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Gut microbiota-derived short-chain fatty acids (SCFAs), key mediators in gut–lung axis interactions, profoundly influence pulmonary immune homeostasis. Toll-like receptor 2 (TLR2) is crucial for initiating innate immunity against bacterial pneumonia by recognizing bacterial molecular patterns, but its signaling requires precise regulation to balance pathogen clearance and prevent excessive inflammation-induced tissue damage. The major SCFAs—acetate, propionate, and butyrate—modulate immune responses via distinct mechanisms, including G protein-coupled receptor (GPR) activation and histone deacetylase (HDAC) inhibition. However, direct evidence on how these SCFAs differentially regulate the pulmonary TLR2 signaling pathway in pulmonary cells is critically lacking. This review reviews current knowledge, examining TLR2’s role in pulmonary immune defense and bacterial pneumonia, along with its regulatory network, and the molecular details of SCFA immunomodulation through GPR activation and HDAC inhibition. Crucially, we propose and thoroughly discuss a central hypothesis based on indirect evidence and molecular understanding: acetate and propionate likely inhibit early TLR2 signaling activation via GPR-mediated rapid pathways, while butyrate predominantly promotes late-stage inflammation resolution and tissue homeostasis by remodeling gene expression through its HDAC inhibitory activity. We further analyze the potential biological significance of this postulated differential regulatory pattern in maintaining inflammatory balance during bacterial pneumonia. This review integrates literature and mechanistic analysis, highlights critical knowledge gaps in SCFA–pulmonary TLR2 axis research (such as lack of direct evidence, unclear in vivo differential effects, and local concentration influence), and outlines future research directions to deepen understanding of gut–lung axis-mediated pulmonary immune regulation, providing a theoretical foundation for innovative bacterial pneumonia prevention and treatment strategies.

Necrotizing enterocolitis (NEC) is one of the most severe intestinal diseases affecting preterm infants, characterized by high mortality rates and significant long-term complications, which present substantial challenges to clinical management. The primary pathological mechanism underlying NEC is the immature development of the intestinal barrier in preterm infants, which fails to adequately resist luminal pathogen invasion, triggering uncontrolled inflammatory responses and tissue damage. Additionally, intestinal dysbiosis further compromises the integrity of the intestinal barrier. In recent years, growing attention has been given to the role of tryptophan metabolites in maintaining intestinal barrier integrity. As an essential amino acid, tryptophan metabolites—particularly those derived from gut microbiota, such as indole compounds—have been shown to exert significant barrier-protective effects through multiple mechanisms, including the activation of the aryl hydrocarbon receptor (AhR), upregulation of tight junction protein expression, inhibition of inflammatory responses, and promotion of epithelial cell repair. This review aims to summarize the major biological pathways of tryptophan metabolism, with particular emphasis on the molecular mechanisms by which microbial indole derivatives enhance the physical, chemical, and immune barriers. By synthesizing both preclinical studies and clinical evidence, this article explores the translational potential of tryptophan metabolite-targeted strategies for NEC prevention, providing a theoretical foundation for the development of precise preventive interventions.

Background The human brain is a dynamic neural system with time-varying functional connectivity (FC) strengths between brain regions. Evidence indicates that adolescents with major depressive disorder (MDD) exhibit decreased average FC strength in cognitive tasks. Nevertheless, research focused on dynamic FC analysis in this population remains limited. This study aims to identify cognitive task-related dynamic FC features as valuable biomarkers to characterize clinical symptoms in adolescents with MDD. Methods A total of 83 adolescents with MDD and 78 age/sex-matched healthy controls (HCs) were recruited. We utilized functional near-infrared spectroscopy (fNIRS) to record brain functional data from participants while they performed the verbal fluency task (VFT). An analytical framework for fNIRS data was proposed, in which the average FC strength values over the entire VFT duration and the principal components (PCs) of dynamic (time-varying) FC strength values were extracted as static and dynamic FC features, respectively. A random forest model was built to distinguish adolescents with MDD from HCs. Statistical analyses of the FC features were conducted to identify between-group differences, as well as their relationships with clinical symptoms in adolescents with MDD. Results The random forest model achieved an accuracy of 86.32% (95% confidence interval: 83.75%-89.38%) for distinguishing adolescents with MDD from HCs. Significant between-group differences emerged in several FC features (false discovery rate-corrected q  < 0.05). For adolescents with MDD, the average FC strength value in the right dorsolateral prefrontal cortex (DLPFC) ~ right medial prefrontal cortex (mPFC) pathway was a significant predictor of depressive and anxious symptoms; the 3rd PC of dynamic FC strength values in the left DLPFC ~ left temporal lobe (TL) pathway and the 5th PC of dynamic FC strength values in the right mPFC ~ right TL pathway were significant predictors of anhedonic symptoms. Conclusions VFT-related static and dynamic FC features in specific brain pathways are potential biomarkers for characterizing clinical symptoms in adolescents with MDD. The developed random forest model holds promise as a diagnostic tool for MDD in adolescents. Clinical trial number Not applicable.

Background The Rho GTPase Rac family small GTPase 1 (RAC1) is considered a promising fibrotic therapeutic target, but the role of its activator, dedicator of cytokinesis 2 (DOCK2), in liver fibrosis is largely unknown. This study aimed to investigate the expression and role of DOCK2 in cholestasis-induced liver fibrosis and to further explore the potential mechanisms. Results Cholestasis was induced in male C57BL/6 mice by bile duct ligation (BDL). DOCK2 knockdown was achieved by tail vein injection of adenovirus containing DOCK2-targeting shRNA. The effect of DOCK2 knockdown on cholestatic liver injury was evaluated at different time points after BDL. Hepatic DOCK2 expression gradually increased after BDL. Knockdown of DOCK2 reduced the necrotic area in BDL liver and downregulated serum levels of liver injury indicators. At 3d post-BDL (acute phase), DOCK2 knockdown alleviated M1 macrophage inflammation in the liver, as evidenced by reduced infiltrating iNOS + macrophages and inflammatory cytokines and mitigated NLRP3 inflammasome activation. At 14d post-BDL (chronic phase), DOCK2 knockdown suppressed hepatic stellate cell (HSC) activation and liver fibrosis as indicated by decreased α-SMA + HSCs and extracellular matrix deposition. In vitro experiments further demonstrated that DOCK2 knockdown suppressed M1 macrophage polarisation and HSC to myofibroblast transition, accompanied by inhibition of RAC1 activation. Conclusions In summary, this study demonstrates for the first time that the RAC1 activator DOCK2 regulates M1 macrophage polarisation and hepatic stellate cell activation to promote cholestasis-induced liver inflammation and fibrosis, suggesting that DOCK2 may be a potential therapeutic target in cholestatic liver injury.

Background and objective: IBS-D is a common functional bowel disease with complex etiology and without biomarker. The pathological and physiological basis of IBS-D focuses on visceral hypersensitivity. However, its epigenetic mechanism remains elusive. Our study aimed to integrate the relationship between differentially expressed miRNAs, mRNAs and proteins in IBS-D patients in order to reveal epigenetic mechanism of visceral hypersensitivity from transcription and protein levels and provide the molecular basis for discovering biomarkers of IBS-D. Methods: The intestinal biopsies from IBS-D patients and healthy volunteers were obtained for high-throughput sequencing of miRNAs and mRNAs. The differential miRNAs were selected and verified by q-PCR experiment followed by target mRNA prediction. Biological functions were respectively analyzed for target mRNAs, differential mRNAs and the previously identified differential proteins in order to explore the characteristic involved visceral hypersensitivity. At last, interaction analysis of miRNAs, mRNAs and proteins was performed for the epigenetic regulation mechanism from transcription and protein levels. Results: Thirty-three miRNAs were found to be differentially expressed in IBS-D and five of them were further confirmed, including upregulated hsa-miR-641, hsa-miR-1843, hsa-let-7d-3p and downregulated hsa-miR-219a-5p, hsa-miR-19b-1-5p. In addition, 3,812 differential mRNAs were identified. Thirty intersecting molecules were found from the analysis on the target mRNAs of miRNAs and mRNAs. Fourteen intersecting molecules were obtained from the analysis on the target mRNAs and proteins, and thirty-six intersecting molecules were identified from analysis on the proteins and different mRNAs. According to the integrated analysis of miRNA-mRNA-protein, we noticed two new molecules COPS2 regulated by hsa-miR-19b-1-5p and MARCKS regulated by hsa-miR-641. Meanwhile some critical signaling pathways in IBS-D were found such as MAPK, GABAergic synapse, Glutamatergic synapse, and Adherens junction. Conclusion: The expressions of hsa-miR-641, hsa-miR-1843, hsa-let-7d-3p, hsa-miR-219a-5p, and hsa-miR-19b-1-5p in the intestinal tissues of IBS-D patients were significantly different. Moreover, they could regulate a variety of molecules and signaling pathways, which were involved in the multifaceted and multilevel mechanism of visceral hypersensitivity of IBS-D.

The principal cause of cervical cancer is sustained high-risk human papillomavirus (HPV) infection. However, some cases remain unrelated to HPV infections. Current HPV screening methods have difficulties identifying HPV-negative patients and implementing them in low-resource settings. Therefore, it is important to explore easily accessible and low-cost biomarkers to optimize the current cervical cancer screening strategies. This cross-sectional study included 6998 women from the US National Health and Nutrition Examination Survey (NHANES), among whom 147 had self-reported cervical cancer. Serum γ - Glutamyltransferase (GGT) was employed as a continuous variable (naturally logarithmically transformed) and a categorical variable (≥50 U/L versus <50 U/L), and multivariate logistic regression models were utilized to progressively adjust for demographic features, sexual history, and clinical behaviors. The restricted cubic spline approach was adopted to further explore the dose-response relationship between GGT levels and cervical cancer to depict the potential nonlinear trends between them in a more elaborate manner. We also conducted subgroup and sensitivity analyses to ensure reliability of our results. This included multiple imputation of missing data and adjustment for crucial covariates, such as body mass index (BMI) and tobacco exposure, to comprehensively evaluate the impact of different factors on the outcomes. Ultimately, through mediation analysis, we probed the mediating function of tobacco exposure in the association between GGT levels and cervical cancer, aiming to obtain a more profound understanding of the underlying mechanisms of this health-related relationship. Serum GGT levels are positively correlated with cervical cancer risk. For each log unit increase in GGT levels, there was a 31% increased risk of cervical cancer (OR = 1.31, 95%CI: 1.01-1.70, P = 0.041) in the model adjusted for multiple risk factors. When the GGT level reached or exceeded 50 U/L, the risk increased by 76% (OR = 1.76, 95%CI: 1.04-2.98, P = 0.034). This tendency was consistent across several crucial subgroups, particularly among HPV-negative women (OR = 1.36, 95%CI: 1.01-1.84), suggesting that GGT may have some significance in different populations. The results of the sensitivity analyses demonstrated that the main findings remained robust, even when multiple imputations were employed to handle missing data. Nevertheless, the significant association between GGT and cervical cancer weakened when tobacco exposure was further adjusted, indicating that tobacco use might be involved. Mediation analysis further showed that the overall impact of GGT on cervical cancer was statistically significant (β = 0.0014; 95%CI: 0.0001-0.0020; P = 0.046), and approximately 18.15% of the impact was accounted for by tobacco exposure (ACME: β = 0.0003, 95%CI: 0.0001-0.0004, P < 0.001), suggesting a partial mediating role. Elevated serum GGT levels are associated with a heightened risk of cervical cancer even in HPV-negative patients. Although this association is partly mediated by tobacco exposure, GGT may still play a role in cervical cancer via nontobacco routes. The potential application of GGT as an auxiliary biomarker requires further validation in prospective studies.

肝脏疾病早期不易被发现，有创性诊断方式如肝穿刺虽然诊断相对准确，但接受度不高，严重制约肝脏疾病诊疗技术的提高，因此寻找新的生物标志物及新的治疗靶点尤为重要。转运RNA衍生小RNA (tsRNA) 作为新兴的液体活检生物标志物，在病毒性肝炎、脂肪性肝病、肝损伤、肝癌等肝脏疾病中异常表达，通过发挥调节基因表达、表观遗传调控、蛋白质翻译等生物学功能，影响肝脏疾病的发生和进展。本文就tsRNA的来源和分类、生物学功能以及tsRNA作为肝脏疾病生物标志物和潜在治疗靶点进行综述，以期为肝脏疾病的早期诊断及治疗提供思路。

Although previous studies using phenotypic or/and genomic approaches monitoring have revealed the spatiotemporal distribution of antimicrobial resistance (AMR) in Salmonella in local areas, their geographical patterns and driving factors remain largely unknown at a global scale. Here, we performed an analysis of publicly available data of 208,233 Salmonella genomes in 148 countries/regions between 1900 and 2023 and explored driving indicators of AMR. Overall, we found that the geographic distribution of AMR varied depending on the location, source, and serovar. The proportion of AMR levels increased across six continents, especially in serovars Agona, Dublin, I 1,4,[5],12:i:-, Muenchen, Senftenberg, Mbandaka mainly from chickens, food, wild animals, and the environment, while decreased in Schwarzengrund and Saintpaul mainly from cattle, pigs, and turkeys. We also found that S . Typhimurium exhibiting macro, red, dry, and rough was detected as early as 1992 in the USA, earlier than in China. Moreover, we identified that antibiotic consumption, agriculture, climate, urban, health, and socioeconomic factors contribute to the development of AMR in Salmonella . We present a globally high-resolution genetic atlas of Salmonella and also identify some factors driving the rise of AMR, which can provide valuable information for understanding the transmission dynamics and evolutionary trajectories of Salmonella . Salmonella is a major cause of foodborne disease worldwide. Authors created a Salmonella database and present a genetic atlas of antimicrobial resistance, identifying some socioeconomic and environmental drivers for the rise of resistance globally.

Cyano‐functionalized sp2‐carbon‐conjugated covalent organic frameworks (CN‐COFs) have been considered as promising candidates for artificial photosynthesis of hydrogen peroxide (H2O2). Nevertheless, the performance of CN‐COFs is inherently limited by constrained oxygen capture capacity, insufficient charge separation, and rapid carrier recombination. Herein, the study rationally reports a strategy for integrating amidoxime groups (AO) into a COF through one‐step cyano hydrolysis process to increase photocatalytic H2O2 production. Combined simulations and characterizations reveal that introducing AO groups enhances hydrophilicity, stabilizes adsorbed Oxygen (O2) via hydrogen bonding, accelerates the charge separation and transfer, as well as lowers the energy barrier for oxygen reduction reaction pathway, thus achieving an unmatched H2O2 production rate of 6024 µmol h−1 g−1. Importantly, the solar‐to‐chemical conversion (SCC) efficiency of PTTN‐AO reaches 0.61%, significantly surpassing that of natural plants (≈0.1%) and most COF‐based photocatalysts. The current findings are encouraging for the molecular design of polymers for green and efficient H2O2 production. Amidoxime‐functionalization sp2‐carbon‐conjugated organic framework (PTTN‐AO) is carefully designed and synthesized to increase hydrophilicity, stabilize adsorbed O2 via hydrogen bonding, and accelerate the charge separation and transfer. This strategy promotes the photocatalytic 2e− oxygen reduction reaction to produce hydrogen peroxide.

Overproduction of reactive oxygen species (ROS), metal ion accumulation, and tricarboxylic acid cycle collapse are crucial factors in mitochondria‐mediated cell death. However, the highly adaptive nature and damage‐repair capabilities of malignant tumors strongly limit the efficacy of treatments based on a single treatment mode. To address this challenge, a self‐reinforced bimetallic Mito‐Jammer is developed by incorporating doxorubicin (DOX) and calcium peroxide (CaO2) into hyaluronic acid (HA) ‐modified metal‐organic frameworks (MOF). After cellular, Mito‐Jammer dissociates into CaO2 and Cu2+ in the tumor microenvironment. The exposed CaO2 further yields hydrogen peroxide (H2O2) and Ca2+ in a weakly acidic environment to strengthen the Cu2+‐based Fenton‐like reaction. Furthermore, the combination of chemodynamic therapy and Ca2+ overload exacerbates ROS storms and mitochondrial damage, resulting in the downregulation of intracellular adenosine triphosphate (ATP) levels and blocking of Cu‐ATPase to sensitize cuproptosis. This multilevel interaction strategy also activates robust immunogenic cell death and suppresses tumor metastasis simultaneously. This study presents a multivariate model for revolutionizing mitochondria damage, relying on the continuous retention of bimetallic ions to boost cuproptosis/immunotherapy in cancer. Self‐reinforced bimetallic Mito‐Jammer is rationally designed and synthesized by loading DOX and CaO2 into the hyaluronic acid‐modified metal‐organic framework‐199. By triggering reactive oxygen species storm and Ca2+ overload, the Mito‐Jammer could enhance the tumor‐specific Cu2+ aggregation and induce cascade mitochondrial damage to further arouse tumor‐specific cuproptosis and cuproptosis‐related immunotherapy.