and mobility. Mechanistically, irisin bound SIRT1 with −12.7 kcal/mol affinity, activating a deacetylation cascade that suppressed FoxO3a transcriptional activity (attenuating proteasomal degradation) and enhanced mTORC1-mediated protein synthesis in C2C12 myotubes. Additionally, irisin potentiated PGC-1α signaling in mouse myocytes, promoting mitochondrial biogenesis and restoring contractile function in dystrophic fibers. Collectively, these findings demonstrate irisin alleviates glucocorticoid-induced muscle atrophy via SIRT1-dependent pathways, rebalancing muscle physiology and systemic energy homeostasis. This highlights irisin-based therapeutics as a promising exercise surrogate for sarcopenia management, offering novel clinical avenues. Full article