Search Results (1,046)

Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage degradation, synovial inflammation, osteophyte formation, joint space narrowing, and persistent pain. During OA progression, synovial inflammation triggers the release of pro-inflammatory cytokines, including IL-1β, TNF-α, and IL-6, which activate matrix metalloproteinases (MMPs) and aggrecanases, driving extracellular matrix (ECM) degradation. Emerging evidence indicates that transient receptor potential (TRP) channels, via calcium (Ca²⁺) signaling, function as molecular sensors in joint tissues, including chondrocytes, synoviocytes, sensory neurons, and regulate cartilage homeostasis, synovial inflammation, and OA pain. In cartilage, TRP channels govern chondrocyte survival, mechanotransduction, autophagy, oxidative stress, and ECM turnover, thereby modulating cartilage homeostasis. In synovial tissue, TRP channels regulate inflammatory signaling and cytokine, chemokine, and matrix-degrading enzyme production, leading to synovitis and joint destruction. In sensory neurons innervating the joint, TRP channels respond to mechanical and inflammatory stimuli, increasing nociceptor excitability, neuropeptide release, and pain sensitization, driving OA pain. TRP channel signaling also modulates immune cell infiltration and macrophage-driven inflammation, sustaining chronic pain and tissue damage in OA. This review summarizes emerging evidence on TRP channel functions in OA pathogenesis and highlights their potential as therapeutic targets to alleviate inflammation, protect cartilage, and reduce OA-associated pain. Full article

Driven by rapid socioeconomic progress and changing lifestyles, the global burden of cardiovascular diseases (CVDs) continues to escalate, with surging morbidity and mortality rates imposing a severe threat to public health. Clinical treatments are focused on the alleviation of treatments, highlighting the need for a deeper understanding of CVDs pathogenesis and the development of targeted therapies. Recent studies have identified imbalances in intracellular Ca²⁺ homeostasis as a key pathological mechanism in the progression of CVDs. Notably, sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase 2 (SERCA2), a membrane protein encoded by the ATP2A2 gene and ranging from 97 to 115 kDa in molecular weight, plays a pivotal role in regulating intracellular Ca²⁺ levels. Extensive evidence links abnormal SERCA2 function to various CVDs, including heart failure, cardiac hypertrophy, atherosclerosis, and diabetic cardiomyopathy. This review systematically explores the regulatory mechanisms of SERCA2 expression and its functional regulation—including transcriptional regulation, post-translational modifications, and protein–protein interactions—and further investigates its pathological roles in cardiovascular diseases as well as its potential as a therapeutic target. By synthesizing current knowledge, this article aims to provide new insights for future basic research and establish a theoretical foundation for clinical applications. Full article

Myocardial ischemia represents a state of reduced coronary perfusion with oxygenated blood, insufficient to meet the metabolic demands of the myocardium. Both acute and chronic ischemia trigger a cascade of cellular events that lead to disturbances in ionic balance, mitochondrial function and energy metabolism. During ischemia, cardiomyocytes (CMs) shift from aerobic to anaerobic metabolism, resulting in adenosine triphosphate (ATP) depletion, loss of ionic homeostasis and calcium (Ca²⁺) overload that activate proteases, phospholipases and membrane damage. Reperfusion restores oxygen supply and prevents irreversible necrosis but paradoxically initiates additional injury in marginally viable myocardium. The reoxygenation phase induces excessive production of reactive oxygen species (ROS), endothelial dysfunction and a strong inflammatory response mediated by neutrophils, platelets and cytokines. Mitochondrial dysfunction and opening of the mitochondrial permeability transition pore (mPTP) further amplify oxidative stress and inflammation and trigger apoptosis and necroptosis. Understanding these intertwined cellular and molecular mechanisms remains essential for identifying novel therapeutic targets aimed at reducing reperfusion injury and improving myocardial recovery after ischemic events. Full article

Cell adhesion molecules (CAMs) are key regulators of tissue structural integrity and functional coordination, yet their specific role in the adaptation of yak lung tissue to high-altitude hypoxia remains unelucidated. Thus, we employed transcriptomic sequencing (RNA-seq), molecular biology assays, and single-cell RNA-seq (scRNA-seq) to analyze the expression characteristics of CAMs in yak lung tissues at high and low altitudes. Trypsin or collagenase digestion showed higher cell counts in high-altitude yak lungs (p < 0.05). RNA-seq analysis revealed significant enrichment of differentially expressed genes (DEGs) in adhesion-related pathways. Inductively coupled plasma mass spectrometry detected elevated Ca²⁺ levels in high-altitude yak lungs (p < 0.05). Quantitative real-time PCR (qRT-PCR) detection of key genes from five major families of CAMs revealed the downregulation of cadherin and integrin family-related genes, and upregulation of immunoglobulin superfamily-related genes, in high-altitude yak lungs (p < 0.05), corroborated by immunohistochemical (IHC) staining. A 10× scRNA-seq revealed adhesion changes in 9 of 15 lung cell subpopulations, with differentially expressed CAMs involving integrins. This study demonstrates that yak lung tissue establishes a sophisticated adhesive homeostasis through differential CAMs regulation. This strategy optimizes pulmonary immune responses and energy allocation, ensures structural integrity and functional coordination, and thereby facilitates superior acclimatization to higher-altitude hypoxia. Full article

The increasing environmental release of nano-titanium dioxide (nTiO₂) due to its widespread industrial application raises concerns about its potential effects on aquatic ecosystems, particularly marine organisms. Fertilization, a critical reproductive process for broadcast-spawning bivalves, is highly sensitive to environmental pollutants. In the present investigation, we explored the effects of nTiO₂ at environmentally relevant concentrations on oocyte quality and the fertilization process in the economically important marine bivalve Tegillarca granosa. nTiO₂ exposure significantly reduced fertilization success and sperm–egg fusion efficiency, while markedly increasing polyspermy incidence. Mechanistically, nTiO₂ triggered oxidative stress in oocytes, elevating ROS and MDA levels and causing structural damage to the oocyte membrane. Moreover, nTiO₂ exposure disrupted cellular energy metabolism by inhibiting PK and PFK activities, depleting ATP content, and reducing MMP. Additionally, nTiO₂ exposure impaired Ca²⁺ homeostasis by suppressing Ca²⁺-ATPase activity, which reduced intracellular Ca²⁺ levels. These cellular disruptions collectively compromised the cortical reaction by inhibiting cortical granule exocytosis and microfilament migration. Our findings suggest that nTiO₂-induced oxidative stress, coupled with an imbalance in energy and Ca²⁺ homeostasis, impairs the cortical reaction and fertilization capacity in T. granosa. This study provides valuable insights into the mechanistic pathway underlying the reproductive toxicity of nTiO₂ in marine invertebrates, offering a basis for evaluating the ecological risks associated with the presence of nanomaterials in marine environments. Full article

This review examines and hypothesizes cytoprotection as a conceptual therapeutic criterion for antiarrhythmic drugs, referring to the possibility of suppressing arrhythmias while avoiding adverse electrophysiological or systemic effects. Toward a theoretically complete cytoprotective profile—preserving benefits and eliminating toxicity—the criterion was the degree of counteraction of arrhythmias (i.e., bradycardia, tachycardia, atrioventricular (AV) block, ventricular tachycardia (VT), ST-segment changes, prolonged P, PR, QRS, and QT/QTc intervals, and repolarization). Conventional and new antiarrhythmics share class I–IV ≈ partial cytoprotection/narrow range; late INa inhibitors, IKs enhancers, RyR2 stabilizers, gap junction modulators, and atrial-selective antiarrhythmics ≈ partial cytoprotection/more extended range. Still predominantly in preclinical models, stable gastric pentadecapeptide BPC 157, in the clinic, has not demonstrated adverse effects in available human trials (non-cardiac) to date. As a prominent cytoprotection mediator (LD1 not achieved in toxicology studies), it demonstrates well-matched cytoprotective–antiarrhythmic effects, BPC 157 ≈ full cytoprotection/wide-range homeostasis. In vivo, this was across models of hypo-/hyperkalemia, hypermagnesemia, ischemia–reperfusion, myocardial infarction, drug-induced arrhythmias (including local anesthetics), and vascular occlusion. BPC 157 restores sinus rhythm, normalizes P/QRS/QT intervals, prevents AV block, suppresses VT, attenuates ST-segment changes, and stabilizes heart rate, even when insults are advanced. In vitro, HEK293 studies confirm direct membrane-stabilizing actions: BPC 157 prevents hypokalemia-induced hyperpolarization, reduces hyperkalemia- and hypermagnesemia-induced depolarization, and mitigates local anesthetic-induced Na⁺/Ca²⁺ dysregulation, reflecting bidirectional homeostatic modulation of membrane potential. Thus, to confirm the hypothesis, these BPC 157 conditional, not constitutive effects, in rodent models or in vitro systems (HEK293 cells), mandate expansion of now limited clinical data and mechanisms in human investigated as a translational cytoprotective strategy for complex arrhythmias. Full article

Background: Intrauterine Growth Restriction (IUGR) is associated with a distinct neonatal metabolic profile, attributable to chronic intrauterine nutritional deprivation and suboptimal placental nutrient exchange. Upon delivery, IUGR neonates typically present with depleted nutrient stores, dysregulated endocrine activity, and a spectrum of micronutrient deficiencies, factors that collectively compromise metabolic homeostasis and significantly influence subsequent health trajectories. Methods: This narrative review systematically synthesizes the current body of evidence from clinical, biochemical, and translational investigations pertaining to the micronutrient status and pivotal endocrine markers in neonates affected by intrauterine growth restriction. The collected findings were integrated to elucidate metabolic adaptation mechanisms, immediate clinical ramifications, and the potential pathways linking neonatal biochemical patterns to long-term metabolic programming. Results: IUGR neonates consistently exhibit reduced cord-blood concentrations of essential micronutrients, including vitamin D, iron (Fe), zinc (Zn), magnesium (Mg), folate (vitamin B9), and cobalamin (vitamin B12), reflecting compromised placental nutrient transfer and limited fetal reserves. Concomitantly, endocrine alterations—most notably reduced insulin (INS) and C-peptide (C-pep) levels—indicate suppressed pancreatic β-cell activity and a prevailing hypoanabolic adaptive state. In parallel, disturbances in mineral metabolism, characterized by lower calcium (Ca) concentrations and increased alkaline phosphatase (ALP) activity, suggest impaired bone mineralization during the critical phase of early postnatal adaptation. Collectively, these biochemical patterns increase vulnerability to early clinical complications such as neonatal hypoglycemia and bone demineralization, disrupt early growth trajectories, and are associated with an elevated long-term risk of insulin resistance and adverse cardiometabolic programming. Conclusions: IUGR neonates consistently demonstrate a synergistic interplay of micronutrient deficiencies and adaptive endocrine responses, profoundly impacting immediate postnatal metabolic stability and predisposing them to long-term health challenges. Therefore, early biochemical screening, followed by tailored nutritional and hormonal interventions, may assist restore metabolic balance, promote growth and decrease long term risk for metabolic diseases. Full article

The Hedgehog (Hh) signaling pathway is a key regulator of adipogenesis and lipid metabolism. However, the specific role of its receptor, Patched2 (Ptch2), in these processes remains unclear. Here, using a CRISPR/Cas9-mediated ptch2 homozygous mutation model in Nile tilapia (Oreochromis niloticus), we found that Ptch2 deficiency induced visceral and perirenal lipomatosis characterized by small, multinucleated adipocytes. Comparative adipose transcriptomics revealed pronounced adipogenic reprogramming, with marked upregulation of genes governing de novo lipogenesis (e.g., acaca, fasn), fatty acid desaturation (e.g., scd, fadsd6), and triglyceride synthesis (e.g., dgat2, lpl). Biochemically, mutants exhibited elevated blood glucose and liver transaminases (alanine aminotransferase, aspartate aminotransferase) activity, and reduced alkaline phosphatase activity, indicating systemic metabolic dysregulation and hepatic stress. Our findings demonstrate that loss of Ptch2 triggers lipoma formation and adipogenic transcriptome reprogramming, highlighting its essential role in maintaining adipose tissue homeostasis. Full article

Ectomycorrhizal (ECM) fungi form key symbioses with forest trees, strongly regulating plant nutrition and stress tolerance. This review synthesizes how ECM fungi redistribute plant-fixed carbon (C) in soil, interact with soil organic matter (SOM), and mediate the uptake and allocation of nitrogen (N), phosphorus (P) and other macro- and micronutrients. We highlight mechanisms underlying ECM enhanced organic and mineral N and P mobilization, including oxidative decomposition, enzymatic hydrolysis, and organic acid weathering. Beyond C-N-P dynamics, ECM fungi also enhance acquisition and homeostasis of elements such as K, Ca, Mg, Fe, and Zn, reshaping host nutrient stoichiometry, productivity, and soil microbial community composition. We further summarize multi-layered mechanisms by which ECM improve host plant resistance to pathogens, drought, salinity–alkalinity, and heavy metal stresses via physical protection, ion regulation, hormonal signaling, aquaporins, and antioxidant and osmotic adjustment. Finally, we outline research priorities, such as using trait-based, multi-omics, and microbiome-integrated approaches to better harness ECM in forestry and ecosystem restoration. Full article

In mammalian sperm, the regulation of intracellular calcium (Ca²⁺) is essential for fertility. Semen processing for assisted reproduction may disturb Ca²⁺ homeostasis. This study aimed to investigate whether chilling boar sperm to 5 °C and subsequent storage affect the function of intracellular Ca²⁺ stores. Semen was stored in BTS-extender at 5 °C or 17 °C (control) for up to five days. Fluo-4/AM-loaded aliquots were incubated in Ca²⁺-free Tyrode’s medium at 38 °C. Sperm preserved at 17 °C had higher free intracellular Ca²⁺ levels compared with those stored at 5 °C (p < 0.05). However, there was no difference between storage groups in Ca²⁺ levels during incubation at 38 °C. Thimerosal, a sensitizer of Ca²⁺ channels, was added, and changes in the free intracellular Ca²⁺ concentration were monitored in viable acrosome-intact sperm by continuous flow cytometry. There was no effect of storage temperature on the kinetic response to thimerosal at days 1 and 3. At day 5, the relative increase in Ca²⁺ was higher in 5 °C-stored samples after 3 min of incubation. At 60 and 120 min of incubation, the thimerosal response was no longer influenced by the storage temperature or storage duration. In conclusion, chilling and storage do not affect the release dynamics of free Ca²⁺ from intracellular stores in viable boar sperm after rewarming. Full article

Aging alters cardiac resilience to anesthetic and surgical stress, yet the molecular basis for these effects remain poorly understood. To define age-dependent transcriptional responses, we profiled cardiac gene expression across young adult (3 m), late middle-aged (17 m), and old mice (27 m) following 2 h isoflurane and operative (Iso/Op) exposure. Across all age groups, 24 h after cessation, Iso/Op induced distinct transcriptional signatures relative to the sham, with conserved perturbations in oxidative stress responses, Ca²⁺ handling, hypertrophy-associated signaling, and energy metabolism. In 3 m hearts, transcriptional alterations were characterized by dysregulation of small-molecule catabolism, fatty acid metabolism, endoplasmic reticulum processing, and cytoskeletal organization. In 17 m hearts, lipid metabolic disruption was amplified and accompanied by suppression of muscle system and calcium signaling pathways. In 27 m hearts, Iso/Op robustly activated PPAR and AMPK signaling and fatty acid catabolic programs while downregulating pathways governing contractility, actin organization, and morphogenesis, consistent with age-associated maladaptive metabolic reprogramming. To assess persistence, we analyzed a longitudinal cohort of 20 m mice five weeks after exposure and observed sustained transcriptomic remodeling driven predominantly by isoflurane, including mitochondrial dysfunction and altered expression of genes linked to diabetic cardiomyopathy, extracellular matrix integrity, and neurodegeneration-associated pathways. Together, these data suggest that isoflurane-based perioperative stress can produce age-amplified and durable metabolic and structural cardiac remodeling, implicating impaired lipid utilization and mitochondrial homeostasis as potential mechanisms of long-term cardiovascular vulnerability. Full article

Chemotherapy remains a cornerstone of systemic cancer treatment, yet dose-limiting toxicities—cardiotoxicity, neurotoxicity, and nephrotoxicity—affect 40–80% of patients, interrupt 20–30% of treatment cycles, and double long-term mortality. We propose that these seemingly distinct organ toxicities converge on a single mechanism: selective disruption of the MQC network. MQC comprises five interdependent modules—biogenesis, dynamics, mitophagy, proteostasis, and the recently characterized migrasome-mediated mitocytosis—collectively maintaining ATP supply, redox balance, and Ca²⁺ homeostasis in high-demand tissues. Chemotherapeutics such as anthracyclines, platinum agents, and taxanes simultaneously repress PGC-1α-driven biogenesis, hyperactivate Drp1-mediated fission, impair autophagosome–lysosome fusion, and inhibit mitocytosis, triggering mitochondrial collapse, ROS overflow, and cell death. This first-in-field review delineates organ-specific MQC pathways and catalogs druggable interventions—including small molecules, natural products, and nano-delivery systems—that restore MQC checkpoints. We present an integrated “MQC disruption–multi-organ toxicity–targeted intervention” framework, identifying Drp1 hyperactivation, late-stage mitophagy arrest, and mitocytosis inhibition as core therapeutic nodes. Targeting these pathways offers a promising strategy to decouple anticancer efficacy from off-target toxicity, potentially enabling optimized dosing, reducing treatment discontinuation, and improving long-term prognosis. Most MQC-targeted agents, however, remain in preclinical or early-phase trials. Full article

Calcium (Ca²⁺)signaling dysfunction is a central contributor to neuronal hyperexcitability and seizure propagation in epilepsy, yet the intracellular mechanisms underlying the actions of valproic acid (VPA) remain incompletely understood. In this study, we investigated whether VPA modulates Ca²⁺ homeostasis at the level of the endoplasmic reticulum (ER) and how this action influences cytosolic Ca²⁺ dynamics associated with epileptiform activity. ER Ca²⁺ levels were directly measured using ER-targeted aequorin in HeLa and PC12 cells, while cytosolic Ca²⁺ signals were monitored by fura-2 fluorescence imaging in bovine chromaffin cells exposed to veratridine, a model of sustained sodium channel activation and Ca²⁺ oscillations. VPA induced a concentration-dependent release of Ca²⁺ from the ER, with an IC₅₀ of approximately 17 µM. This effect was preserved in permeabilized cells and exhibited activation kinetics comparable to those elicited by inositol 1,4,5-trisphosphate (InsP₃). Pharmacological inhibition of InsP₃ receptors (InsP₃Rs), but not ryanodine receptors or SERCA, abolished VPA-induced ER Ca²⁺ release, supporting a selective InsP₃R-mediated mechanism. Functionally, VPA suppressed the repetitive cytosolic Ca²⁺ oscillations induced by veratridine, while simultaneously producing a sustained elevation of cytosolic Ca²⁺ originating from ER stores and facilitating depolarization-evoked catecholamine secretion. Together, these results support the conclusion that VPA induces InsP₃R-mediated Ca²⁺ mobilization from the endoplasmic reticulum and identify ER Ca²⁺ release as a previously unrecognized intracellular mechanism contributing to its modulatory effects on Ca²⁺ signaling and excitability in epilepsy. Full article

Glioblastoma (GBM) is the most aggressive primary brain tumor, marked by molecular heterogeneity and poor clinical prognosis. Lysyl oxidase-like 3 (LOXL3) is frequently upregulated in GBM, but its mechanistic contribution remains insufficiently defined. Here, we investigated the functional role of LOXL3 in GBM using CRISPR-Cas9-mediated LOXL3 knockdown in two genetically distinct GBM cell lines: U87MG (wild-type TP53) and U251 (mutant TP53). Reduced LOXL3 expression markedly reduced α-tubulin acetylation, particularly in U87MG cells, and downregulated genes involved in cell cycle progression and proliferation. Both cell lines exhibited mitotic defects, including delayed cell cycle progression and spindle abnormalities; however, cell fate diverged according to TP53 status. U87MG cells, sustained spindle checkpoint activation triggered a p53-dependent spindle checkpoint response culminating in apoptosis, while U251 cells underwent mitotic slippage and senescence. Transcriptomic analyses confirmed differential regulation of apoptosis versus senescence pathways in accordance with TP53 functionality. Additionally, reduced LOXL3 expression markedly impaired adhesion and migration in U87MG cells, whereas U251 cells were minimally affected, consistent with more pronounced microtubule destabilization. Collectively, these findings identify that LOXL3 is a key regulator of microtubule homeostasis, mitotic fidelity, adhesion, and invasive behavior in GBM. Targeting LOXL3 may therefore provide a therapeutic opportunity for genotype-informed intervention in GBM. Full article

This study aims to investigate the protective effect of the natural phthalide compound Levistolide A (LA) against myocardial ischemia–reperfusion injury (MIRI) and to elucidate its underlying mechanisms. Utilizing network pharmacology, potential targets of LA in the treatment of MIRI were predicted. Subsequently, a hypoxia/reoxygenation (H/R) model was established using rat H9C2 cardiomyocytes to simulate MIRI, and the mechanisms of action were validated through cellular experiments. Network pharmacology analysis indicated that the potential targets of LA in treating MIRI were significantly enriched in calcium signaling pathways, with the adenosine A2B receptor (ADORA2B), a G protein-coupled receptor (GPCR), identified as a key protein. Cellular experiments demonstrated that 24 μM LA significantly alleviated H/R-induced damage in H9C2 cells, enhanced cell viability, and reduced the release of lactate dehydrogenase (LDH), creatine kinase isoenzyme MB (CK-MB), and cardiac troponin I (cTnI). Pre-treatment with LA significantly activated the ADORA2B/Cyclic adenosine monophosphate (cAMP)/Protein kinase A (PKA) signaling axis, promoting the phosphorylation of phospholamban (PLB), enhancing the activity and protein expression of sarco/endoplasmic reticulum Ca²⁺-ATPase 2 alpha (SERCA2α), and effectively mitigating intracellular calcium overload induced by H/R. However, the ADORA2B antagonist MRS 1754 partially reverses the aforementioned protective effects of LA. The findings of this study reveal a novel mechanism by which LA exerts cardioprotective effects through the ADORA2B/cAMP/PKA/PLB/SERCA2α signaling axis, preventing calcium overload and improving calcium homeostasis, and identify potential candidate compounds and precise targets for the treatment of MIRI. Full article