Search Results (183)

Muscle wasting associated with gastric cancer represents a complex, multifactorial systems disorder involving inflammatory, anabolic, mechanosensory, calcium-regulatory, mitochondrial, and proteostatic disruption. This review synthesizes current evidence regarding the cellular and physiological mechanisms involved in skeletal muscle dysfunction in gastric cancer and provides a unifying framework centered on loss of signaling coherence. Specifically, it examines IL-6/STAT3 and NF-κB inflammatory signaling, the myostatin–activin–ACVR2B–SMAD pathway, PI3K/Akt/mTOR signaling, mechanotransduction, excitation–metabolism coupling, calcium homeostasis, mitochondrial function, and proteostasis. Although individual components of these pathways have been implicated in muscle wasting associated with chronic disease, current evidence suggests that they interact through positive feedback loops. Inflammation, anabolic resistance, impaired force-to-signal conversion, mitochondrial stress, altered intracellular calcium homeostasis, and disrupted protein quality control may reinforce one another, contributing to metabolic, structural, and transcriptional instability. Within this context, muscle wasting reflects not only loss of muscle mass or strength, but also loss of functional integrity resulting from disrupted integration of mechanical, metabolic, inflammatory, and anabolic signals. Given the systemic nature of these effects, this review proposes kinesitherapy as a potentially useful nonpharmacological adjunctive strategy that may modulate inflammation, restore responsiveness to mechanical stimuli, support calcium homeostasis and mitochondrial function, improve anabolic sensitivity, and maintain protein quality control. Overall, this review presents a systems-biology model of gastric cancer-associated muscle wasting and supports further investigation of exercise-based therapies for this condition. Full article

Cardiovascular disease (CVD) remains the leading cause of mortality worldwide, and residual inflammatory risk persists despite optimal lipid and glucose control. Emerging evidence indicates that metabolic reprogramming within immune cells constitutes a central driver of cardiovascular immune injury. In this review, we propose a unifying framework in which glyco-lipotoxicity acts as a primary metabolic trigger, inducing mitochondrial dysfunction, oxidative stress, and activation of the NLRP3 inflammasome and cGAS–STING pathways. Hyperglycaemia and dyslipidaemia reshape intracellular metabolic circuits, enhancing glycolysis and disrupting oxidative phosphorylation, thereby promoting sustained pro-inflammatory phenotypes. Crucially, metabolic intermediates function as cofactors for epigenetic remodelling. This establishes trained immunity in both circulating innate immune cells and haematopoietic stem/progenitor cells, which serves as the cellular basis for persistent metabolic memory. This persistent immunometabolic imprint amplifies sterile inflammation and accelerates vascular and myocardial remodelling. Furthermore, these processes are systemically propagated through cross-organ communication networks, including the heart–adipose, gut–heart, and cardio-hematopoietic axes, forming a multidimensional inflammatory amplification loop. We also summarise emerging therapeutic strategies targeting the metabolic–epigenetic axis, aiming to reverse maladaptive trained immunity and mitigate residual CVD risk. By integrating immunometabolism, epigenetic regulation, and organ crosstalk, this review highlights metabolic reprogramming as a pivotal mechanistic nexus and potential precision target for cardiovascular protection. Full article

Store-operated Calcium (Ca²⁺) entry (SOCE), mediated by stromal interaction molecule 1 (STIM1) and Orai1, is a central pathway controlling intracellular Ca²⁺ homeostasis. Gain-of-function (GoF) mutations in STIM1 cause a spectrum of clinically overlapping disorders historically classified as Stormorken Syndrome (STK), tubular aggregate myopathy (TAM), and York Platelet Syndrome (YPS). However, increasing evidence indicates that these entities could represent a shared disease spectrum rather than distinct conditions. At the molecular level, STIM1 activation is governed by a series of autoinhibitory checkpoints that maintain the protein in a tightly controlled resting state. GoF mutations disrupt these regulatory constraints, leading to dysregulated SOCE activity that is frequently, but not uniformly, associated with constitutive channel activation depending on the specific mutation and cellular context. While many disease-associated variants localize to the EF hand, a highly conserved helix–loop–helix Ca²⁺ binding motif, and the CC1 (coiled-coil 1) domain involved in molecular regulation of STIM1 activation, an increasing number of mutations in the C-terminal region further expands the mechanistic and clinical spectrum. In this review, we summarize current concepts of molecular STIM1 activation and discuss how distinct mutations perturb specific regulatory elements of the protein. By systematically integrating published case reports into a comprehensive overview, including a mutation–phenotype correlation table, we highlight the remarkable variability in and incomplete penetrance of clinical manifestations. Full article

Background/Objectives: Neutrophils express the receptor for advanced glycation end products (RAGE), yet its role in antibacterial responses remains incompletely defined. This study aims to elucidate the dual functionality of RAGE as a membrane-bound signaling sensor and a source of soluble RAGE (sRAGE) in human neutrophils challenged with Salmonella typhimurium, a clinically relevant Gram-negative pathogen. Methods: Human peripheral neutrophils from healthy donors were isolated and stimulated with S. typhimurium, LPS, or fMLP. Calcium flux, ROS/RNS production, and phagocytosis were assessed using fluorescent probes and spectroscopy. RAGE expression and localization were analyzed by immunofluorescence microscopy and flow cytometry. Soluble RAGE in supernatants was quantified by ELISA, and its molecular forms were characterized by Western blotting. Results: Resting neutrophils exhibited minimal surface RAGE but a substantial intracellular pool. RAGE inhibition with FPS-ZM1 attenuated bacteria-induced Ca²⁺ mobilization, oxidative burst, nitrosative output, and phagocytosis, with the most pronounced defect at the pathogen-attachment stage—consistent with impaired cytoskeletal remodeling. Upon activation, neutrophils rapidly released sRAGE (peak at ~10 min) via combined metalloprotease-dependent shedding and regulated secretion of pre-formed intracellular stores. Paradoxically, FPS-ZM1 amplified sRAGE release while suppressing membrane-proximal signaling. Conclusions: Neutrophil RAGE functions as a dynamic, multi-compartmental regulator: membrane-associated RAGE licenses effector responses to Gram-negative bacteria, while concomitant sRAGE release provides a fast negative-feedback loop to limit excessive inflammation. This self-limiting circuit balances antimicrobial defense with tissue protection, and its dysregulation may contribute to pathological outcomes in acute and chronic infections. Full article

Although the replication mechanism of the F plasmid and its regulatory strategies have been addressed in several studies, a comprehensive understanding of these processes remains incomplete. In this work, we present new observations that contribute to refining the current model of F plasmid replication control. In this work, the results indicate that plasmid copy number control in both the F plasmid and its derivatives is consistent with two previously proposed mechanisms: the titration model and the loop formation model. In both cases, the intracellular concentration and functional state of the RepE protein appear to play a central role. Consistent with earlier reports, the data of this study support the conclusion that the RepE monomer functions as the active replication initiator. Importantly, the transcriptional analyses suggest that not only RepE dimers but also monomers contribute to autoregulatory control of repE expression. These findings support a model in which the monomer–dimer equilibrium of RepE shapes both replication initiation and transcriptional autoregulation of the F plasmid. Full article

Cuproptosis is a copper-dependent form of regulated cell death that is triggered when intracellular copper handling is perturbed and mitochondrial metabolism becomes the primary site of damage. Aging provides a biological context for this process because copper trafficking shifts, mitochondrial quality control and proteostasis decline, and immune function is remodeled toward immunosenescence with persistent low-grade inflammation. These age-associated changes can weaken antioxidant buffering, reshape labile copper pools, and lower the threshold at which copper stress is converted into mitochondrial proteotoxic injury. In parallel, inflammaging-related cytokines and NF-κB programs can alter copper import, export, and sequestration, while impaired efferocytosis prolongs danger signaling, creating feedforward loops that sustain tissue injury. In this review, we summarize the molecular features that distinguish cuproptosis from other death programs and discuss how redox buffering capacity, copper transport machinery, and mitochondrial metabolic state jointly determine cuproptosis sensitivity during aging. We then examine disease contexts in which these pathways are plausibly relevant, including hereditary copper-handling disorders and age-related neurodegenerative, cardiovascular, metabolic, and musculoskeletal disorders. Finally, we discuss key knowledge gaps and experimental priorities for interpreting cuproptosis-related signals in aged tissues, with emphasis on how copper handling, mitochondrial state, and immune remodeling jointly shape disease phenotypes. Full article

Exercise-induced muscle damage (EIMD) has classically been attributed to localized mechanical disruption following eccentric contractions. Emerging evidence, however, indicates that EIMD represents a systems-level failure of stress integration within skeletal muscle rather than a purely mechanical lesion. Mechanical loading initiates disturbances in intracellular Ca²⁺ homeostasis, which interact with metabolic stress, redox imbalance, and immune activation to form self-reinforcing feedback loops. When compensatory capacity is exceeded, transient injury may shift toward maladaptive remodeling marked by mitochondrial dysfunction, ferroptosis, chronic inflammation, and impaired regeneration. Recent studies identify reactive oxygen species accumulation, iron-dependent lipid peroxidation, dysregulated energy sensing, and aberrant immune polarization as key molecular tipping points governing injury reversibility. Beyond their regenerative role, satellite cells act as integrators of metabolic history and epigenetic memory, linking repetitive injury to reduced muscle adaptability, age-related sarcopenia, and heightened metabolic disease risk. Here, we synthesize evidence from animal models, clinical studies, and multi-omics analyses to establish a systems biology framework for EIMD. We delineate the spatiotemporal interactions among mechanical, metabolic, oxidative, immune, and regenerative modules; identify regulatory nodes that determine adaptive repair versus pathological outcomes; and critically evaluate current nutritional, physical, pharmacological, and regenerative interventions from a mechanism-oriented perspective. Finally, we discuss how multi-omics, digital monitoring, and individualized rehabilitation may enable precision management of EIMD and advance understanding of muscle stress resilience and adaptive limits. Full article

Introduction: Acute ischemic stroke demands interventions that restore perfusion and protect neurons within a narrow therapeutic window. We propose a unified theranostic platform that couples adaptive imaging, topology-aware decision-making, and immediate neuroprotective and micro-dosimetric intervention. Methods: The platform integrates three components. First, a topology-preserving MR–PET engine employs adaptive Poisson-disc sampling, partial Fourier constraints, and structured Hankel low-rank priors in a closed loop. Persistent-homology metrics quantify vascular graph uncertainty and guide subsequent k-space and PET projections, reducing acquisition time while preserving collateral topology. Second, immediate post-reperfusion delivery of glycolic acid attenuates glutamate-driven calcium influx and stabilizes mitochondrial function. Third, trace doses of sol–gel-derived, neutron-activated ⁹⁰Y₂O₃ microspheres provide sharply confined beta irradiation for micro-scale metabolic modulation. Results: In a porcine stroke model replicating the human recanalization workflow, the imaging engine maintained vascular Betti-number invariants within three percent of fully sampled reference scans while reducing acquisition time by nearly half. Glycolic acid reduced glutamate-induced intracellular calcium rise by approximately sixty percent in vitro and decreased infarct volume by thirty-eight percent in vivo. Micro-dosimetry confirmed a mean perivascular beta dose of twenty-eight grays, and histology demonstrated a forty-two percent increase in NeuN-positive neuronal survival compared with standard recanalization. Conclusions: These results demonstrate that intelligent compressed-sensing MR–PET, targeted micro-radioembolization, and glycolic acid neuroprotection can act synergistically to bridge diagnostic imaging and immediate intervention. By coupling imaging, decision-making, and therapy in a closed-loop manner and elevating topological fidelity from a reconstruction byproduct to a control variable, the proposed platform reframes MR–PET from passive diagnostics into an active, decision-driven theranostic system and establishes a foundation for future human trials. Full article

Epigenetic dysregulation is a central driver of cancer progression, therapeutic resistance, and phenotypic plasticity. Among epigenetic mechanisms, microRNAs (miRNAs) and DNA methyltransferases (DNMTs) engage in reciprocal regulatory interactions that extend beyond transient gene control. Emerging evidence indicates that DNMT–miRNA feedback loops function as epigenetic memory units, stabilizing malignant cell states and enabling durable phenotypic inheritance even after removal of initiating stimuli under conditions shaped by persistent redox and stress signaling cues. In this review, we synthesize mechanistic, computational, and translational studies demonstrating how double-negative DNMT–miRNA feedback architectures generate bistable regulatory circuits that lock cancer cells into epithelial–mesenchymal transition, stem-like, and therapy-resistant states through redox-sensitive regulatory thresholds rather than static epigenetic alterations. This framework provides a unifying explanation for why transient environmental or therapeutic cues can induce long-lasting epigenetic reprogramming and why conventional single-target epigenetic inhibitors often fail to achieve durable clinical responses. Building on this concept, we propose that herbal medicines and plant-derived phytochemicals act as epigenetic reset signals capable of destabilizing pathological epigenetic attractor states encoded by DNMT–miRNA memory circuits by modulating intracellular redox balance and redox-responsive signaling pathways. Owing to their multi-component and systems-level regulatory properties, herbal interventions modulate miRNA expression, DNMT activity, and upstream stress-responsive pathways in a coordinated manner, facilitating transitions from memory-dominated states toward renewed epigenetic plasticity. We further discuss the translational implications of combining miRNA-based therapies with herbal medicine as a strategy for epigenetic reprogramming rather than transient suppression within a redox-guided therapeutic framework. Finally, we address key challenges and clinical feasibility considerations, including delivery, heterogeneity, and safety, and outline future directions for biomarker-guided and systems-informed epigenetic therapies that incorporate redox state as a functional determinant of epigenetic responsiveness. By reframing DNMT–miRNA interactions through the lens of epigenetic memory, this review highlights miRNA–herbal combination strategies as a forward-looking approach for overcoming therapeutic resistance and achieving durable reprogramming in cancer through selective manipulation of redox-sensitive epigenetic signaling circuits. Full article

Phytoplasmas are obligate intracellular parasitic bacteria that infect over 1000 plant species globally, causing devastating diseases characterized by yellowing, witches’ broom, phyllody, and significant yield losses in economically important crops. The unculturable nature of these pathogens has historically hindered their study; however, advances in molecular biology and genomics have substantially accelerated progress over the past two decades. This review provides a comprehensive overview of current knowledge on phytoplasma diseases and control technologies. In terms of taxonomy, phytoplasmas are currently classified into 37 16Sr groups with over 150 subgroups based on 16S rRNA gene analysis, and approximately 50 ‘Candidatus Phytoplasma’ species have been formally named. Genomic studies have revealed that phytoplasmas possess highly reduced genomes (530–1350 kb) lacking many essential metabolic pathways, reflecting their obligate parasitic lifestyle. Regarding pathogenesis, secreted effector proteins such as SAP (Secreted Aster Yellows Witches’ Broom Protein), TENGU (tengu-su inducer), and SWP (Secreted Wheat Blue Dwarf Protein) manipulate plant hormone signaling and developmental processes, leading to characteristic disease symptoms. Detection technologies have evolved from traditional microscopy to molecular methods, including nested PCR, real-time quantitative PCR, loop-mediated isothermal amplification (LAMP), and CRISPR/Cas-based systems (Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated protein), with AI-based image recognition and remote sensing emerging as promising tools for large-scale field monitoring. Integrated management strategies encompassing agricultural practices, insect vector control, biological control agents, induced resistance, and breeding for resistance are discussed. Finally, future research directions, including functional genomics, microbiome-based approaches, and precision agriculture technologies, are highlighted. This review aims to provide researchers and practitioners with a systematic reference for understanding phytoplasma biology and developing effective disease management strategies. Full article

Pannexins are transmembrane glycoproteins that share structural and functional similarities with the gap junction proteins innexins and connexins. They play a critical role in paracrine and intracellular signalling, including purinergic signalling via the release of extracellular ATP. The role of pannexins in renal function and the pathophysiology of renal diseases is being intensely studied. However, there are no data on the subcellular localization of pannexin 1 expression in the rat kidney. We studied the distribution of pannexin 1 in the rat kidney, combining light microscopy with immunofluorescent immunohistochemistry and transmission electron microscopy with immunogold pannexin labelling. We found strong expression of pannexin in glomerular podocytes, proximal tubules and collecting ducts; moderate expression in the endothelium of glomerular and peritubular capillaries; thin descending and thick ascending limbs of the loop of Henle; and weaker pannexin 1 expression in the distal tubular epithelium. We described the detailed ultrastructural localization of pannexin 1 expression. This is the first study describing the ultrastructural distribution of pannexin 1 in the rat kidney, one of the most used preclinical models in renal physiology and pathology research. These results provide previously missing data on the precise distribution of pannexin 1 in the rat kidney, which is a prerequisite for a proper understanding of its role in renal physiology and pathophysiology. Full article

This study investigated a phototrophic approach to close nutrient loops by using landfill leachate as a culture medium to produce biomass and polyhydroxybutyrate (PHB) from a thermotolerant strain of Potamosiphon sp. A multi-cycle reuse scheme in which post-culture leachate was partially replenished with fresh leachate and reused in successive cultivation rounds to increase the biomass concentration (g/L) and the intracellular PHB content (% w/w) was tested. Three operational variables were optimized (leachate replenishment percentage, number of reuse cycles, and sanitation method (autoclaving, UV irradiation, or no treatment)) via the Box–Behnken response surface method. Both response variables were modeled with high predictive accuracy (R² = 0.98 for biomass and R² = 1.00 for PHB content). According to the experimental data, leachate replenishment emerged as the key factor influencing nutrient availability—particularly nitrogen and phosphorus—and thus PHB accumulation. The optimized conditions (2.17% v/v fresh leachate, three reuse cycles, and UV sanitation) yielded predicted values of 0.29 g/L biomass and 3.48% w/w PHB. These results demonstrate the feasibility of a controlled multicycle reuse process that integrates effluent treatment and biopolymer synthesis, offering a low-input, circular biotechnological approach for sustainable leachate valorization. Full article

Dopamine is one of the most important neurotransmitters for regulating retinal function and adjusting vision to the diurnal cycle. It exerts its regulatory effects, in part, through the cAMP pathway. Previous studies have demonstrated that dopamine affects phototransduction in amphibian rods, and that elevated intracellular levels of cAMP modulate the function of vertebrate rods and cones. Lamprey, the most primitive vertebrate, could be valuable for studying the evolution of dopamine regulatory loops in the retina. We examined whether the photoresponse properties of long (cone-like) and short (rod-like) photoreceptors in the river lamprey could be regulated by dopamine via the cAMP pathway. Using suction pipette recording, we demonstrated that forskolin-induced elevation of cAMP has no effect on long or short photoreceptors. At the same time, dopamine modifies the photoresponse properties of long, but not short, photoreceptors at high, potentially non-physiological concentrations. Immunohistochemical analysis of the lamprey retina revealed the expression of both D1 and D2 dopamine receptors in lamprey photoreceptors; however, their distribution differs from jawed vertebrates. Taken together, our results suggest that, in lampreys, dopamine does not regulate photoreceptor sensitivity to light in the circadian rhythm, but, rather, adjusts other retinal functions based on widespread distribution of its receptors. Full article

Insulin resistance (IR) is a central driver of cardiometabolic disease and an increasingly recognized modifier of inflammatory and vascular pathology. Beyond impaired glucose homeostasis, IR emerges from chronic, metabolically induced inflammation (“meta-inflammation”) and convergent cellular stress programs that propagate across tissues and organ systems, ultimately shaping endothelial dysfunction, atherogenesis, and cardiometabolic complications. Here, we synthesize multilevel links between insulin receptor signaling, intracellular stress modules (oxidative, endoplasmic reticulum, inflammatory, and fibrotic pathways), tissue-level dysfunction, and systemic inflammatory amplification. This work is a conceptual narrative review informed by targeted database searches and citation tracking, with explicit separation of mechanistic/experimental evidence from human observational and interventional data; causal inferences are framed primarily on mechanistic and interventional findings, whereas associative statements are reserved for observational evidence. We propose an integrative framework in which stress-response pathways are context-dependent and become maladaptive when chronically activated under nutrient excess and persistent inflammatory cues, generating self-reinforcing loops between IR and inflammation that accelerate vascular injury. This framework highlights points of convergence that can guide mechanistic prioritization and translational hypothesis testing. Full article

The epidermal growth factor receptor (EGFR), as an important target protein for inhibiting and intervening in osteoporosis, is associated with cell migration, proliferation, and apoptosis. Peptides derived from food have been shown to have a strong affinity for EGFR, thereby regulating downstream cellular-signaling pathways and participating in stimulating bone formation. However, it is still a “black box” as to how active peptides affect the conformational changes in the EGFR-binding domain when interacting with its ligand EGF. To shed light on the roles, peptides in EGFR binding, which is involved in the osteoblast differentiation, a high EGFR affinity soybean peptide (HEP) was isolated and purified from soy yogurt. Firstly, the osteogenic activity of HEP was identified through cellular alkaline-phosphatase (ALP) and calcium influx. HEP promoted ALP activity from 0.01897 ± 0.00165 to 0.04051 ± 0.00402 U/mg after 100 μM of peptide treatment, and free intracellular calcium ions and calcium deposition both increased in a dose-dependent manner at 1–100 μg/mL. Secondly, the interaction between HEP and EGFR was detected by bioinformatics, spectroscopy analysis, and Western blot. The Molecular docking results showed that HEP (VVELLKAFEEKF) exhibited high affinity among all the peptides, with -CDOCKER energy values of 184.077 kcal/mol on one EGFR. Moreover, a different loop conformation has been detected in HEP, comparing it to that of EGF, which influences HEP interactions with EGFR. GlU3, LEU4, and LEU5 (HEP) match GLU40, LEU26, and GLU40 (EGF). Moreover, the CD data showed that HEP could interact with extracellular domain protein of EGFR, but the secondary structure did not change after HEP was mixed with Mutant extracellular domain protein. Furthermore, treatment with HEP increased the expression of EGFR and the activation of the PI3K-RUNX2-signaling pathway. These results suggested that HEP may have the function of promoting bone remodeling, which could promote the binding between EGF and EGFR and may be used as a potential active factor for functional food development to prevent osteoporosis. Full article