Search Results (449)

Chronic liver disease (CLD) constitutes a major global health burden, with high morbidity and mortality, limited treatment options for several etiologies, and an urgent need for novel therapeutic targets. Fibroblast growth factor 1 (FGF1) is a unique member of the FGF family capable of binding all four FGFR subtypes, thereby regulating multiple signaling pathways including PI3K/AKT, Ras/MAPK, and PLCγ, which are involved in metabolism, cell survival, proliferation, and tissue repair. Emerging evidence highlights the multifaceted and context-dependent roles of FGF1 in CLD. In drug-induced liver injury (DILI) caused by anti-tuberculosis drugs, acetaminophen, or doxorubicin, FGF1 confers protection by restoring bile acid homeostasis, reducing oxidative stress, inflammation, and apoptosis. In Metabolic dysfunction-associated steatotic liver disease (MASLD), FGF1 ameliorates hepatic steatosis, oxidative injury, and insulin resistance through downregulation of SREBP1, upregulation of PPARα, and activation of Nrf2-mediated antioxidant responses. Conversely, in primary sclerosing cholangitis (PSC), FGF1 aggravates ductular reaction, biliary senescence, and liver fibrosis via upregulation of SASP and TGF-β1, suggesting that inhibition of the FGF1/FGFR axis may be therapeutic. For alcohol-related liver disease (ALD), although direct experimental evidence is lacking, FGF1 is hypothesized to confer protection given its known activities against oxidative stress, lipid dysregulation, and cell death. Despite its promise, the mitogenic potential of FGF1 raises safety concerns; however, N-terminally modified FGF1 analogs (e.g., FGF1Δ) retain metabolic benefits with reduced proliferative activity. Collectively, FGF1 represents a versatile and disease-dependent regulator in CLD, warranting further mechanistic studies, safety evaluations, and development of targeted analogs as a novel therapeutic strategy for difficult-to-treat liver diseases. Full article

Sea cucumbers (Apostichopus japonicus) show fleeing, adhesion, and thanatosis patterns upon exposure to various stressors. However, the molecular mechanisms underlying these contrasting stress response patterns remain largely unknown. In the present study, we performed a transcriptomic analysis of coelomocytes on stressed sea cucumbers to elucidate the potential molecular mechanisms. The RNA-seq results revealed that several matrix metalloproteinase (MMP) family genes, along with HTR4, HRH2, and ADRA1D (which are involved in neuroactive ligand–receptor interactions), were significantly upregulated in the fleeing pattern. These genes may facilitate rapid movement. In the adhesion pattern, PHKA and PGK were significantly downregulated, and the differentially expressed genes (DEGs) were significantly enriched in the longevity regulating pathway, accompanied by downregulation of KRAS and HSPA1. These genes and the pathway may be involved in the reallocation of energy resources during the adhesion pattern. In the thanatosis pattern, DEGs were significantly enriched in the MAPK signaling pathway (including upregulation of ANGPT1 and FGFR1) and in the Rap1 and Ras signaling pathways (with downregulation of key genes: RAPGEF4, RRAS2, and RaLA). These genes potentially contribute to sustaining the thanatosis pattern. These transcriptomic profiles provide novel insights into the distinct molecular signatures underlying each stress response pattern in A. japonicus. Full article

GLP-1 receptor agonists (GLP-1RAs) are widely used in the treatment of type 2 diabetes and obesity and are increasingly relevant in periodontal and implant practice. This review covers mechanisms, preclinical and early human evidence, and practical periodontal considerations; the structured database search is conducted in accordance with the Scale for the Assessment of Narrative Review Articles (SANRA) and the International Committee of Medical Journal Editors (ICMJE) principles. Two pathways explain GLP-1RAs’ relevance: indirect effects from better glycemic control, weight loss, and reduced inflammation; and direct tissue effects involving GLP-1R signaling and the GLP-1/dipeptidyl peptidase-4 (DPP-4) axis. Preclinical studies show reduced inflammation, osteoclast activity, and alveolar bone loss, along with improved periodontal stem cell function under hyperglycemia or inflammation via Nuclear Factor-kappaB (NF-kappaB), Wingless-related integration site (Wnt)/beta-catenin, and Mitogen-Activated Protein Kinase (MAPK) pathways. Animal studies on implants and local delivery, including exendin-4 platforms, suggest osteometabolic benefits. Human data are limited and mostly observational, and confounders include metabolic status, smoking, medication, and nutrition. Oral side effects such as xerostomia and dehydration are also noted. At present, GLP-1RA therapy should be regarded as a contextual modifier of periodontal risk and healing capacity rather than as a stand-alone periodontal therapy. Full article

Anaplastic thyroid carcinoma (ATC) is a rare but highly aggressive malignancy characterized by rapid progression, early metastasis, and extremely poor survival outcomes. Effective therapeutic options remain limited, highlighting the need for efficient and biologically relevant preclinical drug-discovery platforms. In this study, high-throughput compound screening using human ATC cell lines identified ANC-3 as a potential anticancer candidate. Its antitumor activity was evaluated through cytotoxicity and functional assays, zebrafish xenograft validation with live fluorescence imaging, colony-formation assays, and bulk RNA sequencing with pathway enrichment analyses. ANC-3 demonstrated consistent antitumor effects by significantly inhibiting cell viability, migration, invasion, and clonogenic survival, while also suppressing tumor growth in zebrafish xenograft models. Transcriptomic analyses revealed modulation of multiple oncogenic pathways, including MAPK, Ras, and NF-κB signaling. Collectively, these findings support zebrafish xenograft-based screening as a rapid and scalable platform for ATC drug discovery and suggest ANC-3 as a promising multi-pathway inhibitor warranting further preclinical development. Full article

Cervical neuroendocrine carcinoma (NECC) is a rare but highly aggressive cervical malignancy, accounting for approximately 1% of invasive cervical cancers. Diagnosis is challenging because NECC overlaps morphologically with other poorly differentiated cervical and metastatic tumors, may show crush artifact in small biopsies, and can display variable expression of conventional neuroendocrine markers. This narrative review provides a practical synthesis of the histopathological, immunohistochemical, molecular, and clinical features of NECC, with emphasis on diagnostic pitfalls and differential diagnosis. Recent English-language literature on cervical neuroendocrine carcinoma was reviewed and qualitatively integrated, focusing on morphology, immunohistochemistry, HPV association, molecular alterations, prognosis, and management-relevant diagnostic issues. Accurate diagnosis requires integration of morphology, epithelial differentiation, neuroendocrine marker expression, HPV-related context, and clinic-radiological correlation. Useful markers include broad-spectrum cytokeratins, synaptophysin, chromogranin A, CD56, INSM1, p16, and Ki-67, with additional markers selected according to the differential diagnosis. Diffuse block-type p16 expression and high-risk HPV detection support a cervical HPV-associated origin but are not specific for neuroendocrine differentiation. Molecular studies show frequent association with HPV18 and recurrent alterations involving PI3K/AKT, RAS/MAPK, and TP53-related pathways, although these findings remain insufficiently validated for routine prognostic or therapeutic stratification. NECC requires early recognition and a multimodal diagnostic approach because of its aggressive behavior and poor prognosis. A practical, stepwise integration of morphology, immunohistochemistry, molecular findings, and clinical–radiological data may improve diagnostic consistency and support multidisciplinary management. Full article

Background: Endometrial cancer is a common gynecological malignancy, and elucidating its molecular basis may provide new clues for targeted intervention. This study investigated the role of ERBB3 in endometrial cancer cells and explored whether Ras-ERK/MAPK signaling is involved in ERBB3-mediated regulation. Methods: Bioinformatic screening was performed using public databases to identify candidate genes associated with endometrial cancer. ERBB3 was selected for further analysis. ERBB3 expression was evaluated in public datasets and examined in endometrial cancer cells. Loss-of-function experiments, rescue assays, Western blotting, and co-immunoprecipitation were used to assess the biological function and potential mechanism of ERBB3. Results: ERBB3 knockdown significantly inhibited proliferation, migration, and invasion, and promoted apoptosis in Ishikawa and RL95-2 cells. These changes were accompanied by decreased Ras-ERK/MAPK signaling. Moreover, Ras overexpression partially reversed the effects induced by ERBB3 knockdown. Co-immunoprecipitation suggested a molecular association between ERBB3 and Ras within a protein complex, but did not demonstrate direct physical binding. Conclusions: ERBB3 appears to promote malignant behaviors in endometrial cancer cells, and the Ras-ERK/MAPK pathway may be one of the downstream mechanisms involved. Further validation in additional experimental models and clinical samples is needed. Full article

Bovine mastitis is a persistent and challenging illness in dairy industry, bringing about devastating economic losses to the sector. The longstanding over-reliance on antibiotic therapy has raised severe public health concerns, highlighting the critical need to develop safe and effective alternative regimens. Pulsatilla saponin B4 (PSB4), a plant-derived triterpenoid saponin, has been shown to regulate inflammation. However, the effect of PSB4 on mastitis in lactating cows has not been elucidated. The aim of this study was to explore the anti-inflammatory property and the molecular mechanisms of PSB4 in bovine mammary epithelial cells (BMECs) and mouse mastitis model. In cultured cells, PSB4 alleviated LPS-induced inflammatory reaction by suppressing the expression of pro-inflammatory mediators in BMECs. Notably, RNA-seq analysis indicated that the anti-inflammatory effect of PSB4 was correlated with IL-17RA and NF-κB signaling, with subsequent Western blot validation. Moreover, BMECs were stimulated with recombinant interleukin-17A (rIL-17A) to induce inflammation and challenged with Taltz to specifically inhibit IL-17RA signaling. The results showed that PSB4 reversed the rIL-17A-induced upregulation of elements within the IL-17RA pathway and its downstream MAPK/NF-κB cascade, including their downstream effectors. Furthermore, Taltz blocked the efficacy of PSB4 in protecting against LPS-induced inflammation. In vivo, PSB4 alleviated the inflammatory damage of mammary gland, pro-inflammatory mediator levels in mammary gland tissue and se-rum, while blocking the activation of IL-17RA signal along with downstream MAPK/NF-κB signal in LPS-induced mouse mastitis model. Taken together, studies in both BMECs and mice demonstrated that PSB4 alleviates mastitis by inhibiting IL-17RA signaling and downstream MAPK/NF-κB pathway, which may be a new strategy and a target for the management of mastitis. Full article

Background: Intestinal fibrosis is a severe complication of Crohn’s disease (CD) with no effective therapies currently available. Muscleblind-like protein 1 (MBNL1) is an RNA-binding protein that has been implicated in fibrosis across multiple organs, but its role in CD-associated intestinal fibrosis remains unexplored. This study aims to investigate the expression, functional role, and underlying mechanism of MBNL1 in intestinal fibrosis. Methods: MBNL1 expression was examined in a TNBS-induced mouse model and in stenotic intestinal tissues from CD patients. In vitro, human colonic fibroblasts (CCD-18Co) were stimulated with transforming growth factor-β1 (TGF-β1) to model fibrosis. MBNL1 was knocked down or overexpressed to assess its effects on fibroblast activation, proliferation (5-ethynyl-2′-deoxyuridine, EdU; Cell Counting Kit-8, CCK-8), and apoptosis (flow cytometry). Potential downstream pathways were predicted using BioGRID and DAVID analyses and validated by Western blot. A rescue experiment with the RAS activator ML-097 was performed to confirm pathway dependency. Results: MBNL1 expression was significantly upregulated in fibrotic tissues from both the mouse model and CD patients, as well as in TGF-β1-stimulated CCD-18Co. MBNL1 knockdown suppressed TGF-β1-induced fibroblast activation and proliferation while promoting apoptosis, whereas MBNL1 overexpression had the opposite effect. Mechanistically, MBNL1 positively regulated the RAS-MAPK signaling pathway. Reactivation of this pathway with ML-097 reversed the inhibitory effects of MBNL1 knockdown on fibroblast activation and proliferation. Conclusions: MBNL1 promotes colonic fibroblast activation and proliferation by activating the RAS-MAPK signaling pathway, establishing it as a potential therapeutic target for intestinal fibrosis in Crohn’s disease. Full article

Interleukin-17A (IL-17A) is a proinflammatory cytokine that plays a pivotal role in immune responses and tissue homeostasis. Its expression is strictly regulated by transcription factors including RORγt, and it is mainly produced by Th17 cells, γδ T cells, and innate lymphoid cells. IL-17A signals through a heterodimeric receptor complex consisting of IL-17RA and IL-17RC, activating NF-κB, MAPK, and C/EBP pathways via the adaptor protein Act1. IL-17 signaling is counterbalanced by negative regulators including A20 and Regnase-1. Beyond its classical roles in antimicrobial defense and autoimmune inflammation, recent studies have highlighted its functions in the central nervous system, with associations to multiple sclerosis, autism spectrum disorder, and Alzheimer’s disease. The development of IL-17A inhibitors, including the dual IL-17A/F antagonist bimekizumab, has advanced markedly, with demonstrated efficacy in immune-mediated diseases such as psoriasis and psoriatic arthritis. This review provides a comprehensive overview of current knowledge of IL-17A, from its molecular characteristics to clinical applications. Full article

Juvenile myelomonocytic leukemia (JMML) is a rare, aggressive myeloproliferative neoplasm of early childhood characterized by constitutive activation of the RAS-MAPK signaling pathway. RASopathies are a heterogeneous group of complex genetic disorders arising from germline mutations that dysregulate RAS-MAPK signaling. Noonan syndrome, CBL syndrome, and neurofibromatosis type 1 (NF1) are the three major RASopathies predisposing to JMML. More than 90% of JMML cases harbor germline or somatic mutations in one of five canonical driver genes—PTPN11, NRAS, KRAS, NF1, or CBL—establishing JMML as the prototypical malignant manifestation of RASopathy biology. The fifth edition of the World Health Organization Classification of Tumours reclassified JMML as a myeloproliferative neoplasm while the International Consensus Classification adopted JMML under pediatric and/or germline mutation-associated disorders, introducing a JMML-like category for cases lacking five canonical mutations but harboring emerging drivers such as SH2B3::LNK alterations and ALK::ROS1 fusions. The distinction between germline and somatic mutations profoundly influences prognosis: e.g., germline PTPN11-associated myeloproliferations and many germline CBL cases undergo spontaneous resolution, whereas somatic PTPN11- and NF1-mutated JMML is more aggressive and requires prompt allogeneic hematopoietic stem cell transplantation. DNA methylation profiling has emerged as the most robust prognostic framework, with consensus defining high-, intermediate-, and low-methylation subgroups that independently predict outcome. Both genotype and DNA methylation subclassification have been integrated into clinical decision-making, incorporating pretransplant azacitidine, watch-and-wait approaches for favorable-risk patients, and emerging targeted therapies including MEK inhibitors. This review synthesizes recent advances in understanding JMML as a bona fide RASopathy; provides a diagnostic algorithm, molecular landscapes, and prognostic models; and highlights opportunities for molecularly targeted therapeutic intervention. Full article

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy, with rising incidence and a 5-year survival rate of 13%. Late presentation, early metastasis, and intrinsic resistance constrain the efficacy of cytotoxic chemotherapy, which remains the backbone of PDAC treatment, with only modest survival gains and resistance nearly universal. Although KRAS mutations dominate tumour biology (~90% of cases), PDAC is a heterogeneous disease with distinct molecular subtypes that confer differential therapeutic vulnerabilities. Advances in comprehensive molecular profiling have catalysed a paradigm shift toward precision oncology in PDAC. In KRAS-mutant PDAC, mutation-specific inhibitors have established proof-of-concept, particularly in KRAS G12C disease, while next-generation approaches including KRAS G12D inhibitors, RAS-“ON” inhibitors, proteolysis-targeting chimeras (PROTACs), and KRAS-targeted vaccine strategies are expanding the therapeutic landscape. Combination strategies targeting upstream and downstream effectors of the RAS–MAPK pathway are also being explored to enhance the depth and durability of response. In parallel, KRAS-wild-type PDAC has emerged as a molecularly distinct subgroup enriched for rare but actionable alternative oncogenic fusion drivers including NRG1, NTRK, RET, ALK, and FGFR. Additional molecularly directed strategies targeting HER2 alterations, BRAF mutations, EGFR-dependent signalling, and tumour-selectively exposed surface antigens such as CLDN18.2 are under investigation across PDAC irrespective of KRAS mutation status. Synthetic lethal approaches, including targeting the PRMT5/CDKN2A/MTAP axis, represent a further emerging therapeutic strategy. Germline homologous recombination repair defects, particularly involving BRCA1/2 and PALB2, further define clinically important subsets with sensitivity to platinum chemotherapy and PARP inhibition. This review summarises current and emerging targeted and molecularly directed therapeutic strategies in PDAC, emphasising the importance of molecular stratification and recent advances shaping precision oncology in this historically treatment-refractory disease. Full article

Pacific abalone (Haliotis discus hannai) is a widely cultured and economically important abalone species in aquaculture yet improving growth performance remains a major challenge for stable production. To clarify the molecular architecture associated with growth performance in Pacific abalone, we integrated transcriptome and genome-wide association study (GWAS) data from high-growth and low-growth groups showing significant growth differences. Transcriptome profiles from hepatopancreas and mantle tissues were used to construct a co-expression network of 43,125 genes, summarized into 22 modules associated with tissue specificity and growth-related variation. In parallel, analysis of a custom 60K SNP array identified 67 significant growth-associated SNPs. Integration of these GWAS signals into the co-expression network revealed a core module most strongly correlated with growth index and enriched for SNP-derived candidate genes. Functional enrichment indicated that the core module was associated with proteostasis and growth-related signaling pathways, including insulin, Ras, and MAPK signaling. Protein–protein interaction analysis further identified 11 hub genes with high intramodular connectivity and direct interactions with SNP-derived genes, most of which participate in receptor-mediated and intracellular growth-regulatory functions. These findings provide an integrated molecular framework for growth performance in Pacific abalone and candidate targets for future molecular breeding strategies. Full article

Postnatal loss of cardiac regenerative capacity coincides with profound remodeling of signaling, structural, and metabolic programs in the developing heart. Here, we profiled Insulin growth factor (IGF)/Fibrobrast growth factor (FGF)/insulin receptors (InsR), Ras/Raf/MEK/ERK pathway components, cytoskeletal markers, and cell-cycle/metabolic proteins in mouse whole-heart tissue at P3, P7, P14, P28, and adulthood. IGF-1R- and IGF-2R-associated signals declined sharply during maturation, whereas InsR changed more modestly. FGFR1-derived immunoreactive species showed a transient early postnatal increase before marked reduction at later stages. These receptor-associated changes paralleled strong decreases in B-Raf, MEK1, and MEK2, together with pronounced loss of MEK1/2 activation-loop phosphorylation. MEK1 Thr292 phosphorylation also declined markedly, identifying a previously unrecognized developmental phosphorylation pattern. Structural maturation was accompanied by stable Actn2 expression, downregulation of immature cytoskeletal markers, increased cytochrome c and myoglobin, and significant loss of Aurora B and phospho-histone H3 in adult hearts. Together, these findings describe a coordinated postnatal maturation program in which signaling, cytoskeletal remodeling, metabolism, and proliferative withdrawal change in parallel. These data are consistent with reduced MAPK pathway activity during maturation and highlighting this signaling as node associated with closure of the neonatal regenerative window. Full article

Chronic inflammation contributes to various metabolic and immune disorders. Plant-derived phytochemicals and fermented foods have attracted attention as dietary modulators of inflammation. This study evaluated the anti-inflammatory potential of sword bean (Canavalia gladiata) extract (CG) and its Lacticaseibacillus paracasei SKH 003-fermented derivative (CGF) in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. Cells were treated with CG or CGF (0–400 µg/mL) with or without LPS (0.1 µg/mL). Both CG and CGF significantly attenuated LPS-induced inflammatory responses while maintaining high cell viability. The extracts reduced nitric oxide (NO) and prostaglandin E₂ (PGE₂) production, suppressed mRNA expression of iNOS, COX-2, TNF-α, IL-6, IL-1β, MCP-1, and CXCL10, and upregulated IL-1Ra. Notably, CGF showed broader and stronger suppressive effects on most pro-inflammatory mediators, cytokines, and chemokines than unfermented CG, whereas IL-1Ra induction was comparable between the two extracts. Western blot analysis revealed that CGF inhibited the phosphorylation of NF-κB p65 and all three major MAPKs (p38, JNK, ERK), whereas CG showed limited effects on MAPK activation. These findings demonstrate that fermentation with the specific strain L. paracasei SKH 003 enhances the anti-inflammatory activity of sword bean extract by simultaneously targeting NF-κB and MAPK signaling pathways. Consequently, CGF holds significant potential as a functional food ingredient for managing macrophage-mediated inflammatory responses. Full article

Pediatric gastrointestinal (GI) cancers are rare malignancies that differ fundamentally from their adult counterparts in molecular drivers, histology, and clinical behavior. While adult GI cancers are frequently driven by recurrent oncogenic mutations, pediatric tumors often exhibit pathway-level dysregulation involving developmental signaling networks. Among these, the RAS/MAPK pathway emerges as a central convergent axis integrating growth factor signaling, developmental programs, inflammatory cues, and post-translational regulatory mechanisms. Increasing evidence suggests that aberrant phosphorylation dynamics result from imbalanced kinase activation and phosphatase-mediated signal attenuation, which contribute to sustained MAPK signaling in pediatric GI malignancies, even in the absence of canonical RAS or RAF mutations. This review synthesizes current knowledge on RAS/MAPK signaling in pediatric GI cancers, emphasizing the role of kinase–phosphatase imbalance, signal duration, and regulatory failure in shaping oncogenic outcomes. We highlight how altered phosphorylation control may influence tumor differentiation, therapeutic responsiveness, and resistance mechanisms, and discuss emerging opportunities for targeting signaling dynamics rather than single genetic lesions. This signaling-centric framework provides a biologically grounded rationale for functional biomarker-driven precision therapy in pediatric GI malignancies. Full article