Search Results (730)

Cadmium (Cd) is an environmental toxicant that poses significant risks to food safety and public health through its bioaccumulation in the food chain. The liver is a primary target for chronic Cd toxicity, yet the system-level mechanisms, particularly in physiologically relevant swine models, remain incompletely understood. This study employed an integrated multi-omics approach to elucidate the mechanisms of Cd-exposed hepatotoxicity in weaned piglets. We combined histopathological examination, transmission electron microscopy, and transcriptome sequencing. Our results revealed severe hepatic damage, characterized by disorganized architecture, vacuolar degeneration, mitochondrial dysfunction, and autophagic activation. Network toxicology predicted 3727 potential targets of Cd-exposed liver injury, while transcriptomics identified 1092 differentially expressed genes (DEGs). Crucially, the convergent analysis of both datasets demonstrated that the PI3K-Akt signaling pathway was the central hub, pinpointing it as a pivotal mechanism in Cd-driven hepatotoxicity. Functional enrichment analyses further highlighted dysregulation in immune-inflammatory responses, lipid metabolism, and oxidative stress. Our findings provide a comprehensive systems-level perspective on chronic Cd hepatotoxicity in a translational swine model. We propose the PI3K-Akt pathway and other identified core targets (EGFR, histones, ribosomal proteins) as critical biomarkers for monitoring Cd contamination in swine production chains, offering valuable insights for environmental risk assessment and agricultural product safety. Full article

In recent years, dietary intervention has garnered significant attention for T2DM prevention and adjunctive treatment. Lentinula edodes (commonly known as shiitake mushroom), a common edible fungus, has been demonstrated to improve T2DM, primarily attributed to its main bioactive components like peptides and polysaccharides, while their synergistic characteristics are still not fully explained. Therefore, this study investigated the anti-T2DM molecular mechanisms of L. edodes peptides and polysaccharides by integrating network pharmacology and molecular docking. First, systematic searches of the PubMed and HERB databases using keywords such as “Lentinula edodes peptides”, “Lentinula edodes polysaccharides” and “T2DM” and “Lentinula edodes/shiitake mushroom” yielded 25 peptides and 14 polysaccharides. Second, network pharmacology analysis revealed 541 common interaction targets between these peptides/polysaccharides and T2DM. Topological analysis further identified nine core targets: ESR1, MAPK1, AKT1, SRC, EGFR, STAT3, JUN, PIK3CA, and PIK3R1. Third, pathway enrichment analysis showed that these core targets were significantly enriched within the PI3K-Akt signaling pathway and the AGE-RAGE signaling pathway in diabetic complications, suggesting potential anti-T2DM effects through regulation of these key pathways. Finally, molecular docking validation ensured strong binding affinities between peptides/polysaccharides and some core targets, with particularly prominent binding capacities observed for peptides VF and LDELEK with EGFR; peptides KIGSRSRFDVT, LDYGKL, and EDLRLP along with polysaccharides D-glucan and β-glucan with PIK3CA; and peptide DVFAHF with PIK3R1. In summary, this study revealed that L. edodes peptides and polysaccharides may exert synergistic anti-T2DM effects via the regulation of key signaling pathways, including the PI3K-Akt signaling pathway, EGFR tyrosine kinase inhibitor resistance, and the AGE-RAGE signaling pathway in diabetic complications, through their actions on critical targets such as ESR1, PIK3CA, and PIK3R1. These results offer a synergistic mechanism for the anti-T2DM effect of L. edodes, which could be helpful for the development of functional foods and drugs derived from L. edodes. Full article

Background: Hepatocellular carcinoma (HCC) is characterized by marked intratumoral heterogeneity and poor clinical outcomes. Dysregulated ribosome biogenesis has emerged as a fundamental hallmark of tumor initiation and progression; however, the specific molecular drivers linking this machinery to HCC pathogenesis remain largely undefined. Methods: By integrating multi-omics data from the TCGA and ICGC cohorts, FBLL1 was identified as a key prognostic candidate gene. Its cellular and spatial distribution was analyzed using single-cell RNA sequencing and spatial transcriptomics. Its biological functions in vitro and in vivo were validated through functional experiments, including lentivirus-mediated ectopic expression and siRNA-mediated gene knockdown. Finally, its molecular mechanism was elucidated through transcriptomic analysis and Western blotting. Results: FBLL1 was significantly upregulated in HCC and correlated with poor patient survival. Spatial and single-cell analyses showed that FBLL1 expression was preferentially enriched in malignant hepatocytes within the tumor region. Functionally, knockdown FBLL1 could inhibit the proliferation and clonogenic capacity of HCC cells, while overexpression FBLL1 in non-tumorigenic hepatocytes could promote the tumorigenic phenotype in xenograft models. Transcriptomic analysis indicated that FBLL1 overexpression was associated with the synergistic upregulation of c-Myc and multiple EGFR ligands, as well as decreased expression of hepatocyte functional markers. Consistently, modulation of FBLL1 expression affected the activity of the EGFR–MAPK signaling pathway. Conclusions: Our study identifies FBLL1 as a previously unrecognized regulator associated with malignant state transition in HCC. Rather than acting as a direct regulator of core signaling components, FBLL1 is associated with ligand-dependent activation of the EGFR–MAPK pathway in conjunction with c-Myc upregulation. These findings indicate that FBLL1 represents a promising therapeutic target for disrupting oncogenic signaling programs in liver cancer. Full article

One new pyridinone alkaloid pseudogymnone A (1) and one new tricyclic polyketide penijanthinone C (2), together with six known compounds, harzianic acid (3), 3-methyl-2-(2-nonenyl)-4(1H)-quinolinone (4), emodic acid (5), alaternin (6), violaceol-I (7), and violaceol-II (8), were obtained from the Cordyceps-colonizing fungus Pseudogymnoascus roseus. The structures and absolute configurations of the isolated compounds were elucidated through a combination of NMR and MS spectroscopic analyses, ECD calculations, and X-ray crystallography. Compound 3 exhibited obvious cytotoxicity against A549 (IC₅₀ = 4.2 µM) and MGC (IC₅₀ = 3.8 µM) cell lines. Integrated network pharmacology and molecular docking analyses indicated that compound 3 exerts potential anti-gastric-cancer effects by modulating multiple cancer-related signaling pathways, with EGFR identified as a potential target of compound 3. Full article

Adult astrocytomas, particularly IDH1/IDH2-wildtype infiltrating astrocytic gliomas, represent a significant challenge for medical professionals. Despite recent progress in understanding tumor biology and the use of molecular biomarkers, therapeutic options have not significantly improved patient outcomes. Although targeted therapies, such as small-molecule tyrosine kinase inhibitors (TKIs), have shown benefits in other solid tumors, they have largely failed to improve survival in adult astrocytoma patients. Characterized by remarkable heterogeneity, these tumors develop robust drug resistance mechanisms. The molecular processes driving this resistance are complex and not yet fully understood. In this review, we briefly present the growth factor receptors (GFRs) and their signaling pathways in adult astrocytomas and discuss the known mechanisms of resistance to small-molecule tyrosine kinase inhibitors. Full article

Epigallocatechin-3-gallate (EGCG), the major bioactive polyphenol in green tea, has garnered significant attention for its potential anticancer properties. This review summarizes the current evidence from in vitro, in vivo, and clinical trials examining the effects of EGCG on lung cancer. EGCG exerts its anticancer effects through various mechanisms, including the inhibition of cell proliferation, induction of apoptosis, suppression of metastasis, and modulation of signalling pathways such as epidermal growth factor receptor (EGFR), phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), mitogen-activated protein kinase (MAPK), and nuclear factor kappa B (NF-κB). Additionally, EGCG has been shown to enhance the efficacy of conventional chemotherapeutic agents and mitigate drug resistance. However, challenges related to its bioavailability and metabolic stability remain. Ultimately, this review aims to provide a comprehensive overview of the effects of EGCG against lung cancer. Full article

Inflammatory bowel disease (IBD) is characterized by excessive oxidative stress, mitochondrial dysfunction, and persistent activation of pro-inflammatory signaling pathways. Danthron, a natural anthraquinone derivative from rhubarb, has been reported to possess anti-inflammatory and antioxidant properties, yet its regulatory mechanisms in intestinal inflammation remain unclear. In this study, we combined network pharmacology, transcriptomic profiling, cell-based assays, intestinal organoids, and a dextran sulfate sodium (DSS)-induced colitis model to determine the protective effects of Danthron against oxidative injury. Integrated target prediction and RNA-seq analysis identified EGFR–PI3K–AKT and Nrf2–HO-1 as key signaling axes modulated by Danthron. In macrophages and intestinal epithelial cells, Danthron markedly suppressed LPS- or H₂O₂-induced ROS accumulation, lipid peroxidation, and mitochondrial membrane potential collapse, while restoring superoxide dismutase activity and reducing malondialdehyde levels. Danthron also inhibited M1 macrophage polarization, preserved epithelial tight-junction proteins, and maintained transepithelial electrical resistance. CETSA, DARTS, and molecular docking confirmed direct engagement of Danthron with components of both the EGFR–PI3K–AKT and Nrf2–HO-1 pathways. In vivo, Danthron significantly ameliorated DSS-induced colitis, reducing inflammatory cytokines, epithelial apoptosis, oxidative stress, and myeloid cell infiltration while improving mucosal architecture and enhancing organoid regenerative capacity. These findings demonstrate that Danthron exerts potent antioxidant and anti-inflammatory effects through coordinated inhibition of EGFR–PI3K–AKT signaling and activation of the Nrf2–HO-1 axis, suggesting its promise as a multi-target therapeutic candidate for IBD. Full article

Colorectal cancer (CRC) remains a major cause of cancer-related deaths in advanced disease, and activating KRAS/NRAS mutations limit the use of anti-EGFR antibodies to RAS–wild-type tumors. The cellular prion protein (PrP^C) has been linked to aggressive and chemoresistant CRC, but its extracellular partners and functional relevance in KRAS-mutant disease are not fully defined. Here, we examined extracellular PrP^C complexes and PrP^C-associated signaling in CRC cell lines and xenografts using a neutralizing PrP^C monoclonal antibody. Across a CRC panel that included SNU-C5/WT and its 5-fluorouracil- and oxaliplatin-resistant derivatives, HT-29 (KRAS–wild-type), and HCT-8 and LoVo (KRAS-mutant), co-immunoprecipitation showed that PrP^C forms complexes with the 37/67 kDa laminin receptor (RPSA), with PrP^C–RPSA association particularly increased in KRAS-mutant HCT-8 and LoVo cells. PrP^C protein levels were higher in KRAS-mutant HCT-8, SW620, and SNU-407 cells than in HT-29, and PrP^C neutralization reduced viability in all four lines. Accordingly, we assessed upstream RAS activity and found that active RAS (RAS-GTP) was higher in KRAS-mutant cells than in HT-29, and PrP^C treatment was associated with reduced RAS-GTP levels. In the same KRAS-mutant setting, basal AKT phosphorylation exceeded that in HT-29, and PrP^C treatment lowered AKT phosphorylation without changing total AKT. Moreover, PrP^C treatment was associated with reduced ERK1/2 phosphorylation in KRAS-mutant cells, suggesting attenuation of downstream RAS pathway output. These signaling changes coincided with a decrease in the S-phase fraction and an increase in G1. In an HCT-8 (KRAS G13D) xenograft model, PrP^C monotherapy inhibited tumor growth in a dose-dependent manner, and 5-fluorouracil (5-FU) monotherapy produced an intermediate effect. The combination of PrP^C (10 mg/kg) and 5-FU (20 mg/kg) yielded the greatest tumor growth inhibition among the tested regimens. Consistent with this enhanced tumor control, immunofluorescence of xenograft tissues showed that PrP^C, particularly with 5-FU, reduced intratumoral PrP^C and PCNA and decreased CD31-positive microvessels and α-SMA–positive vessel structures. Taken together, these findings suggest that extracellular PrP^C supports RAS–AKT signaling, proliferation, and tumor-associated angiogenesis in KRAS-mutant colorectal cancer, and that PrP^C neutralization additively enhances 5-fluorouracil activity in KRAS-mutant models. The data provide a preclinical basis for evaluating PrP^C antibodies in combination with fluoropyrimidine-based regimens in patients with KRAS-mutant CRC. Full article

Background: Colorectal cancer (CRC) demonstrates substantial clinical and biological diversity across age groups, ancestral backgrounds, and treatment settings, alongside a rising incidence of early-onset disease (EOCRC). The mitogen-activated protein kinase (MAPK) pathway is a major driver of CRC development and therapy response; however, the distribution and prognostic value of MAPK alterations across distinct patient subgroups remain unclear. Methods: We analyzed 2515 CRC tumors with harmonized demographic, clinical, genomic, and treatment metadata. Patients were stratified by ancestry (Hispanic/Latino [H/L] vs. non-Hispanic White [NHW]), age at diagnosis (early-onset [EO] vs. late-onset [LO]), and FOLFOX chemotherapy exposure. MAPK pathway alterations were identified using a curated gene set encompassing canonical EGFR-RAS-RAF-MEK-ERK signaling components and regulatory nodes. Conversational artificial intelligence (AI-HOPE and AI-HOPE-MAPK) enabled natural language-driven cohort construction and exploratory analytics; findings were validated using Fisher’s exact testing, chi-square analyses, and Kaplan–Meier survival estimates. Results: MAPK pathway disruption demonstrated marked heterogeneity across ancestry and treatment contexts. Among EO H/L patients, FGFR3, NF1, and RPS6KA6 mutations were significantly enriched in tumors not receiving FOLFOX, whereas PDGFRB alterations were more frequent in FOLFOX-treated EO H/L tumors relative to EO NHW counterparts. In late-onset H/L disease, NTRK2 and PDGFRB mutations were more common in non-FOLFOX tumors. Distinct MAPK-associated alterations were also observed among NHW patients, particularly in non-FOLFOX settings, including AKT3, FGF4, RRAS2, CRKL, DUSP4, JUN, MAPK1, RRAS, and SOS1. Survival analyses provided borderline evidence that MAPK alterations may be linked to improved overall survival in treated EO NHW patients. Conversational AI markedly accelerated analytic throughput and multi-parameter discovery. Conclusions: Although MAPK alterations are pervasive in CRC, their distribution varies meaningfully by ancestry, age, and treatment exposure. These findings highlight NF1, MAPK3, RPS6KA4, and PDGFRB as potential biomarkers in EOCRC and H/L patients, supporting the need for ancestry-aware precision oncology approaches. Full article

Background: Lung adenocarcinoma in non-smoking women represents a distinct clinical entity that cannot be fully explained by traditional exposure-centered carcinogenic models. Although ambient air pollution is a recognized risk factor, sex-specific vulnerability suggests the involvement of additional biological modulators shaping inflammatory, immune, and proliferative responses. Main body: In this conceptual review, we integrate epidemiological, experimental, and mechanistic evidence to propose a multisystem framework of lung carcinogenesis in non-smoking women. We delineate a central carcinogenic spine encompassing lung epithelial injury, chronic inflammation, growth factor signaling activation—particularly epidermal growth factor receptor (EGFR) pathways—and tumor microenvironment remodeling. Within this framework, three interacting domains function as biological modulators that amplify carcinogenic processes: chemosensory–neural–immune modulation, hormonal–endocrine signaling including estrogen–EGFR crosstalk, and psychosocial stress–hypothalamic–pituitary–adrenal (HPA) axis dysregulation. These domains converge through feedback mechanisms that reinforce systemic dysregulation and tumor-promoting microenvironments. Implications: This integrative model provides a biologically grounded perspective on female-specific vulnerability to lung adenocarcinoma and informs precision prevention, risk stratification, and ESG-informed public health strategies beyond conventional exposure reduction. Full article

HIV/AIDS continues to pose a significant global public health concern, with Sub-Saharan Africa having the highest number of people living with HIV (PLHIV). Traditional medicines have been increasingly essential in treating and managing PLHIV. Product Nkabinde (PN), a polyherbal formulation derived from traditional medicinal plants, has recently demonstrated significant potential in the treatment of HIV. This study aims to elucidate the molecular mechanisms underlying the therapeutic effects of phytochemicals identified from PN in HIV treatment, utilizing network pharmacology and molecular docking. The intersecting (common) genes of the 27 phytochemicals of PN and HIV were computed on a Venn diagram, while the protein–protein interaction (PPI) network of the intersecting genes was plotted using STRING. The hub (10) genes were computed and analyzed for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment pathways using ShinyGO. Molecular docking and protein–ligand interaction analysis of the 27 phytochemicals with each of the 10 hub genes were performed using the Maestro Schrodinger suite. The KEGG analysis reveals an important network with lower False Discovery Rate (FDR) values and higher fold enrichment. The pathway enrichments reveal that the 10 hub genes regulated by PN focus on immune regulation, metabolic modulation, viral comorbidity, carcinogenesis, and inflammation. GO analysis further reveals that PN plays key roles in transcription regulation, such as miRNA, responses to hormones and endogenous stimuli, oxidative stress regulation, and apoptotic signalling, kinase binding, protein kinase binding, transcription factor binding, and ubiquitin ligase binding enriched pathways. Consequently, molecular docking unveils complexes with higher binding energies, such as rutin-HSP90AA1 (−10.578), catechin-JUN (−9.512), quercetin-3-O-arabinoside-AKT1 (−9.874), rutin-EGFR (−8.127), aloin-ESR1 (−8.585), and quercetin-3-0-β-D-(6′-galloyl)-glucopyranoside-BCL2 (−7.021 kcal/mol). Overall, the results reveal pathways associated with HIV pathology and possible anti-HIV mechanisms of PN. Therefore, further in silico, in vitro, and in vivo validations are required to substantiate these findings. Full article

The mesenchymal–epithelial transition (MET) receptor is a tyrosine kinase activated by its sole known ligand, hepatocyte growth factor (HGF). MET signaling regulates key cellular processes, including proliferation, survival, migration, motility, and angiogenesis. Dysregulation and hyperactivation of this pathway are implicated in multiple malignancies, including lung, breast, colorectal, and gastrointestinal cancers. In non–small cell lung cancer (NSCLC), aberrant activation of the MET proto-oncogene contributes to 1% of known oncogenic drivers and is associated with poor clinical outcomes. Several mechanisms can induce MET hyperactivation, including MET gene amplification, transcriptional upregulation of MET or HGF, MET fusion genes, and MET exon 14 skipping mutations. Furthermore, MET pathway activation represents a frequent mechanism of acquired resistance to EGFR- and ALK-targeted tyrosine kinase inhibitors (TKIs) in EGFR- and ALK-driven NSCLCs. Although MET has long been recognized as a promising therapeutic target in NSCLC, the clinical efficacy of MET-targeted therapies has historically lagged behind that of EGFR and ALK inhibitors. Encouragingly, several MET TKIs such as capmatinib, tepotinib, and savolitinib have been approved for the treatment of MET exon 14 skipping mutations. They have also demonstrated potential in overcoming MET-driven resistance to EGFR TKIs or ALK TKIs. On 14 May 2025, the U.S. Food and Drug Administration granted accelerated approval to telisotuzumab vedotin-tllv for adult patients with locally advanced or metastatic non-squamous NSCLC whose tumors exhibit high c-Met protein overexpression and who have already received prior systemic therapy. In this review, we summarize the structure and physiological role of the MET receptor, the molecular mechanisms underlying aberrant MET activation, its contribution to acquired resistance against targeted therapies, and emerging strategies for effectively targeting MET alterations in NSCLC. Full article

Glioblastoma (GBM) is characterized by its unique molecular features, such as self-renewal and tumorigenicity of glioma stem cells that promote resistance, largely resulting in treatment failure. Among the molecular alterations significant to GBM biology and treatment, mutations in isocitrate dehydrogenase (IDH) have assumed particular relevance. IDH-mutant and IDH-wild-type tumors exhibit significantly different metabolic characteristics, clinical behavior, and therapeutic sensitivities, making IDH status a critical determinant in determining prognosis and treatment strategies for GBM. In the context of cancer, chaperones were shown to promote tumor progression by supporting malignant cells over healthy ones. While heat shock proteins (HSPs) have long been implicated in the molecular mechanisms of tumor phenotype progression, recent attention has turned to CCT (chaperonin containing TCP1), orchestrating proteostasis. The chaperonin CCT is being explored as a diagnostic and therapeutic target in many cancers, including GBM, owing to its involvement in key oncogenic signaling pathways such as Wnt, VEGF, EGFR, and PI3K/AKT/mTOR. However, its role in the GBM-tricarboxylic acid (TCA) cycle cascade is still not well understood. Therefore, the present review highlights the potential role of the CCT complex in regulating hypoxia-inducible factor (HIF) activation by modulating enzymes responsive to metabolites derived from glucose metabolism and the TCA cycle in a manner dependent on oxygen availability and IDH mutation status. Full article

Background: Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) with high efficacy in treating patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR-activating mutations. Although osimertinib is a frontline anticancer agent for NSCLC, several patients inevitably develop tumor recurrence caused by osimertinib resistance. The activation of anexelekto (AXL) or fibroblast growth factor receptor 1 (FGFR1) is reported as a major factor driving osimertinib resistance in NSCLC. Thus, targeting AXL and FGFR1 offers the potential to overcome osimertinib resistance. Methods: In this study, we generated osimertinib-resistant cell lines from EGFR-mutant NSCLC cell lines in vitro and investigated the biological significance of AX-0085 on these cell lines by conducting transcriptomic analyses. Results: The expression of several genes associated with MAPK, ERK, and FGF receptor signaling pathways, including AXL, was altered upon AX-0085 treatment of osimertinib-resistant cells. Furthermore, AX-0085 treatment effectively blocked AXL and FGFR1 activation and sensitized osimertinib-resistant cells. Additionally, AX-0085 inhibited AXL and FGFR1-dependent oncogenic events, including cell proliferation, clonogenicity, and migration. Conclusions: The dual inhibition of AXL and FGFR1 by AX-0085 can overcome acquired osimertinib resistance, supporting its potential as a therapeutic strategy for treating patients with osimertinib-resistant tumors. Full article

Background/Objectives: Signaling imbalances involving epidermal growth factor receptor (EGFR) and aldose reductase (ALR2) are frequently associated with the biology of several solid tumors, including non-small-cell lung cancer (NSCLC) and breast cancer. This work sought to prepare and investigate a small set of hydrazonylthiazole derivatives as potential modulators of both targets with relevance to cancer therapy. Methods: Thirteen compounds (1–13) were synthesized and examined for their effects on A549 (NSCLC), MCF-7 (breast cancer), and Jurkat leukemia cells, together with peripheral blood mononuclear cells (PBMCs) to determine selectivity. The most active molecules were further analyzed through apoptosis studies, EGFR and ALR2 inhibition assays, docking calculations, and 200 ns molecular dynamics (MD) simulations. SwissADME was used to estimate pharmacokinetic and drug-likeness features. Results: Among all derivatives, compound 13, prepared here for the first time, showed the strongest activity on A549 and MCF-7 cells (IC₅₀: 1.33 ± 0.41 µM; 1.74 ± 0.38 µM) and displayed a very high selectivity index (SI = 138.9). It also triggered apoptosis in A549 cells and reduced EGFR activity by 74% at 10 µM. In contrast, compound 5 acted as the most efficient ALR2 blocker (K_I = 0.08 ± 0.01 µM). MD simulations showed that both compounds maintained stable contact patterns with essential residues in the EGFR and ALR2 binding pockets. SwissADME analysis suggested suitable oral absorption and drug-likeness for both molecules. Conclusions: Compound 13 behaves as a selective EGFR-directed agent capable of inducing apoptotic cell death in NSCLC, while compound 5 shows strong affinity toward ALR2. These outcomes indicate that both structures may serve as useful starting points for further development of small molecules acting on EGFR- and ALR2-related pathways. Full article