Search Results (1,327)

Neuroinflammation is a key feature of neurological disorders such as Alzheimer’s or Parkinson’s disease, depression or amyotrophic lateral sclerosis. This study investigates the anti-neuroinflammatory effects of three cardenolide derivatives, digitoxigenin, digitoxigenone, and coroglaucigenin (all at concentrations of 1, 5, 10, and 25 µM), in IL-1β-stimulated human neuroblastoma SK-N-SH cells. All compounds significantly reduced PGE₂ production without affecting cell viability by downregulation of cyclooxygenase (COX)-2 and microsomal prostaglandin E synthases (mPGES)-1 expression and synthesis. Among them, digitoxigenin notably inhibited phosphorylation of p38 mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) and suppressed interleukin (IL)-6 and IL-8 expression and release. These findings demonstrate that cardenolide derivatives exert potent anti-neuroinflammatory effects by at least partially targeting key enzymes of the arachidonic acid pathway and modulating MAPK/NF-κB signaling, highlighting their potential as novel therapeutic candidates for neuroinflammatory diseases. Future research should focus on effects of the cardenolides in mixed-cell cultures, organoids and in vivo experiments, to evaluate possible side effects and the potential in disease models. Full article

Despite decades of effective statin therapy, a clinically important proportion of patients with atherosclerosis continue to experience ischemic events, even when low-density-lipoprotein cholesterol (LDL-C) is at guideline-recommended levels. This shortfall is increasingly attributed to residual inflammatory, oxidative, and gut microbial pathways that lipid lowering therapy was never designed to address. This review establishes the mechanistic rationale for combining two emerging dietary intervention classes, probiotics and phytoantioxidants, as adjuncts acting on the gut vascular axis. We systematically trace the evidence for each class. For probiotics, we elucidate the restoration of gut-barrier integrity, short-chain fatty acid (SCFA) signaling, bile acid metabolism, and suppression of the trimethylamine to trimethylamine-N-oxide (TMA-TMAO) axis, including strain-specific efficacy and sex-based disparities in microbial composition. For phytoantioxidants, we detail the activation of nuclear factor erythroid 2-related factor 2 (Nrf2), suppression of mitogen activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) signaling, and sirtuin 1 (SIRT1)-dependent endothelial protection. We critically appraise the biological plausibility of their combined administration while explicitly defining where this rationale remains a testable hypothesis rather than an established strategy. To date, only one small randomized trial has evaluated a combined probiotic and phytoantioxidant formulation against an atherosclerosis relevant biomarker, and it lacked single-agent comparator arms necessary to attribute benefit to synergy rather than individual components. Furthermore, evidence for each class alone remains constrained by small sample sizes and heterogeneous dosing. Finally, we propose a novel, sex-stratified, strain-specified combination trial framework designed to rigorously evaluate this dual-target approach. This synthesis is intended to generate testable hypotheses for future research rather than to establish an evidence base for current adjunctive clinical use. Full article

The gut microbiota is recognized as important to maternal and child health through associations with immune maturation, metabolic programming, barrier integrity, and early-life disease susceptibility. Indigenous food systems, fermented foods, probiotics, and postbiotics may influence gut microbial communities and functions, suggesting potential avenues for investigation into nutritional resilience, particularly in low-resource settings. This review synthesizes evidence on microbiome-informed maternal and child nutrition, focusing on indigenous foods, fermented foods, probiotics, postbiotics, and microbiome-mediated mechanisms. Literature was searched in PubMed, Scopus, Web of Science, ScienceDirect, and Google Scholar for studies, systematic reviews, and meta-analyses published between 2015 and 2025. Evidence indicates that microbiome-directed nutritional interventions may influence microbial metabolites, particularly short-chain fatty acids, and pathways associated with barrier integrity, immune regulation, and cellular signaling, including adenosine monophosphate-activated protein kinase (AMPK), mechanistic target of rapamycin (mTOR), mitogen-activated protein kinase (MAPK), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), toll-like receptor (TLR), and peroxisome proliferator-activated receptor (PPAR). Artificial intelligence, multi-omics, and precision nutrition may support the investigation and future development of more targeted approaches. However, gaps remain regarding population-specific microbiome profiles, standardized probiotic and postbiotic formulations, longitudinal maternal–infant relationships, and evidence from African and other low-resource settings. The Microbiome-Informed Nutrition Framework (MINF) is proposed as a hypothesis-generating model integrating indigenous food systems, microbiome-directed interventions, precision nutrition, and community-based primary healthcare as potential areas for future research, rather than established clinical or public health interventions. Full article

Mitogen-activated protein kinase (MAPK) cascades play a central role in eukaryotic signal transduction, regulating diverse biological processes including development and stress responses. However, despite Lentinula edodes being the most widely cultivated edible mushroom worldwide, its MAPK cascade gene families remain uncharacterized, and their involvement in cadmium (Cd) stress responses is completely unknown. In this study, we performed genome-wide identification of MAPK cascade genes in L. edodes, uncovering 16 members comprising three LeMAPKKK genes, four LeMAPKK genes, and nine LeMAPK genes. Phylogenetic and homology analyses classified these genes into three putative MAPK cascade pathways. qRT-PCR analysis demonstrated strain-specific, concentration-dependent, and temporally dynamic expression patterns under Cd stress. Notably, four genes (LeMAPK1, LeMAPK7, LeMAPKK2, and LeMAPKKK1) exhibited consistent upregulation across both strains and high Cd concentrations (1 and 10 mg/L) at the 7 h time point. Based on these findings, we propose a working model for Cd stress response in L. edodes centered on these core regulatory genes. These findings may inform breeding strategies for low-Cd-accumulating cultivars and the optimization of cultivation practices to reduce Cd content, with potential implications for the sustainable development of the L. edodes industry and human health. Full article

Microalgae endemic to desert ecosystems possess exceptional stress-resistance traits; however, the physiological and molecular drought-adaptation mechanisms of desert-dwelling Chlorella remain largely uncharacterized. Herein, we combined physiological–biochemical assays, ultrastructural observation, transcriptomics and metabolomics to dissect drought responses in Taklamakan-desert-origin Chlorella sp. under polyethylene glycol 6000 (PEG-6000)-simulated mild (10%), moderate (20%), and severe (30%) drought stress, with mechanistic focus on moderate-drought conditions. Moderate drought repressed algal biomass (−26.32%), chlorophyll a (−24.40%), maximum photosystem II quantum yield (Fv/Fm, −16.55%) and effective quantum yield of photosystem II (ΦPSII, −24.35%). Malondialdehyde (MDA) accumulated (+50.69%), alongside elevated activities of superoxide dismutase (SOD, +156.74%) and catalase (CAT, +11.61%). Compatible solutes, including proline, soluble sugars, total protein and total lipid, increased significantly by 39.00%, 39.36%, 26.35% and 23.06%, respectively (p < 0.05). Moderate drought triggered cell swelling, partial cell-wall rupture and prominent enlargement of intracellular starch granules and lipid droplets. Transcriptomic profiling demonstrated up-regulation of transcription–translation and DNA-repair machinery, ATP-binding cassette (ABC) transporters, abscisic acid (ABA)/jasmonic acid (JA) signaling, and biosynthetic pathways for protective metabolites, whereas catabolic pathways and mitogen-activated protein kinase (MAPK) signaling were suppressed. Untargeted metabolomics further validated accumulation of trehalose, stress-protective amino acids, vitamins and functional lipids, while chloroplast-membrane-related metabolites and catabolic intermediates declined. This multi-omics study systematically reveals physiological and molecular regulatory cascades underlying drought tolerance in desert Chlorella sp., providing candidate genes and metabolites to support microalgal resource exploitation for arid-zone applications. Full article

Coronary artery bypass grafting (CABG) utilizing cardiopulmonary bypass (CPB) remains a cornerstone of treatment for advanced multivessel coronary artery disease. During the ischemic period, myocardial cells become injured and increasingly depend on anaerobic metabolism. After reperfusion, exposure of blood components to artificial surfaces, combined with ischemia–reperfusion injury, surgical trauma, and gut translocation of endotoxins, triggers a complex systemic inflammatory response syndrome (SIRS). This inflammatory cascade involves a tightly regulated network of humoral cascades (complement, contact, coagulation, and fibrinolytic systems) and cellular effectors (neutrophils, monocytes, endothelial cells, and platelets). Molecular signaling pathways, notably Toll-like receptor 4 (TLR4) activation, nuclear factor kappa B (NF-κB) nuclear translocation, mitogen-activated protein kinase (MAPK) phosphorylation, and NLRP3 inflammasome assembly, drive a cytokine storm characterized by massive releases of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-8 (IL-8). These molecular events lead to endothelial barrier disruption, vasoplegic shock, acute lung injury, myocardial dysfunction, and acute kidney injury. This comprehensive narrative review provides a detailed synthesis of the cellular and molecular mechanisms underlying CPB-induced SIRS, highlights recent advances in neutrophil extracellular trap (NET) dynamics and microvascular injury, and evaluates contemporary pharmacological and bioengineering therapeutic strategies designed to mitigate postoperative organ dysfunction. Full article

Plant oxylipins are a diverse group of oxygenated fatty acid derivatives that function as important signaling molecules in plant responses to abiotic stress. Although jasmonates, particularly jasmonic acid (JA) and its derivatives, have been extensively studied, increasing evidence demonstrates that other oxylipin classes, including 12-oxophytodienoic acid (OPDA), green leaf volatiles (GLVs), reactive electrophilic oxylipins (RES), and peroxygenase (PXG)-derived oxylipins, also contribute to stress adaptation. This review summarizes current understanding of the molecular mechanisms underlying oxylipin signal perception, transduction, and regulation, with particular emphasis on interactions with other plant hormone pathways, reactive oxygen species (ROS), Calcium (Ca²⁺), and mitogen-activated protein kinase (MAPK) signaling. We further examine transcriptional, post-transcriptional, and post-translational mechanisms that regulate oxylipin responses and discuss their integration across individual and combined abiotic stresses. Particular attention is given to experimentally established mechanisms while distinguishing emerging or unresolved signaling processes. Understanding these interconnected signaling mechanisms will be important for developing strategies to improve crop resilience under global climate change. Full article

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

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

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