Search Results (4,392)

Background/Objectives: Ulcerative colitis (UC) involves inflammatory response, oxidative stress, changes in metabolites, and the gut microbiota. Jingangteng capsule (JGTC) has been utilized clinically for the treatment of inflammatory diseases for many years. However, the efficacy of JGTC in ameliorating UC remains unclear, and the underlying mechanisms have not yet been elucidated. This study aims to investigate the effect and mechanism of JGTC on UC. Methods: The chemical compositions of JGTC were examined using ultra-high-performance liquid chromatography with quadrupole time-of-fight mass spectrometry. The anti-UC effect of JGTC was evaluated by assessing the disease activity index (DAI), colon length, intestinal barrier recovery, and inflammatory factors in a dextran sulfate sodium (DSS)-induced colitis model. Mechanisms were investigated through fecal 16S rDNA sequencing, metabolomics analysis, enzyme-linked immunosorbent assay (ELISA), Western blotting, and network pharmacology analysis. Results: JGTC significantly reduced the DAI scores in UC mice, increased their body weight and colon length (p < 0.001), repairing damaged intestinal tissue. It decreased the levels of inflammatory cytokines TNF-α, IL-6, IL-1β, and LPS (p < 0.01, p < 0.001), alleviating intestinal inflammation. It also raised the expression of tight junction proteins ZO-1, Claudin-1, and Occludin (p < 0.05, p < 0.001), thereby enhancing intestinal barrier function. Fecal metabolomic analysis revealed that the favorable alterations in amino acid and lipid metabolites were more pronounced. Heat maps showed strong correlations between pharmacological indicators and gut microbiota, as well as between the main differential metabolites and gut microbial communities. UPLC-QTOF-MS detection yielded 33 components of JGTC, and network pharmacology analysis based on these components predicted pathways of action of JGTC in UC. Functional pathways closely associated with significantly differential metabolites and metabolic pathways were also investigated. The PI3K-AKT-mTOR pathway was one of them, which is consistent with the conclusions drawn from network pharmacology. JGTC significantly modulated key factors in this pathway, inhibiting the expression of PI3K, Akt, PDK1, and mTOR, while augmenting the expression of PTEN (p < 0.05, p < 0.01, p < 0.001). It also mitigated the levels of related oxidative stress factors MDA, MPO, and D-LA, and raised SOD levels (p < 0.01, p < 0.001). Conclusions: JGTC improved the excessive inflammatory response in UC by regulating intestinal flora and metabolic disorders, affecting the PI3K-AKT-mTOR signaling pathway, restoring intestinal tissue damage and intestinal barrier, and inhibiting inflammatory and oxidative stress factors. Full article

With the widespread adoption of anonymity networks such as Tor, I2P, and JonDonym, reliably classifying darknet traffic remains challenging due to feature redundancy and severe class imbalance in encrypted flows. Existing approaches often rely on static feature-selection strategies and generic oversampling methods, which limit robustness and may distort traffic semantics. This study proposes an adaptive classification framework integrating Adaptive Weighted Feature Aggregation (AWFA) for reliability-aware feature selection and Traffic-Aware SMOTE (TA-SMOTE) for semantically constrained perturbations of packet-size and timing features while preserving flow-level structure. The framework is evaluated on a two-layer hierarchy comprising browser-level (L1) and application-level (L2) classification. At the L2, the proposed AWFA and TA-SMOTE pipeline attains a macro-F1 score of 73.81%, significantly exceeding PCA-based reduction and traditional RF-based selection with SMOTE. At the browser level (L1), macro-F1 rises from 91.58% to 96.09% while reducing the feature space from 84 to 40 attributes, highlighting both performance improvements and structural efficiency gains. Additional semantic validation confirms that the balancing process preserves the statistical and structural characteristics of genuine darknet traffic. These results indicate that reliability-aware feature aggregation and traffic-aware balancing provide a practical, trustworthy approach to modern darknet traffic classification. Full article

Animal studies have shown that early life exposure to general anesthetics may impair brain development. However, the implications of this phenomenon in human patients remain unclear. In this study, we use an induced pluripotent stem cell (iPSC)-derived human brain microphysiological system (bMPS) to investigate the effects of early sevoflurane (SEV) exposure on human brain development. Human iPSCs were cultured and differentiated into neural progenitor cells (NPCs) and then into bMPS. At week 8, bMPSs were exposed to 2.4% SEV for 4 h. Four weeks after exposure, immunofluorescence (IF), Western blotting (WB), and quantitative real-time polymerase chain reaction (qPCR) were conducted to evaluate the alteration of nerve cells in bMPS. After SEV exposure, the number of apoptotic cells increases, and the level of neural differentiation markers decreases. The ratios of mature neurons over NPCs and mature oligodendrocytes over oligodendrocyte progenitor cells (OPCs) are reduced, which leads to a reduction in myelination. SEV also impedes the development of astrocytes and synaptogenesis, especially the formation of excitatory synapses. Meanwhile, SEV increases the expression of molecules in the mammalian target of rapamycin (mTOR) signal pathway. In conclusion, early SEV exposure substantially disrupts the development of human brain tissue, and the mTOR signal pathway is likely to be involved in this alteration. Full article

Alpha-Ketoglutarate (AKG), a central intermediate of the tricarboxylic acid cycle, is a crucial metabolic and signaling molecule that connects mitochondrial function with cellular homeostasis, immunological modulation, epigenetic remodeling, and lifespan. While mitochondrial AKG maintains energy metabolism, the nuclear AKG pool influences chromatin remodeling through DNA and histone modifications, which together control hypoxia responses and shape gene expression patterns. This dual role demonstrates AKG’s significance in mediating metabolic state, gene expression, and long-term cellular adaptability. AKG modulates immunological responses, reduces reactive oxygen species (ROS), promotes the polarization of anti-inflammatory macrophages, and suppresses nuclear factor kappa B (NF-κB) activation, thereby reducing chronic inflammatory processes. AKG restricts pro-inflammatory cytokine production, increases extracellular matrix synthesis, and reduces cartilage degradation in arthritic models, suggesting potential therapeutic benefits in autoimmune diseases and joint degeneration. Additionally, AKG affects lifespan in several model organisms, where supplementation enhances metabolic resilience, lowers age-related inflammation, modifies mTOR signaling, and preserves youthful epigenetic profiles. Additionally, because endogenous AKG levels decrease with age, oral supplementation of AKG, especially with calcium and arginine, has drawn attention to its potential benefits in longevity and metabolic health. Thus, AKG is versatile and has encouraging therapeutic promise for cancer, aging, and inflammatory illnesses. However, a lack of human clinical evidence prompts further research to determine ideal dosage, tissue selectivity, and long-term safety. The goal of this review is to critically examine the current mechanistic knowledge related to AKG biosynthesis and breakdown and its future implications in maintaining cellular homeostasis and controlling chronic inflammation. Full article

In water injection development of tight oil reservoirs (TORs), the complex fracture network formed by hydraulic fracturing and water injection induction is the key factor determining the development effectiveness. Accurate inversion of water injection-induced fracture parameters holds significant importance for enhancing reservoir development outcomes. This paper innovatively proposes a parameter inversion framework that integrates the Embedded Discrete Fracture Model (EDFM) with intelligent optimization algorithms. EDFM efficiently characterizes complex unstructured fracture systems while maintaining mass conservation between the matrix and fractures; intelligent optimization algorithms automatically invert parameters such as fracture half-length, orientation, and conductivity. First, a three-dimensional geological model of the TOR is constructed, utilizing EDFM to handle the impact of fractures on the seepage field. Based on considerations of fracture geometry, conductivity, and stress sensitivity, a coupled fluid dynamics model for fractures and matrix is developed. Subsequently, an objective function is built based on water injection production dynamic data, and the Projection-Iterative-Methods-based Optimizer (PIMO) algorithm is employed to achieve efficient inversion of fracture parameters. Taking a TOR in the Ordos Basin as an example for verification, through synthetic model validation, this method significantly improves the accuracy and efficiency of history matching, with inversion results reliably guiding numerical simulation predictions. The results demonstrate that this method can effectively enhance the precision of fracture parameter identification, offering clear advantages in inversion speed and accuracy over traditional trial-and-error approaches. This study provides new insights for modeling induced fractures in TORs and optimizing water injection development strategies. Full article

Cellular homeostasis is a dynamic process which balances anabolic processes with catabolic and recycling processes. These processes require nutrients, which are converted to energy to fuel the complex interactions of intracellular signalling. Cellular health requires that, on average, energy input and energy requirements are matched. Cells contain a nutrient-sensing mechanism which controls the balance between anabolism and catabolism. Normal intracellular functions generate products which regulate signalling pathways, and health at a cellular level requires a fluctuation between relative nutrient abundance and relative nutrient scarcity. This allows clearance of damaged intracellular molecules and organelles. When nutrient supply exceeds cellular requirements, adaptations to intracellular signalling occur, resulting in energy being stored as glycogen in muscle and the liver and fatty acids in adipose tissue. Overfuelling and aberrant fuelling of mitochondria result in oxidative stress, which not only disrupts cellular homeostasis but can alter epigenetic expression, with intergenerational effects. If the recycling mechanisms of the cell are insufficient to clear metabolic products, apoptosis may result or expression of Damage-Associated Molecular Patterns (DAMPs) on the cell surface may occur, activating immunity and inflammation at a systemic level. Disrupted cellular signalling affects cells with different “professional” functions in different organs, and it is the mechanism which underlies the associations between chronic non-communicable diseases such as cancer, type 2 diabetes, cardiovascular disease, neurodegenerative disease, autoimmune diseases, and macular degeneration. Mitochondria are the controllers of energy production and are pivotal in cell signalling. Mitochondrial function governs health at cellular and organismal levels. This paper reviews the influence of nutrition on mitochondrial function, nutrient sensing, autophagy, insulin signalling, and apoptosis—the key pathways in cellular homeostasis. Full article

Background: Osteoarthritis (OA) is a multifactorial disease, including inflammation, autophagy and senescence. Published work has indicated that empagliflozin (EMP) exhibits robust anti-inflammatory and anti-senescence effects, while its role in autophagy appears paradoxical. Here, we aim to identify the chondroprotective effect of EMP on OA. Methods: An OA model was established both in vitro, by stimulating primary chondrocytes (isolated from C57BL/6J mice) with IL-1β, and in vivo, by performing (Destabilized medial meniscus) DMM surgery on C57BL/6J mice. (Western blot) WB and (quantitative real-time polymerase chain reaction) qRT-PCR analysis were employed to detect the gene expression. (Immunofluorescence) IF staining was employed to detect the expression and location of target protein. SA-β-gal staining was employed to evaluate cellular senescence. Autophagic flux was assessed using a GFP-RFP-LC3 adenoviral vector. Network pharmacology was applied to identify potential pathways for experimental validation. The effects of EMP in vivo were evaluated by μ-CT, histological and (Immunohistochemistry) IHC staining. Results: EMP promoted anabolism, inhibited the inflammatory response and catabolism in IL-1β stimulated chondrocytes. EMP enhanced autophagic activity and attenuated senescent phenotype in vitro. Mechanistically, EMP regulated the PI3K/Akt/mTOR and AMPK pathways. The chondroprotective effects of EMP were reversed by (3- methyladenine) 3-MA. EMP also ameliorated OA-related phenotype in DMM models. Compared with (Kartogenin) KGN, EMP showed more pronounced suppression of inflammatory and catabolic markers, while both compounds similarly promoted anabolic marker expression. Conclusions: These in vitro and in vivo data collectively indicates that EMP can alleviate OA both in IL-1β stimulated chondrocytes and DMM induced models. Beyond its established role in diabetes management, EMP is evaluated in the context of OA, emerging as a novel and promising therapeutic agent for OA. Full article

The anticancer ruthenium complex indazolium trans-[tetrachlorobis(1H-indazole) ruthenate (III)—also known as KP1019—inhibits cancer cell proliferation in vitro, causes tumor regression in animal models, and showed no dose-limiting toxicity in a phase I clinical trial. Previous studies found that KP1019 damages DNA in both cancer cells and the budding yeast Saccharomyces cerevisiae. To identify other potential targets of KP1019 along with pathways that modulate the drug’s cellular effects, we screened the yeast gene deletion strain library by quantitative high-throughput cell array phenotyping (Q-HTCP). Fitness differences, as judged by growth curve analysis, identified genes for which loss of function (gene deletion) interacts with (enhances or suppresses) KP1019 effects. Drug-enhancing deletions were enriched for DNA repair functions, consistent with DNA damage being a primary target of KP1019 in yeast. pH homeostasis also modified the effects of KP1019. Drug-suppressing deletions prominently involved ribosomal proteins. A mechanistic link between ribosomal protein function and KP1019 toxicity was supported by dose-dependent accumulation of Rpl7a-GFP in the nucleolus, which is a hallmark of ribosomal biogenesis stress. Furthermore, KP1019 acted synergistically with the TOR pathway inhibitor everolimus to inhibit cell proliferation. The resulting model, wherein KP1019 perturbs ribosome assembly, can inform the design of future combination therapies. Full article

Colorectal cancer (CRC) remains a leading cause of cancer morbidity and mortality worldwide, with nearly one quarter of patients presenting with metastatic disease at diagnosis. The epidermal growth factor receptor (EGFR) plays a central role in CRC pathogenesis through activation of downstream RAS/RAF/MAPK and PI3K/AKT/mTOR signaling pathways, and has become a major therapeutic target. Anti-EGFR monoclonal antibodies, cetuximab and panitumumab, have demonstrated survival benefit in selected patients, particularly those with left-sided, RAS wild-type tumors. However, primary and acquired resistance limit their efficacy, underscoring the need for predictive biomarkers and novel strategies. This review synthesizes current knowledge of EGFR biology, therapeutic integration, and biomarker development, including RAS and BRAF mutations, MSI status, HER2 amplification, EGFR ligands (AREG/EREG), consensus molecular subtypes, and liquid biopsy applications. We also discuss mechanisms of resistance such as pathway reactivation, receptor mutations, and epithelial-to-mesenchymal transition, alongside emerging approaches, including combination regimens, ctDNA-guided rechallenge, and genotype-specific inhibitors. Collectively, these insights highlight the evolving landscape of precision oncology in CRC and the importance of molecular stratification to optimize EGFR-targeted therapy and overcome resistance. Full article

Targeted therapies are reshaping oncology by enabling treatment selection based on actionable molecular alterations, improving precision, and reducing unnecessary toxicity. This review provides an up-to-date overview of current targeted treatment modalities and the medicinal chemistry principles that support their discovery and optimization. We synthesize evidence on small-molecule and biologic strategies spanning receptor and non-receptor kinases and their major signaling axes (PI3K-AKT-mTOR and RAS-RAF-MEK-ERK), apoptosis regulation (BCL-2 family), DNA repair via poly(ADP-ribose) polymerase (PARP) inhibition, and epigenetic or metabolic targets including histone deacetylases (HDACs), bromodomain and extra-terminal proteins (BET), and mutant isocitrate dehydrogenases (IDH1/2). Across these areas, we summarize recurrent resistance mechanisms and the rationale for combination or sequential approaches. Biologic targeted therapy is discussed in parallel, including immune checkpoint blockade, antibody–drug conjugates, bispecific antibodies (BsAb), and cell therapies such as chimeric antigen receptor T cells, with emphasis on biomarker-guided patient stratification. Finally, we outline emerging directions beyond canonical nodes, including modulation of the p53-MDM2/MDM4 axis, ferroptosis control through AIFM2/FSP1, and innate immune pathways such as CD47-SIRPa and the stimulator of interferon genes (STING). Overall, the field is shifting from single-target inhibition toward integrated strategies that combine precise molecular targeting with an understanding of signaling network dynamics, resistance evolution, and therapeutic vulnerabilities. Full article

Background: The ORF3 protein of swine hepatitis E virus (HEV-4) is a key virulence factor involved in viral assembly, egress, and host signaling regulation. The mammalian target of rapamycin (mTOR) pathway plays a pivotal role in autophagy, metabolism, and immunity, and is often modulated by viruses to promote replication. However, it remains unknown whether HEV-4 ORF3 modulates the mTOR pathway via circular RNAs (circRNAs). Methods: Using an adenovirus-mediated ORF3 overexpression system in HepG2 cells, we integrated circRNA and transcriptome high-throughput sequencing data, followed by KEGG enrichment analysis to identify mTOR-associated differentially expressed genes. A circRNA–miRNA regulatory network was constructed using bioinformatics tools, and the expression changes of m6A-related genes, including YTHDF3, were evaluated. Results: ORF3 overexpression significantly activated the mTOR pathway (p < 0.05) and led to the identification of 20 mTOR-related circRNAs (e.g., circRNA5142). These circRNAs regulated downstream autophagy and lipid metabolism genes by sponging miRNAs such as hsa-let-7d-5p and hsa-miR-132-3p. Altered YTHDF3 expression indicated possible m6A-dependent epitranscriptomic regulation of the mTOR pathway. Conclusions: Our integrated analysis suggests that HEV-4 ORF3 may modulate the mTOR pathway through a circRNA–miRNA network, perturbing host autophagy and metabolic balance, which may contribute to viral immune evasion. Targeting the ORF3-mediated circRNA-mTOR regulatory axis represents a promising therapeutic approach and provides a theoretical basis for novel anti-HEV-4 strategies. Full article

Kidney disease is an alarming universal health concern and a leading cause of morbidity and mortality. About 861 million individuals around the world suffer from kidney complications. However, current treatment alternatives are limited. These limitations underscore the urgent need for new therapeutic approaches. Autophagy is a dynamic and cellular housekeeping mechanism. The use of conditional autophagy-related gene knockouts in kidney cells has led to a better understanding of autophagy’s significance. Basal autophagy in the kidney serves as a quality control mechanism, vital for cellular metabolism and organelle homeostasis. Under stressful conditions, kidney cells adapt their autophagic activity. This process is intricately controlled by signaling pathways that control autophagic flux, with sirtuins, AMP-activated protein kinase (AMPK), and mammalian target of rapamycin (mTOR) acting as key regulators. Additionally, autophagy plays a role in the natural aging process of renal tissue. Small-molecule natural products have demonstrated efficacy in regulating autophagy and mitigating kidney damage in several experimental studies. However, specific mechanisms by which small molecules regulate autophagy across different renal disorders have yet to be fully understood. This study shows that the recent advancements in using small molecules in autophagy research have reignited interest in the related signaling pathways and their role in the pathophysiology of renal diseases. Further research on autophagy and its regulatory signaling networks could provide new therapeutic targets for small-molecule intervention in renal disorders. Full article

Aging is closely linked to oxidative stress and inflammation. This review provides a critical overview of the antioxidant compounds present in apple pomace and explores how they may mitigate age-related oxidative damage and inflammatory responses. We focus on the nutritional profile of apple pomace including its macro- and micronutrients, with particular focus on polyphenols, such as procyanidin tannins, quercetin glycosides (rutin, quercetin-3-glucoside), phloridzin, dietary fiber, vitamins, and lipids alongside current techniques for isolating its bioactive components. Special attention is given to biological pathways through which these compounds influence aging: redox regulation via Nrf2, inflammatory modulation via NF-κB, and metabolic regulation via AMPK, SIRT1 and PI3K/Akt/mTOR. Evidence from in vitro cellular models (HepG2, CCD-986Sk fibroblasts), in vivo rodent studies and limited human pilot trials is summarized, as well as existing and emerging applications of apple pomace in functional foods, cosmeceuticals, and other sectors. Finally, we discuss the challenges and future opportunities in harnessing this by-product of the food industry. Although clinical data remain limited, preclinical findings support the repurposing of apple pomace as a sustainable functional ingredient contributing to healthier aging and circular economy goals. Future long-term randomized controlled trials are necessary to confirm efficacy in humans. Full article

Most patients with advanced/metastatic hormone receptor-positive, HER2-negative breast cancer receive first-line therapy with cycline-dependent kinase 4/6 inhibitors plus endocrine therapy. Almost universally, these patients eventually progress due to the emergence of resistant cancer clones. Targeting the PIK3CA/AKT1/PTEN pathway is a way of overcoming resistance. Recently, the oral, selective AKT kinase inhibitor capivasertib has been approved for the treatment of estrogen receptor-positive/human HER2-growth factor receptor-2 advanced BC with alterations in PIK3CA/AKT1/PTEN, in combination with fulvestrant after progression on endocrine therapy. We performed a narrative review to recapitulate the available evidence about capivasertib in the management of advanced hormone receptor-positive, HER2-negative breast cancer, focusing on studies that address preclinical rationale, pharmacology, and clinically relevant problems. Full article

Gastrointestinal malignancies remain among the leading causes of cancer-related morbidity and mortality worldwide, largely due to late diagnosis, aggressive tumor progression, and resistance to conventional therapies. Tumor angiogenesis and the tumor microenvironment (TME) play crucial roles in the initiation, growth, and metastatic dissemination of gastrointestinal cancers. Hypoxia-driven signaling pathways, including hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), transforming growth factor-β (TGF-β), and inflammatory mediators such as NF-κB and MAPK, are key regulators of these processes. Increasing evidence suggests that natural products derived from medicinal plants and other biological sources may modulate these pathways and exhibit anti-angiogenic, anti-inflammatory, and anti-fibrotic properties. This review summarizes recent findings on natural compounds that influence angiogenesis and tumor microenvironment dynamics through the regulation of molecular pathways involved in hypoxia signaling, extracellular matrix remodeling, fibroblast activation, and inflammatory responses. Compounds such as neotuberostemonine, aloperine, silymarin derivatives, tanshinone IIA, berberine, asiatic acid, and phloretin demonstrate promising biological activities in experimental models by targeting pathways including HIF-1α, PI3K/AKT/mTOR, TGF-β/Smad, and NF-κB signaling. However, further studies focusing on gastrointestinal cancer models and clinical validation are required to translate these preclinical observations into effective therapeutic strategies. Full article