Search Results (4,614)

Chronic liver injury is characterized by sustained activation of transforming growth factor-β (TGF-β) signaling within the fibrotic microenvironment, yet the contribution of TGF-β-associated metabolic remodeling to hepatic stellate cell (HSC) activation remains incompletely understood. Here, we investigated whether TGF-β signaling is associated with lipid metabolic remodeling in HSCs and whether pirfenidone (PFD) interferes with this process. We found that TGF-β1 was spatially associated with lipid accumulation in fibrotic liver tissue and that TGF-β1/2 promoted HSC proliferation. In vitro, TGF-β1/2 coordinately upregulated sterol regulatory element-binding protein 1 (SREBP1) and fatty acid synthase (FASN), accompanied by increased intracellular lipid accumulation and enhanced oleic acid (OA)-associated lipid responses. Low-dose OA further activated AKT/ERK/p70 S6K signaling in HSCs, whereas PFD attenuated these signaling events. In parallel, PFD suppressed TGF-β-associated lipid accumulation in vitro, reduced SREBP1/FASN expression in activated HSC-rich regions in vivo, and alleviated CCl₄-induced liver fibrosis. Together, these findings support a model in which TGF-β-associated lipogenic remodeling contributes to HSC activation and suggest that interference with this metabolic state may represent one component of the antifibrotic action of pirfenidone. Full article

Background: Acquired resistance to the third-generation EGFR tyrosine kinase inhibitor osimertinib, often mediated by EGFR triple mutations, poses a major clinical challenge in non-small cell lung cancer (NSCLC) treatment. Among these, some rare mutations, such as L858R/T790M/L792H and L858R/T790M/G796R, create steric hindrance that directly interferes with osimertinib binding, yet effective targeted therapeutic strategies for these specific mutations remain lacking. Cudratricusxanthone A (CTXA), a natural xanthone derivative isolated from Cudrania tricuspidata Bur., has demonstrated various pharmacological activities, but its effects against EGFR triple-mutant NSCLC have not been systematically investigated. Methods: Stable Ba/F3 and NIH/3T3 cell lines expressing EGFR L858R/T790M/L792H or L858R/T790M/G796R triple mutations were generated via electroporation. The antiproliferative effects of CTXA were evaluated by MTT/MTS assays, colony formation, and wound healing assays. Cell cycle distribution and apoptosis were analyzed by flow cytometry. Protein expression of EGFR signaling pathway components (p-EGFR, p-ERK, p-AKT, p-STAT3) and cell cycle regulators (Cyclin D1, CDK4) were examined by Western blotting. Molecular docking and 200 ns molecular dynamics simulations were performed to investigate the stability and binding modes of CTXA to the mutant EGFR kinase domains. Results: The successfully established triple-mutant cell lines exhibited high EGFR expression, IL-3-independent growth, and significant resistance to osimertinib. CTXA inhibited the proliferation of all triple-mutant cell lines in a time- and concentration-dependent manner, with 48 h IC₅₀ values ranging from 0.362 to 2.488 μM. Mechanistically, CTXA suppressed EGFR autophosphorylation and downregulated downstream p-ERK, p-AKT, and p-STAT3. CTXA induced G1 phase cell cycle arrest by downregulating Cyclin D1 and CDK4, significantly promoted apoptosis, and inhibited cell migration. Molecular docking revealed that while osimertinib binding was blocked by steric hindrance from His-792 or Arg-796, CTXA adapted to the mutated ATP-binding pockets through multiple hydrogen bonds and extensive hydrophobic interactions. Molecular dynamics simulations confirmed the stable binding of CTXA to both mutant EGFR proteins over the 200 ns simulations. Conclusions: This study demonstrates for the first time that the natural compound CTXA possesses antitumor efficacy against EGFR L858R/T790M/L792H and L858R/T790M/G796R mutants by regulating EGFR-ERK/AKT/STAT3 signaling. Our findings position CTXA as a promising lead compound for tackling this challenging form of acquired resistance and highlight the value of natural products in multi-target antitumor drug discovery. Full article

Neurodegenerative disorders, including Parkinson’s disease (PD), are largely treated with symptomatic therapies, underscoring the need for strategies that target underlying disease mechanisms. Glucagon-like peptide-1 (GLP-1) and its receptor (GLP-1R), a class B G protein-coupled receptor best known for metabolic regulation, have attracted interest due to the increasing evidence of central nervous system (CNS) actions. This review synthesises mechanistic, preclinical, and clinical evidence examining GLP-1R signalling in PD and related neurodegenerative contexts. We integrate findings from cellular and animal models with early-phase clinical studies of GLP-1 receptor agonists (GLP-1RAs). Across experimental systems, GLP-1R activation engages conserved intracellular pathways—cAMP/PKA, PI3K/Akt, and ERK—that regulate mitochondrial function, oxidative stress, autophagy-lysosomal dynamics, and inflammatory signalling. In PD-relevant models, these pathways intersect with key pathogenic features, including α-synuclein accumulation, dopaminergic neuron vulnerability, and glial reactivity. Clinical studies to date demonstrate acceptable safety and tolerability, alongside biomarker evidence of central pathway engagement and variable effects on motor and non-motor outcomes. However, uncertainties remain regarding CNS target engagement, peripheral versus CNS mechanisms, and disease-stage dependence. Overall, the current evidence positions GLP-1R signalling as a biologically plausible therapeutic pathway in PD that warrants further mechanistic clarification and rigorous evaluation in ongoing and future clinical trials. Full article

Adipogenesis is a critical factor in causing obesity, which is a global health problem associated with metabolic disorders, such as insulin resistance and cardiovascular diseases. Natural compounds with anti-adipogenic activity may represent potential approaches for modulating adipocyte function. However, despite increasing interest in natural products, the anti-adipogenic potential of acridone alkaloids, particularly prenylated derivatives, remains largely unexplored. This study examined the effects of N-methylatalaphylline (NMA), a prenylated acridone alkaloid, on adipocyte differentiation, lipid accumulation, and glucose uptake. NMA exhibited anti-adipogenesis, particularly toward preadipocytes, and significantly reduced lipid accumulation in murine 3T3-L1 and human PCS-210-010 adipocytes at nontoxic doses (1.5–6 µM). At 3–6 µM, NMA downregulated adipogenic regulators, including PPARγ, C/EBPα, and SREBP1, along with adipogenic effectors, such as FABP4, adiponectin, LPL, PLIN1, and FAS. Mechanistic studies indicated that NMA treatment was associated with reduced phosphorylation of AKT, ERK, and p38, accompanied by cell-cycle arrest and inhibition of mitotic clonal expansion. Meanwhile, activation of AMPK-ACC signaling, which may contribute to suppression of adipogenesis and reduced glucose uptake, was observed in differentiated 3T3-L1 cells after treatment with 6 µM NMA for 48 h. Additionally, molecular docking and molecular dynamics simulations suggested potential interaction between NMA and ERK1, supported by hydrogen bonding and hydrophobic contacts. Overall, these findings suggest that NMA exerts anti-adipogenic effects in vitro by modulating adipocyte proliferation, differentiation, and lipid metabolism. These findings highlight NMA as a promising acridone alkaloid scaffold for anti-adiposity applications, warranting further in vivo validation. Full article

Background: Hepatic ischemia–reperfusion injury (IRI) remains a major challenge in liver transplantation (LTx) and hepatectomy. Previous studies identified a 12/15-lipoxygenase (12/15-LOX)-driven lipid peroxidation cascade promoting cell death, whereas glutathione peroxidase 4 (GPx4)-dependent metabolism acts antagonistically. This study investigated whether tacrolimus protects against hepatic IRI through this redox axis. Methods: Male C57BL/6 mice underwent 65% partial hepatic warm ischemia and reperfusion with or without tacrolimus preconditioning. Liver tissue and serum were analyzed by spectral photometry, Western blotting, TUNEL assay, and serum enzyme measurement. Results were statistically analyzed and compared with previously published results of 12/15-LOX inhibition by baicalein pretreatment and its carrier DMSO. Also, the combination of both tacrolimus and baicalein was investigated. Results: Tacrolimus increased the oxidative glutathione activity quotient (GSSG/GSH) by 75.1% (p = 0.0302), attenuated MAPK signaling, reduced SAPK/JNK by 84.6% (p = 0.0059), with ERK1/2 showing a downward trend, decreased Caspase-3 activation by 66.9% (p < 0.001) and PARP cleavage by 59.9% (p = 0.0330), and lowered TUNEL-positive cell death by 61.8% (p = 0.0015). Tacrolimus achieved hepatoprotection comparable to 12/15-LOX inhibition, but without hepatotoxicity, whereas combined treatment conferred no additional benefit yet bore toxic properties. Conclusions: Tacrolimus preconditioning mitigates hepatic IRI through a glutathione-linked redox–signaling–cell death axis and exerts cytoprotective effects beyond immunosuppression. Full article

Neurotensin (NTS) binds to the G protein-coupled receptors (GPCRs) NTSR1 and NTSR2. NTSR1 regulates transactivation of the EGFR, HER2, and HER3, but its effects on HER4 are unknown. By Western blot, NTSR1 and HER4 were present in six lung cancer cell lines examined. In NCI-H522 or NCI-H661 cells, adding NTS increased phosphorylation (P) of tyrosine (Y) 1284 on HER4. Because SR48692 antagonized NTS’s ability to increase P-HER4 or P-ERK, NTSR1 may play an important role in NSCLC. SR48692, HER4 siRNA, reactive oxygen species inhibitors, and the tyrosine kinase inhibitor ibrutinib inhibited NTS-induced P-HER4. Adding NTS to NCI-H661 cells increased the formation of HER4/HER4, HER4/ EGFR, and HER4/HER2 dimers. Adding NTS to NSCLC cells increased both P-ERK and P-AKT, which were inhibited by PD98059 and LY294002, respectively. The growth of NCI-H522 or NCI-H661 cells was stimulated by NTS or neuregulin 1 (NRG1), a HER4 ligand, but inhibited by SR48692 or ibrutinib. The results indicate that NTSR1 regulates HER4 transactivation, thereby increasing the proliferation of lung cancer cells. Full article

Background/Objectives: Chronic glomerulonephritis (CGN) is a progressive chronic kidney disease that can ultimately advance to end-stage renal disease (ESRD). Zhuangyang Bushen Pill (ZYBSW) is a traditional Chinese herbal formulation derived from the Yi ethnic medicine of Yunnan Province, and it has been widely employed in folk practice for the amelioration of chronic nephritis and renal dysfunction. This study was designed to evaluate the therapeutic efficacy of ZYBSW against CGN and to provide preliminary insights into its underlying mechanisms of action. Methods: The nephropathy model was induced in mice by tail vein injection of ADR (10 mg/kg). Renal function was evaluated by measuring relevant biochemical parameters, and renal histopathological alterations were examined using HE staining. Chemical constituents of ZYBSW were analyzed by LC-MS/MS. Its mechanisms of action were investigated using network pharmacology, WGCNA, molecular docking, multiplex immunofluorescence, and Western blotting. Results: ZYBSW significantly reduced ACR by 88.9%, SCr by 56.4%, and BUN by 30.4%, increased ALB by 32.4%, and alleviated renal histopathological damage (all p < 0.01). LC-MS/MS analysis identified 419 chemical constituents in ZYBSW. Network pharmacology, WGCNA, and molecular docking experiments identified EGFR and DUSP1 as potential targets, and indicated the MAPK pathway as a key pathway. Mechanistic studies revealed that ZYBSW significantly inhibited EGFR expression in renal tissue, enhanced DUSP1 expression, and reduced the phosphorylation levels of ERK, JNK, and p38. Conclusions: This study reveals ZYBSW can effectively alleviate CGN, with EGFR and DUSP1 as likely therapeutic targets, and its mechanism of action primarily involves regulating the MAPK signaling pathway. Full article

Inflammatory bowel diseases (IBD), including ulcerative colitis and Crohn’s disease, are chronic inflammatory disorders of the gastrointestinal tract associated with epithelial barrier dysfunction, dysregulated immune responses, and an increased risk of cancer. Persistent inflammation is a key driver of IBD-associated tumorigenesis, yet the transcriptional regulators linking inflammatory signaling to epithelial transformation remain incompletely defined. FOSL1 (FOS-like antigen 1), a member of the activator protein-1 (AP-1) transcription factor family, has emerged as a critical mediator at the intersection of inflammation, epithelial homeostasis, and cancer progression. FOSL1 is induced by pro-inflammatory pathways commonly activated in IBD, including MAPK/ERK, NF-κB, and cytokine signaling, and regulates gene programs involved in cell proliferation, migration, barrier integrity, immune modulation, and survival. Accumulating evidence demonstrates that FOSL1 expression is elevated in inflamed intestinal mucosa and in IBD-associated malignancies, where it contributes to epithelial dysfunction, chronic inflammation, tumor initiation, metastasis, angiogenesis, and therapeutic resistance. Moreover, FOSL1-driven transcriptional networks show mechanistic overlap between IBD-associated colorectal cancer (CRC) and other inflammation-linked gastrointestinal cancers, such as pancreatic ductal adenocarcinoma (PDAC). In this review, we summarize current knowledge on the regulation and function of FOSL1 in intestinal inflammation and IBD-associated cancers, highlight its context-dependent roles in epithelial and immune compartments, and discuss emerging therapeutic strategies aimed at indirectly targeting FOSL1 signaling pathways. Full article

Introduction: Gastric cancer is a prevalent and aggressive malignancy driven by complex signaling networks. Estrogen receptor-α36 (ER-α36), a membrane-localized receptor, mediates non-genomic signaling and promotes tumor progression. ER-α36 can interact with epidermal growth factor receptor (EGFR) to activate downstream mitogen-activated protein kinase (MAPK) signaling, but the detailed mechanism in gastric cancer remains unclear. This study aimed to explore whether ER-α36 promotes gastric cancer progression by regulating serum and glucocorticoid-regulated kinase 1 (SGK1)-mediated Erk1/2 activation. Methods: We collected 53 human gastric adenocarcinoma specimens and detected ER-α36 expression by immunohistochemistry. Bioinformatics analysis was used to identify ER-α36-related kinases. Gastric cancer cell lines (SGC7901, HGC27, NCI-N87, and MFC) were used for in vitro studies. Western blotting, qRT-PCR, immunofluorescence, co-immunoprecipitation (Co-IP), wound healing, MTT, and Transwell invasion analyses, and nude mouse orthotopic tumor models were applied to investigate the function and mechanism of the ER-α36/SGK1/Erk1/2 axis. Results: ER-α36 was positively expressed in 62.3% of gastric adenocarcinoma tissues and was associated with poor differentiation and prognosis. SGK1 was identified as a key kinase downstream of ER-α36. ER-α36, SGK1, and p-Erk1/2 were co-upregulated in gastric cancer tissues and cells. ER-α36 regulated Raf/MEK1/2/Erk1/2 phosphorylation in an SGK1-dependent manner. EGF-induced Erk1/2 activation required both ER-α36 and SGK1. Overexpression of ER-α36 promoted the proliferation, migration, and invasion of gastric cancer cells, while SGK1 knockdown abolished these oncogenic effects. In vivo experiments confirmed that ER-α36 promoted gastric tumor growth and EGFR/Erk signaling, which was attenuated by SGK1 knockdown. Conclusions: ER-α36 contributes to the malignant progression of gastric adenocarcinoma by activating the Erk1/2 pathway through SGK1. The ER-α36–SGK1–Erk1/2 axis may serve as a novel therapeutic target for gastric cancer. Full article

Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with a poor prognosis. While sorafenib serves as the first-line therapy for advanced HCC, its efficacy is frequently hampered by side effects and the development of drug resistance, necessitating the development of novel agents to enhance HCC sensitivity to sorafenib. In this study, we demonstrate that the antihistamine astemizole significantly enhanced the antitumor efficacy of sorafenib in HCC cell lines. This combination treatment cooperatively inhibited HCC cells’ proliferation and induced cell cycle arrest at the G1 phase, as evidenced by decreased cyclin D1 and p-Rb levels and increased p27 expression. Furthermore, the combination of astemizole and sorafenib synergistically inhibited HCC cells’ migration, invasion, and adhesion. It also reduced F-actin polymerization and the expression of metastasis-regulating proteins, including p-Integrinβ1, FAK, and MMP1. Additionally, the combination treatment suppressed tube formation in HUVECs, accompanied by downregulation of HIF-1α and reduced VEGF secretion. Co-inhibition of Eag1 and the ERK/MAPK signaling pathway may underlie the enhanced anti-HCC effects of sorafenib by astemizole. Collectively, these findings indicate that astemizole significantly enhanced the antitumor activity of sorafenib by inhibiting proliferation, metastasis, and angiogenesis in HCC cells, suggesting its potential as a promising adjuvant to improve sorafenib-based therapy in HCC. Full article

Background: Inflammatory bowel disease (IBD) is frequently complicated by secondary bone loss driven by chronic inflammation and gut–bone axis dysregulation. Although dried ginger has pharmacological activities relevant to intestinal inflammation, the effects of dried ginger milk extract (DGME), a lipophilic constituent-enriched preparation, on IBD-associated bone loss (IBD-BL) remain unknown. This study evaluated the preventive and therapeutic effects of DGME on IBD-BL and explored the underlying mechanisms. Methods: Mice with DSS-induced IBD-BL were treated with DGME (250, 125, or 62.5 mg/kg) or sulfasalazine. Colitis severity, bone microarchitecture, osteoclast activity and Th17 cells were assessed by histology, micro-computed tomography, histomorphometry and flow cytometric analysis. UHPLC-Q-TOF MS, network pharmacology, 16S rRNA sequencing, fecal metabolomics, and in vitro assays were used for mechanistic investigation. Results: DGME ameliorated colitis, improved trabecular bone microarchitecture, and reduced osteoclast-related bone destruction. These effects were associated with selective suppression of pathogenic bone marrow TNF-α⁺ Th17 cells and downregulation of Il17a, Rorc, Tnfα, Ccr2, Ccr6, Cxcr4, Csf1, and Tnfsf11. Compared with aqueous extract, DGME was enriched in 19 lipophilic constituents. Multi-omics analyses showed that DGME remodeled gut microbiota and metabolite profiles, characterized by enrichment of Lactobacillus, Anaerotruncus, vanillin, and spermidine. Both vanillin and spermidine suppressed Th17 effector genes and inhibited MEK/ERK signaling in vitro. Conclusions: DGME alleviated IBD-BL by suppressing pathogenic TNF-α⁺ Th17 responses and remodeling the gut microbiota–metabolite axis. This study not only extends the therapeutic application of dried ginger from intestinal inflammation to IBD-BL, but also identifies vanillin and spermidine as candidate functional mediators linked to MEK/ERK inhibition. Full article

Garrya flavescens S. Wats. (GF) has been traditionally used to treat gastrointestinal spasms, yet its bioactivity within the central nervous system remains unexplored. This study aimed to characterize the bioactive constituents of GF and evaluate its anti-inflammatory and metabolic regulatory effects in lipopolysaccharide-activated microglia. Phytochemical profiling using LC-HRMS and HPLC identified rutin as a primary bioactive component, present at an exceptionally high concentration (9309 μg/g). In BV-2 microglial and RAW 264.7 cells, GF treatment significantly suppressed the expression of pro-inflammatory cytokines and mediators in a dose-dependent manner. Mechanistic studies revealed that GF specifically modulated the ERK signaling pathway. Furthermore, Seahorse XF analysis demonstrated that GF restored mitochondrial homeostasis by reducing basal respiration and proton leak while significantly enhancing spare respiratory capacity. Finally, conditioned medium from GF-treated microglia improved the viability of N2A neuronal cells. These findings highlight GF as a potent botanical source with significant neuroprotective potential, offering a promising candidate for functional food or nutraceutical applications targeting neuroinflammatory disorders. Full article

Acinetobacter baumannii, a prominent opportunistic pathogen in healthcare settings, causes severe infections and poses significant challenges for clinical treatment. This study investigates the synergistic effects of α-pinene combined with meropenem (MEM) on A. baumannii biofilm formation and lung injury in mice, aiming to develop new strategies to combat persistent infections and antibiotic resistance. α-pinene combined with MEM exhibited strong synergistic antibacterial activity against carbapenem-resistant A. baumannii (CRAB 5E9). The combination significantly inhibited biofilm formation, extracellular polymer production, surface motility, and quorum sensing. The expression of key genes such as ompA, bfmR, bap, csuAB, abaI, and abaR was reduced by up to 61%. In vivo, the treatment alleviated weight loss, decreased the bacterial load in lung tissue, and reduced lung inflammation. Furthermore, it significantly suppressed proteins involved in the inflammatory response and the MAPK pathway, including TLR4, NF-κB, NLRP3, TRAF6, ERK2, p38 MAPK, JNK, and TNF-α. The combination of α-pinene and MEM synergistically inhibits A. baumannii biofilm formation and alleviates the inflammatory response in a mouse model, offering a potential therapeutic approach for combating A. baumannii infections. Full article

This study concurrently addressed the separation method for carbon dots derived from Glycyrrhizae Radix et Rhizoma Praeparata cum Melle (GRRPM) and the in vitro evaluation of their anti-allergic biological activity. Glycyrrhizae Radix et Rhizoma Praeparata cum Melle Carbon Dots (GRRPM-CDs) were prepared via decoction followed by dialysis, and their properties were characterized using High-Performance Liquid Chromatography (HPLC) and nanomaterial techniques. Anti-allergic activity was evaluated using a C48/80-induced RBL-2H3 mast cell degranulation model. Safety and efficacy were assessed using the CCK-8 assay, direct intervention, and drug-containing serum methods. The release of β-hexosaminidase (β-hex), histamine (HIS), interleukin-4 (IL-4), and tumor necrosis factor-α (TNF-α) was measured by ELISA, and key proteins in the MAPK signaling pathway were analyzed by Western blot. GRRPM-CDs inhibited mast cell degranulation and the release of allergic and inflammatory mediators in a dose-dependent manner. They also significantly downregulated the phosphorylation levels of the JNK, ERK, and p38 proteins in the MAPK signaling pathway. GRRPM-CDs exhibit significant anti-allergic activity, likely via suppression of the MAPK pathway. These findings provide new insights into the bioactive components of processed Glycyrrhiza and suggest potential avenues for developing novel therapies for allergic diseases. Full article

Thyroid cancer is the most common malignancy of the endocrine system and represents a biologically heterogeneous disease driven by the interplay between endocrine regulation, oncogenic signaling pathways, and tumor microenvironment dynamics. Although most follicular cell-derived thyroid cancers follow an indolent clinical course, a subset progresses toward aggressive, therapy-refractory phenotypes, underscoring the need for refined molecular understanding and improved biomarkers. This review comprehensively examines the molecular determinants of thyroid cancer progression, with particular emphasis on Thyroid Hormone (TH) signaling, the Mitogen-Activated Protein Kinase (MAPK) and Phosphoinositide 3-Kinase (PI3K)/AKT pathways, and the emerging role of microRNAs (miRNAs). We discuss how oncogenic alterations, most notably the ^V600EBRAF mutation, act as central drivers of tumor initiation and aggressiveness by sustaining MAPK/ERK signaling, promoting dedifferentiation, metabolic reprogramming, immune evasion, and resistance to targeted therapies. The cooperative role of PI3K/AKT signaling in reinforcing survival, invasion, and treatment resistance is highlighted, emphasizing the network-level integration of oncogenic pathways rather than linear dependency on single drivers. In parallel, thyroid hormones exert context-dependent effects on tumor biology through both genomic actions mediated by nuclear thyroid hormone receptors and non-genomic mechanisms initiated at the integrin αvβ3 receptor, linking endocrine status to cancer progression and therapeutic response. Finally, we review the expanding evidence supporting miRNAs as critical regulators of thyroid carcinogenesis and as promising diagnostic, prognostic, and predictive biomarkers. The clinical validation of miRNA-based panels and circulating miRNAs offers new opportunities to improve preoperative risk stratification, reduce overtreatment, and guide personalized therapeutic strategies. Collectively, these insights support a multidimensional framework for understanding thyroid cancer progression and highlight future directions for precision oncology. Full article