Search Results (4,329)

Triple-negative breast cancer (TNBC) remains one of the most challenging subtypes of breast cancer to treat, defined by its molecular heterogeneity, absence of hormone receptors, and poor clinical outcomes. While this difficulty with cancer cells persists even in the presence of chemotherapy and immune checkpoint inhibitors (ICIs), one critical factor linked to both chemoresistance and immune escape is autophagy. Autophagy is a cellular process with lysosomal recycling function. In TNBC, autophagy paradoxically shifts from tumor-suppressive to a tumor-promoting role. Autophagy was initially known to maintain genomic stability and alleviate oxidative damage. In TNBC, cancer cells use autophagy to detoxify platinum-induced DNA. damage, clear damaged mitochondria via mitophagy, recycle critical macromolecules, and sustain dormancy in cancer stem-like cells (CSCs). At the same time, the process of autophagic flux facilitates immune evasion, including PD-L1 expression stabilization, MHC-I degradation, and the establishment of an immunosuppressive tumor microenvironment (TME). The review encapsulates the progressive concepts of molecular regulation of autophagy, which involve key factors such as ULK1, VPS34, and non-coding RNAs (ncRNAs). These factors play a significant role in chemoresistance, taxanes, anthracyclines, and platinum compounds. The review also discusses various strategies for translation that aim to circumvent or suppress autophagy-mediated chemoresistance, including autophagy inhibitors, natural compounds, and nanoparticle-based formulations, with a focus on their synergistic potential with ICIs and chemotherapeutic agents. Targeting autophagy has shown considerable potential for effectively addressing chemoresistance in TNBC. Future studies should focus on addressing chemoresistance and immunoresistance through autophagy-based therapies. Full article

Uterine microbiome homeostasis and antioxidant capacity are critical for sow fertility. While high-fiber diets and N-carbamylglutamate (NCG) individually enhance sow fertility, their synergistic effects on the antioxidant status, microbiota, metabolites, and transcriptome remain unclear. Here, sows were assigned to the low-fiber (3.73%) or high-fiber (7.46% crude fiber) group, each without or with 0.05% NCG, throughout the 114-day gestation. Sex hormones and antioxidants in serum were detected. Multi-omics approaches were employed to investigate the impact of a high-fiber diet supplemented with NCG (H + N) on uterine microbiota, metabolites, and gene expression profiles. The study revealed that H + N significantly increased total antioxidant capacity (T-AOC) level in serum. Metagenomic analysis revealed an increased abundance of Clostridium disporicum in the uterine microbiota. Plasma metabolomics identified hydroxylysine as a key metabolite mediating this effect, and this metabolite was positively correlated with elevated abundance of Clostridium disporicum. Subsequent transcriptomic profiling revealed activation of the PI3K-Akt signaling pathway, closely linked to improved T-AOC level. Overall, these findings demonstrated that H + N could modulate the uterine microbiota (specifically Clostridium disporicum), increase hydroxylysine production, and activate the PI3K-Akt signaling pathway. These effects further enhanced hormonal activity and antioxidant capacity, ultimately improving sow reproductive efficiency. Full article

Non-arteritic anterior ischemic optic neuropathy (NAION) is a leading cause of sudden vision loss, yet no effective therapy exists to preserve retinal ganglion cells (RGCs) after ischemic injury. Nostoc commune (NC), an edible cyanobacterium with established antioxidant and anti-inflammatory activities, has emerged as a potential functional bioresource with relevance to ocular health. Here, we investigated the therapeutic effects of a crude aqueous extract of NC using a rodent model of anterior ischemic optic neuropathy (rAION). NC treatment significantly improved RGC survival, reduced apoptosis, attenuated macrophage and microglial activation (ED-1, Iba1), suppressed proinflammatory cytokine expression (IL-6), enhanced the reparative marker Ym1+2, and preserved optic-nerve myelination. Functionally, NC administration restored visual signaling as demonstrated by improved Flash Visual Evoked Potential amplitudes. Immunoblot analysis showed increased phosphorylation of PI3K/AKT/mTOR/p70S6K signaling components in retinal tissue following NC treatment. Proteomic profiling further demonstrated that NC extract comprises a coordinated repertoire of phycobiliproteins, antioxidant enzymes, and stress-response proteins that may collectively contribute to its biological effects. Together, these findings suggest that Nostoc commune extract may serve as a promising functional food-derived candidate for protecting RGCs and preserving visual function following ischemic optic neuropathy. Further studies are required to identify its active constituents, optimize formulation strategies, and evaluate its translational potential. Full article

Mastitis is a common disease in dairy cows, mainly caused by Staphylococcus aureus and Escherichia coli. Berberine (BBR) has antibacterial and anti-inflammatory potential, but its application is limited due to poor oral absorption and difficulty in reaching mammary tissue. To address this, this study developed a BBR-loaded composite ethosome hydrogel (BBR-CEH) to achieve targeted mammary delivery through local transdermal administration. The experimental results showed that BBR-CEH has good chemical stability and biosafety. Subsequently, a mouse mastitis model was established by intraductal injection of 50 µL of bacterial mixture (E. coli:S. aureus = 1:1, each at 1 × 10⁷ CFU/mL). The results showed that after BBR-CEH treatment, the mRNA expression of TNF-α (tumor necrosis factor-alpha), IL-6 (interleukin-6), and IL-1β (interleukin-1 beta) was significantly decreased, the mRNA expression of ZO-1 (zonula occludens-1), Occludin, and Claudin-4 was significantly increased, and Bax/Bcl-2 (Bcl-2-associated X protein/B-cell lymphoma 2) was significantly reduced (p < 0.01), indicating alleviation of mastitis by reducing inflammation, improving tight junctions, and inhibiting apoptosis. Finally, network pharmacology and in vivo experiments confirmed that its mechanism involves the NF-κB (nuclear factor kappa-B) and PI3K/Akt (phosphoinositide 3-kinase/protein kinase B) pathways. Thus, topical BBR-CEH may represent a promising new strategy for mastitis treatment. Full article

With limited therapeutic progress despite aggressive multimodal treatment, glioblastoma (GBM) remains one of the deadliest primary brain tumors. Emerging evidence suggests that GSCs are key drivers of tumor initiation, intratumoral heterogeneity, therapeutic resistance, and recurrence. GSCs retain self-renewal capacity, multilineage differentiation potential, and remarkable plasticity, enabling them to adapt to diverse microenvironmental cues. These properties are upheld by dysregulated developmental and oncogenic signaling pathways, including Notch, Wnt/β-catenin, Hedgehog, PI3K/AKT/mTOR, and STAT3, as well as epigenetic and metabolic reprogramming. In addition, dedicated niches such as hypoxic and perivascular microenvironments critically support GSC maintenance and immune evasion. In this review, we summarize the current understanding of the molecular pathways governing GSC biology, examine their interactions with the tumor microenvironment, and discuss emerging therapeutic strategies targeting GSCs, including pathway inhibition, differentiation therapy, immunotherapy, and nanomedicine-based drug delivery. We highlight key challenges and future directions for translating GSC-targeted approaches into effective clinical interventions for GBM. Full article

Dickkopf-1 (DKK1) is a 266-amino-acid secreted glycoprotein originally identified as a high-affinity antagonist of the canonical Wnt/β-catenin signaling pathway and has emerged as a complex regulator in oncology. While historically considered as a tumor suppressor due to its ability to abrogate Wnt-driven proliferation, recent discoveries highlight a paradoxical pro-oncogenic role across various malignancies. The molecular mechanisms by which DKK1 promotes tumor progression, metastasis, and immune evasion are driven by its interaction with cell-surface receptors, specifically LRP5/6 and CKAP4. The DKK1-CKAP4 axis independently activates PI3K/AKT signaling, facilitating epithelial–mesenchymal transition (EMT), chemoresistance, and the formation of osteolytic bone lesions. Furthermore, DKK1 serves as a critical orchestrator of the tumor microenvironment (TME) by driving comprehensive immune reprogramming. It mediates the recruitment of myeloid-derived suppressor cells (MDSCs) and inactivates cytotoxic CD8⁺ T cells and natural killer (NK) cells, thereby fostering an immunosuppressive tumor microenvironment and resistance to checkpoint inhibitors. Interestingly, cancer-associated fibroblasts (CAFs) are a primary source of DKK1 in the stroma, where they facilitate immune evasion. Clinically, elevated circulating DKK1 levels correlate with advanced disease stages, increased metastatic potential, and poor overall survival in solid and hematological tumors. When used in combination with established biomarkers, serum DKK1 levels demonstrate significant utility for early detection and therapeutic monitoring. Given its intricate impact on malignancy, DKK1 has become a promising therapeutic target, with ongoing clinical trials investigating neutralizing antibodies such as DKN-01 to disrupt its oncogenic and immunosuppressive signaling. Understanding the context-dependent nature of DKK1 signaling remains essential for refining its application as both a biomarker and a component of emerging precision immunotherapy strategies. By prioritizing the literature from the last decade, this review characterizes DKK1 as a key mediator of tumor progression and immune reprogramming, while assessing its clinical potential as a biomarker and therapeutic target. Full article

Chronic kidney disease (CKD) is a progressive global health challenge. While empagliflozin, a selective SGLT2 inhibitor, is known to attenuate CKD progression through mechanisms beyond glycemic control, the precise molecular pathways remain incompletely characterized and warrant further investigation. This study employed an integrated network pharmacology and molecular docking approach to elucidate the multi-target mechanisms of empagliflozin in CKD. Initial evaluation demonstrated that empagliflozin exhibits favorable physicochemical properties, drug-likeness, and ADMET profiles, supporting its potential as an effective orally administered therapeutic option for CKD management. Network analysis identified 221 shared molecular targets between empagliflozin and CKD-associated genes. Topological analysis of the protein–protein interaction (PPI) network revealed ten critical hub proteins—GAPDH, IL6, EGFR, HSP90AA1, NFKB1, HSP90AB1, MTOR, MAPK3, IL2, and PIK3CA—which serve as key regulators in CKD pathophysiology. Gene Ontology and KEGG pathway enrichment analyses indicated that these shared targets are significantly involved in phosphorylation, signal transduction, and central signaling cascades associated with CKD progression, including the PI3K-Akt, FoxO, HIF-1, and AGE-RAGE pathways. Molecular docking simulations corroborated empagliflozin’s multi-target affinity, demonstrating particularly strong binding energies toward HSP90AB1 (−10.85 kcal/mol), MAPK3 (−9.46 kcal/mol), and EGFR (−9.38 kcal/mol). Empagliflozin maintained stable hydrogen bonding throughout the 200-ns molecular dynamics simulation, primarily with GLN18, GLU42, SER45, ASN46, ASN101, GLY130, and TYR134, underscoring its persistent and well-anchored interaction with HSP90AB1. Collectively, these findings provide crucial mechanistic insights, suggesting that empagliflozin might exerts therapeutic effects by modulating interconnected pathways regulating inflammation, oxidative stress, and metabolic homeostasis, thereby reinforcing its role as a comprehensive, multi-target therapeutic strategy for CKD management. Nonetheless, validation through in vitro experiments remains necessary. Full article

This study aimed to investigate the effects of pterostilbene (PTE) on the intestinal barrier function, antioxidant capacity, lipid metabolism, and microbial and metabolite homeostasis of suckling piglets via its action on breast milk. Findings indicate that PTE supplementation enhanced the antioxidant status of mature milk and strengthened intestinal barrier function in piglets. Specifically, PTE enhanced intestinal antioxidant status and fatty acid β-oxidation in piglets by regulating the PI3K-AKT and SIRT1-Nrf2/Keap1 signaling pathways. 16S rDNA sequencing and Liquid Chromatography–Mass Spectroscopy (LC–MS) identified breast milk and gut microbiota and their metabolites, respectively. Results indicate that PTE significantly elevated levels of amino acid derivatives in colostrum (Glutathione Reducedform (GSH) and N-acetyl-L-glutamate (NAG)), whilst concurrently reducing levels of glycerophospholipid-related metabolites in both colostrum and mature milk (p < 0.05). Moreover, PTE supplementation markedly altered the composition of the colonic mucosal microbiota in piglets, with Faecalibacterium, Mucispirillum and Ruminococcus identified as key beneficial microbial markers of the colonic mucosa. Combined multi-omics revealed strong correlations in microbial community composition between mature milk and the colon, identifying glycerophospholipid metabolism as a key metabolic pathway that may be associated with the regulatory effects of PTE on milk and the piglet colon. In conclusion, the PTE supplement can improve the quality of breast milk and have a positive impact on the intestinal homeostasis of the offspring. Full article

Thyroid cancer is the most common malignancy of the endocrine system and represents a biologically heterogeneous disease driven by the interplay between endocrine regulation, oncogenic signaling pathways, and tumor microenvironment dynamics. Although most follicular cell-derived thyroid cancers follow an indolent clinical course, a subset progresses toward aggressive, therapy-refractory phenotypes, underscoring the need for refined molecular understanding and improved biomarkers. This review comprehensively examines the molecular determinants of thyroid cancer progression, with particular emphasis on Thyroid Hormone (TH) signaling, the Mitogen-Activated Protein Kinase (MAPK) and Phosphoinositide 3-Kinase (PI3K)/AKT pathways, and the emerging role of microRNAs (miRNAs). We discuss how oncogenic alterations, most notably the ^V600EBRAF mutation, act as central drivers of tumor initiation and aggressiveness by sustaining MAPK/ERK signaling, promoting dedifferentiation, metabolic reprogramming, immune evasion, and resistance to targeted therapies. The cooperative role of PI3K/AKT signaling in reinforcing survival, invasion, and treatment resistance is highlighted, emphasizing the network-level integration of oncogenic pathways rather than linear dependency on single drivers. In parallel, thyroid hormones exert context-dependent effects on tumor biology through both genomic actions mediated by nuclear thyroid hormone receptors and non-genomic mechanisms initiated at the integrin αvβ3 receptor, linking endocrine status to cancer progression and therapeutic response. Finally, we review the expanding evidence supporting miRNAs as critical regulators of thyroid carcinogenesis and as promising diagnostic, prognostic, and predictive biomarkers. The clinical validation of miRNA-based panels and circulating miRNAs offers new opportunities to improve preoperative risk stratification, reduce overtreatment, and guide personalized therapeutic strategies. Collectively, these insights support a multidimensional framework for understanding thyroid cancer progression and highlight future directions for precision oncology. Full article

Ubiquitin-specific protease 13 (USP13) is a deubiquitinating enzyme that stabilizes phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a well-established tumor suppressor involved in PI3K/AKT signaling. This study aimed to evaluate the relationship between USP13 immunohistochemical staining intensity and clinicopathological factors associated with prostate cancer progression. USP13 staining was scored as grade 0 (negative), 1 (weak), 2 (moderate), or 3 (strong) in 242 prostate cancer tissues and 22 adjacent non-neoplastic control tissues. Higher USP13 grades were exhibited by adjacent non-neoplastic tissues than prostate carcinoma. In comparison, lower USP13 grades were observed in 88.6% of the neoplastic regions (p < 0.001). No differences in PSA level, Gleason’s score, disease stage, involvement of either the seminal vesicle or lymph nodes, surgical margin positivity, biochemical or clinical recurrence rates, or overall survival statistics were found. Cox proportional hazards modeling showed no significant association between USP13 expression and biochemical recurrence-free survival or overall survival. Kaplan–Meier analysis demonstrated no statistically significant differences in survival outcomes according to USP13 expression, although a descriptive trend was observed. USP13 immunohistochemical staining distinguished malignant prostate tissue from adjacent non-neoplastic tissue in tissue microarrays. However, USP13 expression was not independently associated with pathological aggressiveness or survival outcomes in this cohort. Full article

Background: Colorectal intraepithelial neoplasia (CR-EN) is a precursor lesion of colitis-associated colorectal cancer (CAC). This study investigated the interventional effects and molecular mechanisms of Rhapontici Radix extract on CR-EN. Methods: An azoxymethane/dextran sulfate sodium (AOM/DSS)-induced mouse model of colonic intraepithelial neoplasia, bioinformatics analysis, organoid models, and HCT116 cell experiments were employed, coupled with histopathological examination, inflammatory cytokine detection, Western blot, immunofluorescence, and HPLC-MS/MS. Results: The results showed that the YAP/AKT-PI3K signaling pathway is aberrantly activated in CRC. Rhapontici Radix extract ameliorated colonic pathology, suppressed inflammatory responses, and remodeled gut microbiota composition in model mice. The extract selectively inhibited the proliferation of CR-EN organoids by downregulating Ki67 and β-catenin while upregulating p53, and suppressed the proliferation, colony formation, and migration of HCT116 cells. Mechanistically, the extract modulated the YAP/PI3K/AKT pathway by upregulating phosphorylated YAP (p-YAP) and downregulating phosphorylated AKT (p-AKT), phosphorylated PI3K (p-PI3K), and their downstream targets p-SRC and c-MYC. Conclusions: This study suggests that Rhapontici Radix extract intervenes in inflammation-associated carcinogenesis through a multi-pathway, multi-target strategy, offering potential therapeutic targets for CAC prevention and treatment. Full article

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

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