Search Results (7,653)

Liver fibrosis induced by Schistosoma japonicum Katsurada, 1904 (S. japonicum) infection lacks effective diagnostic markers and specific anti-fibrotic therapies. Although dysregulated iron homeostasis and ferroptosis pathways may contribute to its pathogenesis, the core regulatory mechanisms remain elusive. To unravel the ferroptosis-related molecular features, this study integrated transcriptomic datasets (GSE25713 and GSE59276) from S. japonicum-infected mouse livers. Following batch effect correction and normalization, ferroptosis-related differentially expressed genes (FRDEGs) were identified. Subsequently, core hub genes were screened through the construction of a protein–protein interaction (PPI) network, functional enrichment analysis, immune infiltration evaluation, and receiver operating characteristic (ROC) analysis. The expression patterns of these hub genes were further validated in an S. japonicum-infected mouse model using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The study identified 7 hub genes (Lcn2, Timp1, Cth, Cp, Hmox1, Cbs, and Gclc) as key regulatory molecules. Functional enrichment analysis revealed that these hub genes are closely associated with sulfur amino acid metabolism and oxidative stress responses. Specifically, key enzymes involved in cysteine and glutathione (GSH) synthesis (Cth, Cbs, Gclc) were consistently downregulated, suggesting a severe impairment of the host antioxidant defense capacity. Conversely, pro-fibrotic and pro-inflammatory markers (Timp1, Lcn2, Hmox1) were upregulated. This molecular pattern was significantly associated with a remodeled immune microenvironment, characterized by increased infiltration of neutrophils and eosinophils. In vivo validation confirmed the expression trends of 6 hub genes, corroborating the bioinformatics predictions, while the discrepancy in Cp expression highlighted the complexity of post-transcriptional regulation in vivo. The identified hub genes demonstrated excellent diagnostic potential, with Timp1 achieving an area under the curve (AUC) of 1.000. This study elucidates the molecular link between S. japonicum infection and the ferroptosis pathway, suggesting that these hub genes may drive liver fibrosis progression by regulating sulfur metabolism and the immune microenvironment. These findings offer potential diagnostic biomarkers and novel therapeutic targets for schistosomal liver fibrosis. Full article

Wee1-like protein kinase 2 (WEE2) is an oocyte-specific kinase that regulates meiotic arrest and fertilization. Its largely restricted expression in female germ cells and absence in somatic tissues make it a highly selective target for reproductive health interventions. Despite its central role in human fertility, no clinically approved WEE2 modulator is available. In this study, we employed an integrated in silico approach that combines structure-based virtual screening, molecular dynamics (MD) simulations, and MM-PBSA free-energy calculations to identify repurposed drug candidates with potential WEE2 inhibitory activity. Screening of ~3800 DrugBank compounds against the WEE2 catalytic domain yielded ten high-affinity hits, from which Midostaurin and Nilotinib emerged as the most mechanistically relevant based on kinase-targeting properties and pharmacological profiles. Docking analyses revealed strong binding affinities (−11.5 and −11.3 kcal/mol) and interaction fingerprints highly similar to the reference inhibitor MK1775, including key contacts with hinge-region residues Val220, Tyr291, and Cys292. All-atom MD simulations for 300 ns demonstrated that both compounds induce stable protein–ligand complexes with minimal conformational drift, decreased residual flexibility, preserved compactness, and stable intramolecular hydrogen-bond networks. Principal component and free-energy landscape analyses further indicate restricted conformational sampling of WEE2 upon ligand binding, supporting ligand-induced stabilization of the catalytic domain. MM-PBSA calculations confirmed favorable binding free energies for Midostaurin (−18.78 ± 2.23 kJ/mol) and Nilotinib (−17.47 ± 2.95 kJ/mol), exceeding that of MK1775. To increase the translational prioritization of candidate hits, we place our structure-based pipeline in the context of modern machine learning (ML) and deep learning (DL)-enabled virtual screening workflows. ML/DL rescoring and graph-based molecular property predictors can rapidly re-rank docking hits and estimate absorption, distribution, metabolism, excretion, and toxicity (ADMET) liabilities before in vitro evaluation. Full article

The multidrug and toxic compound extrusion (MATE) protein plays a crucial role in mediating plant responses to aluminum (Al) toxicity. The key candidate gene BnaMATE43b related to Al toxicity stress in rapeseed was identified using GWAS and transcriptome analysis. In this study, the BnaMATE43b gene was cloned and functionally characterized in rapeseed. Compared with wild-type rapeseed (WT), the BnaMATE43b overexpression lines (OE) demonstrated stronger aluminum tolerance, specifically manifested in higher relative elongation of taproots (RETs) and relative total root length (RTRL); under Al toxicity stress, the enzyme activities (SOD and POD) and root activity were significantly increased in the OE lines, whereas the MDA content and relative electrical conductivity were reduced in rapeseed root. Further transcriptome analysis of OE-3 showed that the differentially expressed genes (DEGs) were mainly enriched in zeatin biosynthesis (map00908), glucosinolate biosynthesis (map00966), phenylpropanoid biosynthesis (map00940), and ascorbate and aldarate metabolism (map00053). In addition, the yeast cDNA library of rapeseed was constructed, and twenty-two candidate upstream transcription factors (UTFs) of BnaMATE43b were screened; furthermore, four candidate UTFs were obtained through one-on-one interaction validation and luciferase assays, comprising three bHLH transcription factors (BnaA02g28220D, BnaA06g07840D, and BnaA08g24520D) and one ERF transcription factor (BnaA05g23130D). Collectively, these results suggest that BnaMATE43b could improve Al tolerance in rapeseed by mediating antioxidant enzyme activities and the related metabolic pathway, while the obtained UTFs lay the foundation for further analysis of the gene regulatory network under Al toxicity stress. Full article

To enhance the screening efficiency of bioactive peptides, an AI-driven approach was employed to screen DPP-IV inhibitory peptides from goat blood proteins by an integrated in silico, in vitro, and machine learning strategy. Furthermore, the inhibitory mechanism of DPP-IV inhibitory peptides was elucidated by kinetics, molecular docking and simulation. Additionally, their in vitro digestive stability was assessed. In silico results revealed that goat blood proteins were promising precursors of DPP-IV inhibitory peptides, while bromelain was the optimal protease. Their peptide sequences were further identified by peptidomics and predicted by self-developed machine learning models (LightGBM) to identify the potent DPP-IV inhibitory peptides. Two novel DPP-IV inhibitory peptides were identified (FPL and FPHFDL). Enzyme kinetics, molecular docking and molecular simulation data indicated that FPL served as a competitive inhibitor, whereas FPHFDL was a non-competitive inhibitor. Overall, the integrative in silico and in vitro strategy is feasible for rapid screening of DPP-IV inhibitory peptides from goat blood proteins. Full article

Nicotinic acetylcholine receptors (nAChRs) are membrane-bound proteins that mediate fast synaptic transmission throughout the nervous system. A functional nAChR subtype is formed by the combination of multiple subunits arranged as homomeric or heteromeric pentamers, each with a distinct pharmacological profile. Disruption of their neurotransmission contributes to various neuropathologies, emphasizing the need for detailed knowledge of receptor structure, function, subunit composition, dynamics, and potential ligand-binding sites. However, their structural complexity as integral membrane proteins has hindered expression in mammalian cell lines and proven even more challenging to crystallize, limiting insights into ligand interactions. Understanding the molecular determinants governing nAChRs function is essential for the rational design of selective therapeutics targeting neurological disorders. The emergence of a chimeric receptor approach has dramatically improved the ability to study these important proteins and opened new avenues for high-throughput screening in drug discovery efforts. This review explains how the design of chimera constructs using soluble homologs, such as AChBP, provides researchers with an immense opportunity to investigate receptor structure–function relationships and subtype-specific properties, thereby facilitating the development of more effective treatments. Full article

Seed germination is a critical developmental stage exhibiting high vulnerability to salt stress. The role of MYB transcription factors (TFs) in mediating this process in Cannabis sativa L. remains largely unexplored. In this study, we performed a genome-wide analysis and identified 115 CsMYB genes, which were phylogenetically classified into 12 distinct subgroups. In silico promoter analysis revealed a significant enrichment of abscisic acid (ABA)- and methyl jasmonate (MeJA)-responsive cis-elements, suggesting their potential linkage to phytohormone signaling pathways under stress conditions. To investigate their expression during salt stress, we profiled a subset of candidate CsMYB genes during seed germination under 150 mM NaCl treatment based on RNA-seq screening at 24 h post-imbibition (hpi) under salt stress. These candidates exhibited distinct temporal expression profiles: CsMYB33 and CsMYB44 were transiently induced at the early stage (12 h post-imbibition), while CsMYB14, CsMYB78, and CsMYB79 showed sustained upregulation from 24 h to 5 days. In contrast, CsMYB58 and CsMYB110 were downregulated. Synteny analysis indicated a closer evolutionary relationship between CsMYBs and their Arabidopsis thaliana orthologs compared to those in monocots. Protein–protein interaction predictions, based on orthology, further implicated these CsMYBs within putative ABA signaling and reactive oxygen species (ROS) homeostasis networks. Collectively, our findings provide a systematic genomic identification and genomic characterization of the CsMYB family and propose a model for the potential multi-phase involvement of selected CsMYBs in the salt stress response during seed germination. This work establishes a foundational resource and identifies key candidate genes for future functional validation aimed at enhancing salt tolerance in C. sativa. Full article

Postoperative delirium (POD) is a frequent and serious complication among elderly surgical patients. Despite its clinical relevance, reliable biomarkers for early identification and pathophysiological insight remain limited. Recent evidence implicates systemic immune activation and complements dysregulation as contributors to cognitive decline after surgery. This study investigated the association between perioperative levels of selected complement pathway proteins and both the incidence and severity of POD. Methods: We performed a secondary analysis of 22 patients aged ≥ 60 years from the prospective CONFESS cohort undergoing elective spine surgery. Complement proteins (C1q, C2, C4), mannose-binding lectin (MBL), Factor D [FD], Factor B [FB], Factor I [FI] were quantified from blood samples collected at baseline, preoperatively, and on postoperative days 1 and 2. POD was assessed using the Nursing Delirium Screening Scale (Nu-DESC) and Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria. Delirium severity was rated with the Confusion Assessment Method–Severity (CAM-S) scale. Associations were tested using univariate and multivariate regression analyses. Preoperative levels of FD and C2 were significantly elevated in patients who developed POD (FD: p = 0.023; C2: p = 0.044), while C4 levels trended lower. FD remained an independent predictor of POD in multivariate regression (p = 0.049), although cognitive performance was the only significant predictor when adjusted for surgery duration. Delirium severity was associated with perioperative reductions in C1q, FI, and FB and with increased MBL levels, explaining up to 43% of CAM-S score variance. These findings highlight the role of complement activation—particularly FD, C2, MBL—in the development and clinical expression of POD. Complement profiling may offer a novel approach for risk stratification and therapeutic targeting in perioperative neurocognitive disorders. Full article

Introduction/Object: Gastrointestinal cancers are among the most common types of neoplasms and are often associated with malnutrition, which affects physical performance, treatment tolerance and prognosis. This paper aims to synthesize, through a systematic search, the evidence on the impact of nutritional interventions on nutritional status in patients with digestive cancers prone to malnutrition. Methods: A systematic search was performed in PubMed, MDPI, Web of Science and ScienceDirect, for articles published between 2009 and 2025. Overall, 14,503 records were identified, and after screening of titles, abstracts and full-text evaluation, 80 studies (cross-sectional and cohort) were included. Data extraction was performed by a single researcher, using pre-established criteria and a standardized table, and the assessment of study quality was performed qualitatively, taking into account study design, sample size, nutritional assessment methods and clarity of reporting of results. Results: Evidence suggests that individualized and early applied nutritional interventions contribute to maintaining weight and protein status, improve tolerance to oncological treatments and may positively influence patient survival. Conclusions: Nutritional therapy plays a crucial role in preventing complications and supporting the body during oncological treatment, optimizing patients’ quality of life. This review provides a clear synthesis of the current evidence and recognizes methodological limitations related to the qualitative assessment of the included studies. Full article

This study investigates the phytochemical profile, antioxidant capacity, and antimicrobial potential of Crocus sativus L. (saffron) tepal extracts obtained via different solvent systems. Here, a biochemical screening was performed using spectrophotometry and HPLC-DAD, while molecular docking simulations were carried out to evaluate the possible interactions between saffron tepal metabolites and bacterial target proteins. In parallel, antioxidant activity was assessed using radical scavenging assays, whereas antimicrobial potential (i.e., MIC, MBC, and MFC) was tested against selected bacterial strains. Results indicated that aqueous successive and crude extracts yielded the highest concentrations of polyphenols, flavonoids, and condensed tannins. In detail, HPLC-DAD analysis specifically identified significant levels of gallic acid, epicatechin, and various anthocyanins. These extracts demonstrated robust antioxidant and antimicrobial activities. This latter evidence was corroborated by the docking analyses, which revealed that chlorogenic acid and petunidin-3-glucoside exhibited high binding affinities for 2NRK and 2NZF, whereas epicatechin and pelargonidin effectively targeted 8ACR. These findings underscore the therapeutic potential of C. sativus tepals as natural bioactive agents, suggesting a promising role in overcoming antibiotic resistance and supporting their development for pharmaceutical applications. Full article

Background: The current rise in multidrug-resistant pathogens highlights the urgent need for the discovery of novel antibacterial agents with potential clinical applications. A considerable proportion of these developed resistances may be attributable to the intrinsic response of bacteria to antibiotic-induced stress conditions in the environment. Consequently, the identification and characterization of genetic alterations in physiological processes in response to antibiotics represent promising strategies for the discovery and characterization of naturally produced novel antibacterial agents. This study investigated the antimicrobial activity of an antimicrobial active isolate Actinomadura coerulea derived from a meerkat fecal sample. Methods: The production of secondary metabolites that potentially compromise bacterial cell wall integrity was confirmed by the induction of promoter activity in whole-cell biosensors in which an antibiotic-inducible promoter was fused to the luciferase cassette. During plate-based biosensor assays, we identified naturally resistant Bacillus subtilis colonies growing in the zone of inhibition around A. coerulea colonies. After these successive rounds of selection, highly resistant spontaneous B. subtilis mutants had evolved that were subjected to whole-genome sequencing. Results: Non-silent mutations were identified in pssA, which encodes a phosphatidylserine synthase; mdtR, as a gene for the repressor of multidrug resistance proteins, and yhbD, whose function is still unknown. A new cinnamycin-like molecule, coerumycin, was discovered based on the physiological role of PssA and comprehensive genomic analysis of A. coerulea. Additional experiments with cell extracts containing coerumycin as well as the cinnamycin-like compound duramycin confirmed that the interaction between coerumycin and the bacterial cell envelope is inhibited by a loss-of-function mutation in pssA. Conclusion: Our approach demonstrates that combining the exploration of niche habitats for actinomycetes with whole-cell biosensor screening and characterization of natural resistance development provides a promising strategy for identifying novel antibiotics. Full article

Candidozyma auris (formerly Candida auris) is an emerging multidrug-resistant fungal pathogen with confirmed cases in over 30 countries. Although whole-genome sequencing (WGS) analysis defined distinct clades during characterization of underlying genetic mechanism behind multidrug resistance, Clade II remains under-evaluated. In this study, a three-level comparative genomic strategy (Global, Clade, Phenotype) was employed by integration of unbiased genome-wide comparative SNP screening (GATK v4.1.9.0), targeted BLAST profiling (BLAST+ v2.17.0), and in silico protein analysis (ColabFold v1.5.5; DynaMut2 v2.0) for systematic evaluation of mechanisms of antifungal resistance in thirty-nine Clade II C. auris clinical isolates and fourteen reference strains. Global and clade-level analyses confirmed that all the clinical isolates belong to Clade II, according to phylogenetic clustering and mating type locus (MTL) conservation. At the phenotype level, a distinct subclade of fluconazole-resistant mutants was identified to have a heterogenous network of mutations in seven key enzymes associated with cell membrane dynamics and the metabolic stress response. Among these, four core mutations (TAC1B, CAN2, NIC96, PMA1) were confirmed as functional drivers based on strict criteria during multitier in silico protein analysis: cross-species conservation, surface exposure, active site proximity, thermodynamic stability, and protein interface interaction. On the other hand, three high-level fluconazole-resistant clinical isolates (≥128 μg/mL) that lacked these functional drivers were subjected to comprehensive subtractive genomic profiling analysis. The absence of coding mutations in validated resistance drivers, yeast orthologs, and convergent variants suggests that there is an alternative novel non-coding or regulatory mechanism behind fluconazole resistance. These findings highlight Clade II’s evolutionary divergence into two distinct trajectories towards the development of a high level of fluconazole resistance: canonical protein alteration versus regulatory modulation. Full article

Tylorrhynchus heterochaetus is an aquatic food with both edible and medicinal value in China. With a protein-rich body wall, it has strong potential for producing bioactive peptides. To explore its potential as a source of immunomodulatory peptides, in this study, flavor enzymes were selected as the optimal hydrolases, and the hydrolyzed products were subjected to ultrafiltration fractionation. The <3000 Da portion exhibited the most effective immune-stimulating activity in RAW 264.7 macrophages, enhancing phagocytosis and promoting the secretion of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and nitric oxide (NO) in a concentration dependent manner. Peptide omics analysis, combined with the activity and safety screened by bioinformatics, identified 43 candidate peptides. Molecular docking predicts that three novel peptides, LPWDPL, DDFVFLR and LPVGPLFN, exhibit strong binding affinity with toll-like receptor 4/myeloid differentiation factor-2 (TLR4/MD-2) receptors through hydrogen bonding and hydrophobic/π stacking interactions. Synthetic verification confirmed that these peptides were not only non-toxic to cells at concentrations ranging from 62.5 to 1000 µg/mL, but also effective in activating macrophages and stimulating the release of immune mediators. This study successfully identified the specific immunomodulatory peptides of the Tylorrhynchus heterochaetus, supporting its high-value utilization as a natural source of raw materials for immunomodulatory functional foods. Full article

Alzheimer’s disease (AD) involves a constellation of molecular processes that extend well beyond amyloid-β (Aβ) accumulation. Recent anti-amyloid antibodies provide limited clinical benefits, highlighting the need for additional strategies due to their modest efficacy and safety concerns. Increasing proteomic evidence reveals that proteins such as midkine (MDK), pleiotrophin (PTN) and clusterin (CLU) accumulate within amyloid plaques and may shape disease progression, although their precise contributions—protective, pathogenic, or both—remain unknown. In this Perspective, we examine how emerging targeted protein degradation (TPD) technologies, including Proteolysis-Targeting Chimeras (PROTACs), Lysosome-Targeting Chimeras (LYTACs) and molecular glues (MGs), could provide a means to selectively eliminate these co-aggregating proteins. We also discuss advances in degrader design, artificial intelligence (AI)-assisted screening, and strategies aimed at enhancing Central Nervous System (CNS) delivery. We finally outline how integrating TPD modalities with antibody-based and multi-target therapeutic approaches may promote more effective, systems-level interventions for AD. Full article

Artificial metalloenzymes incorporating cobalt protoporphyrin IX (Co-PPIX) are promising for sustainable hydrogen production; however, slow protein preparation and a lack of suitable detection methods limit the systematic optimization of their catalytic performance. Here, we report a streamlined workflow that combines the direct in vivo incorporation of Co-PPIX into cytochrome b₅₆₂ (cyt b₅₆₂) variants with a colorimetric assay for hydrogen evolution, scalable to hundreds of mutants. We screened 103 members of a mutant library and selected the variant Co-Mut25, which displayed activity double than wild type on the screen, and produced over 70% more hydrogen than WT as assessed by gas chromatography. This approach enables the rapid and scalable identification of high-performing cobalt–protein catalysts and expands the toolkit for artificial hydrogenase development. Full article

Chloroplasts are key organelles in plants that carry out photosynthesis, convert light energy into chemical energy, and synthesize organic compounds. In this study, a stably heritable chlorophyll-deficient mutant was screened from the ethyl methanesulfonate-induced mutation library of Wuyunjing 21 (WYJ21). This mutant was designated as chlorophyll deficient 6 (cde6). The cde6 mutant exhibits a low chlorophyll content, photosynthetic defects, an impaired chloroplast structure, a significant reduction in the number of stacked thylakoid layers, and a yellow-green leaf phenotype in the early tillering stage. Through MutMap analysis, it was found that the cde6 mutant harbors a single-base mutation (T→A) in the LOC_Os07g38300 gene. This mutation results in an amino acid substitution from valine (Val) to aspartic acid (Asp) in the encoded protein, thereby affecting the protein’s structure and function. The mutation of CDE6 leads to decreased expression of genes related to chloroplast development and chlorophyll biosynthesis. Further studies revealed that the CDE6, a potential chloroplast ribosome recycle factor, leads to high temperature sensitivity in rice when mutated. As high-temperature stress is a primary constraint to global rice productivity, the identification of CDE6 provides a genetic target for improving thermotolerance. In conclusion, these findings demonstrate that CDE6 plays a crucial role in chloroplast biogenesis and provide new insights into its regulatory function in high-temperature tolerance. Full article