Following acute kidney injury (AKI), a substantial subset of patients experiences an irreversible progression to chronic kidney disease (CKD), yet the molecular determinants governing this maladaptive transition remain elusive, and effective clinical interventions are lacking. Here, we identify lactate as a key metabolic determinant orchestrating the transition from AKI to CKD. Analysis of the UK Biobank cohort reveals that elevated circulating lactate independently predicts CKD development in AKI patients and correlates with fibrotic progression. Using murine ischemia-reperfusion injury models, we demonstrate that lactate drives sustained renal damage through post-translational lactylation of the RNA helicase DDX18. Mechanistically, p300-mediated lactylation of DDX18 at lysine 116 disrupts its nucleolar retention, causing redistribution to the nucleoplasm where it acquires enhanced binding affinity for CD44 mRNA. This subcellular relocalization stabilizes CD44 mRNA through altered RNA-protein interactions, thereby amplifying fibrotic signaling pathways. Therapeutically, we developed a kidney-targeted, cell-penetrating peptide that specifically inhibits DDX18 K116 lactylation, effectively attenuating fibrotic progression in injured kidneys. Our findings establish protein lactylation as a regulatory mechanism governing RNA helicase nucleolar localization and subsequent control of mRNA stability, revealing a potential therapeutic target for interrupting fibrotic processes in chronic kidney disease.

Shift work (SW) has been linked to the occurrence of various chronic diseases. However, its potential correlation with gout has not been established. This study aimed to investigate the effects of the SW schedule on incident gout. A total of 281,500 individuals enrolled in the UK Biobank were included in the cohort study. The Cox proportional hazards model was used to investigate the association between SW and incident gout. Additionally, a genetic risk score (GRS) was constructed to assess the joint effects of SW and genetic predisposition on the risk of gout. During a 13-year follow-up period, we recorded 4,282 new-onset gout cases. In the current SW analysis, individuals with some night shifts had a 15.1

Sepsis is a prominent cause of mortality worldwide, attributed to the overactivation of the immune system. Ginseng is a medicinal plant with strong biological effects, yet the mechanism underlying its limited bioavailability and robust biological activity remains poorly understood. Here, our data revealed that ginseng-derived vesicle-like nanoparticles (GDVLNs) exhibit high biocompatibility and can be rapidly absorbed and distributed to various extraintestinal organs. Moreover, GDVLNs effectively protect against multiple organ dysfunction caused by sepsis in an RNA-dependent manner, as evidenced by the retention of protection after protein degradation, but loss of protective effect following lipid extraction administration and RNA degradation. Furthermore, through de novo miRNA sequencing, we identified pgi-MIR6136a-p3 as the most abundant species-specific miRNA in GDVLNs. We found that GDVLNs deliver pgi-MIR6136a-p3 into macrophages, thereby alleviating sepsis-induced multiple organ injury. Mechanistically, pgi-MIR6136a-p3 derived from GDVLNs inhibits systemic inflammation against sepsis by directly targeting ELF3 and suppressing the activation of the NF-κB signaling. Lastly, we validated that GDVLNs-derived pgi-MIR6136a-p3 also suppresses ELF3/NF-κB signaling in human monocyte-derived macrophages. These findings reveal a novel molecular mechanism that GDVLNs derived pgi-MIR6136a-p3 regulate innate immunity across kingdoms and provide a promising translational therapeutic strategy for sepsis.

Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease. The Shen-Kang Recipe (SKR) is a traditional Chinese medicine formula used clinically to slow DKD progression, but its bioactive constituents and molecular targets remain unclear. Solute carrier family 15 member 2 (SLC15A2/PEPT2), a high-affinity peptide transporter expressed in renal proximal tubules, has been implicated in kidney pathophysiology, yet its potential role in mediating the therapeutic effects of the SKR has not been explored. Here, we evaluated the effects of the SKR in db/db mice and found that SKR treatment significantly improved renal function, attenuated glomerulosclerosis, and reduced interstitial collagen deposition. Wide-target metabolomics and quantitative proteomics revealed that the SKR broadly reversed DKD-associated metabolic and proteomic disturbances, particularly in pathways related to energy and amino acid metabolism. Proteomic analysis identified SLC15A2 as a key proximal tubule protein downregulated in DKD and selectively restored by the SKR. UPLC-Q-TOF/MS-based serum pharmacochemistry and network pharmacology highlighted quercetin as a principal bioactive component of the SKR. Molecular docking, molecular dynamics simulations, and surface plasmon resonance (SPR) confirmed direct, high-affinity binding between quercetin and SLC15A2 (KD = 7.5 µM). In TGF-β1-stimulated HK-2 cells, quercetin suppressed epithelial-mesenchymal transition (EMT), as evidenced by restored E-cadherin and reduced N-cadherin, vimentin, and α-SMA expression; this effect was abrogated by siRNA-mediated SLC15A2 knockdown, demonstrating the functional necessity of this axis. Collectively, these findings identify a quercetin-SLC15A2 axis through which the SKR inhibits EMT and alleviates renal fibrosis in DKD, providing a mechanistic basis for its clinical application and nominating SLC15A2 as a potential therapeutic target.

Shan yao (SY, Dioscorea opposita Thunb.), is a potential industrial crop with high-value bioactive components. It is traditionally used in Chinese medicine for diabetes-related symptoms. Gestational Diabetes Mellitus (GDM) is a specific form of diabetes characterized by abnormal glucose tolerance during pregnancy. However, the mechanisms by which SY manages GDM remain unclear. This study aimed to identify bioactive compounds and assess the mechanisms of SY in managing GDM. We employed computational biomedical modelling and screening to explore the potential pharmacodynamics of the chemical components of SY and their mechanisms. We identified a total of 71 SY phytochemicals and 101 GDM proteins, resulting in 7171 molecular docking interactions. ABCC8 emerged as a primary target due to its high ligand binding affinities (-7.6 kcal/mol) and association scores (0.57). After conducting virtual pharmacokinetic and toxicity prediction analyses to ensure selection of safe compounds, four complexes were prioritized for subsequent molecular dynamics simulations and analysis, which were conducted for 100 ns in triplicate. Certain chemical classes, such as steroids and flavonoids, exhibited strong binding with ABCC8. Notably, batatasin III and abscisic acid (ABA) emerged as promising ligand choices, displaying minimal structural deviations and stable positioning within the binding pocket. The confirmation of batatasin III and ABA in SY samples via LC-MS/MS assays provided further support for these findings. This study

The interplay between gut microbiota and the mucosal immune system critically regulates systemic immunity and disease susceptibility. Here, we demonstrate that intestinal epithelial Toll-like receptor (TLR)4 deficiency reshaped the gut microbiome and subsequently exacerbated atopic dermatitis (AD) in mice. Mechanistically, TLR4 deficiency reduced Akkermansia muciniphila abundance and enriched choline trimethylamine-lyase (CutC)-expressing bacteria. This enhanced microbial choline-to-trimethylamine conversion and elevated circulating trimethylamine oxide (TMAO) levels. Clinically, AD patients exhibited increased plasma TMAO levels that positively correlated with disease severity and immunoglobulin E (IgE) levels. UK Biobank data also showed that higher dietary choline intake was associated with increased AD risk. TMAO promoted T helper (Th)2 differentiation by directly interacting with protein phosphatase 5 (PPP5) and enhancing PPP5-mediated dephosphorylation of PPARγ. CD4+ T cell-specific PPARγ deletion abolished TMAO-driven skin pathology in AD mice. Our results reveal intestinal dysbiosis, as a result of innate immune deficiency, as a driver of inflammatory Th2 cells and AD pathology, highlighting a link among the gut immune environment, microbial metabolites, and skin disease.

BACKGROUND AND AIM:New therapeutic strategies for heart failure are urgently needed. The protective effects of cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) pathway on heart have been widely reported. Despite phosphodiesterase 9A (PDE9A) inhibitors combating cardiac remodeling, clinically available drugs are lacking. Hederagenin (HED) is a natural bioactive compound that possesses a wide range of pharmacological activities. However, the role of HED in cardiac remodeling and its underlying mechanisms remains elusive. This study aimed to investigate the effects of HED on cardiac remodeling and its molecular targets. EXPERIMENTAL PROCEDURE:Through models of cells, zebrafish and mice, we investigated the effects of HED on cardiac hypertrophic response. In mice subjected to ISO-induced hypertrophy, HED was administered orally at doses of 1.25, 2.5, and 5 mg/kg once daily for 3 weeks. HuProt v4.0 20K Human Proteome Microarray was used to identify the molecular target of HED, followed by validation using surface plasmon resonance (SPR), molecular docking, and site-directed mutagenesis. KEY RESULTS:HED attenuated hypertrophy and fibrotic responses in vitro and in vivo. Proteome microarrays identified PDE9A as the molecular target of HED. HED directly bound to PDE9A through hydrogen bonds of Asp 293, and inhibited its activity. Functional tests demonstrated that the protective effects of HED were mediated by targeting PDE9A and then activating cGMP-PKG signaling. Overexpression of PDE9A abolished the protective effect of HED on cardiac remodeling and the activation of the cGMP-PKG pathway. CONCLUSIONS AND IMPLICATIONS:Our study suggested that HED, as a novel PDE9A inhibitor, ameliorated cardiac hypertrophic response by activating the cGMP-PKG signaling pathway, presenting a potential therapeutic strategy for heart failure.

Objectives:The aims of this study were to investigate the distribution of traditional Chinese medicine (TCM) constitution types in individuals with prediabetes and to identify high-risk constitutions, thereby providing an evidence-based foundation for the prevention and treatment of prediabetes. Methods:We systematically searched PubMed, Embase, Web of Science, the Cochrane Library, and four Chinese databases for literature examining the association between prediabetes and TCM constitution types. A single-proportion meta-analysis of cross-sectional studies and a comparative meta-analysis of case-control studies comparing individuals with prediabetes and the general population were performed using the Stata17.0 software. Effect sizes were expressed as odds ratios (ORs) with 95% confidence intervals (CIs). Study quality was assessed independently by two reviewers. The primary outcomes included the distribution of TCM constitution types in the prediabetes population and the comparative ORs between groups. Results:A total of 30 cross-sectional studies and 5 case-control studies, involving 8,469 participants, were included. Among individuals with prediabetes, the pooled prevalence rates of phlegm-dampness constitution (PDC), balanced constitution (BC), yin-deficiency constitution (YIDC), qi-deficiency constitution (QDC), and damp-heat constitution (DHC) were 20% (95% CI: 16%-24%), BC 16% (10%-22%), 12% (10%-15%), 11% (9%-14%), and 10% (7%-13%), respectively. Meta-analysis of case-control studies indicated that the ORs for prediabetes risk in individuals with PDC, qi-stagnation constitution (QSC), QDC, and YIDC were PDC 2.49 (95CI%: 1.27-4.87), 2.03 (1.06-3.90), 1.78 (1.11-2.84), and 1.52 (1.09-2.10), respectively, while the OR for BC was 0.45 (0.30-0.66). Subgroup analyses revealed variations in TCM constitution distribution across regions and age groups, as well as difference associated with study quality. Conclusion:PDC, YIDC, QDC, DHC, and BC are the most common TCM constitution types (prevalence ≥10%) observed in individuals with prediabetes. PDC, QDC, YIDC, and QSC may represent risk factors for prediabetes, whereas BC appears to be a protective factor. Further high-quality case-control and cohort studies are warranted to strengthen the evidence regarding the relationship between prediabetes and TCM constitution types. Systematic Review Registration:https://www.crd.york.ac.uk/prospero/, identifier CRD42024607164.

Abstract Objective: This study aimed to investigate the effects of Wuling San (WLS) on nonalcoholic fatty liver disease (NAFLD) progression and to elucidate its underlying mechanisms, with particular emphasis on mitochondrial dynamics and protein kinase B (AKT)-mediated signaling. Materials and Methods: Ultra-performance liquid chromatography tandem mass spectrometry and network pharmacology were employed to identify the major bioactive components of WLS and predict their potential molecular targets. Both in vivo (db/db mice) and in vitro (free fatty acid-induced alpha mouse liver 12 hepatocyte) models were used to evaluate the effects of WLS. A series of biochemical assays, histological evaluations, metabolomic analyses, mitochondrial function assessments, and molecular docking studies were performed to elucidate the mechanisms of action. Results: WLS significantly reduced hepatic lipid accumulation, improved liver function, and attenuated inflammatory responses. Metabolomic profiling revealed substantial modulation of lipid metabolites, whereas mitochondrial assays confirmed restored dynamics and structural integrity. AKT was identified as a key regulatory target, and inhibition by MK2206 abolished the beneficial effects of WLS and ursolic acid. Conclusions: WLS alleviates NAFLD by enhancing mitochondrial dynamic function through AKT activation, suggesting that it may represent a promising therapeutic strategy for metabolic liver disease.

Renal injury is a common complication of hyperuricemia (HUA), which has been recognized as an independent risk factor for chronic kidney disease (CKD). The gut-kidney axis theory suggests that targeting the gut microbiota may be a potential treatment option for kidney disease. In this study, we utilized a spontaneous HUA rat model to demonstrate that Simiao decoction (SMD), a traditional Chinese medicine formula, can effectively alleviate HUA-induced renal injury by modulating gut microbiota and bacterial metabolism of tryptophan and tyrosine, thereby reducing gut-derived uremic toxins such as indoxyl sulfate (IS) and p-Cresol (PC). Fecal microbiota transplantation (FMT) further confirmed that the therapeutic effect of SMD was mediated by gut microbiota. Finally, in vitro studies revealed that IS promotes epithelial-mesenchymal transition (EMT) while PC induces cellular senescence in tubular cells. Collectively, our findings suggest that SMD can effectively alleviate HUA-induced renal injury through regulating gut dysbiosis and decreasing gut-derived uremic toxins. This study sheds light on a novel mechanism by which SMD exerts its effects on HUA-induced renal injury.

Multimorbidity, particularly cardiometabolic multimorbidity (CMM), is a growing global health challenge, defined by the co-occurrence of cardiometabolic diseases (CMDs) like type 2 diabetes, ischemic heart disease, and stroke. While serum uric acid (SUA) and gout have been linked to various chronic conditions, their roles in multimorbidity and the CMM trajectory remain unexplored in large populations. Using data from over 400,000 UK Biobank participants, we explored the associations between SUA, gout, 36 chronic conditions, and multimorbidity. A multi-state model was applied to investigate SUA and gout’s roles in the CMM trajectory, including transitions from CMD-free status to first CMD (FCMD), CMM, and death. Analyses were conducted for the overall population and stratified by sex. We observed that higher SUA levels and gout were associated with a higher likelihood of multimorbidity and multiple chronic conditions, particularly CMDs. Multi-state analysis revealed that both SUA and gout increased the risk of most transitions. Classifying FCMDs by specific CMDs further revealed distinct roles of SUA/gout in disease-specific transitions, even at the same stage. Sex-specific analyses showed a stronger impact in females compared to males. These findings highlight the importance of managing SUA levels and gout to prevent multimorbidity and slow CMM progression, particularly in females.

Cervical cancer is a leading cause of female malignancy worldwide. While microRNA-4327 (miR-4327) has been implicated as a potential oncogene, its functional role and molecular mechanisms in cervical cancer pathogenesis remain unclear. This study aimed to determine the oncogenic function of miR-4327 and elucidate its downstream regulatory mechanism in cervical cancer pathogenesis. We measured miR-4327 expression in clinical cervical cancer tissues and cell lines using quantitative real-time PCR (qRT-PCR). We then assessed its effects on proliferation, migration, invasion, and cell cycle progression through functional assays including cell counting kit-8 (CCK-8), colony formation, transwell, and flow cytometry. To evaluate tumor growth in vivo, we established a xenograft model in non-obese diabetic (NOD)-severe combined immune-deficient (scid) mice. Using bioinformatic analysis and luciferase reporter assays, we identified TP53 as a direct target of miR-4327 and further validated this regulatory relationship with gain- and loss-of-function experiments. We found that miR-4327 was significantly upregulated in cervical cancer and promoted malignant phenotypes such as proliferation, migration, invasion, and cell cycle progression in vitro. Consistent with this, overexpression of miR-4327 accelerated tumor growth in vivo. Mechanistically, we confirmed TP53 as a direct functional target of miR-4327. Knocking down TP53 phenocopied the oncogenic effects of miR-4327, while restoring TP53 expression rescued the tumor-promoting effects mediated by miR-4327. These findings reveal a novel miR-4327/TP53 regulatory axis and nominate miR-4327 as a potential therapeutic target for intervention.

Lanatoside C (LanaC), a cardiac glycoside, has been reported to possess therapeutic potential in acute intestinal inflammation; however, its in vivo effects on ulcerative colitis (UC) remain incompletely understood. In this study, we demonstrated that LanaC effectively attenuates DSS-induced colitis in mice by reducing inflammation, mitigating epithelial damage, and preserving barrier integrity. Mechanistically, LanaC treatment was associated with reduced macrophage infiltration in the colon and spleen, suppression of pro-inflammatory M1 macrophage markers, and enhancement of M2-associated markers. In vitro, LanaC inhibited LPS-induced M1 polarization and pro-inflammatory cytokine production in BMDMs, while promoting IL-4-driven M2 polarization and anti-inflammatory cytokine expression. These effects were accompanied by attenuation of STAT1/STAT3 signaling and enhancement of STAT6 activation, suggesting a selective reprogramming of macrophage responses. Collectively, these findings reveal that LanaC alleviates DSS-induced colitis, at least in part, through regulating macrophage infiltration and repolarization supporting its potential as a macrophage-targeted therapeutic candidate in UC.

Background Hederagenin is a naturally occurring pentacyclic triterpenoid found in several medicinal plants traditionally used for treating renal and metabolic disorders. Its ability to mitigate renal senescence in diabetic kidney disease (DKD) and the associated epigenetic mechanisms have not yet been fully elucidated. Methods db/db mice were used in vivo to model DKD-associated renal senescence, while palmitic acid-treated human renal proximal tubular epithelial cells (HK-2 cells) were used in vitro as a senescence model. Renal injury, senescence, DNA damage, and Klotho expression were evaluated using histological, biochemical, and molecular analyses. GEO datasets derived from human DKD samples and corresponding controls were analyzed to assess Klotho expression. Integrated target-binding and methylation analyses were performed to examine the interaction between hederagenin and DNA methyltransferase 1 (DNMT1), as well as the effects of hederagenin on Klotho promoter methylation and DNMT1 occupancy. Results Hederagenin reduced renal senescence, fibrosis, and DNA damage in vivo and in vitro, while restoring Klotho expression, which was decreased in patient datasets and experimental models. Mechanistically, hederagenin directly bound DNMT1, diminished DNMT1 recruitment to the Klotho promoter, and attenuated aberrant promoter hypermethylation, thereby reactivating Klotho. Conclusion Hederagenin mitigates renal senescence in DKD through a DNMT1-Klotho DNA methylation axis, supporting its ethnopharmacological potential for DKD management.

BACKGROUND:Gut microbiota has been widely recognised as playing a critical role in maintaining immune imbalance and the development of rheumatoid arthritis (RA). As key roles mediating interkingdom crosstalk among plants, microbiomes and mammals, plant-derived exosome-like nanoparticles (ELNs) could use lipids and microRNA components to precisely modulate gene expression of gut microbiota, showing potential as a dietary intervention for RA treatment. OBJECTIVE:We aimed to investigate gut microbiota-immune interactions inducing immune dysregulation in RA and explore potential applications of edible plant-derived ELNs for RA treatment through gut microbiota manipulation. DESIGN:Combinations of microbial analysis of clinical cohort, metabolomics, in vivo and in vitro examination were performed to establish potential gut-immune mechanisms for interventions. Several representative edible plants ELNs were chosen to compare the modulation effects based on the above mechanism. Small RNA sequencing and lipidomic analysis were performed to identify key components and reveal the related mechanisms mediating therapeutic effects. RESULTS:Ruminococcus gnavus was significantly enriched in RA and aggravated arthritis through secreting phenylethylamine (PEA) to induce excessive neutrophil extracellular traps (NETs) formation. Among several plants ELNs, Pueraria lobata-derived ELNs (Pu-ELNs) were preferentially taken up by R. gnavus and decreased PEA production. Mechanistically, the lipid components of Pu-ELNs induced intestinal accumulation of ELN-derived gma-miR4412, which reduces phenylalanine decarboxylase (PDC) expression, relieving the arthritis aggravation caused by R. gnavus through acting on the PEA-Bruton's tyrosine kinase (BTK)-NETs axis. CONCLUSIONS:Our findings suggest the crucial role of R. gnavus in aggravating RA and underscore the application of plant-derived ELNs for microbiota manipulation.

Ethnopharmacological relevance: Early-phase cardiovascular complications triggered by hyperlipidemia (HL) are fundamentally characterized by the breakdown of the vascular endothelial barrier. Danggui-Shaoyao-San (DSS), a sophisticated traditional Chinese herbal formula, has long been employed to manage circulatory imbalances, though the molecular choreography behind its vasoprotective properties in HL remains insufficiently defined.Materials and methods: In this study, ApoE-/- mice subjected to a high-fat diet (HFD) served as the experimental model to evaluate the therapeutic potential of varying DSS concentrations. We utilized mass spectrometry to profile the absorbed phytochemicals within the systemic circulation. Beyond monitoring glucolipid profiles and inflammatory markers, we performed a detailed histopathological examination of the aorta. Integrating transcriptomic landscapes with molecular docking was implemented to decipher the operative mechanisms, with findings subsequent confirmed through western blotting and immunofluorescence assays.Results: Mass spectrometry successfully identified 19 DSS-related bioactive metabolites in serum. Data indicated that DSS intervention not only suppressed HFD-induced obesity and metabolic derangements but also markedly dampened systemic inflammation. Notably, DSS treatment effectively reinforced the endothelial boundary, as evidenced by diminished tracer leakage and the preservation of aortic junctional architecture. Systems biology analysis, reinforced by docking simulations, highlighted the Ras-related protein 1 (Rap1) and the PI3K/AKT signaling cascade as the primary therapeutic targets. At the molecular level, DSS robustly enhanced the expression of essential junctional proteins (including ZO-1, occludin, claudin-1, and VE-cadherin) while stimulating the phosphorylation of PI3K and AKT within the vascular tissue.Conclusion: Collectively, our findings demonstrate that DSS exerts a potent protective effect against HL-mediated vascular barrier impairment. This efficacy is achieved through the dual action of metabolic regulation and the restoration of endothelial junctional homeostasis, processes predominantly driven by the activation of the Rap1/PI3K/AKT signaling axis. These insights provide a rigorous scientific foundation for utilizing DSS as a therapeutic strategy for hyperlipidemic vascular injury.

Background/Objectives Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths worldwide. Although microRNAs (miRNAs) are known to play crucial roles in tumor progression, the biological function and mechanistic role of miR-4788 in NSCLC remain undefined. This study investigates the role and mechanism of miR-4788 in NSCLC proliferation and metastasis.Methods miR-4788 expression and its prognostic significance were analyzed using The Cancer Genome Atlas (TCGA) data. In vitro assays were conducted in NSCLC cell lines transfected with miR-4788 mimics, DLG5 siRNA, or a 3 '-UTR-truncated DLG5 overexpression plasmid. In vivo functional validation was performed in zebrafish and murine xenograft models. Functional assays included assessments of cell viability (CCK-8), proliferation (EdU incorporation, colony formation), cell cycle distribution, migration/invasion (wound healing, Transwell), and mitochondrial function (ATP, MMP, ROS, mitophagy markers). A dual-luciferase reporter assay was used to confirm DLG5 as a direct miR-4788 target, and rescue experiments were conducted to validate its downstream role.Results miR-4788 was significantly upregulated in NSCLC tissues and was associated with a lower disease-specific survival rate. Its overexpression in vitro and in vivo promoted the proliferation, migration, and invasion of non-small cell lung cancer cells. This oncogenic effect was accompanied by enhanced mitochondrial function, evidenced by increased mitochondrial membrane potential, ATP production, and reactive oxygen species (ROS) levels, along with suppression of mitophagy (reduced Pink1/Parkin expression). Mechanistically, miR-4788 directly targets the 3 '-UTR of DLG5, downregulating its expression, and restoring the function of DLG5 could alleviate the carcinogenic phenotype caused by miR-4788.Conclusions miR-4788 functions as an oncogenic regulator in NSCLC, promoting tumor development by targeting DLG5 and promoting mitochondrial metabolic reprogramming. These findings provide new insights into the miR-4788-DLG5 axis in NSCLC and suggest its potential role in tumor metabolism and immune microenvironment remodeling.

Sepsis-induced acute kidney injury (SAKI) remains a major contributor to mortality, yet the impact of environmental factors-particularly humidity-on disease progression is poorly understood. Here, we investigated how short-term high-humidity exposure shapes host susceptibility to SAKI and explored the underlying microbiota- and metabolite-mediated mechanisms. Mice pre-exposed to high humidity exhibited markedly attenuated renal injury and improved survival following cecal ligation and puncture (CLP). Notably, this protective effect persisted after bacterial depletion, but was abolished by amphotericin B treatment, indicating a fungus-dependent mechanism. Internal transcribed spacer sequencing and microbiota manipulation experiments identified Meyerozyma caribbica (M. caribbica) as a humidity-enriched commensal fungus essential for renal protection. Metabolomic profiling further revealed syringic acid (SA) as a key M. caribbica-derived metabolite responsible for the observed benefits. SA suppressed MAPK and NF-κB activation, reduced inflammatory cytokine release, and inhibited macrophage pyroptosis in vitro. Together, these findings demonstrate that high humidity confers protection against SAKI through an M. caribbica-SA axis that modulates macrophage inflammation and pyroptosis, highlighting a previously unrecognized environment-microbiota-host interaction in septic immunoregulation.IMPORTANCESepsis outcomes are traditionally attributed to host immunity and microbial infection, whereas environmental influences remain largely overlooked. This study reveals that short-term environmental humidity profoundly shapes septic kidney injury through a commensal fungus-derived metabolite, establishing M. caribbica and its product syringic acid as key mediators of renoprotection. These findings challenge the conventional bacteria-centered view of sepsis-microbiota interactions and uncover humidity-driven mycobiota remodeling as a critical regulator of immune responses. By defining an environment-fungus-host axis that mitigates macrophage inflammation and pyroptosis, this work provides a conceptual framework for leveraging environmental modulation or fungal metabolites as novel therapeutic strategies for sepsis.

BACKGROUND:Clear cell renal cell carcinoma (ccRCC) is one of the most predominant pathological types of renal cell carcinoma (RCC), with a high metastatic rate and poor prognosis. There is growing appreciation that miR-181a-5p plays a crucial role in various cancers, but the relevance of miR-181a-5p to disease progression in ccRCC and its mechanism of action in ccRCC remain poorly reported in detail. This study purposed to explore new biomarkers related to the prognosis of ccRCC and to uncover their potential mechanisms in influencing ccRCC progression. METHODS:The dbDEMC and GEO databases were used to screen differential miRNAs and differential genes in ccRCC, respectively. KEGG pathway analysis was performed to further search for differential genes in ccRCC. The miRWalk database was used to predict target genes of miR-181a-5p. The miR-181a-5p and its target genes expression, clinicopathological correlation, prognosis analysis, and immune infiltration correlation were performed in the data obtained from TCGA. STRING database was performed to construct a PPI network of the target genes of miR-181a-5p and immune-related genes of ccRCC from TISIBD database. In vitro experiments were conducted to verify the effect of miR-181a-5p on the growth, invasion and migration of ccRCC cells and to verify the target genes of miR-181a-5p. RESULTS:As a differential miRNA of ccRCC, miR-181a-5p is significantly up-regulated in ccRCC patients and has a high diagnostic accuracy. High expression of miR-181a-5p is related to poor progress free interval (PFI). KIT, MECOM, COL4A6, EGF, and MAPK10 are the target genes of miR-181a-5p, which are significantly down-regulated in ccRCC patients and have high diagnostic accuracy. Low expression of these genes is associated with disease progression and poor prognosis of ccRCC. In addition, miR-181a-5p and its target genes were found to be associated with the immune infiltration of ccRCC. In vitro experiments proved that miR-181a-5p promote the growth, invasion and migration of ccRCC cells, and it was found that COL4A6, EGF, and MAPK10 are more likely to be the target genes of miR-181a-5p. CONCLUSIONS:MiR-181a-5p may work together with its target genes to affect tumor-induced immune cell infiltration, and thus affect ccRCC. MiR-181a-5p and its target genes, such as EGF and MAPK10, may be novel prognostic markers and therapeutic targets for ccRCC patients.

BACKGROUND:Erectile dysfunction (ED) is a prevalent male sexual dysfunction that remarkably impacts patients' quality of life and is also recognized as a precursor to cardiovascular disease (CVD) events. Branched-chain amino acids (BCAAs) are derived from dietary intake and mainly involved in energy metabolism. Previous studies have underscored the association between BCAAs and CVD, but the causal link between BCAAs and ED remains uncertain. METHODS:The bidirectional Mendelian randomization (MR) study used the genetic data from genome-wide association studies (GWAS) to identify single nucleotide polymorphisms (SNPs) associated with total BCAAs, leucine, isoleucine, and valine. The genetic data for ED were acquired from the FinnGen study (n = 95,178). The primary method used to assess causal associations was the inverse variance-weighted (IVW) method, supplemented by MR-Egger, weighted median, and simple median analyses. Cochrane's Q test was utilized to evaluate heterogeneity within the results, while the MR-Egger intercept test was utilized to evaluate the Level pleiotropy. A sensitivity analysis was performed employing leave-one-out analysis. RESULTS:The MR analysis results indicate a positive correlation between levels of total BCAA (OR = 1.984, 95 % CI = 1.018-3.868, P = 0.044), leucine (OR = 2.277, 95 % CI = 1.121-4.626, P = 0.023), isoleucine (OR = 2.584, 95 % CI = 1.167-5.722, P = 0.019), valine (OR = 1.894, 95 % CI = 1.119-3.206, P = 0.017), and the risk of ED. Sensitivity tests confirmed the accuracy and robustness of the study findings. Moreover, the reverse MR analysis found no association between ED and the BCAAs. CONCLUSION:The results of this analysis indicate a positive association between the circulating BCAA concentrations and the risk of ED, but their underlying mechanisms require further investigation.