Search Results (455)

Cetuximab and panitumumab are anti-EGFR monoclonal antibodies widely used for the treatment of colorectal cancers. However, due to various mechanisms of resistance to these targeted therapies, the patients’ responses vary. These resistances remain a major obstacle in treatment and overcoming them has become a key emphasis of current therapeutic strategies. Intrinsic and acquired resistance often lead to reactivation of downstream signaling pathways, mainly the RAS-RAF-MEK-ERK (MAPK pathway) and PI3K-AKT axes. Prior existing mutations in KRAS, NRAS, and BRAF result in primary resistance by constantly activating the signals, irrespective of EGFR inhibition. That said, acquired resistance manifests under therapeutic burden through the process of clonal evolution via KRAS and BRAF alterations, restoring MAPK pathway activity despite EGFR inhibition. In addition to those mutations, tumor cells exploit mechanisms independent of EGFR, such as the pathway bypass, which includes amplification of ERBB family receptors like HER2 (ERBB2) and activation of MET signaling. To overcome these resistances, novel strategies have emerged, which target multiple nodes within the oncogenic networks. Such methods include vertical pathway inhibition, multi-kinase inhibition, liquid-biopsy-guided therapy, and anti-EGFR rechallenge. Reactivation driven by secondary mutation can be prevented by targeting multiple nodes within the MAPK cascade simultaneously, which is referred to as the vertical pathway inhibition. Overall, this review underscores that overcoming therapeutic resistance requires a multidimensional approach that integrates molecular profiling, rational combination therapies, and adaptive treatment. Finally, these advances underscore the shift toward precision oncology, where therapy is tailored to tumor evolution, leading to improved response and patient outcome. Full article

Toll-like receptors (TLRs) are essential components of the innate immune system that enable host cells to sense microbial and endogenous danger signals and to initiate inflammatory and antimicrobial responses. Activation of TLRs triggers complex intracellular signaling networks that culminate in the induction of pro-inflammatory cytokines, type I interferons, and co-stimulatory molecules. In addition to the well-characterized nuclear factor κB (NF-κB) and interferon regulatory factor (IRF) pathways, mitogen-activated protein kinases (MAPKs) play a critical modulatory role in TLR signaling. MAPK/ERK kinase (MEK) inhibitors were originally developed for the treatment of cancer and are widely used in clinical oncology. Accumulating evidence indicates that pharmacological inhibition of MEK/extracellular signal regulated kinase (ERK) signaling profoundly affects immune cell function and TLR-driven responses. Depending on timing, dose, and disease context, MEK inhibition can attenuate excessive inflammation but may also interfere with protective host defense mechanisms. This duality highlights the context-dependent role of MEK/ERK signaling in infection and inflammation. In this review, I summarize current knowledge on the integration of MEK/ERK signaling into TLR-mediated innate immune responses and discuss the immunological consequences of MEK inhibition in infectious and inflammatory settings. By synthesizing mechanistic and translational studies, I aim to provide a framework for understanding MEK inhibitors as immune modulators rather than as broadly acting anti-inflammatory agents. Full article

Oxidative stress is a major contributor to the development of age-related macular degeneration (AMD), and excessive oxidative stress can induce retinal pigment epithelium (RPE) dysfunction, apoptosis, and retinal degeneration. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) is a major enzymatic source of reactive oxygen species (ROS); however, its mechanistic role in sodium iodate (NaIO₃)-induced oxidative injury remains unclear. Tetrahydrocurcumin (THC), the major metabolite of curcumin, exhibits potent antioxidant and cytoprotective activities, but its protective effects against AMD-associated retinal degeneration have not been fully elucidated. In the present study, we investigated whether THC protects against NaIO₃-induced ROS-mediated apoptosis in RPE cells through regulation of NOX2 signaling. In vitro, THC significantly attenuated NaIO₃-induced cytotoxicity and prevented apoptosis by suppressing hydrogen peroxide (H₂O₂) production and intracellular ROS accumulation in ARPE-19 cells. THC also preserved mitochondrial membrane potential by inhibiting the Src/p47^phox/NOX2 signaling pathway and subsequently attenuated mitochondria-mediated apoptotic signaling. Furthermore, THC markedly reduced the expression of apoptotic proteins, including Bax, cleaved caspase-3, and cleaved PARP, concomitantly with suppression of Ras/Raf/MEK/ERK signaling. Mechanistically, treatment with the selective NOX2 inhibitor GSK2795039 significantly attenuated NaIO₃-induced ROS accumulation and mitochondrial depolarization, while co-treatment with THC further enhanced these protective effects. In vivo, THC ameliorated NaIO₃-induced retinal structural abnormalities by preserving the outer nuclear layer (ONL), reducing caspase-3 expression, and improving pupillary light responses in mice. Collectively, these findings demonstrate that THC protects against NaIO₃-induced retinal degeneration through suppressing NOX2-dependent oxidative stress and downstream Ras/Raf/MEK/ERK-mediated apoptotic signaling, highlighting its potential as a therapeutic candidate for AMD and other oxidative stress-related retinal disorders. Full article

Multidrug resistance remains a major obstacle in gastric cancer therapy and is frequently associated with aggressive phenotypes. Although ABCG2 is a well-known drug efflux transporter, its functional contribution to paclitaxel (PTX) resistance and its relationship with ERK signaling in gastric cancer remain incompletely understood. In this study, PTX-resistant gastric cancer cell models were established through prolonged drug exposure. Resistant cells exhibited cross-resistance to cisplatin and 5-fluorouracil together with enhanced drug efflux activity, invasion capacity, spheroid formation, stemness-associated marker expression, and G0/G1 enrichment. ABCG2 expression was markedly increased in resistant cells. Stable knockdown of ABCG2 restored PTX sensitivity and significantly reduced drug efflux, invasion, spheroid formation, and stemness-associated phenotypes, while increasing apoptosis and altering cell cycle distribution. ABCG2 depletion was associated with reduced ERK phosphorylation and decreased expression of ERK downstream target genes. Pharmacological inhibition of ERK signaling similarly suppressed resistance-associated phenotypes and reduced ABCG2 expression. Whereas reactivation of ERK signaling by constitutively active MEK1 partially rescued the effects of ABCG2 depletion, restoring aggressive and multidrug-resistant phenotypes. Our findings indicate that ERK signaling functionally contributes to ABCG2-associated multidrug resistance and aggressive phenotypes in PTX-resistant gastric cancer cells. Full article

Cucurbitacin B belongs to a group of tetracyclic triterpenoids and exerts a number of biological effects, including anti-inflammatory and anticancer activities. We previously demonstrated that cucurbitacin B down-regulated tumor necrosis factor (TNF) receptor 1 (TNF-R1) expression and prevented activation of the transcription factor nuclear factor κB in response to a TNF-α stimulation. The present study shows that cucurbitacin B promoted the ectodomain shedding of TNF-R1 by generating a soluble form that accumulated in the culture medium of human lung adenocarcinoma A549 cells. Of the eight tetracyclic and pentacyclic triterpenoids consisting of an α,β-unsaturated carbonyl group that were examined, only cucurbitacin B promoted TNF-R1 ectodomain shedding. Cucurbitacin B-induced TNF-R1 shedding was attenuated by TNF-α protease inhibitor 2 and the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitor U0126, but not by the p38 MAPK inhibitor SB203580 or the c-Jun N-terminal kinase (JNK) inhibitor SP600125. Consistent with these results, cucurbitacin B promoted the rapid phosphorylation of rapidly accelerated fibrosarcoma 1 (RAF1) and ERK, but exerted minimal effects on the phosphorylation of p38 MAPK and JNK. Collectively, these results demonstrate that cucurbitacin B selectively activated the RAF1-MEK-ERK pathway, which was essential for TNF-R1 ectodomain shedding. Full article

Background: The retinal pigment epithelium (RPE) plays a pivotal role in the visual process by maintaining the blood–retina barrier, protecting the retina from oxidative stress, and regulating immune responses. Consequently, dysfunction or degeneration of the RPE is implicated in a broad spectrum of retinal disorders that lead to progressive and irreversible vision loss. In this context, inflammation of the RPE has emerged as a critical factor in the pathogenesis of retinal degenerative diseases, underscoring its dual role as both a target and mediator of retinal inflammatory processes within the retina. Objectives: This study aims to preliminarily investigate, mainly by assessment of proinflammatory cytokine gene expression and immunoblotting, the molecular mechanisms underlying RPE inflammation induced by interactions between the RPE and microglia of the central nervous system. Methods/Results: Using in vitro models of human RPE cells, the ARPE 19 cell line was exposed to conditioned media from microglia (CHME-5 cell line) under basal and proinflammatory conditions. We observed increased activation of the MAPK signaling pathway, (evidenced by a 4-fold increase in the phosphorylation ratio of MEK and ERK) alongside elevated expression of proinflammatory cytokines, assessed by RT-PCR and immunoblotting, and a 2-fold increase in reactive oxygen species levels in RPE cells, evaluated by colorimetric assays, after exposure with conditioned media. Specifically, IL-1β and IL-8 levels increased more than 40-fold, while IL-6 expression showed a 4-fold increase compared to controls. Conclusions: These findings emphasize the central role of the RPE in retinal inflammation and suggest potential therapeutic targets to modulate immune responses and preserve retinal function. Full article

Dihydrosanguinarine (DHSA) is a naturally occurring benzo[c]phenanthridine alkaloid primarily isolated from plants of the Papaveraceae family. DHSA exhibits broad pharmacological activities, including antitumor, anti-inflammatory, hypoglycemic, neuroprotective, analgesic, anxiolytic, antiarrhythmic, and antimicrobial effects. Mechanistically, DHSA regulates multiple signaling pathways and molecular targets, including TMEM16A, p53, Ras/Raf/MEK/ERK, PI3K/AKT, NF-κB, PPARγ, GABA_A receptors, and voltage-gated sodium channels. Compared with its biosynthetic precursor sanguinarine (SA), DHSA exhibits a comparatively favorable safety profile while retaining considerable biological activity. Pharmacokinetic studies further suggest that DHSA possesses acceptable membrane permeability, gastrointestinal absorption potential, enterohepatic circulation characteristics, and sustained systemic exposure. In addition, structure–activity relationship (SAR) and electrostatic surface potential (ESP) analyses indicate that the chemically accessible C6 position may provide opportunities for rational structural optimization. Nevertheless, the clinical translation of DHSA still faces several challenges. Therefore, this review systematically summarizes the physicochemical properties, pharmacological activities, molecular mechanisms, SAR characteristics, ESP distribution, toxicity, pharmacokinetic behavior, and clinical prospects of DHSA, aiming to provide a theoretical basis for its future drug development and translational application. Full article

Pancreatic tumors frequently exhibit calcification, suggesting potential osteogenic-related phenotypic plasticity. This study aimed to systematically evaluate whether pancreatic ductal adenocarcinoma (PDAC) cells acquire osteogenic-like features under induction conditions and to assess the associated phenotypic and molecular changes. PDAC cell lines and non-malignant pancreatic epithelial cells were subjected to osteogenic induction. Mineralization, alkaline phosphatase (ALP) activity, osteogenic marker expression, and malignant phenotypes were evaluated. RNA sequencing was performed at defined time points to characterize transcriptional changes. Pharmacological inhibition of MEK and siRNA-mediated knockdown of RUNX2 were applied to examine the involvement of MAPK–ERK signaling and downstream transcriptional regulation. Osteogenic induction led to calcium deposition and increased ALP activity in a subset of PDAC cell lines, accompanied by upregulation of osteogenic-associated markers, including RUNX2 and SPP1. Induced cells exhibited reduced migration, clonogenicity, invasion, and proliferation. Transcriptomic analysis revealed activation of osteogenesis-related and calcium-transport pathways, along with downregulation of cell cycle programs. MAPK–ERK signaling was activated during induction, and MEK inhibition attenuated RUNX2 and ALP expression as well as mineralization-associated changes. Furthermore, RUNX2 knockdown reduced ALP expression and mineralization levels, indicating its contribution to the osteogenic-like phenotype. PDAC cells can acquire osteogenic-like features under defined induction conditions, accompanied by coordinated transcriptional reprogramming and reduced malignant phenotypes. The observed mineralization-associated phenotypes may reflect a combination of active processes and passive calcium deposition. In addition, the MAPK–ERK–RUNX2 axis appears to be involved in this process, although it may reflect a broader adaptive or stress-associated reprogramming rather than lineage commitment. These findings provide insight into the potential relationship between tumor calcification and phenotypic plasticity in PDAC. Full article

Uterine leiomyoma (UL) is characterized by excessive proliferation, extracellular matrix accumulation, and inflammatory activation, yet its upstream regulatory mechanisms remain incompletely defined. Here, we investigated the role of METTL3-associated signaling in mediating the anti-leiomyoma effects of quercetin. Quercetin significantly inhibited proliferation and induced apoptosis in UL cells, accompanied by suppression of inflammatory cytokine production. Transcriptomic profiling revealed that METTL3 silencing was associated with enrichment of MAPK and inflammation-related pathways. Mechanistically, quercetin downregulated METTL3 expression and suppressed phosphorylation of MEK, ERK, JNK, and p38, whereas METTL3 overexpression partially reversed these effects, supporting a functional role of METTL3 in mediating MAPK pathway activation. Consistently, METTL3 knockdown recapitulated the anti-proliferative, pro-apoptotic, and anti-inflammatory effects of quercetin. In a hormone-induced UL rat model, quercetin attenuated uterine enlargement, fibrosis, and proliferative activity, accompanied by decreased METTL3 expression and MAPK activation. Collectively, these findings demonstrate that quercetin suppresses UL progression, at least in part, through modulation of METTL3-mediated MAPK signaling, highlighting METTL3 as a critical regulatory node and a potential therapeutic target in UL. 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

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

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

(1) Different classes of antidepressant drugs have been shown to activate lysophosphatidic acid (LPA) receptors, but their effects on the receptor signaling stimulated by LPA have not been fully investigated. In the present study, we examined the effect of the tricyclic antidepressant amitriptyline on the LPA-induced activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and Rho signaling in C6 glioma cells and cultured rat astrocytes. (2) LPA receptor signaling was investigated by using Western blot and microscopic immunofluorescence assays. Rho activation was determined by a pull-down assay. (3) Amitriptyline potentiated the LPA-induced activation of ERK1/2 signaling, as indicated by the more than additive increases in the phosphorylation/activation of key components of this pathway including fibroblast growth factor 1 receptor, MEK1/2, ERK1/2, Elk-1, and cyclic AMP response element binding protein (CREB). Amitriptyline also enhanced the expression of brain-derived neurotrophic factor (BDNF) elicited by LPA. In contrast, the antidepressant failed to mimic the LPA-induced activation of Rho and Rho-dependent responses, such as the reversal of astrocyte stellation, accumulation of stress fibers, and the phosphorylation of focal adhesion kinase and myosin target subunit of myosin phosphatase isoform 1. Moreover, when combined with LPA, amitriptyline curtailed Rho activation and the Rho-mediated cellular responses. (4) These results demonstrate that in astroglial cells, amitriptyline exerts a balanced action on LPA-activated receptors by enhancing the neuroprotective ERK1/2-CREB-BDNF signaling and dampening the potentially detrimental Rho–ROCK pathway, and suggest that this unique property may contribute to the antidepressant activity of the drug. Full article

Chronic liver diseases, including fibrosis and hepatocellular carcinoma (HCC), are primarily driven by oxidative stress, yet traditional antioxidant therapies often lack the specificity and efficacy required for clinical success. This review evaluates the emerging therapeutic potential of two atypical globins, cytoglobin (CYGB) and neuroglobin (NGB), exploring their unique hexacoordinated heme structures that enable potent reactive oxygen and nitrogen species (ROS/RNS) scavenging and redox-regulated signaling. We summarize a broad range of in vitro and in vivo evidence demonstrating that these globins deactivate hepatic stellate cells, reduce extracellular matrix accumulation, and function as tumor suppressors by modulating pathways such as Raf/MEK/ERK and NRF2. In human cohorts, CYGB expression levels inversely correlate with the progression of Metabolic Dysfunction-Associated Steatohepatitis (MASH) and HCC, highlighting its potential as a clinical biomarker. Furthermore, recombinant protein therapies involving CYGB and NGB show promise in promoting collagen degradation and inhibiting malignant transformation. We conclude that CYGB and NGB represent sophisticated catalytic redox regulators that offer a novel therapeutic paradigm for restoring redox homeostasis. While delivery and pharmacokinetic barriers remain, these globins are highly promising candidates for first-in-class biologics in hepatology. Full article

Targeted therapies are reshaping oncology by enabling treatment selection based on actionable molecular alterations, improving precision, and reducing unnecessary toxicity. This review provides an up-to-date overview of current targeted treatment modalities and the medicinal chemistry principles that support their discovery and optimization. We synthesize evidence on small-molecule and biologic strategies spanning receptor and non-receptor kinases and their major signaling axes (PI3K-AKT-mTOR and RAS-RAF-MEK-ERK), apoptosis regulation (BCL-2 family), DNA repair via poly(ADP-ribose) polymerase (PARP) inhibition, and epigenetic or metabolic targets including histone deacetylases (HDACs), bromodomain and extra-terminal proteins (BET), and mutant isocitrate dehydrogenases (IDH1/2). Across these areas, we summarize recurrent resistance mechanisms and the rationale for combination or sequential approaches. Biologic targeted therapy is discussed in parallel, including immune checkpoint blockade, antibody–drug conjugates, bispecific antibodies (BsAb), and cell therapies such as chimeric antigen receptor T cells, with emphasis on biomarker-guided patient stratification. Finally, we outline emerging directions beyond canonical nodes, including modulation of the p53-MDM2/MDM4 axis, ferroptosis control through AIFM2/FSP1, and innate immune pathways such as CD47-SIRPa and the stimulator of interferon genes (STING). Overall, the field is shifting from single-target inhibition toward integrated strategies that combine precise molecular targeting with an understanding of signaling network dynamics, resistance evolution, and therapeutic vulnerabilities. Full article