Search Results (2,206)

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

Fungal mycoparasitism, where one fungus preys on another, offers a sustainable, eco-friendly alternative to synthetic chemical fungicides in agriculture and conventional antifungal therapies to manage clinical pathogens. The budding yeast Saccharomycopsis schoenii has emerged as a compelling model for contact-dependent, necrotrophic predation. Belonging to the CUG-Ser2 clade, its obligate predatory lifestyle is characterized by extensive genomic restructuring, including the loss of the sulfate assimilation pathway, which couples methionine starvation to a predatory behavioral switch. In this review, we highlight recent comparative genomics and functional studies as they relate to S. schoenii predation. For example, S. schoenii uses rewired mitogen-activated protein kinase (MAPK) signaling, actin-based penetration pegs and a large tandem expansion of secreted aspartic proteases (SAPs) to breach prey cell walls. Analysis of its genome reveals structural adaptations, including AT-rich regional centromeres and dispersed mating-type (MAT) loci. The more we learn about S. schoenii’s contact-dependent attack, the greater the opportunities to deploy S. schoenii as a safe, mycotoxin-free biocontrol agent against both multi-drug-resistant Candida auris and post-harvest Penicillium molds. Full article

Skin pigmentation is regulated by intrinsic and extrinsic factors and is closely associated with melanogenesis and cellular homeostasis. Autophagy is a cellular self-digestion process that contributes to homeostatic regulation, but its role in melanogenesis remains to be further clarified. This study investigated whether berberine chloride (BBC), an isoquinoline alkaloid, modulates melanin production through autophagy-related signaling in B16-F1 melanoma cells. Tyrosinase activity was examined by tyrosinase zymography, extracellular melanin levels in the culture supernatant were measured after BBC treatment, and the expression of melanogenesis-, mitogen-activated protein kinase (MAPK)-, and autophagy-related proteins was analyzed by Western blotting. BBC inhibited tyrosinase activity and reduced extracellular melanin levels in a dose-dependent manner. BBC also increased phosphorylated extracellular signal-regulated kinase (p-ERK) levels while decreasing melanogenesis-related protein expression. In addition, BBC modulated MAPK signaling and the expression of autophagy-associated proteins. Small interfering RNA-mediated knockdown of Atg5, Beclin1, or ERK partially restored extracellular melanin levels in BBC-treated cells. These findings suggest that BBC suppresses melanogenesis in B16-F1 melanoma cells in association with ERK and autophagy-related signaling. Full article

Background and Objectives: Alzheimer’s disease (AD) is the most common neurodegenerative disorder, and current therapies provide only limited symptomatic relief without effectively slowing its progression. Increasing evidence suggests that aberrant activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling cascade contributes to AD-associated neuroinflammation. This study investigated the therapeutic potential and molecular mechanisms of JAK inhibitors in AD using integrated bioinformatics and network pharmacology approaches. Materials and Methods: Potential anti-AD targets of JAK inhibitors were identified using the SwissTargetPrediction and GeneCards databases. Functional enrichment, protein–protein interaction (PPI) analysis, transcriptomic validation using public datasets, regulatory network construction, molecular docking, normal mode analysis (NMA), and absorption, distribution, metabolism, excretion, and toxicity (ADMET) prediction were performed to investigate the potential mechanisms of action of these drugs in AD. Results: Our analysis identified 163 shared targets between JAK inhibitors and AD. Enrichment analysis revealed that these genes were primarily involved in protein phosphorylation and were enriched in key signaling pathways, including the neurotrophin, phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), and mitogen-activated protein kinase (MAPK) signaling pathways. PPI analysis identified AKT1, BCL2, SRC, STAT3, and TNF as five highly ranked hub targets across multiple topological algorithms. Transcriptomic validation confirmed significantly higher expression of these targets in the prefrontal cortex of individuals with AD compared with normal subjects. Molecular docking indicated that pacritinib and momelotinib showed relatively favorable predicted interactions with the hub proteins, while NMA revealed differences in the predicted flexibility of the docked complexes. Furthermore, ADMET prediction showed that pacritinib possesses favorable pharmacokinetic properties for the treatment of AD. Conclusions: Collectively, these findings provide mechanistic insights into the potential effects of JAK inhibitors in AD and identify pacritinib as a computationally prioritized candidate that warrants experimental validation in appropriate AD models. However, as this study is based solely on computational analyses without wet-lab validation, the findings should be considered hypothesis-generating in silico evidence, and the potential safety concerns of pacritinib require further investigation. Full article

Objectives: This study focuses on exploring the mechanism by which Schisandrin B (Sch B) regulates metabolic dysfunction-associated steatotic liver disease (MASLD) mice induced by a high-fat methionine–choline-deficient (MCD) diet through the activation of peroxisome proliferator-activated receptor γ (PPARγ). Methods: Male C57BL/6 mice were fed a high-fat MCD diet for 8 weeks to establish a mouse MASLD model, and the effects of Sch B on MASLD and the mechanisms were investigated. PPARγ overexpression (OE) was induced by adeno-associated virus (AAV) administration via intrahepatic portal vein injection in mice, and a negative control (NC-OE) was also established. Body weight; wet liver weight; hepatic index; serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β); and hepatic triglyceride (TG) levels were measured in the mice. The histopathology and lipid deposition were observed by hematoxylin and eosin (H&E) staining and Oil Red O staining, while the fibrosis was assessed using Masson staining. Western blot was employed to detect the expression levels of PPARγ, sterol regulatory element-binding protein 1c (SREBP-1c), carnitine palmitoyltransferase 1A (CPT1A), transforming growth factor β1 (TGF-β1), α-smooth muscle actin (α-SMA), collagen type I (collagen I), Smad family members 2/3 (Smad2/3), c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (p38), and extracellular signal-regulated kinase 1/2 (ERK1/2), along with the phosphorylation activation status of these kinases. Results: It was confirmed that Sch B caused effects similar to those induced by PPARγ overexpression, reducing the hepatic index, AST, and ALT levels while alleviating lipid accumulation and fibrosis; and upregulating PPARγ and CPT1A while inhibiting SREBP-1c; and the phosphorylation of the TGF-β/Smad and MAPK pathways were involved in the mechanisms. Conclusions: Sch B can alleviate high-fat MCD-induced MASLD by activating PPARγ in mice. Full article

Background/Objectives: Excessive inflammation is a critical contributor to impaired oral mucosal wound healing, yet effective therapeutic strategies are still lacking. Although dehydrocorydaline (DHC) has been reported to exhibit anti-inflammatory and analgesic properties, its role in wound healing and the underlying mechanisms have not been fully elucidated. This study aimed to investigate whether DHC accelerates palatal wound healing and to elucidate the role of the p38 mitogen-activated protein kinase (MAPK)/CCL2 signaling axis in DHC-mediated regulation of macrophage chemotaxis. Methods:In vitro, macrophages were stimulated with 1 μg/mL lipopolysaccharide (LPS) and treated with DHC at 0.1, 1, and 10 μM. The chemotactic response and inflammatory function of macrophages were assessed using real-time PCR, ELISA, Western blotting, and Transwell assays. Molecular docking simulations and Western blotting analyses were performed to examine the regulatory effect of DHC on MAPK signaling pathway. In vivo, a full-thickness palatal mucoperiosteal wound extending from the left maxillary first to third molars was established in mice by scalpel scraping. The effects of topical 10 μM DHC gel on wound healing were evaluated using stereomicroscopy, histological staining, and real-time PCR at 0, 3, and 5 days post-modeling. Results:In vitro, DHC effectively downregulated the expression of chemokines, including C-C motif chemokine ligand 2 (Ccl2), Ccl5, Ccl22, C-X-C motif chemokine ligand 10 (Cxcl10), and Ccl24, with the most significant inhibitory effect on Ccl2 (70.8% inhibition). In Transwell assays, DHC reduced macrophage migration by 68.2%. Mechanistically, DHC prominently inhibited the activation of the MAPK signaling pathway. In vivo, DHC treatment accelerated wound healing and markedly reduced macrophage infiltration in mouse palatal wound tissues. Conclusions: These findings demonstrated that DHC accelerated palatal wound healing 1.6-fold in mice. DHC suppressed macrophage chemotaxis by 68.2% through modulation of the MAPK signaling pathway. Full article

Antiretroviral therapy (ART) is essential for controlling human immunodeficiency virus (HIV) infection, requiring strict daily adherence for lifelong viral suppression. However, this continuous oral dosing results in persistent exposure of the gastrointestinal tract (GIT), raising the need to investigate the effects of TC-ART (Tri-combinationL: Abacavir, Dolutegravir, Lamivudine–ART) on epithelial integrity, barrier recovery mechanisms, and surface barrier architecture. TC-ART exposure (125 µM to 4000 µM) showed marked alterations in transepithelial resistance, permeability, and wound-healing abilities even at sub-cytotoxic doses. The dose exposure range at the mid-dose level showed the highest transcriptional activity, characterized by a downregulation of junctional genes [claudins (CLDNs), desmogleins (DSGs), and junctional plakoglobin (JUP)] and signaling mediators [the signal transducer and activator of transcription 3 (STAT3), mitogen-activated protein kinase 1 and 3 (MAPK1/3), and catenin beta 1 (CTNNB1)], along with reduced IL-9 expression that is linked to mucin loss. These transcriptional changes were consistent with structural findings, including partial transepithelial electrical resistance (TEER) recovery followed by a decline, delayed wound closure, and waning of the apical mucin layer in a dose-dependent manner. However, several cytokines, like IL-2 and IL-6, showed increased secretion despite lower transcriptional levels, suggesting alternative regulatory control during early stress responses. Together, these results support that TC-ART exposure alters epithelial responses in a way that may transition from early adaptation to signs of impaired recovery, leading to a gradual decline in mucosal barrier function. Such concentration- and time-dependent epithelial stress may contribute to gastrointestinal disturbances observed in treated HIV populations, emphasizing the need for incorporating intestinal epithelial health endpoints in drug safety evaluations. Full article

Wound healing is a dynamic and highly coordinated process that involves inflammation, cell proliferation, angiogenesis, re-epithelialization, extracellular matrix remodeling, and tissue maturation. The altered expression of important signaling pathways, such as transforming growth factor-β (TGF-β)/Smad, nuclear factor-κB (NF-κB), phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), mitogen-activated protein kinase (MAPK), and Wnt/β-catenin, may be responsible for slower wound healing, chronic inflammation, excessive fibrosis, and impaired tissue regeneration. Multifunctional nanomaterials are a promising strategy for tuning these highly coordinated processes due to their tunable physicochemical properties, high surface area, and the ability to deliver cargo, as well as the integration of antimicrobial, antioxidant, anti-inflammatory, and pro-angiogenic properties. The aim of current review is to summarize the potential of multifunctional nanomaterials to promote wound healing, with a focus on mechanisms of action and modulation of key cellular signaling pathways. A systematic review of the literature was conducted using PubMed, Scopus, Web of Science, and Google Scholar, searching for publications from 1996 to June 2026, and representative experimental, mechanistic, preclinical, and translational studies were critically evaluated. In this review, the authors discuss the role of nanomaterial properties, therapeutic payload, molecular targets, modulation of cellular signaling pathways, and regenerative effects. These platforms have been shown in in vitro and animal studies to influence inflammatory signaling, oxidative stress, angiogenesis, collagen remodeling, re-epithelialization, cellular proliferation, and migration. However, the modulation of these pathways are dose-responsive, time-dependent, and cell- and wound-stage-specific. Despite the promising therapeutic potential of nanomaterial-based wound care strategies, the available evidence remains predominantly preclinical, with relatively limited clinical data supporting their use in humans. Concerns regarding long-term toxicity, biodistribution, batch-to-batch reproducibility, sterilization, scalable manufacturing, regulatory approval, and commercial feasibility further challenge translation into clinical practice. Multifunctional nanomaterials may offer a promising approach for pathway-specific and multimodal wound management; however, comprehensive mechanistic studies, long-term safety and biodistribution assessments, and well-designed clinically relevant investigations are required to establish their efficacy, safety, and true translational potential. Full article

Sertoli cells (SCs) are essential for spermatogenesis and provide structural and nutritional support to germ cells in the Chinese Holstein cattle testis. Although microRNAs (miRNAs) are known to regulate SC function, the specific role of Bta-miR-146a in bovine SCs is unclear. This study investigated the mechanisms by which Bta-miR-146a regulates bovine immature SCs. Using molecular cloning, we constructed Bta-miR-146a overexpression and interference vectors and transfected them into SCs via lipofection. Quantitative real-time PCR (RT-qPCR), 5-ethynyl-2′-deoxyuridine (EdU) proliferation assays, Cell Counting Kit-8 (CCK-8) viability assays, and flow cytometry revealed that Bta-miR-146a overexpression inhibited SC proliferation and promoted apoptosis, whereas Bta-miR-146a inhibition increased proliferation and suppressed apoptosis. Dual-luciferase reporter assays confirmed that SMAD4 is a direct target of Bta-miR-146a; SMAD4 interference reduced SC proliferation and increased apoptosis, whereas overexpression had the opposite effect. Furthermore, activity of this gene modulates the TGFβ/MAPK signaling pathway; SMAD4 interference reduces the expression of TGFβ, TGF-βRII, DAXX, MAP3K5, P38, and MAX. These findings indicate that the Bta-miR-146a/SMAD4/TGFβ/MAPK axis is a key regulator of SC proliferation and apoptosis, offering insights into the molecular mechanisms underlying bovine spermatogenesis and potential targets for improving reproductive performance. Full article

Cholangiocarcinoma (CCA) is an aggressive malignancy with limited treatment options and poor clinical outcomes. Kinesin light chain 1 (KLC1), a component of the kinesin-1 motor complex involved in intracellular transport, has been implicated in cancer biology; however, its role in CCA remains unclear. This study investigated the functional role and molecular alterations associated with KLC1 silencing in CCA. Analysis of publicly available datasets showed that KLC1 mRNA expression was significantly elevated in CCA tissues, and immunohistochemical images from the Human Protein Atlas demonstrated stronger KLC1 protein expression in tumor tissues. siRNA-mediated KLC1 knockdown markedly suppressed cell proliferation, migration, and invasion in KKU-213A and KKU-055 cells and altered the expression of epithelial–mesenchymal transition-associated proteins. Transcriptomic profiling identified 2074 differentially expressed genes following KLC1 knockdown. Functional enrichment analyses revealed significant alterations in cytoskeleton-associated processes and mitogen-activated protein kinase (MAPK) signaling. Protein–protein interaction network analysis identified interconnected gene networks associated with these pathways. Selected differentially expressed genes were validated by RT–qPCR, supporting the transcriptomic findings. Collectively, these results suggest that KLC1 contributes to aggressive phenotypes in CCA cells and is associated with transcriptomic alterations involving cytoskeletal regulation and MAPK signaling, highlighting KLC1 as a potential contributor to CCA progression and warranting further investigation. Full article

This study investigated the pathological processes by which two Salmonella strains induce orchitis and impair spermatogenesis in mice, with emphasis on inflammation and blood–testis barrier (BTB) integrity. Thirty male Kunming mice were randomly assigned to the human-derived Salmonella enterica serovar Enteritidis H71 group, the sheep-derived Salmonella enterica serovar Agona W42 group, or the phosphate-buffered saline control group (n = 10 per group). An acute orchitis model was established by intrascrotal injection. Histopathological examination revealed marked testicular and epididymal lesions, disruption of the spermatogenic epithelium, and reduced sperm abundance in infected mice. Transcriptomic analysis identified 4546 differentially expressed genes shared by the two infected groups and showed enrichment of the Toll-like receptor (TLR), nuclear factor kappa B (NF-κB), and mitogen-activated protein kinase (MAPK) signaling pathways. Real-time quantitative PCR further showed increased expression of interleukin 6 (Il6), interleukin 1 beta (Il1b), and tumor necrosis factor (Tnf), accompanied by reduced expression of tight junction protein 1 (Tjp1), occludin (Ocln), and synaptonemal complex protein 3 (Sycp3) in infected mice (p < 0.05), except for Tjp1 in the W42 group. These findings indicate that Salmonella-induced inflammatory activation is associated with BTB disruption and impaired spermatogenesis, providing a basis for further investigation of bacterial orchitis and zoonotic reproductive risks. Full article

Background: Mitogen-activated protein kinase 3 (MAPK3/ERK1) plays a central role in cellular proliferation, inflammation, apoptosis, and survival signalling and has been implicated in oral squamous cell carcinoma (OSCC), periodontitis, oral lichen planus, and other chronic oral inflammatory diseases. The present study employed an integrated computational workflow combining machine learning (ML)-based quantitative structure–activity relationship (QSAR) modelling, molecular docking, density functional theory (DFT), molecular dynamics (MD) simulation, and MM-GBSA analysis to identify and characterise potent MAPK3 inhibitors. Methods: A curated dataset of 907 experimentally validated MAPK3 inhibitors was retrieved from the ChEMBL database and processed using molecular descriptors and Morgan fingerprints. Multiple ML algorithms were evaluated under scaffold-based validation, with Light Gradient Boosting Machine (LightGBM) demonstrating the best predictive performance. Results: The final model achieved strong classification capability with ROC-AUC values of 0.898 and 0.926. Feature importance analysis revealed that local structural motifs captured by fingerprint descriptors played dominant roles in MAPK3 inhibitory activity. The top-ranked compounds were subjected to molecular docking, where compounds 58324148 and 137531515 exhibited strong binding affinities of −11.9 and −11.0 kcal/mol, respectively. DFT calculations demonstrated favourable electronic properties with low HOMO–LUMO energy gaps, while MD simulations confirmed stable receptor–ligand interactions throughout 200 ns trajectories. MM-GBSA analysis further supported strong binding stability dominated by van der Waals interactions. Conclusions: Overall, the integrated computational framework successfully identified promising MAPK3 inhibitor candidates with potential therapeutic relevance for oral inflammatory and proliferative diseases. Full article