Search Results (14,026)

Obesity is increasingly recognized not only as a metabolic disorder but also as a condition marked by the structural and functional deterioration of skeletal muscle and tendon tissues. Central to this process is the dysregulation of the extracellular matrix (ECM) resulting in fibrosis and ectopic fat accumulation, factors that contribute to impaired tissue mechanics. Myostatin (GDF-8), a member of the TGF-β superfamily, is known as a negative regulator of muscle mass. It can also mediate interaction between adipose and other tissues including muscles and tendons. In obesity, elevated myostatin levels have been reported to be associated with insulin resistance, muscle atrophy, and activation of SMAD2/3 signaling, while experimental and preclinical studies indicate that myostatin inhibition can improve glucose homeostasis and increase lean mass. Emerging evidence suggests that myostatin also plays a critical role in muscle ECM and tendon remodeling. Restoring its physiological levels may help reverse ECM disorganization and reduce tissue fragility associated with musculotendinous dysfunction. This review highlights the multifaceted role of myostatin in obesity, beyond its role in muscle catabolism, to include modulation of structural integrity, metabolism, and mechanical adaptability of the musculotendinous system. Understanding how myostatin responds to metabolic stress and affects biomechanical remodeling offers novel insights into obesity-related muscle and tendon dysfunction. Full article

Coronary artery bypass grafting (CABG) remains the gold standard for patients with advanced multivessel coronary artery disease. Optimal myocardial protection versus ischemia during reversible and controlled cardiac arrest is a cornerstone of successful outcomes. Myocardial ischemia represents a state of reduced coronary perfusion with oxygenated blood, insufficient to meet the metabolic demands of the myocardium. Conventional cardioplegic solutions offer controlled and reversible cardiac arrest while actively modulating the molecular and cellular mechanisms that mediate ischemia–reperfusion injury. Cardioplegia dramatically elongates the reversible period of ischemic injury and restricts cardiomyocyte death by shutting down electromechanical activity, lowering metabolic demand, stabilizing ionic homeostasis, protecting mitochondrial integrity, and slowing oxidative stress and inflammatory signaling. During ischemia, cardiomyocytes shift from aerobic to anaerobic metabolism, resulting in adenosine triphosphate (ATP) depletion, loss of ionic homeostasis and calcium 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, particularly in coronary surgery. Full article

Obesity is a systemic metabolic disorder characterized by chronic low-grade inflammation and insulin resistance, with growing evidence indicating that the brain represents a primary and particularly vulnerable target organ. Beyond peripheral metabolic consequences, obesity induces region-specific structural, functional, and biochemical alterations within the central nervous system, contributing to cognitive impairment, dysregulated energy homeostasis, and increased susceptibility to neurodegenerative diseases. This narrative review examines key neurometabolic and neuroinflammatory mechanisms underlying obesity-related brain vulnerability, including downstream neuroinflammation, impaired insulin signaling, mitochondrial dysfunction, oxidative stress, blood–brain barrier disruption, and impaired brain clearance mechanisms. These processes preferentially affect frontal and limbic networks involved in executive control, reward processing, salience detection, and appetite regulation. Advanced neuroimaging has substantially refined our understanding of these mechanisms. Magnetic resonance spectroscopy provides unique in vivo insight into early neurometabolic alterations that may precede irreversible structural damage and is complemented by diffusion imaging, volumetric MRI, functional MRI, cerebral perfusion imaging, and positron emission tomography. Together, these complementary modalities reveal microstructural, network-level, structural, hemodynamic, and molecular alterations associated with obesity-related brain vulnerability and support the concept that such brain dysfunction is dynamic and potentially modifiable. Integrating neurometabolic and multimodal neuroimaging biomarkers with metabolic and clinical profiling may improve early risk stratification and guide preventive and therapeutic strategies aimed at preserving long-term brain health in obesity. Full article

Breast cancer is a significant cause of death worldwide. Recent research has focused on identifying natural compounds for developing effective cancer treatments. Resiniferatoxin, a transient receptor potential vanilloid 1 (TRPV1) agonist, is a common diterpene in Euphorbia bicolor Engelm. & A. Gray (Euphorbiaceae), a plant native to the southern United States that has not been studied before. We investigated the antiproliferative activities and mechanisms of action of E. bicolor xylene extract in estrogen receptor-positive T47D and triple-negative MDA-MB-231 cell lines. The extract significantly reduced the viability of T47D and MDA-MB-231 cells in a dose-dependent manner. In MDA-MB-231 cells, the extract induced apoptosis via intracellular calcium overload, triggered by TRPV1 activation. This effect was diminished by the TRPV1 antagonist capsazepine and the calcium chelator BAPTA-AM. Intracellular calcium influx was confirmed through Fura-2 AM staining, revealing that E. bicolor phytochemicals activated TRPV1 in MDA-MB-231 cells. Treatment of T47D cells with E. bicolor xylene extract resulted in apoptosis associated with reactive oxygen species (ROS) generation (10-fold higher in T47D cells than in MDA-MB-231 cells) and mitochondrial calcium overload. These effects were significantly blocked when cells were pretreated with N-acetyl-l-cysteine (NAC), a ROS inhibitor. Both cell lines underwent apoptosis via multiple mitochondrial- and endoplasmic reticulum stress–mediated pathways. This was supported by the activation of caspases 3, 8, and 9; increased expression of FAS, XBP1s, and CHOP; upregulation of BAX; and downregulation of BCL-2. In addition, PI3K, AKT, and pAKT protein expressions were also reduced in both cell lines, indicating downregulation of PI3K/Akt signaling pathway. Phytochemicals in E. bicolor xylene extract could become promising ingredients for developing breast cancer therapeutics. Full article

Gut microbial metabolites play a crucial role in modulating cognitive function. In a previous animal study, oral administration of Lactiplantibacillus plantarum MWFLp-182 (L. plantarum MWFLp-182) significantly increased inosine levels in both the serum and feces of D-galactose (D-gal)-induced mice, which was accompanied by improved cognitive performance. Building on this finding, we further investigated the neuroprotective mechanisms of inosine derived from L. plantarum MWFLp-182 in alleviating D-gal-induced neuronal damage in HT-22 cells. Reverse transcription-quantitative PCR (RT-qPCR) was used to analyze the addition of inosine (250 μg/mL, 500 μg/mL), which considerably reduces oxidative stress induced by D-gal (20 mg/mL), on the regulation of mRNA expression of the nuclear factor erythroid 2-related factor (Nrf2)/hemeoxygenase 1 (HO-1) signaling pathway factors. Compared to the D-gal group, the inosine-treated group exhibited a 4.3-fold and 8.7-fold increase in HO-1 and Nrf2 levels, respectively. Furthermore, inosine alleviates neuroinflammation by modulating the mRNA expression of the Toll-like receptor 4 (TLR4)/myeloid differentiation primary response protein 88 (MyD88)/nuclear factor kappa B (NF-κB) signaling pathway. Compared to the D-gal group, the inosine-treated group showed reductions of 41.75%, 28.29%, and 32.17% in TLR4, MyD88, and NF-κB levels, respectively. Moreover, immunofluorescence staining revealed that inosine exhibits anti-apoptotic properties by enhancing the levels of neurotrophic factors, including nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), while simultaneously lowering the expression of the pro-apoptotic protein bcl-2-associated X (Bax). These findings suggest that inosine, a differentially expressed metabolite identified in a probiotic-intervention mouse model, alleviates D-gal-induced neuronal damage in HT-22 cells by modulating oxidative, inflammatory, and apoptotic pathways, providing mechanistic insights into the neuroprotective effects of this metabolite. Full article

The functional deterioration of granulosa cells (GCs), essential for follicular growth, steroidogenesis, and oocyte competence, indicates ovarian aging and reduced fertility. An expanding corpus of research indicates that oxidative stress is a primary molecular contributor to granulosa cell dysfunction, culminating in mitochondrial impairment, reduced metabolic support for oocytes, and the activation of regulated apoptotic pathways that end in follicular atresia. Ferroptosis, an emergent type of iron-dependent lipid peroxidation, has been identified as a crucial mechanism contributing to chemotherapy-induced ovarian insufficiency, polycystic ovary syndrome (PCOS), and granulosa cell death in aging ovaries, in addition to conventional apoptosis. The SIRT1-Nrf2 axis acts as a crucial anti-oxidative and anti-ferroptotic system that protects GC viability, maintains mitochondrial homeostasis, and upholds redox equilibrium. SIRT1 promotes mitochondrial biogenesis and metabolic resilience by deacetylating downstream proteins, including FOXO3 and PGC-1α. Nrf2 simultaneously controls the transcriptional activation of detoxifying and antioxidant enzymes, including HO-1, SOD2, NQO1, and GPX4, which are critical inhibitors of ferroptosis. Disruption of SIRT1-Nrf2 signalling accelerates GC senescence, follicular depletion, and reproductive aging. In contrast, pharmaceutical and nutraceutical therapies, including metformin, melatonin, resveratrol, and agents that increase NAD⁺ levels, may reverse ovarian deterioration and reactivate SIRT1-Nrf2 activity. This narrative review highlights innovative treatment prospects for ovarian aging, fertility preservation, and assisted reproduction by synthesising current evidence on ferroptotic pathways, SIRT1-Nrf2 interactions, and oxidative stress in granulosa cells. An understanding of these interrelated biological networks enables the development of tailored therapies that postpone ovarian ageing and enhance reproductive outcomes for women receiving fertility therapy. Full article

Adhesive fracture in layered structures is governed by subsurface crack evolution that cannot be accessed using surface-based diagnostics. Methods such as digital image correlation and optical spectroscopy measure surface deformation but implicitly assume a straight and uniform crack front, an assumption that becomes invalid for interfacial fracture with wide crack openings and asymmetric propagation. In this work, terahertz time-domain spectroscopy (THz-TDS) is combined with double-cantilever beam testing to directly map subsurface crack-front geometry in opaque adhesive joints. A strontium titanate-doped epoxy is used to enhance dielectric contrast. Multilayer refractive index extraction, pulse deconvolution, and diffusion-based image enhancement are employed to separate overlapping terahertz echoes and reconstruct two-dimensional delay maps of interfacial separation. The measured crack geometry is coupled with load–displacement data and augmented beam theory to compute spatially averaged stresses and energy release rates. The measurements resolve crack openings down to approximately 100 μm and reveal pronounced width-wise non-uniform crack advance and crack-front curvature during stable growth. These observations demonstrate that surface-based crack-length measurements can either underpredict or overpredict fracture toughness depending on the measurement location. Fracture toughness values derived from width-averaged subsurface crack fronts agree with J-integral estimates obtained from surface digital image correlation. Signal-to-noise limitations near the crack tip define the primary resolution limit. The results establish THz-TDS as a quantitative tool for subsurface fracture mechanics and provide a framework for physically representative toughness measurements in layered and bonded structures. Full article

Systemic sclerosis (SSc) is a rare multisystemic autoimmune disease associated with progressive fibrosis, vasculopathy, and immune dysregulation. Despite advances in its management, the disease remains associated with substantial morbidity and mortality, with limited therapeutic options. This systematic review aimed to identify phytocompounds and medicinal plants that had demonstrated efficacy in SSc. A comprehensive literature search was performed in PubMed and ScienceDirect, yielding 7797 records, of which 32 studies met the inclusion criteria. A second search was performed using the SwissTargetPrediction tool to identify new putative molecular targets for these phytocompounds, whose relevance for SSc pathogenesis was verified by a third search in PubMed and ScienceDirect databases. Our search found 24 phytocompouds (e.g., halofunginone, crocetin, and tanshinone IIA) and 5 plant extracts (e.g., caper bush and ciplukan) reported to modulate key pathogenic processes in SSc. These phytochemicals were mainly associated with effects on endothelial to mesenchymal transition, oxidative stress, inflammation, and profibrotic signaling pathways, particularly TGF-β/Smad. The SwissTargetPrediction tool indicated 93 new potential molecular targets of the selected phytochemicals, among which only 41 showed relevance to SSc pathogenesis. In conclusion, available evidence is scarce but promising. Further studies, especially human investigations, are required to clarify clinical efficacy, safety, and potential interactions with drugs used in SSc. Full article

Piglets weaning is a critical developmental stage marked by significant metabolic and inflammatory challenges. The hepatic responses during this period may differ among pig breeds with distinct genetic backgrounds. To explore the phenotypic and molecular differences in the livers between the Zaozhuang Heigai (HG) pig and Duroc×Landrace×Yorkshire (DLY) piglets and elucidate the regulatory mechanisms of genetic background on liver function, five 35-day-old piglets from each breed were selected. Body weight and liver coefficients were measured; histological features of liver sections were observed, and the transcriptome and metabolome of the liver were determined using mRNA sequencing and non-targeted metabolomics analysis. The results showed that HG piglets had significantly lower body weight (p < 0.01) and slightly higher liver coefficients than DLY piglets. Histological examination revealed that the hepatic lobule structure was intact in both breeds, while mild hepatic congestion was observed in some DLY piglets. Transcriptome analysis identified 429 differentially expressed genes (DEGs) with criteria of FDR adjusted p-values < 0.01 and |log₂(Fold Change)| > 1, and they were significantly enriched in oxidoreductase activity, peroxisome proliferator-activated receptor (PPAR) signaling, and arachidonic acid metabolism pathways. Metabolome analysis identified 169 differentially expressed metabolites (DEMs) with criteria of p < 0.05, VIP > 1, and |log₂(Fold Change)| > 1, and they were significantly enriched in nucleotide metabolism, arginine biosynthesis, and arachidonic acid metabolism pathways. Integrative analysis of DEGs and DEMs showed that arachidonic acid metabolism was the common pathway. Within this pathway, key genes (GPX3, ALOX5, and CBR3) were significantly associated with specific metabolites (15-deoxy-PGJ₂ and phosphatidylcholines) (FDR adjusted p < 0.05), suggesting a gene–metabolite interaction network that coordinates inflammatory regulation and oxidative stress. These findings provide molecular evidence for breed-specific hepatic metabolic regulation during the weaning period and are therefore conducive to the management of weaned piglets and the investigation of local pig characteristics. Full article

The brain’s extracellular matrix (ECM) serves as a dynamic and instructive regulator of glioma progression. The ECM provides structural support while integrating pharmacological and mechanical signals that influence glioma initiation, progression, and treatment resistance. Deviant ECM remodeling fosters tumor heterogeneity, invasion, and immune evasion by altering stiffness, composition, and cellular matrix signaling. We proposed that ECM remodeling in gliomas not only facilitates tumor growth and heterogeneity but also establishes advantageous biophysical and metabolic conditions that foster treatment resistance and recurrence. Our objective is to analyze current findings regarding the structural, biochemical, and mechanical roles of the brain ECM in glioma growth, emphasizing its contribution to tumor heterogeneity, mechanotransduction, immunological modulation, and its potential as a therapeutic target. Method: A comprehensive literature review was conducted using scientific databases including PubMed, Web of Science, and Scopus. Peer-reviewed literature published between 2000 and 2025 was selected for its relevance to ECM composition, stiffness, remodeling enzymes, extracellular vesicles, and mechanobiological processes in gliomas. Results: Recent investigations demonstrate that glioma cells actively alter the ECM by secreting collagens, laminins, and metalloproteinases, establishing a feedback loop that facilitates invasion and resistance. Discussion: Mechanical variables, such as ECM stiffness and solid stress, influence glioma growth, metabolism, and immune exclusion. Moreover, extracellular vesicles facilitate significant extracellular matrix remodeling and improve communication between tumors and stromal cells. The disruption of ependymal and subventricular extracellular matrix niches enhances invasion and cerebrospinal fluid-mediated signaling. The remodeling of the ECM influences glioma growth through interconnected biochemical, mechanical, and immunological mechanisms. Examining ECM stiffness, crosslinking enzymes, and vesicle-mediated signaling represents a potential therapeutic approach. Integrative methodologies that combine mechanobiology, imaging, and multiomics analysis could uncover ECM-related vulnerabilities to improve glioma treatment. Full article

Cisplatin (CDDP) is a cornerstone chemotherapeutic drug, yet its efficacy is frequently compromised by renal toxicity, primarily manifesting as acute kidney injury (AKI). Magnolol (MG) is a polyphenol from Magnolia officinalis and has been widely documented for its pronounced antioxidant and anti-inflammatory properties. This study evaluated the renoprotective effects of MG in a murine model of CDDP-induced AKI. Male C57BL/6 mice received MG (20 mg/kg) via daily intraperitoneal injection for four consecutive days, starting one day before a single CDDP injection. MG significantly reduced the serum concentrations of blood urea nitrogen and creatinine. Histopathological assessment revealed attenuated tubular damage and reduced expression of tubular injury markers. MG inhibited pro-inflammatory cytokines at both systemic and renal levels, alleviated endoplasmic reticulum stress, and suppressed activation of mitogen-activated protein kinase signaling pathways. Apoptotic damage was mitigated, as shown by the fewer TUNEL-positive cells and lowered expression of pro-apoptotic markers. In parallel, ferroptotic processes were alleviated through downregulation of pro-ferroptotic proteins and preservation of key antioxidant regulators. Importantly, MG restored nuclear factor erythroid 2-related factor 2 activity and upregulated downstream antioxidant effectors. These findings highlight the multi-targeted renoprotective actions of MG and support its possible utility as a therapeutic agent to prevent CDDP-induced renal injury. Full article

Necroptosis and dysfunction of ovarian granulosa cells are major contributors to follicular atresia and reduced fertility in cattle, processes that are closely associated with endoplasmic reticulum stress (ERS). Ginseng polysaccharides (GPSs) are known to reduce ER stress, display anti-inflammatory properties, and modulate reproductive function; however, whether GPS can protect against granulosa cell injury and the underlying mechanisms remain unclear. To address this gap, this study aimed to investigate the protective effects of GPS on ERS-induced bovine granulosa cell damage and to elucidate the associated mechanisms. An ERS model was established in bovine granulosa cells using tunicamycin (Tm), and cellular responses were evaluated via flow cytometry, ELISA, and EdU assays. Further, a mouse model was used to validate the protective effects of GPS against Tm-induced ovarian injury. The results showed that 40 μg/mL of GPS significantly alleviated ERS-induced granulosa cell damage, inhibited necroptosis, and mitigated ERS. Moreover, using the PI3K/Akt pathway inhibitor LY294002, we demonstrated that the inhibitor antagonized the effects of GPS, indicating that GPS promotes granulosa cell proliferation and restores estrogen secretion via activating the PI3K/Akt pathway. In vivo experiments further confirmed that GPS effectively attenuates ERS-induced ovarian damage in mice. Collectively, these findings reveal that GPS improves granulosa cell function and ovarian tissue integrity by modulating the ERS network and the PI3K/Akt pathway, yielding a theoretical basis for preventing follicular atresia and enhancing reproductive efficiency in cattle. Full article

Grapevine (Vitis vinifera L.) is a globally significant crop increasingly affected by a variety of biotic and abiotic stresses. Plant biostimulants offer a promising approach to enhance plant resilience by modulating key physiological and metabolic processes. This study aimed to demonstrate that the preventive application of a Fabaceae-based biostimulant can prime grapevine defense pathways, thereby improving plants’ ability to endure potential stress conditions. Indeed, resistance to both biotic and abiotic stresses in plants involves common pathways, including Ca²⁺ and ROS signaling, MAPK cascades, hormone cross-talk, transcription factor activation, and induction of defense genes. Grapevine leaves were subjected to high-throughput transcriptomic analysis coupled with qPCR validation 6 and 24 h following treatment application. Differentially expressed genes were visualized using MapMan to identify the major metabolic and signaling pathways responsive to the treatment. This integrative analysis revealed several defense-related pathways triggered by the biostimulant, with representative protein families showing both up- and downregulation across key functional categories. Overall, the results indicate that a wider array of pathways associated with stress tolerance and growth regulation were stimulated in treated plants compared to untreated controls. These findings support the conclusion that a preventive biostimulant application can effectively prime grapevine metabolism, enhancing its preparation to cope with forthcoming environmental challenges. Full article

Background: Solenopsis invicta, commonly known as the red imported fire ant (RIFA), is an important global invasive pest, and its management is challenging because of insecticide resistance and environmental problems. Methods: In this research, we applied transcriptomics to analyze the molecular responses of S. invicta worker ants exposed to different types of pesticides, beta-cypermethrin (BC) and the entomopathogenic fungus Cordyceps cicadae (CC), as well as to different concentrations of these pesticides. Results: A total of 2727 differentially expressed genes (DEGs) were identified across all samples. The number of DEGs in the BC treatment group was significantly higher than that in the CC treatment group (2520 vs. 433), and higher concentrations resulted in more DEGs (an increase of 47 in the BC group and 229 in the CC group). KEGG pathway analysis revealed that the DEGs were significantly enriched in lipid metabolism, carbohydrate metabolism, amino acid metabolism, signal transduction, and membrane transport. Immune-related gene analysis showed more general down-regulation (average FPKM value in BC 741.37 to 756.06 vs. CK 1914.42) of pathogen recognition genes (PGRP-SC2) under BC stress conditions, while CC treatment resulted in increases in expression of important immune effectors such as various serine proteases. Conclusions: Overall, this study provides useful insights into the molecular basis of responses to different pesticides in S. invicta and offers a basis to develop new approaches to control this pest. Full article

Adipose tissue thermogenesis is a promising strategy to counter obesity and metabolic disease, but sustained activation of thermogenic adipocytes elevates oxidative and lipid-peroxidation stress, increasing susceptibility to ferroptotic cell death. Existing models often treat redox buffering, hypoxia signaling and ferroptosis as separate processes, which cannot explain why similar interventions—such as antioxidants, β-adrenergic agonists or iron modulators—alternately enhance thermogenesis or precipitate tissue failure. Here, we propose the Redox–Thermogenesis–Ferroptosis Compass (RTF-Compass) as a framework that maps adipose depots within a space defined by ferroptosis resistance capacity (FRC), ferroptosis signaling intensity (FSI) and HIF-1α-dependent hypoxic tone. Within this space, thermogenic output follows a hormetic, inverted-U trajectory, with a Thermogenic Ferroptosis Window (TFW) bounded by two failure states: a Reductive-Blunted state with excessive antioxidant buffering and weak signaling, and a Cytotoxic state with high ferroptotic pressure and inadequate defense. We use this model to reinterpret genetic, nutritional and pharmacological studies as state-dependent vectors that move depots through FRC–FSI–HIF space and to outline principles for precision redox medicine. Although the TFW is represented as coordinates in FRC–FSI–HIF space, we use ‘Compass’ to denote a coordinate framework in which perturbations act as vectors that orient depots toward thermogenic or cytotoxic outcomes. Finally, we highlight priorities for testing the model in vivo, including defining lipid species that encode ferroptotic tone, resolving spatial heterogeneity within depots and determining how metabolic memory constrains reversibility of pathological states. Full article