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AI-driven and computation-based high-throughput methods were developed to mine novel dipeptidyl peptidase IV (DPP-IV) inhibitory peptides from hemp seed proteins. The identified peptide VAMP demonstrates a glucose-lowering effect through dual mechanisms: inhibition of DPP-IV activity and selective promotion of intestinal Akkermansia muciniphila growth.

Hepatocellular carcinoma (HCC) is associated with high mortality rates despite the widespread application of radiofrequency ablation (RFA), which has limited therapeutic efficacy as a monotherapy. This study investigated ribonucleotide reductase M2 (RRM2) upregulation in post-RFA HCC tissues and developed a targeted nanoco-delivery system (red blood cell membrane/cRGD-modified pH-sensitive liposomes [sS@RBCM/cRGD-phLips]) to increase RFA efficacy through specific RRM2 knockout. RRM2 knockout synergistically amplified RFA-induced tumor cell death by promoting ferroptosis and immunogenic cell death. Mechanistically, RRM2 knockout upregulated the STAT1–IRF1–ACSL4 axis, which potentiated lipid peroxidation and ferroptosis. Furthermore, the nanocarrier system enhanced dendritic cell maturation and cytotoxic T cell infiltration, thereby remodeling the tumor immune microenvironment. In vivo experiments revealed that the combination of RFA and RRM2-targeted nanoparticles significantly suppressed tumor growth and prolonged survival in HCC-bearing mice with minimal systemic toxicity. Notably, the dual-loaded nanoparticles also enhanced the efficacy of anti-programmed cell death protein 1 therapy, suggesting a promising combinatorial approach for HCC treatment. This study presents a novel therapeutic strategy that integrates RRM2-targeted gene editing with RFA, offering a robust and synergistic approach for improving HCC outcomes.

Using a robust functional metagenomics approach, we demonstrated that polar environments are important reservoirs of novel antibiotic resistance genes (ARGs). DNA was initially extracted from cultured bacterial consortia in the polar soils and recombined into plasmid vectors and then transformed into Escherichia coli (E. coli) for the subsequent screening of antibiotic resistance. Consequently, we identified 671 novel polar ARGs with experimentally verified resistance against multiple clinical antibiotics (cefotaxime, folate synthesis inhibitors, and clindamycin). Bioinformatics analysis revealed that novel polar ARGs had limited mobility and dissemination potential and were seldom carried by human bacterial pathogens. Overall, this study offers a comprehensive perspective on previously overlooked novel ARGs in polar regions, advancing our understanding of environmental resistomes.

Lipopolysaccharides (LPS) derived from intestinal symbionts plays a critical role in modulating and maintaining mucosal immunity. In this study, we investigated the chemical characteristics and antiobesity properties of Akkermansia muciniphila HW07 LPS (ALPS). ALPS was identified as hypo-acylated, mono/bis-phosphorylated, rough-type LPS. Compared to Escherichia coli LPS (ELPS), ALPS functions as a weak agonist of TLR4/TLR2. Intraperitoneal administration of ALPS in diet-induced obese (DIO) mice suppressed weight gain, improved metabolic parameters, restored gut barrier integrity, and modulated the gut microbiota. Notably, ALPS treatment significantly increased plasma interleukin (IL)-22 levels. Furthermore, neutralizing IL-22 with an antibody eliminated the antiobesity effects of ALPS in DIO mice. Mechanistically, ALPS upregulated the expression of both IL-22 and its upstream cytokine IL-23 in a TLR4-dependent manner. These findings confirm that activation of the TLR4−IL-23−IL-22 immune axis is a key mechanism underlying the antiobesity effect of ALPS. In acute toxicity assessment, no fatalities were observed in ALPS-treated mice, whereas ELPS treatment led to a 40% mortality rate. Collectively, our results demonstrate that hypo-acylated LPS from A. muciniphila functions as a metabolically beneficial immune modulator that exerts immunomodulatory effects through the TLR4−IL-22 axis and suggests ALPS as a promising novel therapeutic strategy for metabolic disorders.

Polycystic ovary syndrome (PCOS) is a prevalent endocrine and reproductive disorder affecting women of reproductive age. While the gut microbiota has been implicated in PCOS pathophysiology, the role of microbial-derived metabolites as mediators of host–microbe interactions remains poorly defined. Here, we integrated untargeted gut metabolomics with metagenomic profiling in patients with PCOS and identified a marked depletion of 3,4-dihydroxyphenylacetic acid (DHPAA), a flavonoid-derived microbial catabolite. Oral administration of DHPAA ameliorated PCOS-like phenotypes in two mouse models by suppressing bone morphogenetic protein signaling and reducing anti-Müllerian hormone (AMH) levels. We found that DHPAA production depends on gut microbial degradation of dietary flavonoids. We further identified a bacterial species, Streptococcus thermophilus, consistently depleted in PCOS across two human cohorts and a mouse model, restored DHPAA levels and improved reproductive outcomes in mice. Conversely, a β-galactosidase-deficient mutant of S. thermophilus failed to confer these benefits, highlighting β-galactosidase as a critical enzyme in DHPAA biosynthesis. Our findings establish DHPAA as a key microbial metabolite linking diet, microbiota, and reproductive health, and propose its potential as a novel therapeutic candidate for PCOS.

Porcine deltacoronavirus (PDCoV) is a significant pathogen of swine with a global distribution, leading to severe gastrointestinal disease and substantial economic losses. Furthermore, PDCoV poses a potential threat to human health, as evidenced by the recent identification of three cases of infection in Haitian children. This study aimed to investigate the effects of PDCoV infection on host intestinal microbiota and bile acid metabolism, as well as the antiviral effects of lithocholic acid (LCA) in vitro and in vivo. Our results revealed that PDCoV infection caused microbiota dysbiosis in piglets, significantly reducing the intestinal abundance of Bacteroides fragilis (B. fragilis), a reduction that correlated with disruptions in bile acid metabolism. Colonization with bile salt hydrolase (BSH)-producing B. fragilis increased the levels of unconjugated bile acids and inhibited PDCoV infection, highlighting the role of microbiota-associated bile acid metabolism in viral pathogenesis. LCA, a prominent unconjugated bile acid, was shown to effectively inhibit PDCoV infection in porcine small intestinal epithelial cells and porcine intestinal enteroids. Notably, LCA inhibited PDCoV replication independently of bile acid receptor signaling and innate immune modulation. Mechanistic studies indicated that LCA prevents PDCoV infection by disrupting the viral entry process, specifically inhibiting the binding between the PDCoV spike protein and its cellular receptor, aminopeptidase N. In vivo experiments further confirmed that LCA significantly inhibited PDCoV infection in piglets. These results collectively highlight the potential of LCA as a therapeutic agent against PDCoV by targeting and disrupting the viral entry process, providing a novel strategy to control zoonotic PDCoV infections.

Extensive herbicide residues in the black soil of northeastern China are considered a significant agricultural pollution threat, yet effective bioremediation of this complex and persistent mixture remains a challenge. We identified 16 bacterial species that associated with these herbicide residues in situ, nine of which were culturable and could degrade multiple herbicides. From these strains, we constructed a four-member synthetic microbial community (SynCom) that degrades multiple herbicides, stabilizes colonization, increases soil bacterial biodiversity, and alters soil enzyme activity. Under laboratory conditions, the SynCom degraded eight herbicides within 48 h with >60% efficiency, and accumulated carbon on the cell surface of the constituent species. In black soil microcosm trials, the SynCom achieved 60%−99% degradation efficiency of the endogenous herbicides over 35 days and was able to consistently maintain biomass above 10⁴ cfu/g soil. Additionally, SynCom application resulted in an accumulation of carbohydrate-active enzymes and microbial necromass-associated carbon, which suggests activation of soil microbial carbon metabolism. In support of this, metagenomic analyses identified a significant increase in the abundance of genes involved in the tricarboxylic acid cycle, pyruvate metabolism, and glycolysis. This SynCom represents a compelling bioremediation solution that simultaneously improves soil microbial carbon metabolism activity in polluted soils.

Randomized double-blind trials have shown that probiotic mixtures significantly increase high-density lipoprotein (HDL) levels and reduce the risk of cardiovascular disease mortality in end-stage renal disease (ESRD) patients. Meta-analysis with prospective cohort studies further confirms that elevated HDL is a protective factor for ESRD outcomes. In severe renal injury models, including 5/6 nephrectomy and apolipoprotein E-deficient (ApoE^−/−) mice, probiotics restored cardiac function, mirroring the cardioprotective effects seen in humans. Mechanistic studies indicate that probiotics enhance intestinal HDL3 production through the insulin-mediated SP1(P)-CYP27A-LXRα/β-ABCA1 pathway, thereby maintaining HDL metabolic homeostasis. This study reveals a novel link between probiotic intervention and host cholesterol metabolism, offering a previously unexplored strategy for reducing cardiovascular risk in ESRD patients.

We developed PMAT2, an advanced toolkit for lineage-specific de novo assembly of plant, animal, and fungal mitochondrial genomes, as well as plant chloroplast genome. PMAT2 leverages optimized graph-based strategies tailored to organelle genome complexity, enabling complete and accurate assemblies, even with approximately 1 × highly accurate PacBio high-fidelity (HiFi) reads. By assembling 150 organellar genomes across diverse lineages, PMAT2 outperformed existing tools in assembly completeness. The source code for PMAT2 is publicly available at https://github.com/aiPGAB/PMAT2.

The study included 163 patients with muscle-invasive bladder cancer (MIBC) from 14 hospitals, categorized into the neoadjuvant immunotherapy-combined-modality therapy (Neoimmu-CMT), trimodal therapy (TMT), and neoadjuvant chemotherapy-combined-modality therapy (NAC-CMT) subgroups. Propensity score matching (PSM) was utilized to mitigate baseline variability. Univariate and multivariate Cox analyses were used to identify potential prognostic factors. Biomarker assessment comprised immunohistochemistry and single-cell RNA sequencing. After PSM, Neoimmu-CMT demonstrated superior efficacy over NAC-CMT and comparability to TMT. A clinical complete response to neoadjuvant treatment and lower clinical T stage were positive prognostic factors for Neoimmu-CMT. Biomarker analysis showed that the immune phenotype of the tumor microenvironment (TME) was closely associated with bladder preservation outcomes. We assessed the potential relationship between various cell types in the TME and bladder preservation outcomes using single-cell RNA sequencing. The results showed that the dynamic distribution of fibroblast and NK/T cell subclusters was associated with bladder preservation outcomes. In the future, the development of Neoimmu-CMT will substantially expand its application in bladder preservation therapies.