Search Results (453)

Panacis Japonici Rhizoma (PJR), a medicinal and edible herb of the Panax genus, exhibits enhanced anti-lung cancer activity after steaming, a phenomenon consistent with other Panax species. However, the active constituents responsible for this improved efficacy and their underlying mechanisms remain unclear. In this study, we integrated UPLC-Q-TOF-MS–based metabolomics, network pharmacology, molecular docking, molecular dynamics simulations, and in vitro assays to identify the key metabolites and elucidate the mechanistic basis of steamed PJR against lung cancer. Metabolomic analysis revealed ten significantly upregulated metabolites following steaming. Network pharmacology analysis identified AKT1, EGFR, HSP90AA1, SRC, and STAT3 as core targets, primarily enriched in the MAPK, PI3K-Akt, and Ras signaling pathways. Molecular docking and molecular dynamics simulations further demonstrated stable interactions between major metabolites and core targets. In vitro experiments confirmed that steamed PJR exerted markedly stronger anti-tumor effects than its raw form. Collectively, these findings indicate that steamed PJR acts through a multi-target, multi-pathway mechanism mediated by multiple bioactive constituents, highlighting its therapeutic potential in lung cancer treatment. Full article

Despite continuing improvement in the standard of care, the clinical outcomes in metastatic colorectal cancer (CRC) remain poor, especially among patients whose tumors carry activating mutations in BRAF or RAS-family oncogenes. These mutations initiate a series of oncogenic signal transduction events, known as the mitogen-activated protein kinase (MAPK) cascade. While therapeutic targeting of this pathway achieved impressive results in other malignancies, the effectiveness of this approach remains low in CRC. In the current study, we observed that inhibitors of GTP production synergize with various inhibitors of the MAPK cascade in suppressing a variety of CRC cell lines. Furthermore, we discovered that an inhibitor of guanylate biosynthesis increases the efficacy of MAPK cascade inhibitors against human CRC grown in mice. Moreover, a combination of MEK and guanylate biosynthesis inhibitors is more potent than the MEK inhibitor alone in increasing the efficacy of immune therapy in an immunocompetent mouse model. Considering that guanylate biosynthesis inhibitors are already used in clinical practice for other applications, their use in synergistic combinations with the inhibitors of the MAPK cascade may present an actionable strategy to increase the efficacy of the latter. Full article

Neurofibromatosis type 1 (NF1) predisposes to a spectrum of peripheral nerve sheath tumors, ranging from benign plexiform neurofibromas (PN) to atypical neurofibromatous neoplasms of uncertain biological potential (ANNUBP) and malignant peripheral nerve sheath tumors (MPNST). Tumorigenesis follows a multistep molecular cascade initiated by biallelic NF1 inactivation, followed by CDKN2A loss and disruption of the Polycomb Repressive Complex 2 (PRC2). These events guide chromatin remodeling, widespread epigenetic dysregulation, and activation of oncogenic pathways such as RAS/MAPK and PI3K/AKT. Here, we integrate genomic, transcriptomic, and epigenomic studies to delineate the molecular trajectories underlying tumor progression and to define promising biomarkers for the early detection of malignant transformation. Emerging liquid biopsy approaches, based on circulating tumor DNA (ctDNA) analyses, reveal distinctive copy number variations (CNVs) and methylation patterns that mirror tissue-derived profiles, enabling the detection of malignant transformation. Together, these findings support a model in which cumulative genetic and epigenetic alterations drive the PN–ANNUBP–MPNST continuum. They also underscore the value of multi-omics and liquid biopsy-based strategies to improve early diagnosis, patient risk stratification, and personalized management of NF1-associated tumors, thereby advancing precision medicine in this complex disease spectrum. Full article

Follicular-cell-derived thyroid carcinoma, while typically associated with a favorable prognosis, can undergo dedifferentiation into poorly differentiated (PDTC) or anaplastic thyroid carcinoma (ATC), leading to enhanced aggressiveness and radioiodine resistance. This review systematically examines the genetic and molecular mechanisms driving this pathological progression, highlighting the roles of key mutations—such as BRAF, RAS, TERT, and TP53—and the disregulation of signaling pathways, including MAPK and PI3K/AKT. These alterations promote the loss of thyroid-specific functions, including iodide metabolism, and correlate with poor clinical outcomes. In recent years, therapeutic strategies aimed at tumor redifferentiation have emerged as a promising approach for radioiodine-refractory disease. We summarize recent advances in the use of targeted agents, particularly BRAF and MEK inhibitors, to restore radioiodine avidity and improve treatment response. While early clinical studies show encouraging results, including tumor shrinkage and restored RAI uptake in selected patients, challenges such as treatment resistance and patient selection remain. Future efforts should focus on refining molecular stratification, developing rational combination therapies, and integrating novel modalities such as immunotherapy to overcome resistance. A deeper understanding of redifferentiation mechanisms not only provides insights into thyroid cancer progression but also supports the development of personalized treatment strategies for high-risk patients. Full article

Pepper blight, caused by Phytophthora capsici, significantly impacts plant health and reduces crop yields, resulting in severe economic losses. Developing resistant varieties and identifying resistance targets through transcriptomic sequencing, along with elucidating their underlying resistance mechanisms, represent pivotal strategies for disease control. In this study, 11 resistant pepper varieties were identified from 21 varieties; among these, the highly resistant line 19K23 and the susceptible line QM were selected for further analysis. Transcriptome sequencing of root samples from both varieties was conducted on day 2 and day 5 after inoculation with P. capsici. Analysis of differentially expressed genes between the resistant variety and susceptible variety revealed pathways such as photosynthesis, oxidoreductase activity, plant-pathogen interaction, and secondary metabolism. Six key biological processes were highlighted among the highly differentially expressed genes, with porphyrin and chlorophyll metabolism activated early in 19K23. The Ras family, MAPK signaling, hormone signal transduction, and GPI-anchor biosynthesis were implicated in resistance. Importantly, secondary metabolism and lipid metabolism pathways such as phenylpropanoid biosynthesis, isoquinoline alkaloid biosynthesis, and unsaturated fatty acid biosynthesis appeared to play pivotal roles. Additionally, cell wall synthesis and structure, as well as stress response processes, were important. These findings enhance understanding of pepper resistance mechanisms against P. capsici and offer valuable molecular insights for future research on genetic regulation and resistance breeding. Full article

Melanocyte signaling through the MAPK pathway is orchestrated by NRas and relayed downstream via multiple effectors, such as RAF, Ral, and PI3K. In spite of their significance, the molecular mechanisms of signaling relay by NRas, their dynamics, and their potential as therapeutic targets remain unclear. Using multi-color single molecule localization microscopy (PALM and dSTORM), we resolved the mutual nanoscale organization of NRas, PI3K, and BRAF at the plasma membrane of fixed and live melanoma cells. Surprisingly, NRas and its oncogenic mutation Q61R colocalized with PI3K in mutual nanoclusters, where BRAF was also frequently present. In live cells, NRas and PI3K co-clustering declined, yet persisted over minutes. Clinically relevant perturbations revealed unexpected crosstalk within these nanoclusters and consequently, between the MAPK and PI3K pathways. Specifically, overexpression of the Ras binding domain (RBD) and PI3K inhibition by wortmannin disrupted NRAS-PI3K interactions, and reduced both pAKT and pERK levels and cancer cell proliferation. MEK inhibition with trametinib resulted in similar, yet more pronounced effects. Thus, our findings provide novel insights into NRAS-mediated signaling through nanoscale clusters and underscore their potential as therapeutic targets. Full article

Arteriovenous malformations (AVMs) are fast-flow vascular malformations formed by direct artery-to-vein shunts without an intervening capillary bed, which increases the risk of hemorrhage and organ-specific damage. A synthesis of recent advances shows that AVMs arise from interplay between germline susceptibility (ENG, ACVRL1, SMAD4, RASA1, EPHB4), somatic mosaicism (KRAS, MAP2K1, PIK3CA), perturbed signaling (TGF-β/BMP, Notch, VEGF, PI3K/AKT, RAS/MAPK), hemodynamic stress, and inflammation. Multimodal imaging—digital subtraction angiography (DSA), MRI/MRA with perfusion and susceptibility sequences, CTA, Doppler ultrasound, and 3D rotational angiography—underpins diagnosis and risk stratification, while arterial spin labeling and 4D flow techniques refine hemodynamic assessment. Management is individualized and multidisciplinary, combining endovascular embolization, microsurgical resection, and stereotactic radiosurgery (SRS); a non-surgical approach and monitoring remain reasonable for some asymptomatic AVMs. Device and technique innovations (detachable-tip microcatheters, pressure-cooker approaches, and newer liquid embolics such as PHIL and Squid) have broadened candidacy, and precision-medicine strategies, including pathway-targeted pharmacotherapy, are emerging for syndromic and somatic-mutation–driven AVMs. Animal models and computational/radiomics tools increasingly guide hypothesis generation and treatment selection. We outline practical updates and future priorities: integrated genomic-imaging risk scores, genotype-informed medical therapy, rational hybrid sequencing, and long-term outcome standards focused on hemorrhage prevention and quality of life. Full article

Background/Objective: Colon cancer, the third most diagnosed cancer worldwide, is anatomically classified into right- and left-sided colon cancers based on embryonic origin and vascular supply. The aim of this study was to investigate molecular differences between patients with right- and left-sided colon cancer. Methods: In this pilot study, Blood samples from right-sided (n = 6) and left-sided (n = 6) colon cancer patients, as well as healthy controls (n = 6), were analyzed for 92 cancer-related genes via RT-qPCR. KEGG pathway analysis was performed with ShinyGO 0.82, and gene–metabolite interactions were assessed using EnrichR and MetaboAnalyst 6.0. Additionally, patients’ sociodemographic and clinical data were analyzed. Results: KEGG analysis revealed that p53, HIF-1, TNF, PI3K/Akt, MAPK, and Rap1 signaling pathways were enriched in right-sided colon cancer, whereas VEGF, HIF-1, MAPK, PI3K/Akt, Rap1, and Ras signaling pathways were implicated in left-sided colon cancer. In the gene–metabolite analysis, key metabolites identified in right-sided colon cancer included palmitic acid, adenosine triphosphate (ATP), glycerol, and adenosine diphosphate (ADP), associated with genes such as ACSL4, TP53, MAPK14, FLT1, AURKA, KDR, ERCC3, and PFKL. For left-sided colon cancer, glucose-6-phosphate (G6P), ATP, ADP, glycerol, and palmitoyl-CoA were key metabolites forming the basis of the gene–metabolite network, along with genes including G6PD, PFKL, MAPK14, FLT1, CDK4, AURKA, MAP2K1, ERCC3, TP53, WEE1, and GPD2. Conclusions: These findings highlight distinct molecular profiles between right- and left-sided colon cancers, particularly in pathways related to angiogenesis, apoptosis, ferroptosis, and fatty acid metabolism, which may inform therapeutic strategies. Full article

Carfilzomib (CFZ) is a cornerstone in the treatment of relapsed multiple myeloma (MM). However, its efficacy is limited by resistance mediated by the overexpression of the ABC-transporter P-glycoprotein (P-gp). The signaling pathways driving the emergence of P-gp in MM remain unclear. To investigate this, we generated CFZ-resistant AMO-1/CFZ cells with P-gp overexpression by long-term selection. RNA sequencing of control AMO-1 and AMO-1/CFZ, sorted into two subpopulations, P-gp HIGH and P-gp LOW, implicated the Ras/MEK/ERK pathway as the most likely signaling cascade involved in P-gp upregulation. We therefore evaluated two clinically used MAPK pathway inhibitors, cobimetinib and ulixertinib, for their ability to re-sensitize AMO-1/CFZ cells to CFZ. Co-administration at non-toxic concentrations enhanced sensitivity 5-fold with cobimetinib and 17-fold with ulixertinib. Analysis of the combined MTT assay results, rhodamine efflux experiments, molecular docking, and Western blotting revealed distinct actions. Ulixertinib primarily functions as a potent direct P-gp inhibitor. Conversely, non-toxic concentrations of cobimetinib sensitizes cells by suppressing MAPK signaling, though it also exhibits P-gp inhibition at higher concentrations. At the IC₅₀ concentration, both inhibitors reduced P-gp expression. In conclusion, combining CFZ with MAPK pathway inhibitors like cobimetinib or ulixertinib represents a promising strategy to overcome P-gp-mediated resistance in MM. Full article

Residential radon is a leading environmental cause of lung cancer, but circulating biomarkers linking home exposure to pathogenic biology are not well defined. We conducted an exposure-contrast study in Hang Dong District, Chiang Mai, measuring indoor radon in 48 homes and enrolling adults from <50 Bq/m³ (low) and ≥100 Bq/m³ (high) households for serum profiling. Mean indoor radon was 61.8 ± 18.4 Bq/m³ (range 34–126), with 6.2% of homes ≥100 Bq/m³. Small RNA sequencing identified 55 differentially expressed miRNAs (12 up, 43 down) in high-radon serum. Notably, miR-200b-3p, miR-200c-3p, and miR-194-5p were increased, while miR-3913-5p, miR-584-5p, miR-30a-3p, miR-22-3p, and miR-125a-5p were decreased. Target enrichment (KEGG/GO) implicated PI3K–Akt and MAPK hubs with Ras/Wnt/VEGF alongside focal adhesion/ECM–receptor/actin–cytoskeleton and immune-regulatory modules. Untargeted LC–MS metabolomics showed exposure-aligned shifts: higher PUFAs and oxylipins (e.g., AA, EPA; 9-HEPE, 8-HETE, 5,12-DiHETE), elevated acyl-carnitines (β-oxidation), and increased inosine/hypoxanthine, consistent with lipid/steroid remodeling, mitochondrial fuel reprogramming, oxidative stress, and nucleotide turnover. Integrated interpretation supports DDR/ATM → PI3K/Akt–MAPK activation with EMT/adhesion remodeling, angiogenic signaling, and immune modulation—linking residential radon to lung cancer mechanisms. Given the small sample size (n = 10), these findings should be interpreted as preliminary and hypothesis-generating, warranting validation in larger cohorts. Nevertheless, findings support household testing, remediation at ≥100 Bq/m³, and integrated exposure studies considering PM2.5 co-exposures. Full article

Background: Adolescents and young adults (AYA) with papillary thyroid carcinoma (PTC) often present with more extensive cervical lymph node metastasis (LNM) than older adults (AD). We aimed to identify age-associated molecular and immune features that might explain this phenotype and to explore potential translational implications for managing aggressive AYA PTC. Methods: We analyzed clinical and transcriptomic data from 501 PTC cases in The Cancer Genome Atlas (TCGA), stratified as AYA (<30 years, n = 64) and AD (≥30 years, n = 437). An institutional RNA-seq cohort (n = 13; 7 AYA, 6 AD) was used to screen for differentially expressed genes (DEGs). DEGs were defined by p ≤ 0.05 and |log2 fold change| ≥ 1. Intersection with invasion- and dissemination-related gene sets yielded a final age-related DEG list. Functional enrichment (GO/KEGG via DAVID), PPI network analysis (STRING, Cytoscape/cytoHubba), and immune deconvolution (CIBERSORT LM22) were performed. Protein-level validation was carried out by immunohistochemistry (IHC) in an independent cohort (n = 56; 28 AYA, 28 AD). Statistical comparisons used chi-square/Fisher’s exact tests for categorical variables, t-tests or nonparametric tests for continuous variables, and EdgeR with FDR correction for transcriptomic analyses. Results: In TCGA, LNM was more frequent in AYA than in AD (62.1% vs. 47.8%, p = 0.031). From intersected analyses, we identified 239 core DEGs distinguishing highly invasive, age-related tumors. Key upregulated genes in AYA included CXCR4, OPCML and S100A2; downregulated genes included ATP1A3, CHL1, HLA-DRA and IL-1β. Enriched pathways involved extracellular matrix organization, cell adhesion, calcium signaling and canonical oncogenic cascades (PI3K-Akt, MAPK, Wnt, Ras). Immune deconvolution showed reduced naïve B cells, M1 and M2 macrophages and resting mast cells and an increased proportion of M0 macrophages in AYA tumors. IHC validated differential protein expression for seven markers. Collectively, the data indicate an immune-suppressed, immune-excluded microenvironment in AYA PTC. Conclusions: AYA PTC exhibits distinct molecular and immune features that may underlie its propensity for lymphatic dissemination. These findings support evaluation of translational strategies, such as CXCR4 inhibition, restoration of antigen presentation, and macrophage reprogramming, to convert “cold” tumors into immune-permissive lesions. Validation in larger, prospective, multicenter cohorts is required. Full article

Colorectal cancer (CRC) classification has progressed from consensus molecular subtypes (CMS) to epithelial–intrinsic consensus molecular subtypes (iCMS) and the layered intrinsic subtype-MSI-fibrosis (IMF) system that combines intrinsic state, MSI status, and fibrosis. This article reviews biological underpinnings of iCMS/IMF, their relationships to tumor-microenvironment crosstalk, and how single-cell and spatial transcriptomics refine therapeutic stratification by resolving tumor microenvironment heterogeneity and its impact on fibrosis. Prognostic and therapeutic implications are covered, including PD-1 blockade in MSI-high (MSI-H), MAPK-directed therapy in BRAF-mutant disease, and EGFR targeting in selected RAS wild-type (WT) left-sided tumors, and we suggest decision points specifically informed by the activity of the fibrosis axis. A step-by-step procedure is presented for the analysis of bulk and single-cell RNA and formalin-fixed, paraffin-embedded (FFPE) resources, along with open-source tools and reporting standards to make iCMS/IMF calling reproducible in clinics and trials. Future outlooks are outlined with near-term biomarker–drug hypotheses for microsatellite-stable (MSS)-iCMS3 and high fibrosis tumors and key gaps to close for clinical translation. This review outlines a roadmap for precision medicine in colorectal cancer by leveraging the iCMS/IMF framework to integrate pathology and digital pathology, molecular diagnostics, and therapy mapping with FAP-targeted imaging and therapy. Full article

Di(2-ethylhexyl) phthalate (DEHP), a widely employed exogenous plasticizer, has become pervasive in the environment and living organisms due to its extensive use in food packaging, medical devices, and daily consumer products, and is established as a typical endocrine-disrupting chemical. Growing evidence indicates a strong association between DEHP exposure and the incidence of chronic bone disorders, including osteoporosis (OP), osteoarthritis (OA), and osteonecrosis of the femoral head (ONFH). However, the molecular mechanisms underlying its pathogenic effects across these diseases remain poorly defined. In this study, we applied an environmental network toxicology approach to integrate predicted protein targets of DEHP with known disease-associated targets of the three bone disorders using multiple databases. Through Venn analysis, protein–protein interaction (PPI) network construction, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, we identified core targets and key signaling pathways. Molecular docking and molecular dynamics (MD) simulations were further employed to validate the binding modes and stability between DEHP and the core targets, thereby elucidating common and distinct mechanisms of DEHP across these bone diseases. A total of 109 overlapping targets of DEHP and the three bone diseases were identified, among which 7 core targets—AKT1, SRC, ESR1, CASP3, MMP9, BCL2, and BCL2L1—were common to all three disorders. These are implicated in critical biological processes such as apoptosis regulation, inflammation, extracellular matrix degradation, and estrogen signaling. KEGG enrichment analysis revealed significant involvement of the PI3K-Akt, MAPK, Ras, TNF, and estrogen signaling pathways across all three diseases. Molecular docking and MD simulations confirmed stable binding of DEHP to key targets including AKT1, ESR1, and MMP9, supporting its potential to disrupt bone metabolic homeostasis via multi-target and multi-pathway mechanisms. Further analysis indicated that DEHP exerts both shared and disease-specific effects: it disrupts osteoblast/osteoclast balance in OP, amplifies inflammatory responses and matrix degradation in OA, and contributes to impaired angiogenesis and osteocyte necrosis in ONFH. This study systematically reveals how DEHP disrupts bone homeostasis through a multi-target and multi-pathway network, constructing a cross-disease osteotoxicity framework. It is the first to delineate the common and distinct molecular mechanisms of DEHP in OP, OA, and ONFH. Although these insights are derived from computational models and require further experimental validation, they provide a novel theoretical basis for combined intervention strategies targeting multiple bone diseases and for environmental health risk assessment. Full article

RASopathies are a heterogeneous group of genetic syndromes caused by germline mutations in genes encoding proteins of the RAS/MAPK pathway, which are essential in the regulation of cell proliferation, differentiation and survival. Although characterized by common phenotypic manifestations such as craniofacial dysmorphism, congenital heart defects, and growth retardation, an aspect of great clinical relevance is the increased risk of sudden cardiac death, especially in relation to hypertrophic cardiomyopathy (HCM) and ventricular arrhythmias. Pathogenic variants in genes such as RAF1, RIT1, PTPN11, BRAF and SHOC2 have been associated with phenotypes with increased incidence of HCM, sometimes with early onset and a rapidly evolving course. The literature highlights the importance of early identification of patients at risk; however, specific surveillance protocols and follow-up strategies are defined in expert guidelines. This literature review aims to provide an updated overview of the main RASopathies with cardiac involvement, highlighting the genotype-phenotype correlations, the pathogenic mechanisms underlying sudden cardiac death, and current diagnosis, monitoring, and prevention strategies. The aim is to promote greater clinical awareness and encourage a multidisciplinary approach aimed at reducing mortality in these rare genetic conditions. Full article

Neurodegenerative disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), stroke, and depression, are marked by progressive neuronal dysfunction and loss, yet current treatments remain largely symptomatic with limited disease-modifying efficacy. Glucagon-like peptide-1 (GLP-1), an incretin hormone traditionally associated with metabolic regulation, has emerged as a promising neuroprotective agent. Its receptor, GLP-1R, is expressed in key brain regions implicated in cognition, emotion, and motor control, including the hippocampus, frontal cortex, and substantia nigra. GLP-1R agonists (GLP-1RAs) activate multiple intracellular signaling cascades—cAMP/PKA, PI3K/Akt, and MAPK pathways—that collectively promote neuronal survival, enhance synaptic plasticity, reduce oxidative stress, inhibit apoptosis, and modulate neuroinflammation. These agents also regulate autophagy, promote remyelination, and reprogram microglial phenotypes toward anti-inflammatory states. Preclinical models have shown that GLP-1RAs reduce amyloid-β and tau pathology in AD, preserve dopaminergic neurons in PD, protect astrocytes and neural progenitors after ischemic stroke, and alleviate depressive behaviors. Notably, GLP-1RAs such as liraglutide, exenatide, and dulaglutide can cross the blood–brain barrier and have demonstrated safety and potential efficacy in early-phase clinical trials. These studies report attenuation of cortical atrophy, preservation of cerebral glucose metabolism, and improvements in quality of life, though changes in core AD biomarkers remain inconclusive. Ongoing large-scale trials (e.g., EVOKE, ELAD) are further exploring their therapeutic impact. This review consolidates the mechanistic basis and translational potential of GLP-1RAs in age-related neurodegenerative diseases, highlighting both their promise and the challenges that must be addressed in future clinical applications. Full article