Search Results (4,700)

Type 2 diabetes and gout are both common metabolic disorders that frequently occur together. Research indicates that disturbances in intracellular calcium balance may be a key molecular factor linking the development of these two diseases. Calcium signaling disturbances promote the synergistic progression of both diseases through multiple pathways: In pancreatic β-cells, endoplasmic reticulum (ER) calcium imbalance triggers ER stress, mitochondrial dysfunction, and apoptosis, autophagy, and pyroptosis, leading to impaired insulin secretion. Concurrently, calcium overload exacerbates insulin resistance by disrupting insulin signal transduction in peripheral tissues, while hyperinsulinemia further inhibits uric acid excretion through activation of the renal URAT1 transporter, creating a vicious cycle. Additionally, calcium homeostasis dysregulation activates the NLRP3 inflammasome and promotes the release of pro-inflammatory cytokines, aggravating chronic low-grade inflammation, which further deteriorates β-cell function and peripheral metabolic disorders, collectively driving the pathological link between type 2 diabetes and gout. Although calcium channel modulators show potential in improving β-cell function and reducing inflammation, their clinical application faces challenges such as tissue-specific effects and a lack of high-quality clinical trials. We propose that intracellular calcium dysregulation serves as a central pathological amplifier in the diabetes–gout nexus. Future research on targeted calcium signaling interventions, guided by this integrative concept, may help overcome the therapeutic challenges in managing type 2 diabetes complicated by gout. Full article

Lumpy Skin Disease Virus (LSDV), a member of the poxvirus family, represents a significant threat to global cattle industries. This review presents an analysis of LSDV-encoded proteins and their interactions with host systems, elucidating the molecular mechanisms governing viral life cycle progression and immune evasion strategies. We provide detailed characterization of the complex architecture of LSDV virions, including Intracellular Mature Virus (IMV), Extracellular Enveloped Virus (EEV), lateral bodies, and the core components, while summarizing the crucial functions of viral proteins throughout various stages of infection—entry, replication, transcription, translation, assembly, and egress. Particular attention is given to the immunomodulatory strategies employed by LSDV to subvert both innate and adaptive immune responses. These mechanisms encompass molecular mimicry of cytokines and chemokines, interference with antigen presentation pathways, inhibition of key immune signaling cascades, and modulation of apoptosis and autophagy processes. Through comparative analysis with homologs from related poxviruses, especially vaccinia virus, we highlight both evolutionarily conserved functions and potential unique adaptations in LSDV proteins. This review further identifies critical knowledge gaps in current understanding and proposes promising research directions. We emphasize that integrating multi-omics approaches with structural biology will be essential for advancing our understanding of LSDV pathogenesis and for developing novel preventive and therapeutic strategies against this important animal pathogen. Full article

In vitro maturation (IVM) of oocytes is a pivotal step in assisted reproductive technologies for livestock. However, oxidative stress (OS) and mitochondrial dysfunction during in vitro culture often lead to oocyte aging, thereby limiting the efficiency of the technologies. To address these challenges, this study investigated the regulatory effects of 1-Palmitoyl-2-Oleoyl-sn-Glycero-3-Phosphocholine (POPC) on bovine oocyte IVM, aging, and developmental competence to determine the optimal concentration and explore underlying mechanisms. Cumulus–oocyte complexes (COCs) were collected from abattoir-derived bovine ovaries and cultured in IVM medium supplemented with 0 (control), 50, 100, 150, or 200 μmol/mL of POPC (n = 300 per group) at 38.5 °C under 5% CO₂ for 22 h. The optimal concentration was determined based on the first polar body extrusion rate, followed by in vitro fertilization (IVF), fluorescence staining, Smart-seq2 transcriptome sequencing, and quantitative PCR (qPCR) analysis. The results demonstrated that 150 μmol/mL of POPC yielded the highest maturation rate, significantly exceeding the control group (p < 0.05), and enhanced 2-4-cell cleavage rates after IVF. Furthermore, POPC markedly reduced intracellular reactive oxygen species (ROS) levels, increased glutathione (GSH) content, improved mitochondrial function, and restored normal spindle morphology. Transcriptomic analysis identified 350 upregulated and 280 downregulated differentially expressed genes (DEGs), which were enriched in pathways related to OS. qPCR validation confirmed upregulation of SIRT1/2 and BCL-2, along with downregulation of BAX and Caspase-1/3. Collectively, these findings suggest that 150 μmol/mL of POPC alleviates OS and activates the “SIRT–antioxidant–antiapoptotic” signaling axis, thereby providing valuable insights for optimizing assisted reproductive technologies in livestock. Full article

Osteocytes translate fluid shear stress into biochemical signals critical for bone homeostasis. Here, we combined 3-dimensional (3D) osteocyte culture, microgravity simulation, fluid shear mimicking reloading after disuse, and real-time calcium signaling analysis to elucidate responses of osteocytes under different mechanical environments. Ocy454 cells were seeded onto 3D scaffolds and cultured under static (control) or simulated microgravity (disuse) conditions using a rotating wall vessel bioreactor. Elevated expression levels of Sost, Tnfsf11 (Rankl), and Dkk1 were detected following disuse, confirming efficacy of the microgravity model. Cell membrane integrity under mechanical challenge was evaluated by subjecting scaffold cultures to fluid shear in medium containing FITC-conjugated dextran (10 kDa). The proportion of dextran-retaining cells, indicative of transient membrane disruption and subsequent repair, was higher in microgravity-exposed osteocytes than controls, suggesting increased susceptibility to membrane damage upon reloading following disuse. Intracellular calcium signaling was assessed under a high but physiological fluid shear stress (30 dynes/cm²). Scaffolds cultured under disuse conditions demonstrated a larger sub-population of osteocytes with high calcium signaling intensity (F/Fo > 10 fold) during fluid shear. The maximum fold change in calcium signaling intensity over baseline and the duration of the peak calcium wave were greater for osteocytes cultured under disuse as compared to static controls, however the bioreactor-cultured osteocytes showed, on average, fewer calcium waves than those cultured under control conditions. Subsequent experiments demonstrated that the sub-population of osteocytes with high calcium signaling intensity following exposure to disuse were those that had experienced a transient membrane disruption event during reloading. Together, these results suggest that simulated microgravity enhances osteocyte susceptibility to formation of transient membrane damage and alters intracellular calcium signaling responses upon reloading. This integrated approach establishes a novel platform for mechanistic studies of osteocyte biology and could inform therapeutic strategies targeting skeletal disorders related to altered mechanical loading. Full article

Astrocytic calcium signaling is a central mechanism of neuron-glia communication that operates across multiple spatial and temporal scales. Traditionally, research has focused on intracellular Ca²⁺ oscillations that regulate gliotransmitter release, ion homeostasis, and metabolic support. Recent evidence, however, reveals that extracellular calcium ([Ca²⁺]o) is not a passive reservoir but a dynamic signaling mediator capable of influencing neuronal excitability within milliseconds. Through mechanisms such as calcium-sensing receptor (CaSR) activation, ion channel modulation, surface charge effects, and ephaptic coupling, astrocytes emerge as active partners in both slow and rapid modes of communication. This dual perspective reshapes our understanding of brain physiology and disease. Disrupted Ca²⁺ signaling contributes to network instability in epilepsy, synaptic dysfunction in Alzheimer’s and Parkinson’s disease, and impaired maturation in neurodevelopmental disorders. Methodological advances, including Ca²⁺-selective microelectrodes, genetically encoded extracellular indicators, and computational modeling, are beginning to uncover the richness of extracellular Ca²⁺ dynamics, though challenges remain in achieving sufficient spatial and temporal resolution. By integrating classical intracellular pathways with emerging insights into extracellular signaling, this review highlights astrocytes as central architects of the ionic landscape. Recognizing calcium as both an intracellular messenger and an extracellular signaling mediator provides a unifying framework for neuron–glia interactions and opens new avenues for therapeutic intervention. Full article

The interaction between the gut microbiota and the skeletal system has evolved into a new research focus. Studies underscore the role of bioactive metabolites in sustaining systemic balance via the “gut microbiota–endocrine–skeleton” axis, where they modulate metabolic processes and organ morphology through intracellular signaling. A key bidirectional relationship exists with the gut: shifts in gut microbiota affect host metabolism and subsequent metabolite profiles, while these metabolites can, in turn, reshape the intestinal microenvironment. This review explores how short-chain fatty acids (SCFAs), estrogen, and vitamin D modulate osteoporosis via the gut–bone axis. It synthesizes evidence of their signaling pathways and metabolic roles, identifies research gaps from recent clinical studies, and evaluates gut microbiota-targeted therapeutic strategies for potential clinical translation. Full article

Wound healing is a complex, multi-phase process involving hemostasis, inflammation, proliferation, and tissue remodeling. Syndecans (SDCs), a family of transmembrane heparan sulfate proteoglycans, serve as co-receptors for growth factors, cytokines, and ECM components, playing critical roles in cell adhesion, migration, proliferation, and angiogenesis. Among them, SDC-1 and SDC-4 are key regulators of skin wound healing. Due to their distinct spatial and temporal expression across various cell types—such as epithelial cells, fibroblasts, and immune cells—SDCs are well-positioned to coordinate regenerative responses. This review focuses on the spatial regulation of SDCs during skin wound healing, highlighting their roles in epidermal and dermal repair, modulation of intracellular signaling, and remodeling of the wound microenvironment. Overall, SDCs are emerging as central modulators of skin wound healing, with promising implications for regenerative medicine in the skin and beyond. Full article

Toxicant-associated steatohepatitis (TASH) is caused by environmental toxicants rather than metabolic factors; however, its pathogenic mechanisms remain poorly understood. Polychlorinated biphenyl 138 (PCB138), a persistent lipophilic contaminant that bioaccumulates in adipose tissue, may promote TASH through unclear mechanisms. In this study, we investigated whether PCB138 induces liver injury via hepatic iron dysregulation and adipose-liver inflammatory signaling. Male C57BL/6 mice received intraperitoneal PCB138 (1, 5, 10, or 50 mg/kg, four injections over six weeks). HepG2 hepatocytes were treated with PCB138 with or without ferric ammonium citrate (FAC), and PCB138-exposed 3T3-L1 adipocytes were co-cultured with HepG2 cells using a Transwell system. PCB138 dose-dependently increased serum transaminase and hepatic non-heme iron levels, with Hamp upregulation, macrophage infiltration, and fibrosis. In HepG2 cells, PCB138 synergized with FAC to elevate intracellular Fe²⁺, induced Hamp, suppressed Slc40a1, and upregulated inflammatory/profibrotic genes. In Transwell co-cultures, TNF-α, IL-6, and IL-1β from PCB138-exposed adipocytes amplified hepatic iron dysregulation and fibrotic responses. These findings demonstrated that PCB138 induced TASH through hepatic iron dysregulation and adipose-derived inflammatory signaling, independent of steatosis. These results highlighted the iron–adipose axis as a novel mechanistic link between PCB138 exposure and liver injury, offering potential therapeutic targets. Full article

Nucleic acid aptamers leverage defined tertiary structures for precise molecular recognition, positioning them as transformative biomedical tools. We engineered AP1-F, a G-quadruplex (G4)-structured aptamer that selectively binds membrane-anchored nucleolin (NCL) non-permeabilizing, overcoming a key limitation of conventional probes. Microscale thermophoresis confirmed nanomolar affinity to NCL. By means of rigorous optimization, AP1-F attained a greater than ten-fold fluorescence signal ratio between malignant and normal cells in co-cultures, exceeding the extensively researched AS1411. Dual-channel flow cytometry demonstrated over 98.78% specificity at single-cell resolution within heterogeneous cell populations, owing to AP1-F’s unique membrane localization—unlike AS1411’s intracellular uptake, which elicited erroneous signals from cytoplasmic NCL. Competitive binding experiments and Laser Confocal Imaging confirmed that AP1-F specifically identifies cancer cells by binding to the NCL recognition site on the membrane. In pathological sections, AP1-F exhibited a 40.5-fold fluorescence intensity ratio between tumor and normal tissue, facilitating accurate tissue-level differentiation. Significantly, it delineated molecular subtypes by associating membrane NCL patterns with morphometric analysis: luminal-like MCF-7 displayed consistent staining in cohesive clusters, whereas basal-like MDA-MB-468 revealed sporadic NCL with irregular outlines—characteristics imperceptible to intracellular-targeted antibodies, thus offering subtype-specific diagnostic insights. This combination biochemical–morphological approach accomplished subtype differentiation with a single-step, non-permeabilized process that maintained lower cytotoxicity and tissue integrity. AP1-F enhances diagnostic accuracy by utilizing spatial confinement to eradicate intracellular interference, connecting molecular specificity to intraoperative margin evaluation or biopsy categorization. Full article

Yersinia enterocolitica is a foodborne pathogen capable of biofilm formation and virulence modulation in response to environmental signals. Among these, glucose—present at physiologically relevant concentrations in the human body—may serve as a regulatory cue affecting infection-associated pathways, including those governed by the pYV virulence plasmid. Although the role of glucose has been investigated under host-mimicking conditions, its impact in non-host environments remains poorly understood. This study was designed to evaluate the glucose-dependent physiological responses of two isogenic Y. enterocolitica strains, KT0001 (pYV-negative) and KT0003 (pYV-positive), under non-host conditions (26 °C). Both strains were cultured in TYE medium containing 0–3% glucose. Comparative analyses were conducted under identical in vitro conditions to elucidate plasmid-associated phenotypic differences. Glucose elicited markedly divergent responses. In KT0001, growth remained unaffected; however, biofilm formation declined by 77.7%, accompanied by a 90% reduction in surface hydrophobicity, a 40% decrease in motility, and a 59% drop in intracellular cyclic AMP—suggesting classical carbon catabolite repression. Conversely, KT0003 exhibited 86% growth inhibition but maintained biofilm levels. This was associated with substantial extracellular polymeric substance induction (~20-fold increase in polysaccharides and ~4.7-fold in extracellular DNA) and nearly fivefold elevation in cyclic AMP levels, despite concurrent decreases in motility (64%) and hydrophobicity (40%). These findings indicate that glucose functions as a strain-specific modulator in Y. enterocolitica. In particular, KT0003’s response suggests that the pYV plasmid enables the bacterium to interpret glucose as a host-associated cue, even under non-host conditions, potentially initiating virulence-related adaptations prior to host contact. Full article

Inherited platelet function disorders (IPFD) are characterized by normal platelet count and morphology but impaired function due to pathogenic variants in genes encoding membrane receptors, granule constituents, or intracellular signaling proteins. Glanzmann’s thrombasthenia, the most representative IPFD, results from ITGA2B or ITGB3 mutations that disrupt the αIIbβ3 integrin complex, producing severe mucocutaneous bleeding. Advances in molecular genetics have expanded the IPFDs landscape to include defects in other platelet receptors (Glycoprotein (GP)-VI, P2Y₁₂, and thromboxane A₂[TxA₂]-R), signaling mediators (RASGRP2, FERMT3, G-protein regulators, PLC, and TxA₂ pathway enzymes), and granule biogenesis disorders such as Hermansky–Pudlak and Chediak–Higashi syndromes. High-throughput sequencing technologies, including long-read approaches, have greatly improved diagnostic yield and clarified genotype–phenotype correlations. Clinically, bleeding severity varies from mild to life-threatening, and management relies on antifibrinolytics, desmopressin, or platelet transfusion; recombinant activated factor VII and hematopoietic stem cell transplantation are reserved for selected cases. Emerging strategies such as gene therapy and bispecific antibodies that link platelets and coagulation factors represent promising advances toward targeted and preventive treatment. A better knowledge of the clinical features and understanding molecular pathogenesis of IPFDs not only enhances diagnostic precision and therapeutic options but also provides key insights into platelet biology, intracellular signaling, and the broader mechanisms of human hemostasis. Full article

The proteasome is a central proteolytic complex that maintains protein homeostasis by eliminating damaged, misfolded, and regulatory proteins. Beyond this quality control role, it generates bioactive peptides that contribute to immune surveillance, intracellular signaling, neuronal communication, and antimicrobial defense. Proteolysis is mediated by the catalytic β1, β2, and β5 subunits, traditionally defined by caspase-like, trypsin-like, and chymotrypsin-like activities. However, these sites display overlapping and flexible specificities, enabling cleavage after nearly all amino acids. This review focuses on proteasome catalytic activity, with particular emphasis on the biochemical and structural features of the catalytic subunits that define cleavage selectivity. We first provide a historical overview of the discovery of proteolytic activities and trace the evolutionary diversification of subunits that gave rise to specialized variants such as the immunoproteasome, thymoproteasome, intermediate proteasomes, and the spermatoproteasome. We then highlight how advances in computational modeling and structural biology have refined our understanding of cleavage preferences. In addition, we examine how regulatory particles, post-translational modifications, and physiological conditions, including inflammation, oxidative stress, and aging, modulate proteolytic activity. Finally, we discuss the development of selective inhibitors targeting individual catalytic sites, emphasizing their therapeutic potential in cancer, autoimmunity, and infectious disease, and outline future directions for the field. Full article

Coxiella burnetii, the causative agent of human Q fever, subverts macrophage antimicrobial functions to establish an intracellular replicative niche. To better understand host–pathogen interactions, we investigated the transcriptional responses of human alveolar macrophages (hAMs) infected with virulent [NMI, G (Q212)], attenuated (NMII), and avirulent (Dugway) strains of C. burnetii. RNA sequencing indicated that all strains activated proinflammatory pathways, particularly IL-17 signaling, though the magnitude and nature of the response varied by strain. Infections with NMI, NMII or G (Q212) resulted in differential expression of roughly the same number of genes, while Dugway infection induced a stronger transcriptional response. Dugway and G (Q212) tended to polarize macrophages toward M1-like states, whereas responses to NMI and NMII were variable. Cytokine assays of NMII-infected THP-1 macrophages suggested the activation of IL-17 signaling, but only at later stages of infection, and single-cell RNA sequencing of NMII-infected THP-1 macrophages indicated heterogeneity in host response to infection, with distinct subpopulations exhibiting M1-like and M2-like inflammatory profiles. These findings highlight the complexity of macrophage response to C. burnetii and underscore the importance of strain-specific and cell-specific factors in shaping host immunity. Understanding these dynamics may inform the development of targeted therapies for Q fever. Full article

Oxidative stress observed in schizophrenia and other psychiatric disorders can induce neuronal damage and modulate intracellular signaling, ultimately leading to neuronal death by apoptosis or necrosis. The aim of this study was to estimate in vitro the possible antioxidant properties of curcumin, the natural polyphenolic antioxidant, and its protective effects against lipid peroxidation induced by the atypical antipsychotic Ziprasidone. Curcumin (5 µg/mL, 12.5 µg/mL, 25 µg/mL, 50 µg/mL) was added to human plasma and incubated for 1 and 24 h, alone and in the presence of Ziprasidone (40 ng/mL, 139 ng/mL, 250 ng/mL). Control plasma samples were incubated for 1 and 24 h. The concentration of thiobarbituric acid-reactive substances (TBARSs; lipid peroxidation marker) was determined by the spectrophotometric method according to Rice-Evans. Curcumin at the tested concentrations significantly inhibited lipid peroxidation in human plasma by about 60%. Ziprasidone (40 ng/mL, 139 ng/mL, 250 ng/mL) significantly increased TBARS levels, but in the presence of the studied curcumin concentrations, its pro-oxidative effects were reduced by about 56%. Our results confirm that Ziprasidone in vitro may induce lipid peroxidation in human plasma, whereas curcumin protects against lipid peroxidation in human plasma caused by the antipsychotic Ziprasidone. Full article

Dysregulated redox signaling, mitochondrial dysfunction and impaired autophagy form an interconnected network that drives inflammatory and immune responses in cardiovascular disease. Among these, disturbances in redox balance, largely mediated by reactive oxygen species (ROS), serve as key drivers linking inflammatory signaling to adverse cardiovascular outcomes. Mitochondria are essential for energy production and cellular homeostasis, but their dysfunction leads to the accumulation of excessive ROS, which triggers inflammation. This pro-oxidative milieu disrupts immune regulation by activating inflammasomes, promoting cytokine secretion, triggering immune cell infiltration and ultimately contributing to cardiovascular injury. Conversely, intracellular degradation processes such as mitophagy alleviate these effects by selectively eliminating dysfunctional mitochondria, thereby decreasing ROS levels and maintaining immune homoeostasis. These interconnected processes influence myeloid cell function, including mitochondrial reprogramming, macrophage polarization and autophagic activity. The modulation of these immune responses is crucial for determining the severity and resolution of cardiac and vascular inflammation, and consequently the extent of cellular injury. This review examines the latest developments and understanding of the intricate relationships between redox signaling, mitochondrial dysfunction, autophagy and oxidative stress in modulating inflammation and immune responses in cardiovascular diseases. Understanding these interrelationships will inform future studies and therapeutic solutions for the prevention and treatment of cardiovascular diseases. Full article