Search Results (13,475)

Viral comorbidities elicit complex host responses by activating redox-sensitive signaling pathways, prominently those regulated by NADPH oxidase (Nox) enzymes. Nox are critical components of host defense, generating reactive oxygen species (ROS) that modulate key cellular signaling cascades. Under normal physiological conditions, Nox activity is tightly controlled; however, viral infections frequently disrupt this regulation, leading to aberrant upregulation of specific Nox isoforms. Elevated expression of individual Nox enzymes has been observed in infections such as influenza A and hepatitis C virus, while simultaneous activation of multiple Nox isoforms occurs in HIV and SARS-CoV infections. Similar patterns of dual or multi-isoform Nox activation are also reported in complex disease states, including diabetes, thrombosis, and fibrosis. MicroRNAs play a crucial role in this process by selectively regulating Nox isoform expression during viral infection, thereby remodeling the host redox environment. Nox-derived ROS influence multiple downstream signaling pathways, including SMAD, MAPK, CXCR-mediated signaling, and the JNK/ERK axis, promoting inflammation and fibrosis that worsen viral disease outcomes. Additionally, several FDA-approved drugs, investigational agents, and microRNA-based therapeutics show promise in modulating Nox activity. Therefore, this article substantiates how viral infections reprogram host transcriptomic and redox signaling networks, contributing to viral pathogenesis and offering potential therapeutic intervention strategies. Full article

Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by abnormal hepatic lipid accumulation and is frequently driven by factors such as a high-fat diet (HFD). Total flavonoids of Apocynum venetum (TFAV), the bioactive constituents of a traditional medicinal plant, have demonstrated antioxidant and lipid-modulating properties. However, their therapeutic potential against MASLD and the underlying mechanisms are not explored. This study aims to evaluate the ameliorative effects of TFAV on HFD-induced MASLD utilizing both in vivo animal and in vitro cellular models. Methods: C57BL/6J were allocated to control, high-fat diet (HFD), TFAV (100 mg/kg/day), and TFAV intervention groups (25, 50, and 100 mg/kg/day). In vitro, WRL68 hepatocytes were stimulated with free fatty acids (FFAs) to establish a cellular model of steatosis. Liver function, serum lipid profiles, hepatic histopathology, and the AMPK signaling pathway were assessed. Results: TFAV intervention significantly improved serum biochemical profiles in the animal models; for instance, co-treatment with 100 mg/kg/day TFAV and HFD reduced TC, TG, and LDL-C levels by 20.59%, 45.26%, and 38.24% respectively (p < 0.05), and effectively alleviated hepatic steatosis and hepatocyte ballooning. Furthermore, TFAV markedly inhibited intracellular reactive oxygen species (ROS) levels and activated the AMPK signaling pathway (p < 0.05). This was accompanied by the downregulation of SREBP-1c and ACC expression (p < 0.05), as well as the upregulation of ATGL and CPT1α expression (p < 0.05). Conclusions: These results demonstrates that TFAV remodel hepatic lipid homeostasis by activating the AMPK signaling pathway, and exerting significant preventive and protective effects against the progression of HFD-induced MASLD in vivo. Full article

Adenosine has emerged as a central metabolic signal linking cellular stress to systemic physiological adaptation. Under conditions such as hypoxia, ischemia, inflammation, and tissue injury, extracellular adenosine triphosphate (eATP) released from stressed cells is sequentially metabolized by the ectonucleotidases CD39 and CD73, generating adenosine that accumulates in the extracellular microenvironment. This stress-responsive nucleoside activates four G-protein-coupled receptors (A1, A2A, A2B, and A3), triggering intracellular signaling networks including the cyclic adenosine monophosphate–protein kinase A (cAMP–PKA), mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase–protein kinase B (PI3K–Akt), and hypoxia-inducible factor-1 alpha (HIF-1α) pathways. Through these integrated mechanisms, adenosine orchestrates diverse physiological processes such as vascular regulation, metabolic adaptation, immune modulation, and cellular survival. In the cardiovascular system, adenosine promotes coronary vasodilation and ischemic preconditioning, limiting reperfusion injury. In pulmonary tissues, it mediates acute anti-inflammatory responses but may also drive chronic fibrotic remodeling. Within the central nervous system, adenosine functions as a neuromodulator regulating neuronal excitability, sleep–wake homeostasis, and neuroprotection. In the tumor microenvironment, hypoxia-driven adenosine accumulation suppresses cytotoxic T cell and natural killer activity, facilitating immune evasion and tumor progression. Collectively, adenosine signaling represents a central integrative network that links metabolic stress sensing to coordinated cellular adaptation while simultaneously emerging as a clinically actionable therapeutic target across cardiovascular, inflammatory, neurological, and oncological diseases. Full article

Background: Baeckea frutescens L. (BF) has been reported as a potential natural source for skin-whitening agents. However, its antimelanogenic activity and mechanisms remain unclear. Methods: The antimelanogenic effects of BF were evaluated in α-melanocyte-stimulating hormone (α-MSH)-stimulated B16F10 cells and in zebrafish embryos. Cell viability, intracellular tyrosinase activity and melanin content were measured. Western blot (WB) analysis was used to examine melanogenesis-related proteins. Network pharmacology and molecular docking were performed to predict potential targets and interactions of BF-derived metabolites. Results: The ethanolic extract of BF reduced intracellular tyrosinase activity and melanin content in cells without cytotoxicity. Western blot analysis showed decreased expression of microphthalmia-associated transcription factor (MITF) and its downstream melanogenic enzymes, including tyrosinase (TYR), tyrosinase-related protein-1 (TRP-1), and dopachrome tautomerase (DCT). In addition, BF reduced phosphorylation of protein kinase A (PKA), cAMP responsive element-binding protein (CREB) and extracellular signal-regulated kinase (ERK), suggesting potential suppression of PKA/CREB and ERK signaling pathways. These regulatory effects may contribute to MITF downregulation and subsequent inhibition of melanogenesis. BF reduced melanin accumulation in zebrafish embryos. Network pharmacology and molecular docking analyses further suggested that BF-derived metabolites, particularly bayogenin, may interact with multiple melanogenesis-related targets. Conclusions: BF may inhibit melanogenesis through coordinated modulation of multiple signaling pathways and may represent a promising skin-whitening candidate. Full article

Pyrrolizidine alkaloids (PAs), a category of naturally occurring secondary metabolites, are commonly found in various botanical sources. Accumulating evidence indicates that PAs and their biologically active metabolites can interact with cellular components and trigger a variety of toxic effects in animals and humans. Notably, PAs exhibit significant hepatotoxic potential via nutritional supplements, environmental dissemination, food chain contamination, and broader ecological pollution. In this review, we summarize PA-induced hepatotoxicity in humans and animals and the underlying molecular mechanisms. It involves oxidative stress, mitochondrial dysfunction, apoptosis, ER stress, inflammation, autophagy, and ferroptosis. Several key signaling pathways, such as nuclear factor-erythroid 2 related factor 2 (Nrf2), mitogen-activated protein kinase (MAPK), protein kinase RNA-like endoplasmic reticulum kinase (PERK), toll like receptor 4 (TLR4), nuclear factor kappa-B (NF-κB), transforming growth factor beta (TGF-β), p53, farnesoid X receptor (FXR), and pregnane X receptor (PXR), are also implicated. Furthermore, this review discusses diagnostic approaches, metabolic activation pathways, and detoxification strategies targeting PA-induced liver injury. Collectively, this review provides a comprehensive understanding of the molecular basis of PA hepatotoxicity and underscores the urgent need for improved risk assessment, early diagnosis, and effective detoxification interventions to mitigate PA-related liver diseases in humans and animals. Full article

Epilepsy is mainly characterized by spontaneous seizures caused by hyperactive neural circuits. To delineate the cell-type-specific mechanisms underlying neuronal hyperexcitability, we resolve the hyperexcitability of excitatory neurons across epileptic human brain trans-foci at single-cell resolution to identify the key drivers and potential diagnostic signatures. We constructed a comprehensive atlas encompassing 240,000 cells derived from the temporal cortex and hippocampus, detecting trans-regional cellular and molecular diversity. We further delineated dynamic trajectories, gene expression patterns, and functional reorganization across cell types. Using the LASSO and random forest algorithms, we prioritized the core genes and developed a logistic regression-based diagnostic model. Despite transregional cellular landscape conservation, major cell types varied in abundance. Detailed analysis delineated various excitatory neuron subtypes’ dynamic trajectories, intricate expression, and functional reorganization, with pronounced dysfunction in the posterior hippocampal and temporal cortex networks, indicating hyperactive pro-epileptic effects. Excitatory neurons exhibit an intrinsic ability to autonomously organize themselves into distinct, highly active modules, characterized by a high activation state during epileptogenesis, as illustrated by ten epilepsy-associated functions. Transcription circuits FOSL2/FOS/EGR3/EGR1 promote neuronal hyperexcitability. Integrating epilepsy bulk RNA-seq data, we identified 24 overlapping genes between differential genes and circuit targets. The LASSO and random forest algorithms prioritized three core genes (IL1B, SOCS6, and COL4A1). A logistic regression model based on these three genes showed variable performance, with an apparent AUC of 1.000 in the discovery cohort (GSE256068) and AUCs of 0.974 and 0.722 in and two validation cohorts, indicating the need for further validation. Our study establishes the FOSL2/FOS/EGR3/EGR1 circuit as a master regulator of pathological neuronal hyperactivity across epileptic foci, linking transcriptional activation to network dysfunction. Identifying overactive factors may represent a candidate molecular pathway for future therapeutic exploration against hyperexcitability. Full article

Ultraviolet radiation (UVR) exposure accelerates skin aging by disrupting cellular homeostasis and inducing epigenetic changes, such as promoter hypermethylation of key regulatory genes. However, the molecular mechanisms underlying UVR-driven epigenetic silencing remain poorly understood. By integrating high-throughput DNA methylation profiling with co-regulatory network analysis, we identified KIT as a hub gene in a photoaging-associated methylation module. Pathway enrichment further revealed coordinated hypermethylation of the canonical Wnt/β-catenin signaling pathway, establishing the Wnt/KIT axis as a critical epigenetic-signaling nexus in UVR-induced skin fibroblast aging. In immortalized human skin fibroblasts (HSFs), UVR suppressed Wnt signaling, leading to KIT promoter hypermethylation, transcriptional silencing, and premature photoaging. Gain-of-function studies revealed that reversing KIT hypermethylation either via Wnt pathway activation or KIT overexpression effectively mitigated photoaging-associated phenotypes. Crucially, we found that puerarin (PUE), a natural isoflavone, reversed UVR-induced epigenetic silencing by directly interacting with β-catenin, reactivating Wnt signaling, and restoring KIT expression. PUE treatment preserved cellular function in UVR-damaged fibroblasts. These findings establish the Wnt/β-catenin-KIT axis as a critical epigenetic driver of skin aging and highlight puerarin as a promising therapeutic candidate for targeted anti-aging intervention. Full article

Psoriasis, a chronic inflammatory skin disease affecting men and women equally, presents distinct gender-based differences in severity and treatment response. While molecular mechanisms underlying psoriasis are well-studied, sex-specific differences remain largely unexplored. To address this, we conducted a comprehensive analysis of transcriptomic data from lesional psoriasis skin and healthy controls, comparing male and female cohorts. Our findings reveal 2760 overlapping differentially expressed genes (DEGs) between sexes, highlighting shared pathways like IL-17 signaling and Th17 differentiation. However, sex-specific pathways emerged, including male-enriched PI3K-Akt signaling and chemokine receptor activity, and female-enriched glycolysis and AHR-NRF2 pathways. Upstream regulator analysis identified sex-specific drivers, including VEGFA activation and CFTR inhibition in males, and AHR activation and FGF21 inhibition in females. Notably, Regulatory T cells (Tregs) and neutrophil abundance differed by sex, aligning with disease severity trends. These results highlight sex-associated molecular and cellular disparities that may be relevant to understanding differences in disease manifestation and treatment response. As an exploratory, hypothesis-generating transcriptomic analysis, this study lays the groundwork for future experimental and clinical validation of sex-specific mechanisms in psoriasis. Full article

Background: Postmenopausal osteoporosis is associated with cellular senescence and the accumulation of the senescence-associated secretory phenotype (SASP). While mesenchymal stem cell (MSC)-derived exosomes show tissue repair potential, the efficacy and mechanisms of MSC-derived apoptotic vesicles (apoVs) remain unclear. This study compared MSC-apoVs and exosomes in postmenopausal osteoporosis and investigated the underlying epigenetic mechanisms. Methods: Therapeutic efficacy was evaluated in an ovariectomized (OVX) mouse model and senescent human bone marrow mesenchymal stem cells (hBMMSCs). Small RNA sequencing identified differential microRNA (miRNA) cargos between vesicle types. SASP-related cytokine expression (IL-6, TNF-α, MCP-1) and pathway activation were assessed by RT-qPCR, ELISA, and Western blot. Results: MSC-apoV treatment attenuated bone loss in OVX mice and reduced SASP expression in senescent hBMMSCs to a greater extent than exosomes. Small RNA sequencing revealed that apoVs were enriched with a specific miRNA cluster, including hsa-let-7b-5p, hsa-miR-92a-3p, and hsa-miR-98-5p. Bioinformatic analyses identified BRAF and CRKL as downstream targets of this miRNA cluster, supported by reduced protein levels after apoV treatment. Subsequent molecular assays showed that apoV treatment inhibited the phosphorylation of both the MAPK (p38 and JNK) and NF-κB (p65) signaling pathways, which correlated with reduced local inflammation in the bone marrow microenvironment and preserved osteogenic differentiation capacity. Conclusions: MSC-apoVs attenuate postmenopausal osteoporosis more effectively than exosomes. This enhanced efficacy is associated with the delivery of an enriched miRNA cluster that inhibits MAPK and NF-κB signaling, together with suppression of BRAF and CRKL protein expression. ApoVs may represent a cell-free therapeutic strategy for age-related bone loss. Full article

Methylglyoxal (MG) is a reactive dicarbonyl compound generated mainly as a byproduct of glycolysis. Excess accumulation of MG can promote protein glycation and the formation of advanced glycation end-products (AGEs), which have been associated with oxidative stress, inflammation, mitochondrial dysfunction, and cellular damage. These processes are implicated in the development of several chronic conditions, including diabetes, neurodegenerative disorders, cardiovascular disease, and age-related decline. The glyoxalase system, comprising Glyoxalase I (Glo1) and Glyoxalase II (Glo2), serves as a key cellular defense mechanism that detoxifies MG and helps maintain dicarbonyl homeostasis. Among these enzymes, Glo1 catalyzes the conversion of MG into less reactive intermediates in a glutathione (GSH)-dependent manner. A range of natural compounds and dietary phytochemicals, including sulforaphane, resveratrol, α-lipoic acid, selenium, vitamin D3, and N-acetylcysteine, have been reported to modulate Glo1 activity through transcriptional regulation, antioxidant effects, or support of intracellular GSH levels. Evidence from preclinical and limited human studies suggests that these compounds may help reduce MG burden and AGE formation, although their effects are often indirect and context-dependent. However, several challenges remain, including variable bioavailability, dose-dependent responses, disease-specific differences in Glo1 regulation, and the lack of standardized biomarkers and adequate clinical validation. This review examines the MG–Glo1 axis as a mechanistic framework linking metabolic stress to disease and evaluates natural compounds as context-dependent modulators of this pathway. By integrating mechanistic insights with emerging in vivo and clinical evidence, this work highlights the potential, while acknowledging the limitations, of targeting Glo1 as a translational strategy for managing glycation-associated disorders. Full article

Bacillus velezensis-based probiotics are increasingly recognized for their potential to enhance intestinal health in companion animals, yet their mechanisms of action in canine epithelial systems remain incompletely defined. This study aimed to evaluate whether a live Bacillus velezensis probiotic consortia (BC) modulates epithelial barrier integrity, immune signaling, apoptosis-renewal pathways, and metabolic activity in canine-relevant intestinal and macrophage cell models. MCA-B1 proximal gastrointestinal epithelial cells and DH82 macrophage-like cells were exposed to BC cultures, followed by quantification of tight-junction expression, permeability (FITC-Dextran), cytokine responses, phagocytic activity, apoptosis-related markers, and metabolomic profiles. BC treatment significantly strengthened the epithelial barrier, inducing a marked upregulation of Claudin 1 (CLDN1) (11.3 fold), CLDN4 (2.4 fold), Occludin (OCLN, 1.7 fold), and increasing key proteins including ZO-2 and cingulin while reducing LPS-induced FITC-Dextran permeability to 94.5%. BC concurrently modulated innate immune signaling, increasing MyD88 (33.2%), IL-8 (14.6 fold), IL-18 (2.6 fold), and IFNB1 protein levels, while enhancing anti-inflammatory regulation, including a robust rise in DH82-derived IL-10. Apoptosis-renewal markers shifted toward physiological turnover, with increased BCL2 (1.9 fold) and reduced BAK1. Metabolomic profiling of BC activity revealed elevated AMP, abundant Peptide Transporter 1 (PEPT1)-transportable peptides, increased γ-glutamyl metabolites, and lower Glutathione disulfide (GSSG), consistent with AMPK-linked tight-junction assembly and glutathione-supported redox buffering. Together, these data indicate that Bacillus velezensis-derived metabolites positively influence barrier-related, immunological, and metabolic responses in a canine proximal intestinal epithelial system and modulate functional responses in macrophage-like cells. These in vitro findings contribute to the mechanistic understanding of host cellular responses to Bacillus-associated metabolites. Full article

Small-cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma characterized by poor survival. Despite a high tumor mutation burden, biomarker discovery in SCLC remains challenging due to rapid tumor plasticity and limited tissue availability, highlighting the promise of liquid biopsy-based approaches. Epigenetic dysregulation of DNA 5-hydroxymethylcytosine (5hmC) has emerged as a cancer hallmark. However, its role in SCLC remains largely unexplored. Here, we characterized the cell-free DNA (cfDNA) 5hmC landscape in SCLC and evaluated its potential applications. We profiled the cell-free hydroxymethylomes of 107 pre-treatment SCLC patients and 53 matched controls using the 5hmC selective chemical labeling (5hmC-Seal) assay. SCLC displayed higher global 5hmC levels and distinct enrichment at neurodevelopmental and synaptic pathways, consistent with the neuroendocrine identity of SCLC. Concordance between plasma and matched circulating tumor cell patient-derived xenograft (CDX) demonstrated that cfDNA 5hmC reflects tumor epigenetic states and correlates with transcriptomic-derived molecular subtypes. Elevated SCLC-specific 5hmC levels and extensive stage (ES) disease were associated with inferior survival, with ES disease showing enrichment of pathways linked to cellular plasticity and neurodevelopment. Together, these findings indicate that cfDNA 5hmC profiling has potential as a biologically informative and clinically relevant biomarker in SCLC, with possible applications in tumor subtyping and risk stratification. Full article

Cancer represents a major global health challenge, contributing to an estimated 19 million new cases annually. While conventional chemotherapeutic approaches continue to advance, target-based therapeutic strategies are increasingly recognized as effective pathways in modern drug development. A prominent biological target in current anticancer research is the selective inhibition of Topoisomerase II alpha (TOP2A). TOP2A, a crucial DNA topoisomerase, is vital for maintaining genomic integrity by mediating the cleavage and re-ligation of double-stranded DNA during essential cellular processes, such as DNA replication and transcription. Inhibiting TOP2A effectively disrupts these processes, leading to cell death. This study employed computer-aided drug design approaches to virtually screen a library of 3000 xanthone derivatives against the TOP2A target, and the results were preliminarily validated through cytotoxicity assays on the A549 and HepG2 cancer cell lines. The computational methods utilized included molecular docking, pharmacological modeling, molecular dynamics simulations, and steered molecular dynamics simulations. The virtual screening identified two highly promising HIT compounds, CID162372098 and CID156619937, that exhibited the most favorable interactions and stability profiles in relation to the TOP2A active site. The experimental results demonstrated that both hit compounds effectively exhibited significant anti-proliferative activities against the HepG2 cell line, with IC50 values of 9.54 ± 0.26 µg mL⁻¹ (CID162372098) and 10.03 ± 0.36 12.69 ± 0.31 µg mL⁻¹ (CID156619937), respectively. Collectively, these findings demonstrate the potential of xanthone-based scaffolds as inhibitors of TOP2A and provide a rational framework for the screening and development of novel anticancer agents. Full article

Cervical cancer constitutes a major global health burden with a high incidence rate. Despite its well-established role in genome stability and cell cycle regulation, its specific anti-tumor mechanism involving the induction of a senescence-like state remains unclear. To determine whether Mg²⁺ impedes cervical cancer progression through the induction of a senescence-like phenotype via the ATM/CHK2/p21 pathway, HeLa cells were used in this study. Cell proliferation, migration, and invasion were measured using CCK-8, EdU, wound-healing, and Transwell assays, while SA-β-gal staining and western blotting served to examine both senescence-related markers and pathway protein expression. A BALB/c nude mouse xenograft model was established to evaluate tumor growth and safety following intratumoral Mg²⁺ injection. The results showed that Mg²⁺ inhibited proliferation, migration, and invasion in a concentration-dependent manner. Treatment with 20 mM Mg²⁺ increased SA-β-gal positivity, decreased Lamin B1 expression, and activated the ATM/CHK2/p21 pathway; moreover, this upregulation of p21 was reversed by an ATM inhibitor. ELISA revealed that 10 mM Mg²⁺ enhanced IL-6 and TNF-α secretion, confirming effective induction of the senescence-associated secretory phenotype, while higher concentrations diminished this effect, which may be partly attributed to the reduction in cell viability. In vivo experiments showed that Mg²⁺ inhibited tumor growth without notable alterations in body weight, liver and kidney function, or serum magnesium levels. In summary, the localized high concentration of magnesium ions induces cells to enter a senescence-like state via the ATM/CHK2/p21 pathway, thereby selectively suppressing malignant cellular behaviors. Notably, its in vivo efficacy and safety profile in vivo are favorable. It is also worth noting that these findings should be interpreted within the context of a preclinical, high-dose local Mg²⁺ model. Full article

Decidualization in the human endometrium is not merely a hormone-dependent differentiation process; rather, it represents a multilayered adaptive program characterized by the tight integration of immune regulation, metabolic reprogramming, and cellular stress responses. In this review, endoplasmic reticulum (ER) stress and the associated unfolded protein response (UPR) are proposed as central regulatory mechanisms governing this process. Triggered by increased protein synthesis and secretory demand, UPR activation under physiological conditions preserves proteostasis and supports the secretory capacity of stromal cells. In contrast, chronic or dysregulated activation leads to a maladaptive response characterized by apoptosis, inflammation, and metabolic dysfunction. UPR signaling pathways shape immune tolerance through their effects on macrophage polarization, uterine natural killer (uNK) cell function, and T cell balance. At the metabolic level, adenosine monophosphate-activated protein kinase (AMPK) regulates cellular adaptation through bidirectional interactions with mitochondrial function and redox homeostasis. Within this framework, the ER stress–immune–metabolic axis operates not as a linear pathway but as a dynamic network incorporating multiple feedback loops, thereby constituting a critical threshold mechanism that determines the success of decidualization. Disruption of this axis provides a shared mechanistic basis for pathologies such as recurrent implantation failure, pregnancy loss, and preeclampsia. From a therapeutic perspective, agents including chemical chaperones, UPR modulators, AMPK activators, and anti-inflammatory compounds hold translational potential by targeting these pathological feedback circuits. However, key knowledge gaps remain, particularly regarding the cell type-specific and temporal regulation of ER stress, the molecular boundaries defining the transition from adaptive to pathological states, and interspecies differences. Future studies employing single-cell omics approaches and functional in vivo models will be essential to elucidate the dynamic organization of this axis and to enable the development of targeted and personalized therapeutic strategies. Full article