Systematic pharmacology-guided analysis of the therapeutic mechanism of Sedum sarmentosum against chronic liver injury.

Semen Sojae Praeparatum ameliorates triptolide-induced liver injury by regulating bile acid homeostasis and the Keap1/Nrf2/p62 axis.

Cajanolactone A alleviates high-fat diet-induced MAFLD by modulating liver de novo lipogenesis, inflammatory signaling, and bile acid composition in the gut-liver axis.

The proteome of goat meat exudate: Temporal proteomics as a new way to uncover the underlying mechanisms of meat tenderization.

ELAVL1 interacts with APP and promotes Aβ-induced apoptosis in Alzheimer's disease by activating Bcl-2/Bax signaling.

Glyphosate promotes calcium oxalate crystal-induced renal injury by modulating the PI3K/Akt-mediated mechanism.

6PPD-quinone promotes ovarian cancer progression: Insights from network toxicology, machine learning, and in vitro validation.

Embryonic diazepam exposure induces innate immune toxicity in zebrafish (Danio rerio).

Oncoviruses are a significant etiological factor in a substantial proportion of human cancers, with a particular impact on cancers of the digestive system. This review provides a comprehensive analysis of the complex molecular mechanisms through which viral oncoproteins, focusing on Hepatitis B Virus (HBV) HBx, Hepatitis C Virus (HCV) core protein, and Epstein-Barr Virus (EBV) latent membrane protein 1 (LMP1), hijack and disrupt host cell signalling networks to induce carcinogenesis. These disruptions include the inactivation of critical tumour suppressor proteins, such as p53 and the retinoblastoma protein (Rb), the constitutive activation of pro-proliferative and pro-survival pathways, including NF-κB and Akt, and the induction of chronic inflammation and metabolic dysregulation. A deeper understanding of these precise molecular interactions is essential to advancing precision oncology, enabling the development of next-generation targeted therapies and immunotherapies that can address the unique vulnerabilities of virus-associated cancers.

Epigallocatechin-3-gallate (EGCG), a major polyphenolic compound in green tea, exhibits anti-viral activity against multiple viruses, including hepatitis B virus (HBV). However, its role in HBV replication and the underlying mechanisms remain incompletely understood. In this study, we investigated the effects of EGCG on HBV replication and its modulation of autophagy using two established HBV cell models. Our results show that EGCG significantly reduces secreted levels of hepatitis B surface antigen (HBsAg) and HBV deoxyribonucleic acid (DNA), as well as intracellular HBV DNA replicative intermediates, encapsidated pregenomic ribonucleic acid (pgRNA), and core protein (HBc), without affecting total HBV messenger RNAs (mRNAs) or pgRNA levels. EGCG enhances autophagic flux, evidenced by increased autophagosome formation and accelerated turnover of the selective autophagy receptor p62 and LC3-Ⅱ. This enhanced autophagy promotes HBc degradation. Pharmacological inhibition of autophagy with 3-methyladenine (3-MA), chloroquine (CQ), or bafilomycin A1 (BafA1) abolished the suppressive effect of EGCG on HBV. Notably, treatment with CQ or BafA1 together with EGCG markedly increased HBV production by blocking autophagic degradation and inducing accumulation of autophagosomes-effects similar to those induced by the autophagy activator rapamycin, which facilitates HBV replication. Mechanistically, EGCG activates the adenosine 5'-monophosphate-activated protein kinase (AMPK)/transcription factor EB (TFEB) signaling axis, leading to enhanced lysosomal biogenesis and ATP production, thereby promoting autophagic clearance. Pharmacological or genetic inhibition of AMPK attenuated TFEB transcriptional activity, suppressed lysosomal biogenesis and ATP generation, impaired autophagic degradation, increased HBc levels, and ultimately enhanced HBV replication. Conversely, pharmacological activation of AMPK produced opposing effects. These findings reveal a novel mechanism by which EGCG inhibits HBV: EGCG promotes autophagic degradation of the viral core protein via activation of the AMPK/TFEB signaling pathway.

Circadian rhythms are fundamental for maintaining physiological homeostasis, influencing processes such as sleep-wake cycles, metabolism, and hormonal regulation. The suprachiasmatic nucleus (SCN), the primary pacemaker in the brain, is necessary to maintain behavioral circadian rhythms and to synchronize peripheral clocks throughout the body in mammals. The vestibular system, responsible for balance and spatial orientation, has been implicated in circadian regulation, yet its intrinsic clock machinery remains unexplored. Previous studies suggest vestibular input influences circadian rhythms, as evidenced by altered locomotor activity and temperature control in animals with vestibular dysfunction. Additionally, vestibular disorders in humans display time-dependent patterns, further supporting a vestibular-circadian interaction. Our study investigates the presence of an autonomous circadian clock in the peripheral vestibular organs (semicircular canals SCC, saccule, utricle and vestibular ganglia) by assessing core clock gene and protein expression in vestibular structures of mice and humans. Using PERIOD2::LUCIFERASE (PER2::LUC) bioluminescence assays from mouse tissues, we observed self-sustained oscillations in SCC, saccule, and utricle, with differential amplitudes and phase relationships. RNA scope (Bmal1) confirmed the rhythmic expression in the peripheral vestibular organ from mice, corroborating their functional circadian regulation. Furthermore, we explored the impact of cisplatin, a chemotherapeutic agent, on vestibular clock rhythms. Cisplatin administration disrupts PER2 oscillations in vestibular explants in a time-dependent manner, mirroring the cochlear findings where the day or night timing of drug delivery modulates drug response. Our findings provide the first direct evidence of a clock within the peripheral vestibular organ of rodents and humans, highlighting its potential role in modulating vestibular function and responses to pharmacological interventions. These findings suggest that vestibular disorders may follow a daily pattern, which could help explain why symptoms worsen or improve at different times of the day. This could lead to better treatment strategies for millions of people affected by vestibular dysfunction. Demonstrating that the chemotherapy drug cisplatin disrupts vestibular rhythms in a time-dependent manner, suggests that administering drugs at the right time of day could minimize side effects like dizziness and nausea while maximizing effectiveness. These results underscore the importance of considering circadian timing in vestibular research and therapeutic strategies.

Integrated network pharmacology, metabolomics, and proteomics analysis of Shiqi Waigan Granules for treating exogenous febrile disease.

Characterizing two subtypes of osteosarcoma using G2M checkpoint-related genes and revealing its immune landscape.

Background: Proteoglycans are a major component of the connective tissue matrix, which consists of a core protein and covalently attached glycosaminoglycan (GAG) chains, which are highly sulfated polysaccharides with a tetrasaccharide linker for the core protein attachment. Impaired synthesis or degradation of GAG causes genetic disorders. In the 1950s, deficient lysosomal GAG degradation was discovered in mucopolysaccharidoses. In the 1990s, a defective enzyme for GAG synthesis was implicated in a variant of Ehlers-Danlos syndrome and an impaired GAG sulfation in diastrophic dysplasia. Newer studies have uncovered that abnormal GAG synthesis causes a large group of genetic skeletal disorders with joint and skin abnormalities. Summary The prototype of this group includes diastrophic dysplasia and Desbuquois dysplasia. The former is attributed to abnormal GAG sulfation, while the latter to impaired GAG chain elongation. Defective linker formation causes distinctive phenotypes termed linkeropathy. Moreover, there remain many disorders with defective GAG synthesis, in which the phenotypes are poorly documented and thus the clinical suspicion and even interpretation of molecular findings are challenging. Here, we attempt to review the skeletal manifestations of abnormal GAG synthesis disorders, based on our own experiences and previous reports. Each disorder has distinct clinical and radiological features, but they share some common skeletal manifestations, such as distal humeral hypoplasia, misshapen proximal femora, accelerated carpal ossification, and malsegmentation of the short tubular bones. Key Message Awareness of the phenotypic similarities and differences among this group of disorders facilitates our clinical and genetic practices for affected individuals.

This study explores Polygonati Rhizoma's therapeutic potential against periodontitis using network pharmacology, molecular docking, and experimental validation to uncover its mechanisms. Active ingredients and targets of Polygonati Rhizoma were sourced from TCMSP and DrugBank, while periodontitis-related targets were retrieved from GeneCards, DisGeNET, and PharmGKB. Core targets were identified via Venny 2.1, and a compound-target network was built using Cytoscape. GO/KEGG analyses and molecular docking were performed. A periodontitis mouse model (C57BL/6) was treated with 500mg/kg Polygonati Rhizoma or water (control). Post-treatment, tissues and serum were analyzed. Twelve active ingredients in Polygonati Rhizoma (e.g., diosgenin, baicalein) exerted therapeutic effects by targeting core proteins such as MMP9, PPARG, and ESR1, and modulating signaling pathways including PI3K/AKT, IL-17/TNF, and HIF-1. In vivo experiments showed that Polygonati Rhizoma significantly suppressed serum IL-6 and TNF-α levels (P < 0.01), alleviated alveolar bone resorption, and reduced inflammatory infiltration in periodontal tissues of periodontitis mice. Additionally, Polygonati Rhizoma ameliorated histopathological damage in the liver and intestine, modulated the gut microbiota structure by increasing the abundance of Prevotella, and enriched ABC transporter-related functions. Polygonati Rhizoma alleviated alveolar bone loss in a periodontitis mouse model, suppressed inflammation by targeting MMP9, PPARG, and ESR1 via the PI3K/AKT, IL-17/TNF, and HIF-1 signaling pathways, reduced the levels of pro-inflammatory cytokines (IL-6/TNF-α), and modulated the gut microbiota composition. Modulation of the gut microbiome was associated with​ attenuated systemic inflammation, suggesting a potential role in the therapeutic effects of Polygonati Rhizoma.

Omics Reveals Signaling-Associated Traits of Extracellular Vesicles Derived from Dental Stem Cells.

The escalating severity of global microplastic pollution has triggered significant public health concerns. Polyethylene terephthalate (PET), a ubiquitous plastic constituent, extensively permeates aquatic systems, food chains, and daily living environments. However, its potential long-term health impacts, particularly its association with Non-alcoholic Fatty Liver Disease (NAFLD), remain poorly understood. In this study, we adopted an integrative network toxicology approach combined with multi-omics data and machine learning to systematically elucidate the mechanistic relationship between exposure to PET nanoplastics and the pathogenesis of NAFLD. Through comprehensive interrogation of multi-source databases, we identified 20 overlapping targets common to both PET nanoplastic exposure and NAFLD. By employing a comprehensive integrative machine learning framework comprising eleven distinct algorithms, we further identified six core candidate genes: CCL2, GRIA3, JUN, PFKFB3, PIM1, and PPARA. The resulting diagnostic model achieving a maximum Area Under the Curve (AUC) of 0.94 in the training set and demonstrating generalizability in an independent validation cohort (AUC > 0.6). Shapley Additive Explanations (SHAP) analysis identified PFKFB3 and PPARA as the most influential predictors. Single-cell transcriptome analysis revealed cell-type-specific expression patterns of these core genes within hepatocytes, macrophages, and endothelial cells, highlighting their pivotal roles in key intercellular communication pathways, such as the chemokine and macrophage migration inhibitory factor (MIF) signaling pathways. Furthermore, molecular docking and molecular dynamics simulations suggest that PET-derived oligomers or surface-associated chemical functional groups may form specific interactions with the active sites of core proteins. Given the current scarcity of clinical cohorts in public databases that concurrently incorporate measures of microplastic exposure and transcriptomic profiles, this study employs a computational toxicology framework to elucidate the interaction networks between these factors through systematic bioinformatic analysis. By integrating PET-microplastic-related targets with NAFLD-associated transcriptomic data via exploratory systems toxicology modeling, we identified a potential molecular nexus linking PET exposure to NAFLD pathogenesis. These findings establish a theoretical foundation for future mechanistic investigations into microplastic exposure and its toxicological implications.

This study aims to explore the antidepressant mechanism of the Guizhi-Baishao herbal pair using network pharmacology and molecular docking methods, providing a basis for fundamental research and clinical application. Active compounds and target proteins of Guizhi and Baishao were retrieved from the TCMSP database using oral bioavailability ≥ 30% and drug-likeness ≥ 0.18 as screening criteria. Depression-related therapeutic targets were identified through databases such as GeneCards, OMIM, TTD, and DrugBank, and the intersection of drug targets and disease targets was obtained. A protein-protein interaction network was constructed using the STRING database, and topological analysis was performed with Cytoscape 3.10.3 software. Gene Ontology functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis of the intersecting targets were conducted via the DAVID database. Molecular docking analyses were performed using AutoDockTools 1.5.7 and PyMOL 3.1.3, with further validation of key compounds through AutoDock Vina. A total of 20 potential active compounds and 87 corresponding targets of the Guizhi-Baishao pair were identified, along with 5502 depression-related targets, yielding 77 intersecting targets. Protein interaction analysis revealed core targets potentially influenced by the active compounds, including RAC-α serine/threonine protein kinase, prostaglandin G/H synthase, interleukin (IL)-6, tumor necrosis factor (TNF), estrogen receptor 1, acetylcholinesterase, sodium-dependent neurotransmitter transporter, peroxisome proliferator-activated receptor γ, cytochrome P450 3A4 enzyme, and NF-κB p65 protein. With P < .05 as the threshold, 415 Gene Ontology functional terms and 127 Kyoto Encyclopedia of Genes and Genomes pathways were enriched for the Guizhi-Baishao pair's antidepressant effects. Molecular docking of core targets with corresponding active compounds indicated affinities of <-5 kJ/mol between the active compounds and target proteins. The antidepressant mechanism of the Guizhi-Baishao pair may involve multiple active compounds (such as kaempferol, dihydroquercetin, β-sitosterol, epicatechin, catechin, and paeoniflorin) regulating core proteins like RAC-αserine/threonine protein kinase, prostaglandin G/H synthase, IL-6, TNF, estrogen receptor 1, acetylcholinesterase, peroxisome proliferator-activated receptor γ, cytochrome P450 3A4 enzyme, and NF-κB p65 protein, as well as pathways related to apoptosis, T helper 17 cell differentiation, TNF, IL-17, and NF-κB signaling. This regulation may inhibit apoptosis of cells and hippocampal neurons, neurotransmitter disturbances, oxidative stress, and inflammatory responses.

In this exploratory pilot study, we profiled human periodontal ligament (PDL) transcriptomes during early orthodontic tooth movement (OTM). Early-stage (0-10 days) transcriptional dynamics under tension and compression remain insufficiently understood, and no dedicated user-friendly resource has been available for exploring large-scale human data. We established tooth extrusion and intrusion models to simulate tension- and compression-side PDL conditions, respectively, and collected human PDL samples within the first 10 days (days 0, 1, 3 and 10; ≤ 4 biological replicates per force-time subgroup). RNA-seq was performed, and five complementary gene selection strategies identified persistent force-specific genes, time-dependent concurrent genes, force-dominant genes, condition-specific markers and integrative network modules. We also developed a Shiny-based web application (HOTM) to integrate the processed data, enabling OTM-related analyses-such as custom comparisons, expression visualisation and correlation assessments-in a simple, code-free environment. Given the pilot design, candidate genes were prioritised using nominal P-values for exploratory screening; multiple-testing-adjusted statistics are provided for reference in the supplementary results and HOTM. Persistent extrusion-upregulated genes (CAR1, ACTB) were consistent with a proliferation-associated program under tension, whereas persistent intrusion-upregulated genes (CXCR6, CCL5) were consistent with immunomodulatory signatures under compression. Concurrently upregulated genes showed a time-related transition from early immune activation (CD28, day 1) to proliferation (MYC, day 3) and metabolic specialisation (GAPDH, day 10). Extrusion-dominant genes (BYSL) suggested controlled growth and metabolic stability, while intrusion-dominant genes (CLDN7) were associated with an osteoclast-favouring remodelling signature. Condition-specific markers suggested a time-dependent progression from early immunoinflammatory cues to advanced tissue reorganisation. Integrative modules pointed to candidate hub genes linking extrusion-associated proliferation (SHCBP1, BIRC5, ARHGAP11A) and intrusion-associated remodelling (ATP6V1A, ATP6V1B2, SNX10) to a core metabolic and protein homeostasis baseline (MRPL47, PSMC2, UBE2V2). This exploratory pilot study presents a hypothesis-generating transcriptomic resource describing early (0-10 day) human PDL responses to orthodontic extrusion and intrusion and a publicly accessible web tool (HOTM) for convenient exploration of candidate genes and pathways. All findings should be interpreted as exploratory and require confirmation in independent, adequately powered cohorts with appropriate multiple-testing correction and orthogonal validation before mechanistic or clinical interpretation.

Cognitive impairment (CI) is prevalent in clinical patients with heart failure (HF). However, there are no effective pharmacological interventions for CI treatment. Astragaloside IV (AS-IV) is the principal constituent of Astragalus Radix and effective in HF, but its action on CI after HF has not yet been studied. Cognitive function was evaluated in behavioural experiments on male rats with HF. Transcriptomics and network pharmacology were used to identify potential pathways. Western blots, quantitative real-time polymerase chain reaction (qRT-PCR), Elisa, and electron microscopy were used to validate changes in identified pathways, brain inflammatory cytokines, postsynaptic membrane glutamate receptors and levels of apoptosis. Molecular docking and molecular dynamics simulation confirmed the binding ability of AS-IV and selected core proteins. AS-IV improved cardiac function and disordered cardiac muscle structure in rats with HF. The advanced glycation end-products-receptor of advanced glycation end-products (AGE-RAGE) signalling pathway was the core pathway. AS-IV reduced the expression levels of RAGE, extracellular regulated protein kinases 1/2 (ERK1/2) and nuclear factor kappa-B (NF-κB). AS-IV also attenuated the expression of proinflammatory factors, increased the levels of anti-inflammatory factors, and up-regulated postsynaptic membrane glutamate receptor expression. Molecular docking and molecular dynamics simulation showed that AS-IV had favourable binding energy with RAGE. AS-IV enhances cognitive function of HF rats by inhibiting the RAGE-ERK1/2-NF-κB signalling pathway to reduce inflammation and apoptosis and thereby improve synaptic function. AS-IV emerges as a promising candidate for the prevention and treatment of HF-CI.