Search Results (1,632)

Formerly recognized as an opioid receptor, the sigma-1 receptor (σ1R) is a multifunctional chaperone protein that plays a crucial role in regulating neuronal signaling, neuroprotection, and synaptic plasticity. Increasing evidence highlights a tight functional association between the σ1R and the N-methyl-D-aspartate receptor (NMDAR), a central mediator of excitatory neurotransmission and calcium-dependent neuronal processes. This review summarizes the shared signaling pathways underlying σ1R and NMDAR activity, including calcium homeostasis, calcium/calmodulin-dependent protein kinases (CaMKs), protein kinase C (PKC), phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), and mitogen-activated protein kinase (MAPK) cascades, as well as transcriptional regulators such as cAMP response element-binding protein (CREB), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and B-cell lymphoma 2 (Bcl-2). Experimental data demonstrate that pharmacological agents initially characterized as NMDAR antagonists—such as ketamine, dextromethorphan, and memantine—also interact with σ1R, suggesting that their therapeutic efficacy may arise from coordinated modulation of both receptor systems. These findings collectively indicate that the σ1R is a key regulatory element enabling proper NMDAR function and that disruption of this interaction may contribute to excitatory imbalance implicated in the pathophysiology of neuropsychiatric disorders. Recognizing the σ1R–NMDAR crosstalk as an integrated signaling axis may thus inform the development of dual-target therapeutic strategies aimed at improving neuronal resilience and clinical outcomes in psychiatric and neurodegenerative diseases. Full article

Alantolactone is a sesquiterpene lactone that possesses anticancer and anti-inflammatory properties. We previously demonstrated that several sesquiterpenes, including alantolactone, induced the ectodomain shedding of tumor necrosis factor receptor 1 (TNF-R1). In the present study, we investigated the upstream signaling pathway underlying alantolactone-induced TNF-R1 ectodomain shedding. Alantolactone down-regulated the expression of full-length TNF-R1 on the cell surface of human lung adenocarcinoma A549 cells, and this was accompanied by an increase in soluble TNF-R1 in the culture medium. TNF-R1 ectodomain shedding was also detected in human embryonic kidney 293T cells and human fibrosarcoma HT-1080 cells, indicating the conservation of this effect in multiple cell lines. The metalloproteinase inhibitor GM6001 markedly suppressed alantolactone-induced soluble TNF-R1 release and restored cell-surface TNF-R1 expression. Among specific inhibitors targeting mitogen-activated protein kinase (MAPK) signaling pathways, TNF-R1 ectodomain shedding was markedly suppressed by the MAPK/extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitor U0126, whereas the suppressive effects of the c-Jun N-terminal kinase (JNK) inhibitor SP600125 or the p38 MAPK inhibitor SB203580 were negligible. Consistent with these results, alantolactone increased phospho-ERK and phospho-RAF1 levels within 60–120 min, while p38 MAPK and JNK were minimally phosphorylated during the 120-min incubation. Collectively, these results indicate that alantolactone-induced TNF-R1 ectodomain shedding is mediated by the activation of the RAF1–ERK signaling pathway. Full article

Background: Interleukin-24 (IL-24) is expressed in synovial myofibroblasts and has been associated with pain severity in female patients with knee osteoarthritis (OA). However, the direct effects of IL-24 on inflammatory responses in synovial fibroblasts and the signaling pathways involved remain unclear. This study investigated IL-24-induced transcriptional and inflammatory responses in fibroblast-enriched synovial cells and examined the effects of STAT3 and p38 mitogen-activated protein kinase (MAPK) inhibition. Methods: Fibroblast-enriched synovial cells isolated from synovial tissue obtained from patients with knee OA undergoing total knee arthroplasty were stimulated with IL-24 for 6 and 24 h. RNA sequencing (RNA-seq) was performed using cells from two patients, and overlapping upregulated genes were subjected to Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. The concentration- and time-course experiment used samples from nine patients; the HJC0152 and SB203580 experiments used ten specimens from eight patients and ten specimens from nine patients, respectively. Selected inflammatory cytokines and chemokines were subsequently evaluated by quantitative polymerase chain reaction and enzyme-linked immunosorbent assay in concentration- and time-course experiments using nine specimens from nine patients. To investigate signaling involvement, cells were treated with IL-24 in the presence or absence of the STAT3 inhibitor HJC0152 or the p38 MAPK inhibitor SB203580, each at 5 or 10 μM. Results: RNA-seq identified 27 and 34 overlapping upregulated genes that independently met the DEG criteria in both patients at 6 and 24 h, respectively. These genes were enriched in inflammatory pathways, including TNF, IL-17, NF-κB, chemokine, cytokine–cytokine receptor interaction, Toll-like receptor, and NOD-like receptor signaling pathways. IL-24 significantly increased the mRNA expression of CCL2, CXCL1, CXCL3, IL6, and IL8. HJC0152 and SB203580 at 10 μM both significantly reduced IL-24-associated CCL2, CXCL1, and IL6 expression. At the protein level, both inhibitors attenuated CCL2, CXCL1, and IL-6 concentrations in IL-24-stimulated cells. HJC0152 also reduced CXCL3 expression at the mRNA level, although its protein-level effect was less pronounced. In contrast, the effects of both inhibitors on CXCL3, CXCL10, and IL-8 were limited or inconsistent. Conclusions: IL-24 induces an inflammatory response in fibroblast-enriched synovial cells characterized by increased chemokine and cytokine expression. STAT3 and p38 MAPK inhibition preferentially attenuated IL-24-associated CCL2, CXCL1, and IL-6 responses, suggesting the possible involvement of these pathways in selected IL-24-associated inflammatory responses. These findings provide a basis for further investigation of IL-24-related signaling in OA synovitis. Full article

The epidemic expansion of maize white leaf spot (WLS) is a substantial threat to the secure and sustained production of maize. Given its diversity and strong environmental adaptability, WLS has the potential to emerge as a globally prevalent disease affecting maize crops. A detailed exploration of genetic segments and genes that are significantly associated with resistance to WLS in maize, an analysis of the genetic mechanisms underlying maize’s response to this disease, as well as the identification and development of resistant germplasm resources and their promotion and application, are of great practical significance for ensuring the safe production of maize. In this study, a genome-wide association study (GWAS) of 11 related traits in 141 maize accessions was conducted, and a total of 1174 significant single-nucleotide polymorphism (SNP) sites were identified. BSA-Seq (Bulked Segregant Analysis Sequencing) identified 6319 sites and 79 candidate genes. Through comprehensive analysis of GWAS and RNA-Seq data, a total of 13 candidate genes associated with maize white spot resistance, including Zm00001eb093900 and Zm00001eb078490, were identified. This study systematically explored genetic regions and genes significantly linked to white spot resistance in maize, thereby providing novel genetic resources for future molecular design-based breeding and improvement of resistance traits. Furthermore, by correlating field disease incidence with the expression of immune response-related gene products, we developed a rapid evaluation system for maize WLS resistance, in which soil plant analysis development (SPAD) value, Fm, SSC, and POD served as key indicators. Using this system, 5 immune germplasm resources such as QB2229 and NP5366 and 89 highly resistant materials such as QB1923 and Chang7-2 were identified. The accurate evaluation of maize WLS resistance will provide essential resistance sources for subsequent breeding programs. RNA-Seq analysis revealed that systemic acquired resistance to maize WLS involves key pathways, including phenylpropanoid metabolism, as well as the synthesis of secondary metabolites such as flavonoids and glutathione. Further analysis of race-specific resistance indicated that the response of highly resistant maize varieties to WLS is primarily characterized by the accumulation of defense-related substances and enhanced activity across multiple energy metabolism pathways. In contrast, highly susceptible maize lines exhibited more pronounced enrichment in hormone signaling, the mitogen-activated protein kinase (MAPK) signaling pathway, and the metabolism of various amino acids. Full article

Doxorubicin (Dox)-induced cardiotoxicity (DIC) is a major clinical challenge in cancer therapy. Camel milk exosomes (CMEs) have been applied in anti-tumor treatments as they have a variety of effects, including on inflammation, oxidative stress, metastasis, and apoptosis. However, their role in DIC treatment remains incompletely understood. This research was designed to evaluate the protection provided by CMEs against DIC. The DIC mice were treated with Dox intraperitoneally and divided into a model group and groups treated with different doses of CMEs. Dox-induced H9c2 cell injury was also established and divided into a model group and groups treated with different concentrations of CMEs. The evaluation parameters in vitro included H9c2 cell viability, reactive oxygen species (ROS), mitochondria, and apoptotic cells. The apoptosis and autophagy markers, as well as the nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways, were assessed via Western blotting both in vivo and in vitro. In addition, transcriptome sequencing of cardiac tissue was also applied to investigate the related mechanisms. Our results indicate that CMEs significantly attenuated the cell viability reduction, apoptosis, and ROS production in H9c2 cells caused by Dox. CMEs also regulated autophagy, inhibited apoptosis, and inhibited the NF-κB and MAPK pathways. In conclusion, our findings demonstrate that CMEs exert a cardiac protective effect against DIC by inhibiting apoptosis and regulating autophagy via NF-κB and MAPK signaling pathways. Full article

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and a leading cause of cancer-related mortality worldwide. Despite advances in diagnosis and therapy, the prognosis for advanced HCC remains poor due to late-stage diagnosis, high recurrence rates, therapeutic resistance, and pronounced molecular heterogeneity. HCC development is driven by complex somatic gene alterations, epigenetic reprogramming, dysregulated signaling pathways, metabolic changes, and an immunosuppressive tumor microenvironment. Molecular profiling studies have identified key oncogenic pathways involved in HCC progression, including MAPK/ERK (mitogen-activated protein kinase/extracellular signal-regulated kinase), Wnt/β-catenin, PI3K/AKT/mTOR (Phosphoinositide 3-kinase/Protein Kinase B/mechanistic Target of Rapamycin), Hippo-YAP/TAZ, (Yes-associated protein/transcriptional co-activator with PDZ-binding motif) cell cycle regulators, and p53-mediated tumor suppression. These pathways coordinate critical cellular processes such as proliferation, survival, metabolism, invasion, and genomic stability. Emerging mechanisms, including cancer stem cell plasticity, immune evasion, epigenetic dysregulation, and steroid receptor coactivator (SRC)-dependent transcriptional regulation, further contribute to tumor progression and therapeutic resistance. Additionally, recent bioinformatic analyses suggest a potential role for progesterone-mediated oocyte maturation pathways in HCC, although their functional relevance remains unclear. A thorough understanding of these interconnected mechanisms could lead to novel therapeutic targets and the development of more effective, personalized treatment strategies for HCC. This review discusses key signaling pathways and emerging mechanisms in HCC and their roles in disease development and treatment. Full article

Inflammatory and autoimmune skin diseases like psoriasis, atopic dermatitis, and hidradenitis suppurativa present significant therapeutic challenges due to their complex immunological and environmental pathogenesis. This review highlights the critical role of microRNAs (miRNAs) as epigenetic regulators of inflammatory processes and investigates the potential of nutrigenomics to modulate their expression. Bioactive dietary components—including polyphenols such as quercetin, resveratrol, and curcumin, alongside vitamins C and D, selenium, and omega-3 fatty acids—demonstrate the ability to alter miRNA profiles like miR-21, miR-146a, and miR-155. These miRNA alterations may contribute to the regulation of key inflammatory pathways, including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and mitogen-activated protein kinase (MAPK), thereby potentially influencing pro-inflammatory cytokine production and keratinocyte proliferation. However, the extent to which individual dietary compounds directly mediate effects on these pathways through miRNA regulation varies and is often supported mainly by preclinical evidence. Clinical data suggests that dietary interventions, such as weight loss and the Mediterranean diet alleviate skin symptoms and lower systemic inflammatory markers. Identifying disease-specific miRNA expression profiles represents an emerging research avenue that may, following analytical and clinical validation, inform future approaches in dermatology. Full article

Hypertension is increasingly recognized as involving chronic inflammation beyond its hemodynamic origins. This review proposes the Mechano-Immune-Vascular Activation Loop as an integrative conceptual framework—a positive feedback circuit in which aberrant mechanical forces in the hypertensive vascular wall may activate immune cells through mechanosensitive sensors, potentially triggering inflammation that drives vascular stiffening and amplifies mechanical stress. We examine molecular force sensors including piezo-type mechanosensitive ion channel component 1 (Piezo1), transient receptor potential vanilloid 4 (TRPV4), integrins, and Yes-associated protein/transcriptional coactivator with PDZ-binding motif (YAP/TAZ), detailing their expression in vascular cells and immune subsets such as T cells, macrophages, dendritic cells(DCs), and neutrophils. Downstream pathways—calcium-nuclear factor of activated T cells (Ca²⁺-NFAT), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), mitogen-activated protein kinase (MAPK), and Hippo—transduce physical stimuli into inflammatory gene programs. Organ-specific manifestations in the kidney, arteries, heart, and brain are discussed. Therapeutic approaches targeting mechanosensitive channels, repurposed antihypertensives, and mechanical environment modification are evaluated, along with challenges including off-target effects, pathway redundancy, and biomarker needs. By centering mechanotransduction in immune-vascular crosstalk, this framework offers new perspectives on hypertension pathogenesis and points toward interventions that may break the vicious cycle beyond conventional blood pressure reduction. Full article

Sacred lotus (Nelumbo nucifera) is an important aquatic crop whose growth and productivity are severely constrained by environmental stresses. Salicylic Acid (SA), Jasmonic Acid (JA), and Abscisic Acid (ABA) are key plant growth regulators (PGRs) involved in stress responses, but their regulatory mechanisms in lotus remain unclear. In this study, transcriptome sequencing was performed in lotus seedlings treated with exogenous SA, JA, and ABA to characterize hormone-responsive regulatory networks. SA predominantly resulted in transcriptional repression, with responsive genes mainly associated with photosynthesis and ribosome-related pathways, whereas JA and ABA showed similar regulatory patterns with enrichment of hormone signaling and Mitogen-activated protein kinase (MAPK) pathways, but distinct roles in defense regulation and stress adaptation. A total of 607 genes were identified as commonly responsive to the three PGRs and were significantly enriched in cold response, defense response, secondary metabolism, and photosynthesis-related pathways. Protein–protein interaction analysis identified two hub genes encoding light-harvesting chlorophyll a/b-binding proteins, suggesting that the photosynthesis–antenna proteins pathway may represent a convergent regulatory node in hormone-mediated stress responses. This study provides new insights into SA-, JA-, and ABA-mediated stress responses and identifies potential candidate genes for improving stress tolerance in lotus. Full article

Background: Triple-negative breast cancer (TNBC) remains a major cause of cancer mortality due to its aggressive behavior, metabolic adaptability, and high therapeutic resistance. Extracellular vesicles (EVs) within the tumor microenvironment contribute to tumor progression and metastasis by transferring pro-tumorigenic cargo. While conventional Tumor Treating Fields use high-frequency alternating fields to disrupt mitosis, low-energy triple-frequency bioelectromagnetic approaches remain poorly characterized. Methods: We evaluated a device–drug strategy combining triple-frequency low-intensity electromagnetic stimulation (EMS2: 396 Hz, 285 Hz, 528 Hz) with the pleiotropic drug Fingolimod (FTY720). Treatments were tested in MDA-MB-231 and ARM-G breast cancer cells, with Paclitaxel as a positive control. Cell proliferation was assessed by MTS assay, and extracellular vesicles were isolated following individual and combination treatments. Quantitative LC-MS/MS proteomics was used to characterize treatment-induced changes in EVs cargo. Results: EMS2 reduced proliferation in both cell lines and produced morphological changes consistent with altered cell-cycle progression. EMS2 alone triggered adaptive metabolic responses, whereas combination with Fingolimod suppressed these compensatory signatures. EVs proteomics revealed combination-specific alterations associated with mitochondrial stress, ER stress, NF-κB suppression, and autophagy-associated pathways. The combination also reduced levels of metastasis- and stroma-associated proteins, including Mitogen-Activated Protein Kinase 12 (MAPK12) and collagen-associated ECM components (Collagen Type I Alpha 1 Chain (COL1A1), Collagen Type VI Alpha 1 Chain (COL6A1), Collagen Type VI Alpha 3 Chain (COL6A3), and Matrilin 3 (MATN3)) in EVs. Bliss independence analysis identified a subset of metastasis-associated proteins suppressed in EVs beyond the level predicted by an additive model, an exploratory finding that will require further validation with dose–response and functional assays. Conclusions: Combined triple-frequency EMS2 and Fingolimod treatment altered the extracellular vesicle proteome, inducing signatures consistent with mitochondrial and endoplasmic reticulum stress, metabolic disruption, and reduced levels of metastasis-associated and stromal/ECM remodeling proteins, along with reduced proliferation. These findings suggest a coordinated anti-cancer effect of this tunable device–drug strategy, warranting further functional and in vivo validation to confirm therapeutic potential. Full article

During growth and metabolism, the budding yeast Saccharomyces cerevisiae is continuously exposed to diverse environmental stresses, and conserved mitogen-activated protein kinase (MAPK) cascades execute core functions in stress sensing and adaptive regulation. The high-osmolarity glycerol (HOG) pathway, a classical MAPK cascade in S. cerevisiae, was initially identified as the core regulator of hyperosmotic stress responses. Over recent decades, accumulating evidence has revealed that the HOG pathway is not merely an osmoregulatory module but a versatile signaling hub that integrates multiple stress inputs and orchestrates a broad spectrum of adaptive responses. This review systematically summarizes the core architecture of the HOG pathway, including its upstream sensing branches (Sln1 and Sho1) and the conserved three-tiered MAPK cascade, with an emphasis on how different stressors engage distinct branches and lead to differential Hog1 phosphorylation kinetics. This review further discusses the multifaceted roles of the HOG pathway in stress adaptation, covering transcriptional reprogramming, cell cycle arrest, metabolic reprogramming centered on glycerol synthesis, and emerging functions such as cell wall remodeling, flocculation, mitophagy, and cross-talk with other MAPK pathways. By integrating classical and contemporary findings, this review presents a comprehensive view of the HOG pathway in S. cerevisiae and provides a reference for future research on stress signaling and engineering of this model organism. Full article

Fatty liver hemorrhagic syndrome (FLHS) is a prevalent metabolic disease in laying hens, causing severe economic losses. A previous study showed that conjugated linoleic acids (CLA) alleviated estrogen-induced FLHS in chickens, but the mechanism remains unclear. In the present study, we found that CLA improved serum lipid homeostasis, reduced hepatic lipid accumulation, and enhanced antioxidant activity in FLHS chickens. Transcriptome analysis identified differentially expressed genes enriched in inflammatory response, lipid homeostasis, carbohydrate metabolism, and mitogen-activated protein kinase (MAPK)/peroxisome proliferator-activated receptor (PPAR)/insulin signaling pathways. Metabolome analysis detected differentially abundant metabolites enriched in bile secretion, thyroid hormone synthesis, the insulin signaling pathway, and glycerophospholipid metabolism. Integrated analyses revealed that CLA reshaped the hepatic metabolic profile by upregulating protective metabolites (such as ubiquinol) and downregulating pro-inflammatory/lipogenic metabolites (such as 15-hydroperoxyeicosa-8Z,11Z,13E-trienoate), which synergized with key gene regulation (fatty acid synthase, jun proto-oncogene, and fatty acid desaturase 2) and core pathway activity (MAPK/nuclear factor kappa-B inhibition, PPARα activation). The multi-omics study using an estradiol-induced rooster FLHS model elucidated the molecular regulatory network of CLA against hepatic steatosis and liver injury, and provided preliminary mechanistic clues for developing CLA functional additives to prevent and treat FLHS in commercial laying hens. Full article

Bioactive polyphenols have emerged as multi-target regulators of cellular processes involved in the pathogenesis of skin diseases. Skin disorders, including inflammatory conditions, photoaging, and skin cancers, are characterized by complex pathogenic mechanisms associated with oxidative stress, mitochondrial dysfunction, dysregulated signaling pathways, and metabolic imbalance. Excessive production of reactive oxygen species (ROS) and persistent inflammatory signaling contribute to disease progression and cellular adaptation under stress conditions. Unlike conventional agents that typically target a single pathway, polyphenols act on interconnected signaling and metabolic networks. These compounds regulate key signaling pathways, including phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK), AMP-activated protein kinase (AMPK), nuclear factor-κB (NF-κB), and nuclear factor erythroid 2-related factor 2 (Nrf2), thereby regulating cell survival, proliferation, inflammatory responses, antioxidant defense, and metabolic adaptation. Polyphenols also influence mitochondrial function by maintaining redox homeostasis, regulating energy metabolism, and affecting apoptosis-related signaling pathways. This review provides a mechanistic overview of the effects of polyphenols on oxidative stress, mitochondrial function, and cell survival signaling in skin diseases. In addition, the therapeutic implications and current limitations of polyphenol-based approaches are discussed, with particular emphasis on the translational gap between experimental findings and physiological relevance. Factors such as concentration, bioavailability, and cellular microenvironment are highlighted as major determinants of polyphenol activity and key challenges for clinical translation. Finally, the need for further in vivo and clinical investigations is emphasized to support the development of effective polyphenol-based therapeutic strategies for skin diseases. Full article

Background: Epstein–Barr virus (EBV) enters the human body via saliva. EBV-encoded latent membrane protein-1 (LMP-1) activates the mitogen-activated protein kinase (MAPK) pathway. MAPK signaling pathway activation due to the BRAF-V600E mutation is widely known as a major event in the pathogenesis of ameloblastoma. It is unclear whether EBV infects ameloblastoma and is involved in the pathogenesis of ameloblastoma. We investigated the relationship between LMP-1 and BRAF-V600E mutant protein expression in ameloblastoma by immunohistochemistry. Methods: We examined a total of 334 samples (ameloblastoma 117 samples, odontogenic keratocyst 127 samples, dentigerous cysts 45 samples, and dental follicle 45 samples). Ephrin type-A receptor 2 (EphA2), BRAF-V600E mutant protein, and γH2AX expression were confirmed by immunohistochemistry. We confirmed that the positive cases of BRAF-V600E mutant protein and γH2AX segregated based on LMP-1 expression: high grade (HG) and low grade (LG). Results: EphA2 expression was high in all lesions. The positive rate of BRAF-V600E mutant protein expression was significantly higher in ameloblastoma, and the positive rate of BRAF-V600E mutant protein in LMP-1 HG cases (71.9%) was significantly greater than in LG cases (39.6%) in ameloblastoma. The positive rate of γH2AX expression was significantly higher in ameloblastoma than in the other lesions. The positive rate of BRAF-V600E mutant protein in LMP-1 HG cases (71.9%) was significantly greater than in LG cases (39.6%) in ameloblastoma. Conclusions: BRAF-V600E mutant protein and γH2AX expression in ameloblastoma were significantly higher in LMP-1 HG cases than in LG cases. Full article

High alkalinity, a major stress in saline–alkaline water, often leads to oxidative damage and apoptosis. Taurine has been shown to enhance the tolerance of aquatic animals to environmental stress, but whether it can reduce toxicity of alkalinity on Chinese mitten crab (Eriocheir sinensis) has not been determined. Thus, in this study, we investigated whether taurine could alleviate the deleterious effects of alkalinity stress on E. sinensis. The results revealed that taurine can improve the survival rate of the crab under 35.00 mmol/L alkalinity stress. Meanwhile, taurine inhibited the production of reactive oxygen species (ROS) and ameliorated the oxidative damage induced by alkalinity stress in crab. Taurine also inhibited alkalinity stress-mediated induction of mitogen-activated protein kinase-related pathways, subsequently suppressing the mRNA expression of Caspase 8 and Bax and preventing the occurrence of alkalinity stress-induced apoptosis in E. sinensis. In addition, inhibition of alkalinity stress-induced apoptosis by taurine may be related to the ability of taurine to bind to MAPK proteins. Overall, these results suggested that taurine can relieve the toxicity of high alkalinity on E. sinensis through mitigating oxidative damage and inhibiting apoptosis, supporting its applicability as a treatment for oxidative damage induced by high alkalinity. Full article