Search Results (1,446)

Small molecule inhibitors targeting BRAF mutations at V600 and downstream MEK represent a significant advancement in treating BRAF-mutant melanoma. However, resistance mechanisms, often involving reactivation of the MAPK pathway via ERK1/2, limit their efficacy. The ERK1/2 inhibitor ravoxertinib (GDC0994) was tested on melanoma cell lines with and without resistance to BRAFi or BRAFi + MEKi. Short-term assays evaluated cell viability, apoptosis induction, and pathway modulation via Western Blot, while long-term effects were assessed using a colony formation assay. Resistant and parental melanoma cells responded to long-term ERKi treatment with reduced growth, independent of sensitivity to BRAF or MEK inhibitors. Adding ERKi to BRAFi/MEKi significantly enhanced apoptosis and growth inhibition, particularly in resistant lines. Although ravoxertinib alone showed limited antitumor activity, its combination with BRAFi/MEKi yielded substantial benefits, especially in chronic settings. These findings suggest that combinatorial regimens incorporating ERK inhibitors represent a promising therapeutic strategy for BRAF-mutant melanoma. Full article

Introduction: Gastrointestinal stromal tumors (GISTs) are primarily driven by mutations in KIT (KIT proto-oncogene receptor tyrosine kinase) or PDGFRA (platelet-derived growth factor receptor alpha), but resistance to tyrosine kinase inhibitors (TKIs) such as imatinib remains a major clinical challenge. Alterations in fibroblast growth factor receptor 2 (FGFR2), although rare, are emerging as important contributors to tumor progression and drug resistance. This review evaluates the molecular mechanisms, expression profiles, detection methods, and therapeutic implications of FGFR2 in GIST. Methods: We searched PubMed, Web of Science, Google Scholar, and ClinicalTrials.gov for studies published between January 2010 and June 2025, using combinations of keywords related to FGFR2, gastrointestinal stromal tumor, resistance mechanisms, gene fusion, amplification, polymorphisms, and targeted therapy. Eligible studies were critically assessed to distinguish GIST-specific data from evidence extrapolated from other cancers. Results:FGFR2 is expressed in multiple normal tissues and at variable levels in mesenchymal-derived tumors, including GIST. Its alterations occur in approximately 1–2% of GIST cases, most commonly as gene fusions (e.g., FGFR2::TACC2, <1%) or amplifications (1–2%); point mutations and clinically significant polymorphisms are extremely rare. These alterations activate the MAPK/ERK and PI3K/AKT pathways, contribute to bypass signaling, and enhance DNA damage repair, thereby promoting TKI resistance. Beyond mutations, mechanisms such as amplification, ligand overexpression, and microenvironmental interactions also play roles. FGFR2 alterations appear mutually exclusive with KIT/PDGFRA mutations but occasional co-occurrence has been reported. Current clinical evidence is largely limited to small cohorts, basket trials, or case reports. Conclusions:FGFR2 is an emerging oncogenic driver and biomarker of resistance in a rare subset of GISTs. Although direct evidence remains limited, particularly regarding DNA repair and polymorphisms, FGFR2-targeted therapies (e.g., erdafitinib, pemigatinib) show potential, especially in combination with TKIs or DNA-damaging agents. Future research should prioritize GIST-specific clinical trials, the development of FGFR2-driven models, and standardized molecular diagnostics to validate FGFR2 as a therapeutic target. Full article

Dendrobium officinale (Orchidaceae) is a commonly used medicinal and edible herb. Although its anti-ageing properties have been demonstrated, the underlying mechanisms remain unclear. We employed network pharmacology and molecular biology techniques to systematically explore its anti-ageing mechanisms. An ageing model was established using D-galactose-induced Kunming mice. D. officinale significantly ameliorated ageing-related symptoms, including behavioural impairment and organ index reduction. It enhanced antioxidant capacity by increasing serum T-AOC levels and restoring renal activities of key antioxidant enzymes (SOD, GSH-Px, CAT) while reducing MDA; it suppressed serum TNF-α levels, indicating anti-inflammatory effects. Histopathological examination revealed that D. officinale alleviated D-galactose-induced renal damage, including tubular cell swelling and glomerular capsule widening. Network pharmacology identified 8 core active compounds (e.g., 5,7-dihydroxyflavone, naringenin) and 10 key targets (e.g., HSP90AA1, EGFR, MAPK3). KEGG analysis highlighted pathways including neuroactive ligand–receptor interaction, cAMP signalling, and calcium signalling. Molecular docking confirmed strong binding affinities between core compounds and key targets. Western blotting and immunohistochemistry validated that D. officinale upregulated EGFR, HSP90AA1, ERK, and GAPDH expression in renal tissues. In summary, D. officinale exerts anti-ageing effects by modulating oxidative stress, suppressing inflammation, and regulating multiple signalling pathways. Our findings provide a scientific rationale for its application in anti-ageing interventions. Full article

Chronic inflammation driven by Cyclooxygenase-2 (COX-2) overexpression plays a key role in lung cancer (LC) progression, making it a critical therapeutic target. This study explores thymoquinone (TQ), a potent bioactive phytochemical derived from Nigella sativa, known for its anti-inflammatory and anti-cancer effects, focusing on its ability to suppress lipopolysaccharide (LPS)-induced COX-2 expression via microRNA hsa-miR-199a-3p modulation in LC cells. Using A549 and SHP-77 LC cells, we tested the effect of TQ under LPS stimulation and miRNA inhibition. Advanced techniques like TaqMan qPCR, luciferase reporter gene constructs, and anti-miRNA transfection confirmed that miR-199a-3p directly silences COX-2. Western blot and ELISA assays revealed that TQ dramatically reduces COX-2 protein and PGE2 levels by boosting miRNA-199a-3p. Importantly, TQ also blocked MAPK (p38, JNK, ERK) and NF-κB activation, even when miR-199a-3p was suppressed, proving its multi-targeted action beyond miRNA regulation. These findings reveal a novel anti-inflammatory mechanism, where TQ curbs COX-2-driven inflammation by enhancing miR-199a-3p, simultaneously shutting down pro-cancer MAPK/NF-κB signaling pathways. Given the strong link between chronic inflammation and LC aggressiveness, this study positions TQ as a promising therapeutic candidate, especially for inflammation-mediated lung cancer progression. Its dual ability to modulate miRNA and key signaling cascades makes it a compelling option for future LC treatment strategies. Full article

Background: Temporal lobe epilepsy (TLE), a prevalent refractory focal epilepsy frequently complicated by comorbid anxiety and depression, poses significant therapeutic challenges due to the inadequate efficacy of current antiepileptic drugs in seizure control. Carbon dots (CDs) demonstrate notable biological activities and represent a promising class of nanomedicines for TLE intervention. Methods: This study established an eco-friendly calcination protocol to synthesize a novel suspension of Crinis Carbonisatus-derived carbon dots (CC-CDs) as a candidate therapeutic for TLE. Results: In a TLE mouse model, the CC-CDs suspension significantly inhibited phosphorylation of the MAPK pathway (p-JNK, p-ERK, p-p38; p < 0.01, p < 0.05), leading to reduced levels of pro-inflammatory cytokines (IL-6, IL-1β, TNF-α; p < 0.01, p < 0.05), upregulation of TGF-β1 (p < 0.01, p < 0.05), and restoration of antioxidant enzyme activities (SOD, GSH, CAT; p < 0.01, p < 0.05). These modifications subsequently regulated the Glu/GABA balance, alleviating excitotoxicity (p < 0.05), attenuating neuronal damage and Nissl body loss in hippocampal CA1/CA3 regions, and improving cognitive function alongside reducing anxiety-like behaviors (p < 0.01, p < 0.05). In vitro, the CC-CDs suspension suppressed LPS-induced apoptosis in BV2 cells. Conclusions: The CC-CDs suspension ameliorates TLE by inhibiting MAPK signaling, thereby reducing neuroinflammation and oxidative stress, rectifying Glu/GABA imbalance, attenuating excitotoxicity, and ultimately improving behavioral deficits. These findings underscore the therapeutic potential of CC-CDs suspension for TLE treatment. Full article

Eucommia ulmoides Oliver (E. ulmoides), a traditional medicinal plant, has been widely used for its antioxidant and anti-inflammatory properties. However, its effects on dental tissue regeneration remain largely unexplored. In this study, we investigated the odontogenic potential of E. ulmoides extract in human dental pulp stem cells (hDPSCs). Cell viability was assessed using the cell counting kit-8 (CCK-8) assay, and antioxidant activity was evaluated via the DPPH radical scavenging method. Odontoblast differentiation was examined using Alizarin Red S (ARS) staining, real-time PCR, and Western blot analysis of key differentiation markers, including dentin matrix protein 1 (DMP-1) and dentin sialophosphoprotein (DSPP). Our results demonstrated that E. ulmoides extract enhanced mineralization and upregulated both gene and protein expression of odontoblast differentiation markers in a dose-dependent manner. Furthermore, signaling pathway analysis revealed that E. ulmoides extract activated the SMAD pathway while downregulating ERK and p38 MAPK phosphorylation during odontogenic differentiation. These findings suggest that E. ulmoides extract promotes odontoblast differentiation in hDPSCs and may serve as a promising natural agent for dental tissue regeneration. These findings further underscore its potential clinical relevance as a therapeutic candidate to enhance dental tissue repair and regeneration. Full article

Background: Abnormal activation of Angiotensin II (Ang II) serves as a primary trigger for myocardial hypertrophy and cardiac injury. Isoquercitrin (IQ) and Quercetin (Que) possess anti-inflammatory and anti-apoptotic properties, but their protective effects against Ang II-induced cardiac injury remain unclear. This study aimed to investigate the mechanisms and therapeutic efficacy of IQ and Que in heart failure. Methods: Cytotoxic effects of IQ and Que on Ang II-induced H9c2 rat cardiomyocyte apoptosis models were assessed in vitro using the CCK-8 assay. Reactive Oxygen Species (ROS) generation and apoptotic fluorescence levels were measured. WB analysis examined protein expression in inflammatory and apoptotic pathways. In vivo heart failure model was established in mice, with cardioprotective effects of IQ and Que evaluated via echocardiography. Molecular docking was employed to analyze ligand–target interactions. Results: IQ outperformed Que in promoting cell viability and decreasing ROS. IQ exhibited a more potent inhibitory effect on apoptosis through regulating Bax, Caspase-3, CytoC, and Bcl-2 and demonstrated superior suppression of cardiac inflammation by inhibiting phosphorylation of ERK, JNK, and P38. Compared with Que, IQ more effectively attenuated Ang II-induced cardiac injury by ameliorating reductions in EF% and FS%, suppressing ST-segment elevation, and significantly reducing serum levels of CK-MB, LDH, ANP, BNP, and FFA in a heart failure model. Molecular docking verified stronger binding affinity of IQ for key targets. Conclusions: IQ demonstrates superior cardioprotection over Que by regulating MAPK signaling and mitochondrial apoptosis pathways, supporting its potential as a therapeutic candidate for heart failure. Full article

Obesity is closely associated with the development of insulin resistance (IR) and type 2 diabetes mellitus (T2DM), primarily due to dysfunctional adipose tissue expansion and the secretion of pro-inflammatory cytokines such as interleukin-1β (IL-1β). 14-Deoxy-11,12-didehydroandrographolide (deAND), a major diterpenoid component of Andrographis paniculata, has demonstrated notable antioxidant and anti-inflammatory activities. This study aimed to investigate the protective effects and mechanisms of deAND against IL-1β-induced IR in 3T3-L1 adipocytes. Network pharmacology analysis indicated that deAND targets several IR-related signaling pathways, particularly the MAPK and IRS-1/AKT pathways. The experimental results show that IL-1β stimulated p67phox membrane translocation and reactive oxygen species (ROS) production, contributing to impaired insulin signaling by activating ERK and JNK and reducing IRS-1/AKT phosphorylation, which ultimately decreased insulin-stimulated glucose uptake. Pretreatment with deAND effectively inhibited NOX2-derived ROS generation, suppressed ERK/JNK activation, restored IRS-1/AKT phosphorylation, and reversed the reduction in glucose uptake caused by IL-1β. These findings suggest that deAND can alleviate IR by inhibiting NOX2-mediated oxidative stress, restoring insulin signaling and improving glucose uptake, highlighting its potential as a therapeutic agent for obesity-related IR. Full article

Efficient utilization of food industry waste supports sustainable development. Idesia polycarpa Maxim cake meal (an oil-processing by-product) is rich in bioactive flavonoids, but the refined purification, anti-non-small cell lung cancer (NSCLC) activity, and mechanism of its total flavonoids (IPTF) remain unclear—restricting high-value use. This study optimized IPTF purification via polyamide resin gradient elution and characterized its chemical composition by HPLC/LC-MS. In vitro assays assessed IPTF’s effects on A549 cell proliferation, migration, invasion, colony formation, and apoptosis; network pharmacology and molecular docking predicted mechanisms, validated via Western blotting for key signaling pathways. Results showed IPTF purity was significantly improved after purification; HPLC/LC-MS identified rutin, quercetin, and six minor components as key constituents. IPTF inhibited A549 proliferation, and network pharmacology indicated it synergistically targets the PI3K/AKT and EGFR-MAPK pathways—validated by reduced phosphorylation of p-AKT, p-EGFR, and p-ERK. This work offers a novel strategy for I. polycarpa cake meal valorization and highlights IPTF’s potential as a multi-target natural candidate for NSCLC therapy. Full article

Skin health is significantly impacted by factors such as melanin production, UV-induced photodamage, and wound healing. Excessive melanin leads to hyperpigmentation, while UVA radiation accelerates skin aging and oxidative stress. This study investigated the multi-functional dermatological potential of S strain LS-derived cell-free supernatant (CFS-LS) to address these concerns. Our findings demonstrate that CFS-LS effectively inhibits melanogenesis in B16F10 cells. It significantly reduced α-MSH-induced melanin synthesis, comparable to arbutin, by downregulating key melanogenic enzymes (tyrosinase, TRP-1, and TRP-2) and regulatory proteins (p-CREB, MITF, SOX9, and SOX10). Mechanistically, CFS-LS suppressed the phosphorylation of MEK, ERK, p38, and JNK, indicating a dual inhibitory effect on both PKA/CREB and MAPK pathways. Furthermore, CFS-LS mitigated UVA-induced photodamage in HaCaT cells by significantly reducing intracellular reactive oxygen species and suppressing the downstream phosphorylation of p53 and α-MSH levels. It also restored UVA-suppressed Nrf-2 and HO-1 expression, enhancing cellular antioxidant defenses. Lastly, CFS-LS promoted skin wound healing by significantly enhancing HaCaT cell migration in a scratch assay, associated with increased p-MEK1/2 and p-ERK1/2 levels, and notably elevated collagen type I synthesis. Collectively, these results highlight CFS-LS as a potent multi-functional agent for skin protection and repair, with significant potential for cosmetic and therapeutic applications. The active components of CFS-LS warrant further investigation. Full article

IGF-1 (insulin-like growth factor 1) is a growth factor primarily secreted by dermal papilla cells on hair-bearing skin that stimulates hair follicle proliferation and vascularization, and promotes the transition to the anagen growth phase of the hair follicle by activating key pathways such as PI3K/Akt and MAPK/ERK. IGF-1 also inhibits apoptosis, prolongs the follicular growth phase, and boosts VEGF expression, which supports microcirculation and nutrient delivery to hair follicles. The combined effects of IGF-1 and other growth factors, including VEGF, KGF (FGF-7), and PDGF, further amplify its effects on follicular cell proliferation and tissue repair. IGF-1’s ability to regulate the hair growth cycle and its interactions with other signaling pathways make it a compelling therapeutic target for hair loss disorders. Both preclinical models and clinical evidence highlight IGF-1 as a promising therapeutic option for conditions like androgenetic alopecia (AGA), where IGF-1 levels are typically diminished. While topical IGF-1 treatments have shown efficacy and safety with minimal systemic absorption, additional research is needed to improve delivery methods, such as liposomal gels and exosome-based carriers, and to evaluate long-term effects. Full article

Hematopoiesis is a complex process of creating new hemocytes and releasing them from hematopoietic tissue. In the present study, the hematopoietic site in oyster Crassostrea gigas was successfully identified in the proximal sector (designated G2–G3) of the gill hinge with a substantial number of newborn cells and a minor presence of stem-like cells. The homologues of VEGF (CgVEGF) and its receptor CgVEGFR were characterized, and they interacted with each other. After the oysters received an injection of rCgVEGF, the number of EdU-positive (EdU⁺) cells increased within the G2–G3 sector and the hemolymph. When the expression of CgVEGFR was inhibited by RNAi, the percentage of EdU⁺ cells in the hemolymph declined dramatically, but increased significantly in the G2–G3 sector and EdU⁺ cells aggregated in this region. Meanwhile, the phosphorylation levels of CgErk and CgJNK, mRNA transcripts of cell proliferation-related and cell migration-related genes, reduced significantly. These results indicate that the proximal region of the hinge in gill was the site producing hemocytes, and CgVEGF-VEGFR-MAPK signaling pathway induced the migration of newborn hemocytes from this site to the circulating hemolymph, which provides new clues about hematopoiesis in primary invertebrates. Full article

Low-grade-serous ovarian carcinomas (LGSOC) are rare tumors characterized by a high recurrence rate and limited treatment options. Most LGSOC are estrogen receptor (ER)-positive and demonstrate alterations in the RAS/MAPK pathway. Avutometinib is a dual RAF/MEK clamp, whereas defactinib and VS-4718 are focal adhesion kinase (FAK) inhibitors. Fulvestrant is an ER antagonist/degrader. We assessed the preclinical efficacy of fulvestrant, avutometinib + VS-4718 (FAKi), and the triple combination in a chemotherapy/aromatase inhibitor-resistant LGSOC patient-derived tumor xenograft (PDX) model. Tissue obtained from a LGSOC patient wild-type for KRAS/NRAS/BRAF mutations in progression after chemotherapy/anastrozole was transplanted into female CB17/lcrHsd-Prkdc/SCID mice (PDX-OVA(K)250). The animals were treated with either saline/control, fulvestrant, avutometinib/FAKi, or the triple combination of avutometinib/FAKi/fulvestrant. Avutometinib and FAKi were given five-days on and two-days off through oral gavage. Fulvestrant was administered subcutaneously weekly. Mechanistic studies were performed ex vivo using Western blot assays. Animals treated with the triple combination demonstrated stronger tumor growth inhibition compared to all the other experimental groups including control/saline (p < 0.001), single-agent fulvestrant (p = 0.04 from day eight and onwards), and avutometinib/FAKi (p = 0.02 from day 18). Median survival for mice treated with saline/control was 29 days while mice in all other experimental groups were alive at day 60 (p < 0.0001). Treatment was well tolerated across all experimental treatments. By Western blot, exposure of OVA(K)250 to the triple combination demonstrated a decrease in phosphorylated MEK (p-MEK) and p-ERK levels. The addition of fulvestrant to avutometinib/FAKi is well tolerated in vivo and enhances the antitumor activity of avutometinib/FAKi in a LGSOC-PDX model with acquired resistance to chemotherapy/aromatase inhibitors. These results support the clinical evaluation of avutometinib/defactinib in combination with fulvestrant or an aromatase inhibitor in patients with recurrent LGSOC. Full article

CD44, a multi-isoform adhesion receptor for hyaluronic acid (HA), plays a crucial role in regulating cell interactions with the extracellular matrix, cell migration, differentiation, and survival in both physiological and pathological contexts. Accumulating experimental evidence suggests that CD44 is not merely a passive marker of mesenchymal cell activation but rather an active signaling hub driving fibrosis in many organs, including the lung, skin, heart, and liver. Its involvement in fibroblast differentiation into myofibroblasts, as well as induction of the invasive phenotype of these cells, shows striking analogies to the mechanisms of epithelial-to-mesenchymal transition (EMT) known from cancer progression. In this paper, we discuss both the molecular mechanisms of CD44-dependent signaling (including through EGFR, MAPK/ERK, CaMKII, lipid rafts, and Smad) and the influence of its modulation (knockout, antibodies, blockade of HA synthesis) on the course of fibrosis in in vitro and in vivo models. In addition, we present the influence of environmental pollutants—such as heavy metals, particulate matter, endocrine disruptors, and microplastics—on the activation of the HA-CD44 axis in connective tissue, with particular emphasis on their role in the induction of chronic inflammation, EMT, and extracellular matrix deposition. The collected evidence suggests that CD44 serves as a central integrator of inflammatory and fibrogenic signals, and its pharmacological modulation may represent a novel therapeutic strategy for treating fibrotic diseases and chronic inflammatory conditions. Full article

The bombesin (Bn) receptor family [Gastrin-releasing peptide (GRPR/BB2R) and Neuromedin B receptors (NMBR/BB1R)] are G-protein coupled receptors (GPCR’s) with potent growth effects on normal tissues/numerous cancers, often by transactivating the ErbB receptor-tyrosine kinase (RTK) family. Whereas GRPR stimulation transactivates ErbB RTKs EGFR, HER2, and HER3 in non-small cell lung-cancer (NSCLC) cells, its effects on HER4 are unknown. This study was designed to address this question. Of 12 NSCLC’s studied, 75% had HER4 mRNA expression and Western-Blotting. NCI-H522 and NCI-H661-cells had high levels of GRPR, HER4, and the HER4-ligand neuregulin (NRG1). Adding GRP to NCI-H522/NCI-H661-cells activated HER4, shown by its increased phosphorylation (P-HER4). The GRPR antagonists PD176252/BW2258U89 inhibited this increase. In NCI-H661-cells, GRP stimulated the formation of HER4-homodimers and HER2-HER4-heterodimers. Adding GRP to these NSCLC-cells increased P-ERK/P-AKT, which was inhibited by siRNA-HER4, PD176252, and ibrutinib, as well as N-acetylcysteine and Tiron, which reduce reactive-oxygen species (ROS). GRP increased secretion of NRG1 from NSCLC-cells, and NRG1 increased P-HER4 and P-ERK, which were impaired by ibrutinib. GRP and NRG1 stimulated proliferation of NSCLC-cells, which was inhibited by PD176252, siRNA-HER4, or ibrutinib and which was mediated by MAPK, not AKT/PI3K, activation. These results show GRPR activation results in HER4 transactivation in a ROS-dependent manner, which stimulates NSCLC-growth through a MAPK-mediated mechanism. Full article