Metabolic dysfunction-associated steatohepatitis (MASH) is a prevalent chronic liver disease for which safe and effective therapeutic options remain scarce. Xiasangju (XSJ), a widely consumed traditional Chinese herbal tea, exhibits diverse pharmacological activities, such as antioxidant, anti-inflammatory, and glucolipid-metabolic regulatory activities. However, its therapeutic potential for MASH has yet to be systematically explored. This study aims to investigate the pharmacological effects of XSJ on a MASH model induced by a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) in mice and to elucidate its potential mechanisms of action. The chemical constituents of XSJ were identified using UPLC-Q-TOF–MS technology. Network pharmacology was employed to predict the potential mechanisms of XSJ in the treatment of MASH. The therapeutic efficacy was evaluated using a CDAHFD-induced mouse model of MASH. Untargeted metabolomics and transcriptomics were utilized to elucidate key regulatory pathways, while RT-qPCR, Western blotting, and molecular docking were used to validate the underlying mechanisms. A total of 74 chemical constituents in XSJ were identified by UPLC-Q-TOF–MS, predominantly phenolic acids and flavonoids. XSJ ameliorated liver injury, lipid deposition, inflammation, oxidative stress, and liver fibrosis in MASH mice. Metabolomic analysis revealed that XSJ could modulate key metabolic pathways, including purine metabolism, arginine biosynthesis, retinol metabolism, and pantothenate and CoA biosynthesis, thereby alleviating liver metabolic dysfunction. Transcriptomic analysis further revealed the regulatory effect of XSJ on the expression of genes related to cholesterol biosynthesis and metabolism, inflammation, and fibrosis. Additionally, XSJ suppressed the progression of liver fibrosis by inhibiting the TGF-β1/Smads and PI3K/AKT/Hmox1 signaling pathways. The findings of this study support the potential of XSJ as a therapeutic agent for MASH, revealing its synergistic mechanisms involving multiple components, targets, and signaling pathways. These results offer valuable insights for the development of novel therapeutic strategies.

ObjectiveTo characterize protein expression of NLRP3 inflammasome pathway components (NLRP3, TXNIP, ASC, IL-1β, IL-18, Caspase-1) in failing myocardium alongside exploratory mRNA profiling, elucidate their correlation with gut microbiota 16S rRNA gene profiles and the metabolite trimethylamine N-oxide (TMAO), and evaluate how dietary protein restriction and probiotic intervention modulate these pathways to influence heart failure progression.MethodsFive groups of male SD rats were established: Control, HF, HF + Pro, LHF, and LHF + Pro, using abdominal aortic constriction. Comprehensive genomic and molecular analyses included: (1) quantitative real-time PCR (qRT-PCR) profiling of six key inflammasome genes (NLRP3, TXNIP, ASC, IL-1β, IL-18, Caspase-1); (2) Western blot protein quantification of the NLRP3 pathway; (3) gut microbiota 16S rRNA gene sequencing (V3-V4 region, Illumina NovaSeq); (4) serum biomarker enzyme-linked immunosorbent assay (IL-18, IL-1β, TNF-α, brain natriuretic peptide, TMAO); and (5) histopathological and ultrastructural analysis of myocardial tissue.ResultsSerum IL-18 protein levels were significantly elevated in the LHF group compared to controls (P < 0.05) by ELISA, with the most pronounced increase observed under dietary protein restriction; however, IL-18 mRNA expression by qRT-PCR showed directionally consistent but statistically non-significant trends across groups (P = 0.929, n = 3 per group). TMAO levels were decreased in HF and HF + Pro groups but paradoxically elevated in the LHF group, a finding discussed in detail in the context of dietary substrate availability and hepatic FMO3 activity. Western blot results showed that the expression of NLRP3, TXNIP, ASC, IL-1β, and IL-18 proteins increased in all heart failure groups compared to the control group, with the most significant increase in the low-protein diet group. Pathological examination revealed increased myocardial fibrosis in heart failure groups, which was further aggravated by low-protein diet, while probiotic intervention partially improved these pathological changes.ConclusionHeart failure is associated with upregulation of NLRP3 inflammasome proteins (NLRP3-TXNIP-ASC-IL-1β/IL-18 axis) alongside gut microbiota dysbiosis; mRNA-level trends were directionally consistent but did not reach statistical significance. Low-protein diet markedly amplifies inflammasome protein expression and cardiac remodeling, while probiotic supplementation is associated with reduced NLRP3 pathway protein expression through microbiome restoration. These findings suggest NLRP3-related protein signatures as candidate biomarkers and potential therapeutic targets in heart failure, warranting further mechanistic investigation.

Calcium oxalate (CaOx), the primary constituent of most urinary calculi, triggers inflammatory responses and tissue damage upon entry into renal tubules, playing a pivotal role in nephrolithiasis pathogenesis. Salidroside (SAL), a phenolic glycoside isolated from Rhodiola plants, exhibits diverse pharmacological activities. This study integrated network pharmacology with experimental validation to investigate the therapeutic potential and mechanistic basis of SAL against urinary stones. In both in vitro and in vivo models of CaOx crystal-induced kidney injury, SAL treatment markedly reduced renal crystal deposition, inflammatory cascades, and associated histological impairments. Network pharmacology analysis suggested the involvement of PANoptosis, a finding subsequently confirmed through experimental assays as the central mechanism underpinning SAL-mediated protection. Molecular docking and further experimental verification indicated that SAL directly engages with core components of the PANoptosome complex. These results collectively demonstrate that SAL mitigates nephrolithiasis-related renal injury and inflammation primarily through suppression of PANoptosis.

BACKGROUND:Chronic inflammation in chronic obstructive pulmonary disease (COPD) arises from prolonged interactions among immune cells, functional cells, and inflammatory cytokines. The Qibai Pingfei Capsule (QBPF), a traditional Chinese medicine (TCM), has been utilized clinically for over two decades to treat COPD. However, robust evidence is required to validate its clinical effectiveness. Single-cell RNA sequencing (scRNA-seq) technology offers comprehensive insights into the immune-inflammatory microenvironment of COPD at the single-cell level, providing valuable strategies for integrating TCM into COPD management. PURPOSE:To clarify the mechanism of QBPF in treating COPD through scRNA-seq. METHODS:A randomized, double-blind, placebo-controlled, multicenter study performed to investigate the QBPF efficacy in COPD patients. PBMCs from these patients were subjected to scRNA-seq, and lung tissue scRNA-seq data were obtained from the public database (GEO: GSE162610). The regulatory mechanism of QBPF was confirmed using a COPD rat model. RESULTS:Acute exacerbation frequency was significantly decreased (p = 0.042), and CAT scores improved (p = 0.008) following QBPF treatment. Nevertheless, no significant changes were recorded in lung function, the 6-minute walk test (6MWT), or the mMRC scale. Within the QBPF group, the 6MWT (p < 0.01) and FEV₁/FVC% (p < 0.01) significantly improved from baseline to 3 months. ScRNA-seq confirmed immune dysfunction, especially the depleted NK cells and impaired activation. QBPF altered the expression of functional markers in NK cells of COPD patients, and animal studies confirmed that QBPF enhanced NK cell activity by modulating the expression of hepatitis A virus cellular receptor 2 (HAVCR2) and killer cell lectin-like receptor C2 (KLRC2). Additionally, scRNA-seq analysis revealed impaired immune function in COPD patients, specifically NK cell exhaustion and dysfunction. CONCLUSION:These findings demonstrated that QBPF can ameliorate and alleviate COPD symptoms, and its therapeutic effects have been linked to its potential to modulate NK cell function. This study provides some evidence that QBPF can improve NK cell activity in COPD.

BACKGROUND:Maternal obesity and high-fat diets disrupt uterine metabolic homeostasis, leading to mitochondrial dysfunction, insulin resistance, and inflammation in uterine smooth muscle cells (USMCs), which may compromise pregnancy outcomes. Here, we investigated the role of the cGAS-STING pathway in mediating high-fat-induced metabolic and inflammatory dysfunction in USMCs and evaluated the therapeutic potential of sesamin, a bioactive compound from Cuscuta chinensis. METHODS:Transcriptomic datasets from maternal serum and myometrium were analyzed to identify differentially expressed genes associated with inflammation, insulin resistance, and cGAS-STING activation. In vitro, USMCs were exposed to palmitic acid to mimic a high-fat environment, and mitochondrial integrity, mtDNA release, cGAS-STING activation, insulin signaling, and glucose uptake were assessed using TEM, ROS and JC-1 staining, qRT-PCR, Western blotting, and ELISA. In vivo, pregnant C57BL/6 mice were fed either a high-fat diet (HFD) or normal diet, with or without oral sesamin administration, and metabolic, mitochondrial, and inflammatory parameters were evaluated. RESULTS:High-fat exposure induced mitochondrial structural damage, ROS accumulation, and mtDNA leakage, which activated cGAS-STING signaling and upregulated pro-inflammatory cytokines (IL-1β, IL-18), impairing insulin signaling in USMCs. Selective mtDNA depletion or STING knockdown attenuated these effects. Sesamin bound STING with high affinity, inhibited cGAS-STING activation, restored insulin signaling, improved glucose uptake, and enhanced mitochondrial respiratory function. In HFD mice, sesamin reduced systemic inflammation, improved uterine insulin sensitivity, and normalized metabolic rates (VO₂, VCO₂, and RER). CONCLUSION:These findings demonstrate that high-fat-induced cGAS-STING activation underlies mitochondrial dysfunction, inflammation, and insulin resistance in USMCs. Sesamin mitigates these effects via dual regulation of STING signaling and mitochondrial function, highlighting its potential as a therapeutic agent for metabolic and inflammatory dysregulation in pregnancy.

Sleep disturbances (SD) are not merely symptoms of posttraumatic stress disorder (PTSD), but also amplify and perpetuate all other PTSD phenotypes. Ginsenoside Rg1 is extensively applied in managing neuropsychiatric diseases. Nevertheless, its impact on PTSD-like SD and mechanisms remain largely unknown. In this study, the PTSD model in mice was produced using single-prolonged stress (SPS) and the improvement effect of ginsenoside Rg1 on PTSD-like behavior in mice, especially the sleep-wake phase was detected. The potential targets and signaling pathways of ginsenoside Rg1 as an intervention for treatment of PTSD with sleep disturbances (PTSD-SD) were predicted using bioinformatics analysis. Thereafter, in vivo experiments were further used to verify the results. Our data showed that 14 days after SPS, the sleep architecture of mice was significantly disturbed, while ginsenoside Rg1 could treat PTSD-like SD in SPS mice. The results of bioinformatics analysis suggested that NLRP-related pathways and apoptosis may be the key factors for ginsenoside Rg1 to treat PTSD-like sleep disturbances. Meanwhile, animal experiments also showed that the NLRP3 inflammasome, oxidative stress and apoptosis-related markers were abnormally expressed in the hippocampus of SPS mice, but the administration of ginsenoside Rg1 could counteract the dysregulated expression of the above proteins in SPS mice. Finally, the results of docking revealed that ginsenoside Rg1 had favorable binding affinity with verified targets including NF-κB, NLRP3, ASC, GFAP, HO-1, and cleaved caspase-3. Collectively, ginsenoside Rg1 is effective to prevent PTSD-like SD, likely by regulating systemic comprehensive responses.

Kidney stones, as prevalent crystalline disorders within the urinary system, pose significant clinical challenges due to their high incidence and recurrence rates. The lack of clear pathological mechanisms has limited therapeutic options to surgical interventions without effective preventive strategies. In this study, integrated in vitro and in vivo models revealed that calcium oxalate (CaOx) exposure induced concurrent accumulation of LC3B-II and p62 autophagy markers. Blockade of autophagic flux at the late stage was validated via mCherry-GFP-LC3 dual fluorescence assays, demonstrating impaired autolysosome formation. Mechanistically, autophagic flux obstruction triggered oxidative stress, apoptosis, and proinflammatory cascades, collectively exacerbating renal tubular injury. Pharmacological inhibition of autophagy initiation with 3-methyladenine (3-MA) disrupted the maladaptive autophagy-reinforcement cycle, improving cellular viability and renal function. Conversely, lysosomal acidification blockade via bafilomycin A1 (BafA1) failed to mitigate cytotoxicity. Molecular screening identified specific downregulation of VAMP7-a SNARE complex component critical for autophagosome-lysosome fusion-as the primary mediator of CaOx-induced fusion defects. Overexpression of VAMP7 restored autophagic homeostasis and attenuated crystallotoxicity. This work pioneers a phase-specific autophagy targeting strategy: either suppression of pathological autophagic overactivation or restoration of terminal fusion machinery effectively alleviates CaOx nephrotoxicity. These findings provide a mechanistic foundation for precision therapeutics in stone disease management.

BACKGROUND: Circular RNAs (circRNAs) constitute a recently discovered class of evolutionarily conserved and robust regulatory RNAs. Their potential as diagnostic biomarkers and therapeutic targets for various diseases is a subject of growing interest. Nevertheless, the precise regulatory roles and underlying mechanisms of circRNAs in the context of kidney stone formation remain largely unexplored. METHODS: Utilizing RNA high-throughput sequencing technology and quantitative real-time polymerase chain reaction (qRT-PCR), we conducted a comprehensive screen for calcium oxalate crystals (CaOx)-induced differential expression of circular RNA (circRSPRY1) in the human renal tubular epithelial cells (HK-2) kidney injury model. Subsequently, we employed a combination of RNA and protein expression analyses, luciferase activity assays, and immunohistochemistry (IHC) to elucidate the regulatory role of circRSPRY1 in targeting the miR-21-5p/PTEN axis, influencing the processes of necroptosis and apoptogenesis. RESULTS: In this investigation, we observed a notable downregulation of circRSPRY1 expression in both the CaOx-stimulated HK-2 renal tubular epithelial cell injury model and a glyoxalate-induced mouse model of renal calcinosis. Notably, overexpressing circRSPRY1 led to reduced crystalline deposition in our in vitro model. Mechanistically, circRSPRY1 overexpression was associated with the downregulation of cleaved-caspase-8, p-MLKL, P-RIPK1, and P-PIPK3 levels, consequently inhibiting necrotic apoptosis. Furthermore, circRSPRY1 appeared to act as a miR-21-5p sponge, resulting in reduced miR-21-5p availability for PTEN binding and, subsequently, increased PTEN expression, thus impeding the progression of necrotic apoptosis and kidney injury. Additionally, inhibiting miR-21-5p levels demonstrated the ability to suppress necrotic apoptosis in renal calcinosis by downregulating the PTEN/MLKL pathway. CONCLUSION: Our findings suggest that circRSPRY1 represents a novel candidate circRNA implicated in the pathogenesis of kidney stones. circRSPRY1 acts as a sponge, sequestering miR-21-5p to modulate PTEN expression, thereby regulating necrotic apoptosis and contributing to the formation of calcium oxalate stones.

Chronic wounds, such as diabetic foot ulcers, often exhibit lower temperatures due to impaired local circulation, leading to reduced cellular metabolism and delayed healing. This study explores a new strategy to accelerate wound healing by enhancing the cell metabolism of essential amino acids through a "hot spring" mimetic photothermal effect. We engineered an extracellular matrix mimetic nanofiber aerogel co-delivering an eight essential-amino-acid cocktail and photothermally active SrCuSi4O10 bioceramic particles to support chronic wound repair. In vitro, fibroblasts cultured at 25°C versus 37°C showed that physiological temperature preserved the pro-healing bioactivity of the amino-acid treatment with minimal cytotoxicity and was associated with enhanced glutathione redox metabolism. In vivo, the amino acid-loaded aerogel combined with SrCuSi4O10-mediated photothermal therapy accelerated wound closure and improved regenerative outcomes, including increased cellular proliferation, collagen deposition, and neovascularization. Immunohistochemical analysis showed a reduction in neutrophil infiltration, M1 macrophage polarization, and pro-inflammatory cytokines, while increasing M2 macrophage polarization and anti-inflammatory cytokine production, thus shifting the local inflammatory response from pro-inflammatory to regenerative. This approach demonstrates potential as an effective therapeutic option for enhancing the healing of chronic wounds.

Delayed diabetic wound healing is a global health issue with unclear pathogenesis. Ferroptosis, a form of cell death involving iron and lipid peroxidation, may contribute to delayed diabetic wound. This study investigates the role of ferroptosis in diabetic wound keratinocytes. We measured lipid peroxidation products (MDA, 4-HNE), ACSL4, and GPX4 protein levels in diabetic keratinocytes and assessed mitochondrial morphology. Ferrostatin-1 (Fer-1) was used to inhibit ferroptosis in diabetic rat wounds, and its effects on healing and expression levels were evaluated. Pull-down assays, silver staining, and mass spectrometry were employed to study ACSL4 mRNA regulation. A YTHDF2 knockdown adenovirus was used to manipulate YTHDF2 expression in rat wounds. Ferroptosis was detected in diabetic keratinocytes, hindering wound healing, a process reversible with Fer-1. High glucose induced ACSL4 expression, driving keratinocyte ferroptosis and delayed healing. YTHDF2 interacts with N6-Methyladenosine-modified ACSL4 mRNA, affecting its stability and expression. YTHDF2 knockdown increased ACSL4, promoting ferroptosis and impairing healing. Our findings illustrate the significant involvement of ferroptosis in the dysfunction of diabetic keratinocytes, suggesting that targeting ferroptosis may offer a viable therapeutic approach for improving diabetic wound healing.

Calcium oxalate (CaOx) crystals are a major component of human kidney crystals and can induce renal tubular inflammation and damage, ultimately leading to renal calcium deposits and kidney stone formation. Umbelliferone (Umb) is a common coumarin compound. In this study, we used in vivo, in vitro experiments and network pharmacology were performed to assess the therapeutic effects of Umb on kidney stones and investigate its pharmacological mechanism. First, we established cellular and mouse models of calcium oxalate renal calcinosis, and we found that Umb reduces renal crystalline deposits, as well as the inflammation and damage they cause. Subsequently, we screened the PI3K/AKT signalling pathway via network pharmacology and experimentally demonstrated that Umb exerts its protective effects through the PI3K/AKT signalling pathway. Finally, molecular docking techniques and experiments were used to find out that Umb acts directly on PIK3CA to play its role.Our results indicate that Umb alleviates inflammation and injury by attenuating renal autophagy induced by kidney stones via the PI3K/AKT pathway.

Emerging evidence implicates lipopolysaccharide (LPS) embedded in the outer membrane of Gram-negative bacteria as a key mediator of intestinal inflammation. A preliminary study found that a potent Lactobacillus brevis strain named ZFM820 showed remarkable antibacterial activity against LPS-producing Escherichia coli compared to other lactic acid bacteria through an unexplored mechanism. This study systematically investigated the anti-LPS phenotypes, responsive factors, and mechanism of ZFM820. The alleviation activity on LPS-induced inflammation and oxidative stress was confirmed both in RAW264.7 cells and C. elegans models. The alleviation efficiencies of live bacteria, dead bacteria, and their cell-free fermentation supernatant were compared, and they present 2.68, 1.04, and 1.12-fold reduction of NO levels and 1.79, 1.07, and 1.15-fold reduction of O2-, respectively, suggesting that the protective effect was achieved via live bacteria. Further mechanical studies revealed that ZFM820 formed a biofilm barrier to physiochemically impede LPS permeation and triggered metabolic reprogramming by suppressing histone synthesis and activating glutathione biosynthesis to biologically enhance epithelial resistance. These findings provide evidence for the anti-LPS activity of ZFM820, offering an innovative horizon to understand the beneficial mechanism of L. brevis.

Oral inflammatory diseases are prevalent yet poorly understood in the context of systemic microbiota interactions along the oral-gastric-intestinal axis. Current interventions primarily target direct inflammation inhibition in situ, leaving the cross-compartmental microbial mechanisms underlying oral inflammation underexplored. Moreover, the therapeutic potential of probiotics in modulating multi-site microbiota dynamics to alleviate oral inflammation remains limited by insufficient mechanistic insights. Using an acetic acid-induced oral inflammatory mouse model, this study systematically tracked alterations in the digestive microbiota across distinct gastrointestinal compartments during oral inflammation progression, thereby elucidating the microbiota-driven mechanisms of oral inflammation through both holistic and site-specific analyses of the digestive tract. Additionally, the potent anti-inflammatory efficacy of the commercially utilized probiotic Lacticaseibacillus paracasei LPC-37 was evaluated. The anti-inflammatory mechanism of LPC-37 was deciphered through microbiota structural analysis, gastrointestinal survival assessment, co-culture characterization, and short-chain fatty acid profiling. LPC-37, exhibiting robust gastrointestinal resistance, demonstrated enhanced intestinal colonization. This promoted a synergistic interaction with same-family bacteria to elevate Ligilactobacillus abundance, enabling antagonism against the marker microbe Aerococcus while upregulating Clostridium saccharolyticum WM1, a butyrate-producing strain. These microbial shifts drove butyrate biosynthesis, ultimately alleviating oral inflammation. The findings unravel a systemic microbiota interplay along the oral-gastric-intestinal axis and propose a novel probiotic-based strategy for anti-oral-inflammatory therapy.

Purpose:This study aimed to construct a comprehensive single-cell transcriptomic atlas of human ureteral scar stricture tissue using single-cell RNA sequencing (scRNA-seq), to uncover cellular heterogeneity, subpopulation dynamics, and intercellular communication networks. Methods:Ureteral tissues were collected from three normal controls (CTR) and three patients with ureteral scar stricture (US). Single-cell suspensions were prepared using the MobiNova-100 platform and sequenced on the Illumina NovaSeq 6000 system. Data were analyzed using Seurat, Harmony, Monocle2 (for pseudotime trajectory analysis), CellChat (for cell-cell communication), and SCP (for GO/KEGG enrichment). Key findings were validated by multiplex immunofluorescence (IF) and immunohistochemistry (IHC). Results:Eleven major cell types were identified, including epithelial, stromal, endothelial, and immune cells, each comprising distinct subpopulations. Compared to CTR tissues, US tissues exhibited an increased proportion of S100A8+ and MT1E+ basal epithelial cells with pro-inflammatory characteristics. Fibroblasts displayed substantial heterogeneity, with expansion of inflammatory fibroblasts and smooth muscle cell subsets. Endothelial cells (ECs) showed upregulated inflammatory and antigen presentation pathways. Macrophages exhibited mixed M1/M2 polarization, with enrichment of APOE+ and APOBEC3A+ subsets. Additionally, Th17, Treg, and CD8+ T cell populations were elevated. Cell-cell communication analysis revealed enhanced signaling among fibroblasts, ECs, and immune subsets, particularly via PERIOSTIN, collagen, and laminin pathways. Conclusion:This study presents the first high-resolution single-cell atlas of ureteral scar stricture tissue, revealing profound cellular heterogeneity and remodeling of the immune-stromal-epithelial landscape. The findings also highlight intensified intercellular communication within the fibrotic microenvironment, offering novel insights into disease pathogenesis and potential therapeutic targets.

BACKGROUND:Liver injury and uveitis pose severe threats to human health. Owing to the close relationship of physiology and pathology between the liver and the eyes, cases in which both conditions occur simultaneously are not uncommon in clinical settings, significantly complicating treatment. However, no suitable comorbid animal model has been reported, and research on the pathological mechanisms of this comorbidity is lacking. Prunella vulgaris L., a well-known traditional Chinese medicine renowned for its liver-clearing and eye-brightening properties. Prunella vulgaris polyphenols (PVPs) hold promise for improving liver injury and uveitis. However, research exploring their dual therapeutic effects within a single organism remains lacking, leaving the key active components and mechanisms of action largely uninvestigated. PURPOSE:This exploratory study aimed to establish a rat model of liver injury combined with uveitis and investigated its pathological mechanisms, evaluating the therapeutic efficacy of PVPs in alleviating liver injury combined with uveitis in rats. Additionally, it explored the mechanism of action and identified key active ingredients of PVPs, offering potential new directions for the development of clinical therapeutic drugs. METHODS:A rat model of liver injury with uveitis was established through intraperitoneal d-GalN/LPS injection. Metabolomics and proteomics were applied to investigate pathological mechanisms, followed by validation using acylcarnitine and S100A9 inhibitors. PVPs were administered to evaluate therapeutic effects and explore mechanisms involved in alleviating liver injury and uveitis. Network pharmacology combined with molecular docking identified critical active components in PVPs. Subsequent animal experiments verified the efficacy of the representative component in improving liver injury and uveitis. RESULTS:d-GalN/LPS (150 mg/kg : 1 mg/kg) induced significant liver injury and uveitis in rats. Metabolomics analysis pointed to acylcarnitine as a key metabolite, and its inhibition reduced inflammation. Proteomics analysis implicated S100A9 in inflammation and immunity. Then, we intervened with S100A9 inhibitors in the model rats. The results suggested that the pathological mechanism of liver injury and uveitis caused by d-GalN/LPS involved the upregulation of S100A9 expression, an increase in PP2A activity, the inhibition of AMPK phosphorylation, and the downregulation of CPT1A, leading to the accumulation of acylcarnitine and promoting the inflammatory response in the liver and retina. Further, experiments involving PVPs demonstrated dose-dependent improvements in liver injury and uveitis caused by d-GalN/LPS. The underlying mechanism of action involved suppression of S100A9 expression, reduction of PP2A activity, activation of AMPK, upregulation of CPT1A, and subsequent reduction in acylcarnitine accumulation in both the liver and retina. This mechanism effectively alleviated the inflammatory effects induced by d-GalN/LPS. Network pharmacology and molecular docking analyses pinpointed several key active components of PVPs-namely, rosmarinic acid, salviaflaside, esculetin, 2-hydroxycinnamic acid, 3,4-dihydroxybenzaldehyde, and 7,8-dihydroxycoumarin-that play significant roles in mitigating liver injury and uveitis. Follow-up experiments using the representative active component rosmarinic acid in rats confirmed its efficacy in improving symptoms of d-GalN/LPS-induced liver injury and uveitis, further validating the therapeutic potential of these key active components. CONCLUSIONS:This study successfully established a rat model of liver injury combined with uveitis and confirmed the efficacy of PVPs in alleviating this condition. Furthermore, it determined that the underlying mechanism involves regulation of the S100A9-PP2A-AMPK pathway, with rosmarinic acid identified as a key active compound. These findings provide a basis for clinical studies on liver-eye comorbidities and offer critical evidence for further research and drug development of PVPs in liver-clearing and eye-brightening.

PurposeThe current clinical guidelines recommend routine stone bacterial culture for patients who have undergone stone surgery. However, the results of bacterial culture are obtained after several days, which delay the implementation of early treatment postsurgery. In this study, we performed stone bacterial culture for several surgical patients and predicted the results and types of stone bacterial culture based on specific parameters on admission. This case provides important clinical data that will guide the implementation of early detection and management of postoperative infections.MethodsPatients who underwent stone surgery between October 2023 and January 2024, all of whom underwent urine and stone bacterial culture were enrolled in the study. Their results were processed and compared using logistic regression analysis.ResultsA total of 165 patients were enrolled in the study, among whom 57 had positive stone cultures, 37 had positive urine culture (UC), and 21 had both positive stone and urine cultures. Univariate analysis indicated that the positive stone cultures were associated with preoperative UC and preoperative use of antibiotics. Multivariate logistic regression analysis further confirmed that positive preoperative UC was a significant risk factor for stone culture (SC). Patients with consistent results in both UC and SC exhibited larger kidney stone diameters. Furthermore, the combination of UC and stone diameter could effectively predict the bacterial species of SC (AUC = 0.817).ConclusionIn patients with large-diameter kidney stones, the bacteria identified in UC were often similar to those detected in the SC.

Excessive Desulfovibrio (Des) forms biofilm to enable dominant occupation of the intestinal niche, representing a common pathogenic driver of multiple inflammatory bowel disease (IBD) types. Colonization resistance constitutes the primary barrier to antagonistic probiotic efficacy, and this is driven by the pathogen-favorable microenvironment established by Des. Here, probiotic Lactiplantibacillus (Lap) is modified by calcium ions (Ca2+) and calcium-regulative polyphenol (kaempferol-3-O-rutinoside, KAE) via coordinate interaction to achieve intestinal niche reconfiguration. Targeting the tripartite mechanisms of Des-mediated colonization resistance, the Ca2+/KAE@Lap platform optimized niche competition through Ca2+-bridged interfacial binding with directional bactericidal activity, and this enables bacterial replacement at occupied sites. Ca2+/KAE@Lap reestablishes calcium homeostasis disrupted by Des via synergistic Ca2+/KAE regulation, dually restoring epithelial energy metabolism and mucus layer reconstitution, counteracting Des-induced colonized sites contraction and regenerated site impairment. This drives phenotypic shift in biofilm composition from Des-dominated to Lap-enriched consortia, which is concomitant with the redirection of intestinal colonization resistance from a pathogen-permissive to a probiotic-favored state. This calcium-based biofilm transformation strategy overcomes the transient colonization limitation inherent in conventional probiotic therapies by effectively disrupting colonization resistance in IBD treatment.

Calcium oxalate (CaOx) crystals cause oxidative damage and inflammation to renal tubular epithelial cells and promote nephrocalcinosis; however, the underlying mechanisms remain unclear and there are no treatment drugs available. This investigation aimed to elucidate how SIRT6 attenuates calcium oxalate nephrocalcinosisinduced renal inflammation and oxidative injury. SIRT6 is a classical deacetylase that is closely associated with both oxidative stress and inflammation. This study investigated the function of SIRT6 in nephrocalcinosis using cellular and mouse models via hematoxylin and eosin (H&E) staining, immunohistochemistry, PCR, Western blotting, and immunofluorescence. Additionally, chromatin immunoprecipitation, Western blot, and double luciferase reporter gene assays were carried out to elucidate the mechanism by which SIRT6 modulates NRF2 transcription. Furthermore, the effects of SIRT6 on mitochondrial function were assessed by measuring ROS and ATP, as well as by JC-1 staining. It was revealed that the inhibition of SIRT6 can effectively alleviate kidney injury. Furthermore, upregulating SIRT6 expression can markedly reduce the inflammatory cell infiltration in mouse kidneys and HK2 cells. Moreover, treatment of SIRT6 overexpressed mice with a NRF2 inhibitor revealed different degrees of changes in the above phenotypes. Additionally, in vitro experiments indicated that SIRT6 can effectively alleviate oxidative injury by protecting mitochondrial function and enhancing the antioxidant capacity of HK2 cells. In conclusion, The results revealed that SIRT6 regulated NRF2 to ameliorate oxidative injury and inflammation via the NRF2/HO-1 axis. Moreover, the scalability of SIRT6-based therapies or potential off-target effects would be explored further, and the potential value of SIRT6-related activators should also be explored in humanized models. These findings indicate new directions and targets for preventing and treating nephrocalcinosis caused by CaOx deposition.

Nisin, derived from Streptococcus lactis, is the only approved bacteriocin for food preservation. With wide application in multitudinous food, progressively increasing studies have focused on its anti-inflammatory activity, while its structure-effect relationship and molecular mechanism remain unclear. In this study, the anti-inflammatory efficiency and structural differences of two typical types of nisin, A and Z, were first compared based on a mouse model. The self-assembly behavior of nisin was uncovered, and the characteristics of the self-assembled nanoscale nisin were explored. Based on the transcriptomic analysis, the anti-inflammatory mechanisms of the ribosomal pathway activation of both nisin A and nisin Z were further analyzed, and the upregulation of atp7b and entpd4 triggered by A and Z, respectively, and the consequent adenosine production levels elucidated the therapeutic differences. This study deepens the understanding of the structural and molecular mechanisms underlying the anti-inflammatory activity of nisin and provides an innovative horizon for the future application of nisin.