Search Results (8,120)

Background: Translocation morphology renal cell carcinoma (tRCC) accounts for nearly half of all pediatric RCC cases. Biological study AREN14B4-Q aimed to characterize the molecular landscape of tRCC using samples acquired from patients enrolled in the Children’s Oncology Group Risk Classification and Biobanking study AREN03B2. Methods: From 2006 to 2014, patients <30 yr old with renal tumors were prospectively enrolled in AREN03B2, a Central IRB-approved biobanking study. All pediatric RCC cases underwent a detailed central pathology review and molecular diagnostics to accurately classify RCC subtypes. Samples with confirmed tRCC and appropriate informed consent were identified with adequate tissue for RNA and DNA extraction, along with germline DNA, for whole-genome sequencing (WGS), RNA sequencing, and DNA methylation analyses. Results: From 41 patients, high-quality samples allowed for 18 tumors and non-tumor DNA to be analyzed via WGS, 19 via DNA methylation, and 36 RNA samples via transcriptome sequencing. Consistent with and extending clinical cytogenetic findings, WGS and fusion transcript analyses confirmed very few additional mutations beyond the tRCC translocation. No recurrent genomic copy number gains/losses were found. RNA and WGS analyses enabled sub-classification of tRCC, closely aligning with the different TFE3 fusion partners. DNA methylation analyses demonstrated less tRCC sub-stratification compared with RNA analyses. Pathways activated in tRCC were involved in epithelial differentiation, extracellular matrix organization, apoptosis, immune regulation, signal transduction, and angiogenesis. Conclusions: Arrested epithelial differentiation is the overarching driver in tRCC and is strongly correlated with the specific subclasses of fusion transcript generated by the genetic translocation TFE fusion partner. Negative regulation of apoptosis, increased M2 macrophage expression, and enhanced angiogenesis also appear to be functional features of tRCCs, as are increased expression of matrix metalloproteinases, PI3K-AKT/mTOR/MAPK signaling, and mitochondrial metabolism, highlighting potential therapeutic options beyond direct targeting of the oncogenic driver fusions. Full article

This study aims to investigate the potential anticancer effects of erucin, an isothiocyanate derived from Eruca sativa, in triple-negative breast cancer (TNBC) by predicting molecular targets and evaluating its in vitro effects on TNBC cell proliferation, apoptosis and cell cycle distribution. Potential protein targets of erucin were identified using SwissTargetPrediction, resulting in 117 targets, of which 84 overlapped with TNBC-related genes sourced from GeneCards, DisGeNET, and OMIM. Protein–protein interaction analysis was performed to identify key hub genes. In vitro experiments were conducted using MDA-MB-231 TNBC cells to assess dose-dependent effects on cell viability. Flow cytometry was employed to evaluate apoptotic cell populations and cell cycle distribution. Protein–protein interaction analysis identified ten hub genes, including AKT1, STAT3, EGFR, and MMP9, representing highly connected nodes within the predicted interaction network. In vitro studies showed dose-dependent reduction in MDA-MB-231 cell viability following erucin treatment, with an IC₅₀ of approximately 48.87 µg/mL. Flow cytometry revealed increased apoptotic cell population and G1 phase accumulation. These findings suggest that erucin is associated with cytotoxic and antiproliferative effects in TNBC cells and may interact with multiple cancer-related targets. However, the identified molecular targets and pathways are based on computational predictions and require further experimental validation. Overall, this study provides a preliminary integrated framework linking computational predictions with experimental observations, which may support future mechanistic and preclinical investigations of erucin in TNBC. Full article

Trastuzumab is the first humanised monoclonal antibody (Mab) developed for breast cancer (BC) therapy. The high affinity of Trastuzumab Fab-domain binding to the human epidermal growth factor receptor 2 (HER2) receptor, with a K_d value of <1 nM, is also accompanied by Fc domain interaction with Fc-receptors in natural killer cells and leukocytes, enabling the killing of tumour cells through antibody-directed cellular cytotoxicity (ADCC). Trastuzumab blocks the over-expressed HER2 receptor-mediated dimerization and consequent intracellular signalling, leading to cancerous growth. However, the trastuzumab resistance (TR) became the major problem within 1 year of treatment. The mutation in phosphatidylinositol 3′-kinase (PI3K) pathway, cross-talk with estrogen receptors, over-expression of Mucin 1 (MUC1) protein, insulin-like growth factor I receptor, etc., are key pathways involved in TR. In this review, we have provided a molecular view of TR and the possible remedies for overcoming TR using BC stem cell (BCSC)-based therapy, PI3K pathway inhibitors, MUC1-based treatment, etc. We have also analysed the patents and clinical trials from the pre-TR and post-TR era to rationalise the possible steps to overcome TR. Our analysis implies that Trastuzumab monotherapy no longer applies to HER2+ BC treatment. Further, combination therapy using other antibodies like pertuzumab and protein kinase inhibitors and targeting pathways like the ubiquitin proteasome pathway will be the future option for BC Treatment. Overall, this review provides a detailed summary of the molecular mechanisms involving TR and its potential ways of evasion, based on updated information from published research articles, clinical trial outcomes, and patent data. Full article

Plant-derived exosomes (PDEs) are gaining attention owing to their key implications in cross-kingdom communication, facilitating bioactive entities among plants and animals. PDEs are tiny nanoscale vesicles generally comprised of RNAs, proteins, and secondary metabolites and are involved in the regulation of physiological processes (immune modulation, cell regeneration, and stress response). An important feature of PDEs is to enable cross-kingdom regulation in skin wound repair. This is because PDEs can modulate several signaling pathways (PI3K-Akt, TGF-β, and mitogen-activated protein kinase) that further direct inflammatory, cell migratory, angiogenic, and extracellular matrix remodeling. Key features of PDEs, including modest immunogenicity, easy crossing of biological barriers, and natural biocompatibility, make them novel alternatives to synthetic wound-healing agents. Therefore, this review disparagingly examines the biogenesis, molecular composition, and diversified biological functions of PDEs, particularly with reference to potential implications in wound healing and overall skin health. The current challenges pertaining to PDE isolation, scalability, and bioavailability and regulatory hurdles for their clinical translation were also explored. In addition, the epigenetic effects of PDEs on human skin cells and wound healing are explained in detail. Finally, this review presents a comprehensive investigation of PDEs in skin wound repair, identifies research gaps, and outlines future directions for dermatological applications. Full article

Background/Objectives: The clinical management of bladder cancer is severely impeded by high recurrence rates and the rapid emergence of chemoresistance, necessitating the discovery of novel therapeutic agents with distinct mechanisms of action. Dehydrodiisoeugenol (DHE), a bioactive neolignan, exhibits potent anti-tumor efficacy, yet its direct molecular targets and mode of action remain elusive. Methods: To deconvolute the mechanism of DHE, we integrated a phenotypic screening approach using 2D cell lines and 3D patient-derived organoids with a chemoproteomics-based activity-based protein profiling (ABPP) strategy. We synthesized a functionalized photoaffinity probe to capture the specific interactome of DHE under physiological conditions and validated targets via cellular thermal shift assays (CETSA), quantitative mass spectrometry, and 100 ns molecular dynamics (MD) simulations. Results: DHE exhibited potent dose-dependent cytotoxicity in bladder cancer cells, with IC50 values of 39.23μM in T24 and 34.58μM in 5637 cells. In 3D patient-derived organoids, DHE significantly reduced viability (p < 0.0001). Using a dual-filtering ABPP strategy, we identified 65 high-confidence candidate targets, prioritizing PTPN1 (PTP1B) as the primary functional interactor. Comparative molecular docking and 100 ns MD analyses showed that multiple stereoisomers of DHE could adopt plausible PTPN1-binding modes. Mechanistically, organoid proteomics indicated that DHE engagement with PTPN1 disrupts ER membrane homeostasis, thereby modulating the PI3K-Akt signaling axes. Conclusions: These findings establish PTPN1 as a critical druggable vulnerability in bladder cancer and define the molecular basis for the therapeutic potential of DHE. This study highlights the power of combining chemoproteomics with physiological 3D models to accelerate the translation of natural products into precision cancer therapies. Full article

Background: Midkine (MDK), a secreted heparin-binding growth factor, is involved in tumor progression and metastasis. While serum MDK is widely recognized as a potential prognostic biomarker for colorectal cancer (CRC), its specific functional role and underlying mechanisms in CRC development are not fully understood. Methods: The four publicly available CRC microarray datasets—GSE41258, GSE44076, GSE81558, and GSE117606—along with TCGA-COAD and TCGA-READ datasets and their associated clinical data were obtained. MDK expression was measured at both the mRNA and protein levels using quantitative real-time PCR (qRT-PCR) and Western blotting. To investigate its oncogenic functions, a comprehensive set of assays was performed: transwell and wound healing assays for invasion and migration; CCK-8 and colony formation assays for proliferation; and tail vein/spleen injection models combined with xenograft models to study metastasis and tumor growth in vivo. To uncover underlying mechanisms, Western blotting was used to examine the involvement of epithelial–mesenchymal transition (EMT) and the PI3K/AKT signaling pathway. Results: MDK is significantly overexpressed in CRC tissues and cells compared to normal tissues and cells. Notably, patients with high MDK levels show poorer overall survival (OS). Overexpression of MDK increases CRC invasion, migration, proliferation, and metastasis both in vivo and in vitro, while its knockdown reverses these effects. Mechanistically, MDK activates the PI3K/AKT pathway, leading to increased AP2A1 expression and promotion of EMT in CRC. Conclusions: MDK promotes invasion, migration, proliferation, metastasis, and EMT in CRC cells through the PI3K/AKT pathway by inducing AP2A1 expression, which could serve as a diagnostic marker. The PI3K inhibitor LY294002 significantly reduces AP2A1 levels and inhibits MDK-induced malignant behaviors. Targeting MDK-related signaling pathways may offer new strategies for CRC treatment. Full article

Background: Polycystic ovary syndrome (PCOS) is a complex endocrine–metabolic disorder characterized by interconnected dysregulation of steroidogenesis and insulin signaling. Multi-target therapeutic strategies are increasingly needed to address its heterogeneous pathophysiology. Methods: An integrative approach combining transcriptomic analysis of GSE137684, including stratification of normoandrogenic and hyperandrogenic PCOS subtypes to capture androgen-related heterogeneity, network pharmacology, molecular docking, and in vitro validation was employed. Principal component analysis (PCA), differential expression analysis, and enrichment analyses were used to identify candidate genes and pathways. Molecular docking evaluated interactions between phytochemicals from Cinnamomum burmannii and Myristica fragrans and key PCOS targets. Functional validation was performed in insulin-resistant 3T3-L1 adipocytes and DHEA-induced KGN cells, assessing cell viability, lipid accumulation, glucose uptake, gene expression, and hormone levels. Results: PCA revealed partial separation between PCOS and the control samples, with PC1 and PC2 explaining 44.8% and 12.5% of variance, respectively. No genes remained significant after multiple testing correction; however, nominally significant candidates (p < 0.01) highlighted pathways related to steroidogenesis and metabolic regulation. Network analysis identified key hub genes including CYP17A1, CYP19A1, AKT1, ESR1, and MAPK1. Molecular docking demonstrated strong binding affinities, with top compounds showing binding energies up to −11.4 kcal/mol (CYP17A1) and −10.9 kcal/mol (AKT1). In vitro, cell viability remained above 80% across all tested concentrations, indicating low cytotoxicity. Treatment significantly reduced lipid accumulation and enhanced glucose uptake in insulin-resistant 3T3-L1 cells (p < 0.05). Additionally, expression of AKT1 and MAPK1 was significantly restored (p < 0.05). In KGN cells, testosterone levels were significantly decreased while the estradiol levels increased (p < 0.05), accompanied by the downregulation of CYP17A1 and upregulation of CYP19A1 (p < 0.05). The combination treatment exhibited more consistent effects across metabolic and hormonal endpoints. Conclusions:Cinnamomum burmannii and Myristica fragrans exert multi-target effects on metabolic and steroidogenic pathways relevant to PCOS. This integrative study demonstrates that transcriptomics-guided network pharmacology combined with experimental validation can identify synergistic phytotherapeutic strategies for complex endocrine disorders. Full article

Periplaneta americana extract can promote wound healing and may play an important role in skin wound healing. In this study, we identified a peptide (DL-13) from Periplaneta americana L. and explored its role and mechanisms in skin wound healing. In vitro, the effects of DL-13 on proliferation, migration, and related gene/protein expression in HaCaT keratinocytes were assessed via qRT-PCR and Western blot. In vivo, rat wound healing assays confirmed its efficacy. Results showed DL-13 accelerated rat wound healing. In in vitro studies, DL-13 activated EGFR and its downstream PI3K/AKT/mTOR, ERK/MAPK, and JAK2/STAT3 pathways, upregulated EMT-related proteins (N-cadherin, MMP-2, p-FAK, β-catenin), partially regulated macrophage cytokine secretion, and promoted HaCaT proliferation/migration, thereby facilitating re-epithelialization at skin injury sites. Overall, DL-13 may enhance the function of HaCaT cells by activating the EGFR signaling pathway and regulate inflammatory factors in macrophages, thereby promoting the healing of skin wounds in rats. The results of this study will lay an experimental and scientific foundation for the discovery of new compounds for wound healing and their application. Full article

Salmonella enterica infection remains a major threat to poultry health and food safety, largely due to its ability to invade the intestinal epithelium, modulate host immunity, and persist intracellularly. Curcumin, a bioactive phytochemical, has shown promising antimicrobial and immunomodulatory potential; however, its precise molecular interplay with host and pathogen systems remains unclear. An integrated computational pipeline was applied, combining target prediction, host immune network construction, Salmonella virulence interaction analysis, STRING-based PPI mapping, KEGG/GO enrichment, and molecular docking validation. Host immune hub genes and Salmonella virulence regulators were identified, followed by docking of curcumin to key host (AKT1, STAT3, TNF) and pathogen proteins (invA, phoP, ssrB). Host network analysis revealed enrichment in the PI3K–AKT, NF-κB, FoxO, and IL-10 signaling pathways, indicating roles in epithelial protection, immune regulation, inflammation suppression, and antioxidant defense. Salmonella virulence hubs were primarily associated with epithelial invasion, Type III secretion, intracellular survival, and global virulence reg-ulation. Docking analysis demonstrated a strong binding affinity of curcumin toward AKT1 (−7.4 kcal/mol), STAT3 (−6.5 kcal/mol) and TNF (−5.8 kcal/mol), supporting host immunomodulation and epithelial protection. Simultaneously, curcumin showed notable affinity for phoP (−6.8 kcal/mol), invA (−6.3 kcal/mol), and ssrB (−5.8 kcal/mol), suggesting the potential suppression of virulence signaling, invasion machinery, and intracellular persistence. This integrated host–pathogen systems analysis demonstrates that curcumin exerts a dual regulatory effect by enhancing host immune protection while concurrently disrupting Salmonella virulence mechanisms. These findings provide mechanistic insight supporting curcumin as a promising natural therapeutic candidate for controlling Salmonella infection in broilers. Full article

Macrophage-mediated inflammation is a key driver of sepsis-induced acute lung injury (ALI). M1 macrophage polarization relies on metabolic reprogramming, yet the upstream regulatory factors remain unclear. Lysine acetyltransferase 6A (KAT6A), a MYST-family acetyltransferase, regulates transcriptional programs in immune cells, but its role in macrophage function and ALI progression remains unknown. Public single-cell and bulk transcriptomic datasets were used to assess KAT6A expression changes and its association with inflammatory and metabolic pathways in macrophages. KAT6A inhibition with WM1119 was used to evaluate effects on M1 polarization, cytokine production, metabolic reprogramming, and PI3K-AKT-mTOR signaling. The therapeutic potential of KAT6A inhibition was validated in a cecal ligation and puncture (CLP)-induced sepsis model by assessing lung injury, bacterial clearance, and survival. KAT6A expression was upregulated in sepsis and particularly enriched in M1 macrophages. Inhibition of KAT6A reduced inflammatory and glycolytic transcriptional programs, suppressed glycolysis and enhanced oxidative phosphorylation, leading to decreased cytokine production and limited M1 polarization accompanied by suppression of PI3K-AKT-mTOR pathway. In CLP-induced septic mice, treatment with the KAT6A inhibitor WM1119 alleviated lung injury, improved bacterial clearance, and prolonged survival. KAT6A expression is associated with macrophage glucose metabolism, pro-inflammatory responses, and M1 macrophage polarization in sepsis-induced acute lung injury. Pharmacologic inhibition of KAT6A may provide a promising therapeutic strategy for reducing macrophage-driven lung injury. Full article

Milk-derived exosomes (MDEs) are bioactive nanocarriers rich in microRNAs (miRNAs) that play critical roles in post-transcriptional regulation during neonatal development and immune adaptation. However, the dynamic changes in miRNA expression across lactation stages and their biological functions remain insufficiently explored. We hypothesized that the miRNA cargo of buffalo MDEs exhibits temporal specificity, thereby dynamically matching the immune requirements of the neonatal calves. Therefore, the present study aimed to systematically characterize the miRNA expression profiles of MDEs derived from colostrum, transitional milk, and mature milk. MDEs were isolated, purified using differential ultracentrifugation, and characterized via transmission electron microscopy, Western blotting, and nanoparticle-tracking analysis. A total of 370 miRNAs were identified in the MDEs, with 220 (59.5%) co-expressed across colostrum, transitional milk, and mature milk. Comparative analysis revealed that colostrum MDEs exhibited the greatest miRNA diversity. Expression patterns of miRNAs showed distinct stage-specific clustering as lactation progressed. Compared to mature milk, 100 differentially expressed miRNAs (DE-miRNAs) were identified in colostrum MDEs, including 39 upregulated and 61 downregulated miRNAs. Bioinformatics analyses indicated that predicted target genes were associated with transmembrane transport, immune response, cell development, and apoptosis. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis identified pathways involved in immune regulation, inflammation, and apoptosis. Moreover, macrophages incubated with buffalo colostrum MDEs showed upregulation of proliferation-related genes and downregulation of pro-inflammatory factors, suggesting an anti-inflammatory effect through activation of the phosphoinositide 3-kinase-protein kinase B (PI3K-Akt) signaling pathway. These findings offer new insights into miRNA profiles of buffalo MDEs across the early postpartum transition and provide a preliminary basis for exploring immunomodulatory potential of buffalo MDEs. Full article

Breast carcinoma is a major cause of cancer-related mortality among women worldwide. Identifying novel molecular targets remains essential, particularly for aggressive triple-negative breast cancer (TNBC). Leucine-rich alpha-2-glycoprotein 1 (LRG1) has been linked to tumor progression and angiogenesis, but its molecular mechanisms in breast cancer are poorly defined. We evaluated the effects of recombinant human LRG1 (rhLRG1) on cell viability and migration in MDA-MB-231 TNBC cells and performed transcriptomic profiling followed by functional enrichment analyses using GenArise, Cytoscape, and R-based tools. RhLRG1 treatment significantly increased cell viability and migration. Transcriptomic analysis revealed activation of key oncogenic cascades, including the PI3K/AKT, MAPK, and RAS signaling pathways. Hub-gene analysis identified upregulated genes involved in proliferation (NRAS, STAT5B, IGF2), angiogenesis (PGF, ANGPT2), and apoptosis (CASP8, BAD), whereas downregulated genes were associated with apoptotic resistance (BCL2, MCL1) and adhesion (LAMB1, ITGB4). Functional enrichment highlighted LRG1’s role in the bioinformatic analysis of differentially expressed genes that were obtained from microarray assays. LRG1 remodels the tumor microenvironment by promoting proliferation, angiogenesis, and apoptotic sensitivity while repressing resistance-related genes. These findings position LRG1 as a potential diagnostic biomarker and therapeutic target for advanced breast carcinoma. Full article

Multiple myeloma (MM) and osteosarcoma (OS) are two biologically distinct osseous malignancies with similar molecular networks that present translational challenges for their computational modeling. This comparative research analyzes MM and OS biology relevant to in silico approaches, focusing on PI3K-AKT-mTOR signaling, the RANK-RANKL-OPG axis, angiogenic factors (VEGF, TGFs), and immune mediators in MM, alongside the transcription factors (SOX9, RUNX2), signaling pathways (PI3K-AKT-mTOR, NOTCH), immune cell state (TAM2), and interleukins in OS. Based on this pathophysiologic foundation, the review outlines five computational paradigms: (i) mechanistic models; (ii) data-driven/machine learning schemes; (iii) hybrid mechanistic approaches; (iv) digital twins/virtual cohorts, and (v) MIDD/PBPK models for real-world applications. A cross-cancer comparison section summarizes common and distinct biological axes and their computational translation as well as the overlapping features from the bone microenvironment. For both MM and OS, the research assesses strengths, limitations, and data needs of current models, outlining the strategic objectives for next-generation multiscale, AI-enabled models providing a roadmap for tissue engineers, oncology scientists, and translational researchers to design clinically relevant preclinical tests and accelerate safer, more effective strategies for tumor-affected bones. The differences between MM and OS impose distinct biological constraints, so their comparisons are rare. Combining all these features with artificial intelligence capabilities will underpin a promising transition in the development of in silico adaptive and learning models. Full article

Keloid is a benign skin disease with excessive growth of fibroblasts, characterized by too much abnormal extracellular matrix deposited in the dermis. It is generally believed that transforming growth factor-β (TGF-β) is the core cytokine that causes keloid. Previously, it was thought that its pathogenic effect was mainly attributed to the classical Smad-dependent pathway. It directly shuttles signals to the nucleus to trigger pro-fibrotic gene transcription. However, accumulating evidence now points to the equally vital role of Smad-independent signaling. Unlike the direct nuclear translocation of Smads, these alternative pathways transmit signals through rapid intracellular kinase cascades. They jointly direct the proliferation, migration, anti-apoptosis, fibrogenesis, and chronic inflammation of fibroblasts in keloids. This review attempts to comprehensively clarify the molecular processes regulated by TGF-β through non-Smad pathways (such as MAPK, PI3K/Akt, Rho GTPase, Wnt/β-catenin, JAK/STAT). Translating these non-Smad insights helps to overcome the high recurrence rates of traditional therapies. Targeting these specific molecular hubs through combination and precision therapies serves to reprogram the fibrotic microenvironment. Full article

Background/Objectives: To investigate the therapeutic potential and mechanistic basis of Bao Jing Tablet (BJT) for chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) via an experimental autoimmune prostatitis (EAP) rat model, through integrating network pharmacology, metabolomics, proteomics, and animal experiments. Methods: UPLC-ZenoTOF 7600-MS/MS was used to analyze the chemical composition of BJT. The therapeutic effect of BJT was evaluated using an experimental autoimmune prostatitis (EAP) rat model. Lipid metabolomics, proteomics, and integrated network pharmacology analyses were performed to investigate the potential mechanisms and active components of BJT in treatment. Results: A total of 174 constituents were identified in BJT, among which 54 major active compounds were screened for further analysis. Network pharmacology and combined multi-omics analysis indicate that the protein targets of HIF-1α, Akt, and PI3K/Akt, as well as the Glycolysis pathway, play important roles in the improvement of CP/CPPS. Conclusions: Our results demonstrated that BJT was an effective drug to improve the development of CP/CPPS. This is associated with the PI3K/Akt–HIF-1α-Glycolysis pathways. Full article