Search Results (24,023)

Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive stage of metabolic dysfunction-associated steatotic liver disease characterized by lipid dysregulation, oxidative stress, inflammation, and fibrosis. Because these processes occur simultaneously, compounds targeting multiple pathways may offer therapeutic benefit. Naringin, a citrus-derived flavonoid, has reported antioxidant and anti-inflammatory properties, but its integrated effects in MASH remain unclear. In this study, the effects of naringin were evaluated using combined in silico analysis and in vivo experiments. Network pharmacology and molecular docking predicted targets related to lipid metabolism, oxidative stress, inflammation, and fibrosis, which were validated in a methionine- and choline-deficient diet-induced mouse model. Naringin reduced hepatic lipid accumulation and improved serum AST and ALT levels. It modulated oxidative stress-related genes, attenuated inflammatory responses, and reduced fibrogenic markers. Naringin also decreased Ly6Chigh inflammatory monocytes and Kupffer cell activation, and reduced hypothalamic microglial activation. These findings suggest that naringin exerts multi-target effects across hepatic, systemic, and central pathways, supporting its potential as a therapeutic candidate for MASH. Full article

Dehydrothyrsiferol (DT), a brominated oxasqualenoid from the red alga Laurencia viridis, represents a compelling example of this framework. This review establishes DT as a model Smart Secondary Metabolite based on the convergence of a unique molecular architecture of rigid stereogroups connected by flexible bonds; a high metabolic yield (0.42% w/w of crude extract); potent selective bioactivity against kinetoplastids and drug-resistant tumors; multi-target modulation of protein phosphatase 2A (PP2A) and cell-surface integrins; and distinctive chemotaxonomic relevance within Macaronesian communities. Its biosynthesis proceeds through stereocontrolled epoxide-opening cascades, generating an evolutionarily refined scaffold. Ecologically, DT operates as a multifunctional shield, providing antifouling protection and deterring herbivory. Pharmacologically, it acts as a selective signaling modulator, triggering integrin-mediated cell death (IMD) in resistant cancer cells and inducing mitochondrial collapse in protozoa. In vivo studies in murine models of cutaneous leishmaniasis have demonstrated an 87% reduction in lesion size, reinforcing its promise as a lead structure. Full article

Background/Objectives: Alzheimer’s disease (AD) remains a progressive neurodegenerative disorder with limited therapeutic options. This study aimed to develop an integrative multi-omics computational pipeline to identify diagnostic biomarkers and prioritize druggable therapeutic targets for AD. Methods: We integrated transcriptomic data from 1047 samples (547 AD, 500 controls) using weighted gene co-expression network analysis (WGCNA) and three machine learning algorithms (LASSO, Random Forest, SVM) with strict separation of training, feature selection, and evaluation. Single-cell RNA sequencing of 48,481 nuclei from entorhinal cortex, two-sample Mendelian randomization (MR) with Bayesian colocalization, and structure-based molecular docking with triplicate 500 ns molecular dynamics (MD) simulations were also employed. Results: Machine learning identified 10 consensus biomarker genes involved in synaptic vesicle cycling, ion transport, and calcium homeostasis (internal test AUC = 0.891, 95% CI: 0.836–0.946; external validation on GSE48350: AUC = 0.847, 95% CI: 0.798–0.896). Covariate-adjusted differential expression and MR with Bayesian colocalization converged on eight immune-related therapeutic targets including APOE, TREM2, and TYROBP ($p<0.05$; Bonferroni-corrected threshold $p<0.00625$). Single-cell analysis revealed oligodendrocyte expansion in AD (28.5% versus 24.8%), with target genes predominantly expressed in microglia and astrocytes. Virtual screening of 2634 FDA-approved drugs prioritized 10 exploratory repurposing candidates; indomethacin–TREM2 and celecoxib–CSF1R are primary exploratory candidates given structurally validated binding pockets. Triplicate MD simulations (15 $\mathsf{\mu }$s aggregate) showed force-field-consistent structural stability (RMSD ≤ 3.2 Å). A quantitative multi-omics convergence framework identified four Tier 1 targets (APOE, TREM2, TYROBP, CX3CR1) supported by ≥5 analytical layers ($P_{\mathrm{perm}}=0.0003$; note: three of five layers share the same transcriptomic input). Conclusions: These findings provide a multi-evidence computational framework linking diagnostic biomarkers and druggable neuroinflammatory targets for AD. All predictions require experimental validation in biochemical and cellular models before clinical conclusions can be drawn. Full article

Background/Objectives: Poor aqueous solubility limits the oral absorption and bioavailability of many active pharmaceutical ingredients. Simple formulation approaches suitable for hospital and community pharmacy compounding are therefore needed. This study aimed to develop and evaluate melt-filled hard capsules containing nifedipine, a model of poorly water-soluble BCS class II drug, using polyethylene glycol (PEG) carriers to improve dissolution performance. Methods: PEG blends of different molecular weights (PEG 400, PEG 1500, and PEG 4000) were prepared by melt mixing, followed by incorporation of nifedipine and manual filling into hard gelatin capsules. The formulations were characterized regarding mass variation, drug content, in vitro dissolution, rheological behavior, and solid-state properties using Fourier transform infrared (FTIR) spectroscopy. Dissolution profiles were kinetically modeled and compared with pure nifedipine. Results: All capsules met pharmacopoeial requirements for mass uniformity and showed acceptable drug content. PEG-based melt-filled formulations exhibited markedly enhanced dissolution compared with crystalline nifedipine. Faster drug release was associated with lower-molecular-weight PEGs and reduced viscosity, with the PEG 400/PEG 1500 blend demonstrating the most rapid dissolution. Rheological analysis confirmed shear-thinning behavior, while FTIR findings suggested intermolecular interactions and partial amorphization of nifedipine within the PEG matrices. Conclusions: This study provides a translational adaptation of solid dispersion principles into a compounding-compatible melt-filling approach. Full article

Background/Objectives: Cervical cancer, primarily driven by persistent high-risk HPV infection, remains a major global health issue. Xiao-ai-fei honey ointment, a traditional Uyghur multi-ingredient preparation, has shown clinical promise in cancer treatment, but its mechanisms against cervical cancer are not fully understood. This study aimed to investigate the potential molecular mechanisms of ethanolic extract of Xiao-ai-fei honey ointment (XAFHO) in cervical cancer using network pharmacology, single-cell RNA sequencing, and experimental validation. Methods: Differentially expressed genes (DEGs) in cervical cancer were identified from TCGA database. Active components and corresponding targets of XAFHO were retrieved from the TCMSP database, and disease targets were obtained from GeneCard, OMIM, and the TTD. Intersection targets were subjected to multivariate Cox and LASSO regression to construct a prognostic model. Immune infiltration, TMB, and MSI were compared between risk groups. Single-cell RNA-seq data were analyzed to determine cellular origins and inter-cellular communication. In vitro assays were performed on HeLa and SiHa cells to assess the anti-cancer activity of XAFHO. Molecular docking evaluated binding affinities between active compounds and core targets. The expression and functional roles of FASN and SPP1 were further validated by RT-qPCR, Western blotting, and siRNA transfection. Results: Sixty-three potential XAFHO targets were identified, and an 11-gene prognostic model was established, effectively stratifying patients into high- and low-risk groups with significantly different overall survival (AUC > 0.7). The high-risk group exhibited an immunosuppressive microenvironment and higher TMB. Single-cell analysis revealed that FASN and ACACA were predominantly expressed in tumor cells, while SPP1 was enriched in macrophages/monocytes. Tumor cells communicated with immune cells via the TGFB1–TGFβR1/R2 axis, promoting immune evasion. In vitro, XAFHO significantly inhibited proliferation, colony formation, migration, and invasion of cervical cancer cells. Molecular docking confirmed the strong binding of quercetin, kaempferol, and isorhamnetin to FASN and SPP1 (binding energy < –6.0 kcal/mol). Functional validation indicated that upregulated FASN and SPP1 contribute to malignant behaviors in cervical cancer cells. Conclusions: This study integrates network pharmacology with single-cell and experimental approaches to demonstrate that XAFHO exerts multi-target and multi-cell anti-cervical cancer effects, potentially by modulating lipid metabolism and immune-related pathways via FASN and SPP1. These findings provide a scientific basis for the therapeutic application of XAFHO in cervical cancer. Full article

Qualitative analysis of biochemical reaction systems reveals fundamental system-level properties that are independent of precise kinetic parameters, often context-dependent, or experimentally inaccessible. By focusing on structural and topological features—such as conservation relations, feedback loops, and pathway interconnections—qualitative analysis identifies invariant behaviors, robustness mechanisms, and potential failure modes inherent to the signaling network. In this study, we use Petri nets as a formal modeling framework to conduct qualitative analysis of the integrated MAPK and PI3K/Akt signaling network. By exploiting structural properties including place invariants, transition invariants, and siphons, the analysis establishes a direct correspondence between the Petri net structure and biologically meaningful conservation laws, signaling modules, and characteristic dynamic behaviors. The results demonstrate that the proposed model is structurally consistent, biologically plausible, and modular. Minimal semi-positive place invariants confirm mass conservation, indicating that proteins and enzymes circulate within closed molecular pools. Minimal semi-positive transition invariants identify canonical kinase–phosphatase cycles underlying sustained and reversible signaling. Hierarchical decomposition reveals a modular organization reducible to reusable enzymatic motifs, reflecting biological reuse across cascades and supporting scalability. Additionally, the identification of sixteen siphons that are also traps highlights persistent subsystems that ensure continuous regulator availability, confirming the robustness and dynamic sustainability of the integrated network. Full article

GDSL esterase/lipase (GELP) proteins constitute an evolutionarily conserved yet functionally diversified hydrolase family in land plants. They participate in cuticle and secondary cell wall biosynthesis, seed lipid remobilization, reproductive development, and hormone-mediated responses to biotic and abiotic stresses. Despite extensive genome-wide and comparative genomic studies that have categorized large GELPs across numerous crops and model species, only a fraction of members have been functionally characterized in plants, and their catalytic mechanisms and regulatory architectures remain poorly understood. Recent population genomics and cross-species orthogroup analyses in 46 angiosperms have uncovered substantial natural variation within GELP coding sequences and regulatory regions, providing a powerful framework to link allelic diversity to evolutionary trajectories and physiological functions. This review synthesizes current knowledge on GELP evolution, biochemical properties, and roles in development and stress adaptation, and critically evaluates how these insights can be translated into biotechnology and molecular breeding strategies. It highlights emerging resources and concepts from orthogroup-based classification and multi-species datasets that enable systematic discovery of GELP alleles affecting agronomic traits. It further outlines research exploiting GELPs in crop improvement, emphasizing the integration of reverse and forward genetics with multi-omics profiling, biochemical and structural characterization, and gene regulatory network reconstruction. Systematic assessment of the phenotypic impacts of single and combinatorial GELP perturbations on yield, quality, and stress resilience is proposed as a key step toward translating basic insights into breeding and engineering strategies. Full article

Seed aging is a critical biological process that leads to progressive loss of seed vigor, thereby constraining germplasm conservation and agricultural productivity. To elucidate the molecular mechanisms underlying this process in grass species, we performed transcriptomic analyses to characterize regulatory networks underlying seed aging in Elymus sibiricus, a dominant forage species on the Qinghai–Tibet Plateau. Seeds were subjected to artificial accelerated aging (45 °C, 80% relative humidity, 1–6 days), followed by physiological evaluation and RNA sequencing. Seed vigor and germination percentage declined markedly with aging, accompanied by extensive transcriptional reprogramming. Integrative analyses identified pyruvate metabolism, MAPK signaling, and peroxisome function as key processes associated with vigor loss during late-stage aging. WGCNA further revealed that genes encoding heat shock proteins and glutathione metabolism-related enzymes were co-localized within the same module, suggesting a possible synergistic role in preserving seed viability during aging. In addition, WRKY24, ARF9, and ARF19 were identified as candidate hub transcription factors. WRKY24 may contribute to aging by modulating antioxidant defense-related genes (e.g., TRX1 and NRPC1), while ARF9 and ARF19 may regulate ROS homeostasis through predicted downstream targets, including FQR1, PER2, MAO1B, ANN5, and MT2B. Together, these findings support a hypothetical regulatory model in which WRKY and ARF transcription factors coordinate redox homeostasis and hormone signaling to regulate seed longevity in E. sibiricus. This study provides a systems-level framework for understanding seed aging in perennial grasses and identifies potential genetic targets for improving seed storability, with implications for germplasm conservation and alpine grassland sustainability. Full article

Both the productive efficiency and physical health of sika deer are strongly linked to their body conformation phenotypes. Breeding sika deer with excellent growth traits using molecular breeding technologies has become essential. Phenotypic data of 12 body conformation traits were measured for 613 sika deer across three age groups, including body traits and cephalic traits. Genetic typing was performed using the Sika Deer 100K SNP Liquid Chip, and genetic parameters were estimated through animal models to obtain the heritability and genetic correlation of traits within each age group. Single-trait and multi-trait GWASs were conducted, using GEMMA software to identify gene variants significantly associated with sika deer body conformation traits. Most of the 12 body conformation traits exhibited moderate to high heritability. The single-trait GWAS identified 49 SNPs (38 candidate genes), while multi-trait GWAS detected 134 SNPs (80 candidate genes), including 114 novel loci. A total of 163 SNPs and 196 candidate genes were identified, with 17 genes detected by both methods. These genes may be involved in pain perception, cell cycle regulation, immune response, and protein ubiquitination. Two significant KEGG pathways were enriched: steroid hormone biosynthesis and drug metabolism–cytochrome P450. Collectively, these detected loci and genes may serve as potential genetic resources for marker-assisted breeding, contributing to subsequent genetic improvement of body conformation in sika deer. Full article

Background/Objectives: Chronic glomerulonephritis (CGN) is a progressive chronic kidney disease that can ultimately advance to end-stage renal disease (ESRD). Zhuangyang Bushen Pill (ZYBSW) is a traditional Chinese herbal formulation derived from the Yi ethnic medicine of Yunnan Province, and it has been widely employed in folk practice for the amelioration of chronic nephritis and renal dysfunction. This study was designed to evaluate the therapeutic efficacy of ZYBSW against CGN and to provide preliminary insights into its underlying mechanisms of action. Methods: The nephropathy model was induced in mice by tail vein injection of ADR (10 mg/kg). Renal function was evaluated by measuring relevant biochemical parameters, and renal histopathological alterations were examined using HE staining. Chemical constituents of ZYBSW were analyzed by LC-MS/MS. Its mechanisms of action were investigated using network pharmacology, WGCNA, molecular docking, multiplex immunofluorescence, and Western blotting. Results: ZYBSW significantly reduced ACR by 88.9%, SCr by 56.4%, and BUN by 30.4%, increased ALB by 32.4%, and alleviated renal histopathological damage (all p < 0.01). LC-MS/MS analysis identified 419 chemical constituents in ZYBSW. Network pharmacology, WGCNA, and molecular docking experiments identified EGFR and DUSP1 as potential targets, and indicated the MAPK pathway as a key pathway. Mechanistic studies revealed that ZYBSW significantly inhibited EGFR expression in renal tissue, enhanced DUSP1 expression, and reduced the phosphorylation levels of ERK, JNK, and p38. Conclusions: This study reveals ZYBSW can effectively alleviate CGN, with EGFR and DUSP1 as likely therapeutic targets, and its mechanism of action primarily involves regulating the MAPK signaling pathway. Full article

DNA methylation constitutes a primary layer of epigenetic regulation in plants, operating across three sequence contexts (CG, CHG, and CHH) through distinct enzymatic pathways. Over the past fifteen years, accumulating evidence has shown that DNA methylation varies substantially among individuals and populations of wild plants, sometimes independently of underlying genetic polymorphism. This variation can influence gene expression, transposable element activity, and phenotypic traits relevant to ecological adaptation. Population epigenetics, the study of methylation variation at the population scale, has matured from initial surveys using methylation-sensitive amplified fragment length polymorphism (MS-AFLP) into a discipline increasingly reliant on reduced-representation bisulfite sequencing (epiGBS, bsRADseq), whole-genome bisulfite sequencing (WGBS), enzymatic methyl-seq (EM-seq), and direct long-read detection by nanopore sequencing. These methodological advances are opening population epigenetics to non-model organisms across the full breadth of the plant phylogeny, from angiosperms and gymnosperms to ferns and bryophytes. We cover (i) the molecular machinery underlying plant DNA methylation, including the debated status of N6-methyladenine (6mA); (ii) empirical evidence for natural epigenetic variation in plant populations, spanning clonal, invasive, and outcrossing species; (iii) the methodological toolkit available for population-scale methylation profiling, with emphasis on approaches suitable for non-model taxa; and (iv) the ecological and evolutionary significance of population epigenetic variation, including transgenerational inheritance, stress memory, epigenetic clocks, conservation applications, and the emerging integration of epigenetics into the extended evolutionary synthesis. We identify critical knowledge gaps, particularly the near-complete absence of population-level epigenetic data for bryophytes, ferns, and lycophytes, and outline priorities for future research. Full article

Prion diseases are fatal neurodegenerative disorders that affect humans and animals, caused by the conformational conversion of the normal cellular prion protein (PrP^C) into its misfolded, infectious isoform PrP^Sc. Recently, camel prion disease (CPrD) was identified in dromedary camels (Camelus dromedarius) in Algeria. Due to the potential implications for animal and human health, as well as the possible socio-economic impact in Mediterranean regions where camels play a pivotal role as a source of food, in-depth characterization of camel prions is important to increase our understanding of camel prion disease. We developed a neuronal cell line model for studying the molecular features of camel prion infection. We genetically edited mouse neuronal CAD5 cells to generate CAD5 PrP knockout (KO) cells. We then used lentiviral transduction to generate CAD5 cells expressing camel PrP (CAD5-camel-PrP). Following infection of these cells with a CPrD-positive camel brain homogenate, we observed PrP^Sc signals at various passages, as indicated by immunoblotting analysis. RT-QuIC (Real-Time Quaking-Induced Conversion) assays further supported these findings, demonstrating transient prion conversion activity in the CPrD-infected CAD5-camel-PrP cells. Taken together, our data describe the first neuronal cell line permissive to camel prion infection, a novel in vitro tool for mechanistic studies of camel prion disease. Full article

N-nitrosamine compounds, a disinfection byproduct of chlorination and chloramination in water and wastewater treatment processes, are classified as a probable human carcinogen. The current review focuses on analysing the feasibility of membrane technology while examining the challenges and opportunities in the elimination of N-nitrosamine compounds, particularly NDMA, from wastewater. To systematically attain this goal, this paper uses a systematic literature review that screens and critically assesses peer-reviewed experimental and numerical published papers on N-nitrosamine removal, occasioning in 37 high-quality papers for synthesis. In this regard, a detailed analysis of experimental and numerical studies elaborates that conventional RO membranes often introduce a specific low removal of NDMA from wastewater due to their low molecular weight and neutral charge, which addresses a critical issue. The critical analysis of the experimental and numerical studies depicts that the membrane type, structural properties, and chemical interaction have a key role in the removal of NDMA. To systematically improve the NDMA removal, a wide set of investigations have explored innovative treatment methods, including Nano pore plugging and hydrophilic coatings. This demonstrates potential for improving NDMA removal, albeit at the penalty of reduced water permeability. Additionally, the heat treatment of membranes has attained a notable improvement, ensuing in NDMA rejection of up to 92%. A multi-stage RO configuration model has depicted a maximum NDMA rejection of 93.1%. The future research should focus on investigating possible improvement of NDMA removal from wastewater such as Nano pore plugging and hydrophilic coatings, besides optimising RO configurations and membrane designs with a deeper understanding of membrane fouling. Full article

Objectives: This systematic review aims to evaluate the effects of Edible Bird’s Nest (EBN) extract on cognitive function and neuroprotection in animal models and systematically review the relevant research evidence. Methods: A systematic search was conducted in the databases of PubMed, Scopus, Web of Science, EMBASE, Taylor Francis, Wiley, and Cochrane Library for relevant research published up to October 2025. Search terms included “Edible Bird’s Nest”, “Bird’s Nest Extract”, “EBN”, “Swiftlet nest”, “Collocalia”, “Cognitive”, “Memory”, “Learning”, “Neuroprotection”, “Brain”, “Neural”, “Neurotrophic”, “Animal”, “Mice”, “Mouse”, “Rat”, “Rats”, “In vivo”, and “Model”. Two researchers independently screened all the relevant articles, extracted relevant data, and assessed the quality of included studies using the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) risk of bias assessment tool. Results: This systematic review included 11 animal studies, primarily focused on rodent models. Preclinical evidence suggests that Edible Bird’s Nest extract (EBN) may improve performance in several cognitive function tests. Animals treated with EBN appeared to show enhanced spatial memory and learning abilities in experimental settings. At the molecular level, the EBN treatment group showed improved antioxidant capacity and reduced neuroinflammation. Additionally, EBN promoted the expression of neuroprotective factors and enhanced synaptic plasticity. Research suggests that appropriate doses of EBN may have beneficial effects on cognitive enhancement and can alleviate cognitive dysfunction and neuropathological changes. Conclusions: Preliminary evidence from this systematic review suggests that EBN appears to show protective and potentially enhancing effects on cognitive function in animal models. EBN works through multiple mechanisms, including antioxidant and anti-inflammatory effects, as well as promoting the expression of neurotrophic factors and synaptic plasticity. These findings provide initial support for further investigation of EBN as a potential neuroprotective agent and cognitive enhancer. However, there is heterogeneity and methodological limitations in the research, and more standardized studies and preclinical translational research are needed to further validate the application potential of EBN in neuroprotection. These results provide an important reference for developing EBN-based functional foods and supplements for the prevention and adjuvant treatment of cognitive impairment and neurodegenerative diseases. Full article

Background: The Xiao Zhong Zhi Tong Patch (XZZTP) has been extensively utilized in China to alleviate many diseases associated with bacterial inflammation. However, its pharmacological mechanism and active components remain unclear. Methods: The anti-inflammatory effects of XZZTP were evaluated in vivo and in vitro models. The characterization of XZZTP and its transdermal components was performed using LC-MS/MS. The underlying pharmacological mechanism was predicted through network pharmacology using the identified transdermal components and verified by Western blotting. Molecular docking and molecular dynamics simulations were performed on key targets to screen active components. Results: XZZTP showed a swelling inhibition rate of 45.96% in xylene-induced ear edema mice in vivo. In vitro, the inflammatory mediators NO, TNF-α, and PGE2 were concentration-dependently reduced by XZZTP in the LPS-induced RAW 264.7 macrophages model, with inhibition rates of 56.53%, 53.75%, and 48.49% at 200 µg/mL, respectively. LC-MS/MS identified 126 chemical components (97 newly reported) in XZZTP, including 52 transdermal potential active components, among which a new iridoid and its isomer were reported for the first time. Network pharmacology analysis demonstrated that XZZTP mainly downregulated the PI3K/AKT/HIF-1 signaling pathway to alleviate bacterial inflammation. The protein expression of core targets p-PI3K, p-AKT, and HIF-1α in the LPS-induced RAW 264.7 macrophages was significantly reduced after XZZTP intervention. Eight active components were screened via molecular docking, and molecular dynamics simulations of three representative complexes validated stable binding interactions, supporting their therapeutic potential. Conclusions: These findings provide a theoretical basis for XZZTP as a potential agent to ameliorate bacterial inflammation-related diseases, serving as a reference for its further application. Full article