In recent years, the two-way regulation of intestinal microorganisms in the pathogenesis of hyperuricemia and gout has attracted increasing attention. Studies have shown that specific probiotics can participate in the regulation of uric acid metabolism in many ways, including promoting intestinal uric acid excretion, inhibiting xanthine oxidase activity, enhancing intestinal barrier function and regulating immune infl ammatory response, thus effectively reducing blood uric acid level and alleviating the onset of gouty arthritis. On the contrary, colonization or flora imbalance of conditional pathogenic bacteria can induce chronic inflammation, destroy intestinal mucosal barrier, inhibit uric acid excretion, and further aggravate metabolic disorder. Metagenomics further revealed that some intestinal flora can degrade purine metabolites and regulate purine homeostasis. To sum up, intestinal microorganisms affect uric acid homeostasis through metabolism and immunity, forming an interactive network of "flora-metabolism-inflammation". In the future, we should develop individualized intervention strategies based on probiotics, prebiotics and synthetic biology techniques, and provide a new path for the accurate prevention and treatment of hyperuricemia and gout.

AIMS:Sarcopenia is an emerging risk factor for cardiovascular disease (CVD). However, previous studies did not take into consideration the cardiovascular impact of the changes in sarcopenia status. We investigated the relationship between changes in sarcopenia status and incident CVD. METHODS AND RESULTS:Participants from two prospective cohorts: the China Health and Retirement Longitudinal Study (CHARLS) and the Health and Retirement Study (HRS) were included. Changes in sarcopenia status were assessed by sarcopenia status at the initial two surveys. Cardiovascular disease was ascertained by self-reported physician-diagnosed heart disease or stroke. A total of 6608 and 4316 adults from CHARLS (mean age: 59.2 years, female: 53.6%) and HRS (mean age: 63.2 years, female: 60.2%) were analysed, with a median follow-up of 5.0 and 7.5 years, respectively. Meta-analysis showed a significant relationship between sarcopenia and CVD risk. Bidirectional Mendelian randomization analysis supported the robustness and causality, and no reverse association was found between CVD and sarcopenia. Compared with stable no sarcopenia participants, multivariable-adjusted incidence rate ratio (IRR) and 95% confidence interval (CI) for incident CVD in those who progressed from no sarcopenia to possible sarcopenia/sarcopenia were 1.29 (1.02-1.64) and 1.39 (1.11-1.74) in both cohorts. In contrast, sarcopenia participants who recovered to no sarcopenia/possible sarcopenia had lower incidence of CVD (CHARLS, IRR = 0.61, 95% CI 0.43-0.87; HRS, IRR = 0.20, 95% CI 0.11-0.39) than stable sarcopenia participants did. CONCLUSION:The progression of sarcopenia status increases the risk of CVD, while the recovery of sarcopenia status reduces the risk of incident CVD.

The global prevalence of gout continues to rise. Baxian Huazhuo Decoction (BHD) has demonstrated significant efficacy in the clinical treatment of acute gouty arthritis (AGA); however, its mechanism of action remains unclear. This study first employed network pharmacology analysis to identify the key components, targets, and pathways of BHD against AGA. Molecular docking studies validated the binding affinity between the components of BHD and their potential targets. Ultrahigh-performance liquid chromatography-high-resolution mass spectrometry (UHPLC-HRMS) was utilized to identify the active components in BHD and elucidate their fragmentation pathways. Subsequently, a monosodium urate crystal-induced AGA rabbit model was established to evaluate the in vivo therapeutic efficacy of BHD. The results revealed 62 predicted active components and 268 target molecules in BHD, identifying core constituents such as gentiopicroside, limonin, and indirubin, which exhibited high affinity for targets including MAPK1, PPARG, and IL-6. In vivo experiments confirmed that BHD significantly suppressed the phosphorylation of MAPK1, reduced the levels of pro-inflammatory factors such as TNF-α and IL-6, mitigated synovial damage, and inhibited the activation of the PI3K-Akt signaling pathway. This study systematically elucidates the pharmacological basis and mechanisms of action of BHD in the treatment of AGA, providing a scientific basis for its clinical application.

AIMS:Cardiac biomarkers independently predict atherosclerotic cardiovascular disease (ASCVD) events but are not integrated into the newly developed AHA PREVENT equations. We evaluated their incremental value and clinical utility of high-sensitivity cardiac troponin T (hs-cTn) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) for primary prevention based on PREVENT equations. METHODS AND RESULTS:We pooled 15 477 ASCVD-free participants from Atherosclerosis Risk in Communities and Multi-Ethnic Study of Atherosclerosis cohorts (mean age 62.0 years; 55.9% female) for primary analysis, with external validation in UK Biobank (UKB) (n = 40 359). Model performance was assessed via C-index, net reclassification improvement (NRI), integrated discrimination improvement (IDI), and decision curve analysis (DCA). Over a median 12.1-year follow-up, 1836 events occurred in primary cohort. Individuals with clinical low/borderline risk (<7.5%) but elevated biomarkers exhibited higher observed event rate and hazards ratio [HR 2.74, 95% confidence interval (CI): 2.45-3.06] than those with high clinical risk (≥7.5%) but normal biomarkers (HR 1.42, 95% CI: 1.22-1.65). The combined high-risk group exhibited the highest risk (HR 4.46, 95% CI: 3.92-5.07). Incorporating biomarkers reclassified 16.4% of low-risk (<5%) and 25.8% of borderline-risk (5-7.5%) individuals into the intermediate-risk category (≥7.5%). The biomarker-augmented PREVENT model was well-calibrated and significantly improved discrimination (ΔC-index: 0.022; P < 0.001) and reclassification (NRI: 0.193; IDI: 0.102). The reclassification improvement was highest in the borderline-risk group. At the 7.5% clinical threshold, DCA demonstrated a three-fold increase in net benefit, identifying 27 additional true-positive cases per 1000 individuals without increasing over-treatment. These findings were robustly confirmed in UKB, where the borderline-risk group showed the highest improvement (ΔAUC = 0.049; P < 0.001). CONCLUSION:Integrating cardiac biomarkers into PREVENT equations identifies high-risk individuals masked by traditional factors, optimizing the clinical yield of primary prevention, especially for borderline-risk populations.

Previous studies have shown that the intake of some specific dietary nutrients is associated with the risk of hyperuricemia (HUA). However, the relationship between dietary calcium intake and HUA remains unknown. Participants aged 18–94 years were identified from the China Health and Nutrition Survey (CHNS) in 2009. Three consecutive 24-h dietary recalls were used to assess estimated dietary intake. Multivariable logistic regression and linear regression were performed to evaluate the relationships between dietary calcium intake and HUA and serum uric acid, respectively, after adjustment for potential confounders. A restricted cubic spline (RCS) was used to visualize the nonlinear or linear relationship of this relationship. A total of 7606 participants were enrolled. The prevalence of HUA was 15.67

Abstract: Objective This study aimed to systematically screen for potential candidate biomarkers and identify therapeutic targets associated with gouty arthritis (GA) through integrated analyses of single-cell and bulk RNA sequencing (RNA-seq) data. Methods The single-cell dataset GSE211783 and the bulk RNA-seq dataset GSE160170 were analyzed using a series of bioinformatic approaches, including cell clustering, differential expression analysis, immune cell infiltration assessment, protein-protein interaction network construction, gene set enrichment analysis, as well as drug sensitivity evaluation. To establish an animal model of GA, monosodium urate crystals were injected intra-articularly into experimental mice. Joint swelling was evaluated, and morphological changes in joint tissues were analyzed through hematoxylin–eosin staining. The presence of TREM1-positive cells was detected by immunohistochemistry and the level of TREM1 protein expression in joint tissues were assessed by Western blotting. Results We identified 102 differentially expressed genes (DEGs) and 14 signaling pathways associated with GA. The PPI network revealed 25 hub genes, of which 17 (including TREM1, TNF, PTGS2, and NLRP3) were highly expressed and 8 (including FCGR3B and CXCR6) showed low expression in the GA samples. These genes correlated significantly with the infiltration levels of macrophages. Among the hub genes, TREM1 was selected for further validation because it correlated significantly with all 14 differential pathways. In animal experiments, GA mice developed marked joint swelling and inflammatory tissue injury, along with a significant increase in TREM1-positive cells and TREM1 protein expression. Conclusion Integrative analysis of single-cell and bulk RNA-seq data identified 102 GA-related DEGs and 14 key pathways, from which 25 hub genes were screened. TREM1 is significantly upregulated in GA and may be linked to macrophage function, providing new insights into biomarker and therapeutic target discovery for GA. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement Yes ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The animal study described in this manuscript was reviewed and approved by the Biomedical and Medical Ethics Committee of the School of Public Health, Jiamusi University (Approval No. 20240318093512277577318). All animal procedures were performed in accordance with the Guidelines for the Care and Use of Laboratory Animals. For human data, this study analyzed publicly available datasets (GSE211783 and GSE160170) from the Gene Expression Omnibus (GEO). These datasets are de-identified and were collected with prior ethical approval by the original contributors, as stated in the respective publications. Therefore, no additional human subject ethics approval was sought for this secondary analysis. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Publicly available datasets were analyzed in this study. This data can be found here: [Gene Expression Omnibus, https://www.ncbi.nlm.nih.gov/geo/]

Background:As an essential part of health services, rehabilitation is of great significance to improve the health and quality of life of the whole population. Accelerating aging calls for a significant expansion of rehabilitation services in China, but rehabilitation needs remain unclear. We conducted the study to explore the rehabilitation needs in China and project the trend of rehabilitation needs from 2020 to 2034.Methods:The data of health conditions that might potentially benefit from rehabilitation were obtained from Global Burden of Disease (GBD) study. Estimated annual percentage changes (EAPCs) were calculated to quantify the trends of the age-standardized rates. Projections of rehabilitation needs were made until 2034 using Bayesian age-period-cohort analysis (BAPC).Results:Approximately 460 million persons (33.3% of the total population) need rehabilitation in China, contributing to 63 million years lived with disabilities (YLDs) in 2019. The number of prevalent cases that need rehabilitation increased from around 268 (95% uncertainty interval [UI]: 257-282) million in 1990 to almost 460 (95% UI: 443-479) million in 2019, representing an increase of 71.3%. The highest contribution to the need for rehabilitation was musculoskeletal disorders with about 322 (95% UI: 302-343) million persons in seven aggregate disease and injury categories, and hearing loss with over 95 (95% UI: 84-107) million people among 25 health conditions. Based on the projection results, there will be almost 636 million people (45% of the total population) needing rehabilitation services in China by 2034, representing an increase of 38.3%. The rehabilitation needs of neoplasms, cardiovascular diseases, and neurological disorders are expected to increase significantly from 2019 to 2034, with increases of 102.3%, 88.8% and 73.2%, respectively.Conclusions:The need for rehabilitation in China substantially increased over the last 30 years. It is predicted that over two in five people will require rehabilitation by 2034, thus suggesting the need to develop rehabilitation services that meet individuals' rehabilitation needs.

Objective: Onychomycosis is characterized by high transmission and low recovery rates, leading to a lack of optimal treatments. This study used dissolving microneedles as drug carriers to design dual-loaded DMN patches with β-1,3-glucanase and terbinafine hydrochloride nanoemulsion. Methods: Dissolving microneedles of terbinafine hydrochloride nanoemulsion for beta-1,3-glucanase (Gls-TBH-NE-DMN) were prepared using the centrifugal molding method. Parafilm®, weight method, mouse skin puncture experiments, and mouse skin tissue sections were used to evaluate the mechanical properties of Gls-TBH-NE-DMN. Gls-TBH-NE-DMN was tested for its in vitro anti-Candida albicans susceptibility, ability to inhibit fungal cell wall synthesis, and fungal biofilm penetration and inhibition capabilities. The in vivo inhibitory effect of Gls-TBH-NE-DMN on fungi was studied using a rabbit nail infection model. Results: Gls-TBH-NE-DMN exhibited a penetration rate of 98% on skin simulants and a compressive bending resistance of 12.75%. It was nonirritating to the dorsal skin of mice, with no edema or erythema on the surface of the skin, suggesting a good safety profile. The accumulative release of Gls-TBH-NE-DMN at 72 h was 78.74% ± 0.64%, and that of terbinafine hydrochloride dissolving microneedles was 49.52% ± 0.80%. In the in vitro transdermal permeation experiment, the cumulative transdermal permeation of Gls-TBH-NE-DMN at 72 h was 73.21% ± 0.84% and that of terbinafine hydrochloride (TBH) was 20.57% ± 0.98%. In vitro inhibition of C. albicans showed that the lowest inhibitory concentration in the Gls-TBH-NE-DMN group was 512 μg mL-1. Furthermore, experiments showed that Gls-TBH-NE-DMN could effectively inhibit fungal cell wall synthesis and disrupt the C. albicans biofilm, inhibiting fungal growth. Conclusions: Gls-TBH-NE-DMN prepared in this study provides new ideas for treating skin fungal diseases and for developing antimicrobial drug formulations.

the high-sensitivity C-reactive protein (hs-CRP) to high-density lipoprotein cholesterol (HDL-C) ratio and hyperuricemia among the population of the United States, the ratio still has predictive value for cardiovascular disease in middle age. Methods 4,780 adult participators from the National Health and Nutrition Examination Survey (NHANES) were involved in this research. Through the NHANES laboratory testing, all biochemical indications were discovered. In order to observe the differences in indications, propensity score methods were used to match age and sex confounders.The relationship between hs-CRP/HDL-C ratio and hyperuricemia was explored using propensity matching and weighted multivariate logistic regression analysis, with the potential nonlinear relationship between hs-CRP/HDL-C ratio and hyperuricemia was investigated using a restricted cubic spline test. Results Sex, age, hypercholesterolaemia, diabetes, fasting glucose, cholesterol, high and low density lipoprotein, did not differ statistically significantly (P > 0.05); however, uric acid, triglycerides, high-density lipoprotein, CRP/HDL ratio, C-reactive protein, ethnicity, and hypertriglyceridemia differed (P < 0.05). In a weighted multifactor model, the relative odds ratio for hyperuricemia increased by 0.383 times at the second quintile (OR = 1.383, 95%CI(1.382–1.385), P < 0.001), 2.001 times at the third quintile (OR = 3.001, 95%CI (2.998–3.005), P < 0.001), and 2.533 times at the fourth quintile (OR = 3.533, 95%CI (3.529–3.538), P < 0.001). In the univariate and multivariate models, the restricted cubic spline test demonstrated a nonlinear correlation between the CRP/HDL ratio and hyperuricaemia, with a growing “log-function” shaped trend (P for overall < 0.001). Conclusion The hs-CRP/HDL-C ratio is significantly positively correlated with hyperuricemia among American adults. Maintaining the ideal hs-CRP/HDL-C ratio may contribute to reducing the burden of hyperuricemia.

Objective This study aimed to investigate the relationship between different types of fatty acid intake and cataract incidence using data from NHANES 2005-2008, with the goal of providing scientific evidence for guiding fatty acid supplementation in the elderly and preventing cataracts. Methods A total of 2,536 participants were selected from the 2005-2008 National Health and Nutrition Examination Survey (NHANES) database. Student’s t-test and Pearson chi-square test were used to analyze the correlation between baseline data, characteristic data, and all dietary fatty acid intakes with cataract incidence. Weighted multivariate logistic regression was employed to examine the relationship between all fatty acid intakes and cataracts. Quartile regression analysis was used to evaluate the effect of dodecanoic acid on cataracts at different intake levels. Results After adjusting for covariates, significant differences were observed in the daily intakes of total fat (69.80 g vs. 62.46 g, p=0.005), total saturated fatty acids (23.06 g vs. 20.60 g, p=0.002), total monounsaturated fatty acids (25.53 g vs. 22.76 g, p=0.009), and total polyunsaturated fatty acids (15.16 g vs. 13.61 g, p=0.014) between the two groups. When cataract was used as the outcome variable, a significant negative correlation was found between daily dodecanoic acid intake and cataract in the weighted multivariate logistic regression model (Model 1: OR=0.79, 95% CI=0.65-0.97; Model 2: OR=0.80, 95% CI=0.65-0.97; Model 3: OR=0.81, 95% CI=0.66-0.99). In the quartile regression analysis, the fourth quartile of daily dodecanoic acid intake was negatively correlated with cataract incidence in all models (Model 1: OR=0.58, 95% CI=0.39-0.86; Model 2: OR=0.58, 95% CI=0.39-0.86; Model 3: OR=0.60, 95% CI=0.40-0.91). Conclusion Increasing the daily intake of dodecanoic acid in the diet may reduce the likelihood of cataract development. Appropriate supplementation of dodecanoic acid in the daily diet can help prevent the occurrence and progression of cataracts. ### Competing Interest Statement The authors have declared that no competing interests exist. ### Funding Statement The author(s) received no specific funding for this work. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Not Applicable The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Jiamusi University I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Not Applicable I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Not Applicable I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Not Applicable https://wwwn.cdc.gov/nchs/nhanes/continuousnhanes/default.aspx?BeginYear=2005 https://wwwn.cdc.gov/nchs/nhanes/continuousnhanes/default.aspx?BeginYear=2007

Gouty arthritis (GA) is a common inflammatory disease which has no effective treatments. Pyroptosis has been reported to exacerbate the progression of GA. We aimed to explore the molecular mechanism by which S-nitrosylated NEDD4 accelerates GA progression by regulating pyroptosis. In our study, we found NOD1 knockdown inhibited pyroptosis and reduced c-Caspase-1, NLRP3, ASC, and GSDMD-N expression, IL-1β and IL-18 levels, and XOD activity in GA in vivo and in vitro. In addition, NOD1 knockdown alleviated inflammatory symptoms of joint tissues in GA mice model. Moreover, downregulation of NEDD4 caused by S-nitrosylation modification at C365 site upregulated NOD1 expression by reducing ubiquitination and degradation of NOD1. Furthermore, iNOS promoted NOD1 expression by mediating S-nitrosylation of NEDD4 thereby inducing GA in vitro. In conclusion, S-nitrosylation of NEDD4 promoted NLRP3-mediated pyroptosis by upregulating NOD1 expression, which ultimately accelerated the development of GA. We are the first to report the expression patterns of NEDD4 and NOD1 in GA, and demonstrated firstly that S-nitrosylation of NEDD4 inhibited ubiquitination-mediated degradation of NOD1, thereby modulating pyroptosis in GA. By elucidating how S-nitrosylation of NEDD4 orchestrates NOD1-mediated pyroptosis, this work opens avenues for developing first-in-class therapies for GA.

ETHNOPHARMACOLOGICAL RELEVANCE:Antler base (Cervus nippon Temminck), a traditional Chinese medicine, is categorized as deer antler. Antler base extracts can delay osteoarthritis (OA); however, the underlying molecular pathways and effective substances remain unclear. AIM OF THE STUDY:to clarify the potential mechanism of action and effective substance structure of Cervus nippon Temminck antler base peptides (CNCPs) in improving OA. MATERIALS AND METHODS:The physicochemical properties, including functional groups, amino acid composition, and molecular weight of CNCPs were characterized using FTIR and HPLC. The protective effect and potential mechanism of action of CNCPs in a papain-induced OA rat model were investigated through histopathological examinations, Elisa kit, western boltting, qRT-PCR, and immunofluorescence. CNCPs were isolated and purified using SephadexG-15, and the purified fractions were screened for bioactivity by IL-1β-induced in vitro model, and LC-MS/MS identified the component with the best activity. RESULTS:CNCPs significantly alleviated the superficial cartilage erosion, protected cartilage surface integrity, regulated OA-related phenotypic proteins expression, and modulated the serum levels of related pro-inflammatory cytokines and oxidative stress-related factors in OA rats. CNCPs inhibited the activation of the NLRP3 inflammatory pyroptosis pathway triggered and upregulated the Nrf2 pathway. The best active fraction, CNCPs-III, contained a notable amount of hydrophobic amino acid residues, including AGPAGA, VGPV, and LLGDV, and had a molecular mass of <1.5 kDa. CONCLUSIONS:CNCPs improve OA-induce inflammation and oxidative stress induced with OA by regulating the NLRP3 inflammatory pyroptosis and Nrf2/HO-1/NQO1 signaling pathways, thereby delaying OA progression.

Basal metabolic rate, resting metabolic rate, and resting energy expenditure are frequently utilised for the same research aims, but the underlying mechanisms separating them from human metabolic rate and metabolic disease remain poorly understood.Furthermore, specific recommendations for the prevention and management of hyperuricemia in populations with different resting metabolic rates have not been proposed, or how to reduce the public health burden of hyperuricemia based on resting metabolic rate and other factors have not been explored.[Methods] From 2011 to 2018, we selected 3268 adult participants from the National Health and Nutrition Examination Survey (NHANES). The modified Harris-Benedict equation was used to compute resting metabolic rate, and NHANES laboratory tests were used to acquire all biochemical parameters. A multivariate logistic regression analysis was performed to look at the relationship between hyperuricemia and resting metabolic rate. [Results] The multifactorial corrected model’s second through fourth quartiles of RMR levels compared to the first quartile had relative advantage ratios of 1.258 (0.883 to 1.793), P > 0.05, 1.569 (1.024 to 2.404), P < 0.05, and 2.570 (1.555 to 4.247), P < 0.001 for men, respectively, following analysis.Subgroups of sexes Following analysis, the relative advantage ratios for the second and third tertiles of RMR levels for males were 1.157 (0.712 to 1.880), P > 0.05, and 1.991 (1.187 to 3.338), P < 0.05, respectively, when compared to the first tertile in the multifactorial corrected model.The female subgroup’s adjusted postmenopausal RMR levels had relative dominating ratios of 1.157 (0.767 to 1.743), P > 0.05; 1.683 (0.955 to 2.967), P > 0.05; and 2.140 (0.965 to 4.747), P > 0.05 for the second through fourth quartiles. For the second through fourth quartiles of adjusted postmenopausal RMR levels in the female subgroup, the relative dominance ratios were 1.186 (1.005 to 3.082), P < 0.05; 2.302 (1.043 to 5.081), P < 0.05; and 1.192 (0.792 to 1.794), P > 0.05.[Conclusion] There was a positive correlation between resting metabolic rate and hyperuricemia. This pattern was also shown when gender subgroups were examined, with women over 45 being particularly susceptible to the association between hyperuricemia and resting metabolic rate.

IntroductionHyperuricemia (HUA) is characterized by metabolic abnormalities in purine metabolism, leading to an excessive accumulation of uric acid in the bloodstream. This condition is not only prevalent but also significantly linked to the exacerbation of various chronic diseases, including renal impairment. Notably, asymptomatic hyperuricemia is frequently associated with inflammatory responses and alterations in intestinal microbiota. Thus, it is imperative to explore effective therapeutic interventions for HUA to mitigate its associated health risks.MethodsThe present study aimed to elucidate the protective effects of Plantaginis Semen polysaccharides (PSP) in a rat model of hyperuricemia induced by adenine (AD) and potassium oxonate (PO) gavage. Over a treatment period of five weeks, the animals received either PSP or allopurinol (AL). Comprehensive assessments were performed, including blood biochemistry analysis, histopathological evaluation, Western blot analyses to investigate the expression levels of key renal transport proteins, as well as 16S rRNA sequencing to explore microbiota shifts.ResultsThe findings demonstrated that PSP significantly decreased serum uric acid (UA) levels and alleviated renal dysfunction through modulation of xanthine oxidase (XOD) and adenosine deaminase (ADA) serum concentrations and the expression of renal transporters, namely glucose transporter protein 9 (GLUT9), urate transporter 1 (URAT1), ATP-binding cassette superfamily member 2 (ABCG2), and organic anion transporter 1 (OAT1). Furthermore, PSP exhibited notable anti-inflammatory properties, reflected in the reduced levels of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β).ConclusionIn summary, the present study substantiates the therapeutic potential of PSP in treating hyperuricemia through its dual action of lowering uric acid levels and imparting anti-inflammatory effects. The observed modulation of gut microbiota further supports the role of PSP in maintaining metabolic homeostasis. Future investigations should focus on the clinical applicability of PSP and elucidate the mechanisms underlying its beneficial impacts on hyperuricemia and associated metabolic disorders.

ETHNOPHARMACOLOGICAL RELEVANCE:Viscum coloratum (Kom.) Nakai is a commonly used traditional Chinese medicine (TCM) in the treatment of diseases such as tumors, diabetes, gout, and hepatitis. Viscum coloratum polysaccharide (VCP) is a major component of this TCM. however, its mechanism of action in hyperuricemic nephropathy (HN) remains unclear. AIM OF THE STUDY:This study aimed to elucidate the mechanisms and pathways by which VCP exerts its effects in HN rats. MATERIALS AND METHODS:The functional groups, molecular weight, monosaccharide compositions, and micromorphologies of VCP were characterized using FT-IR, HPGPC, HPAEC, and SEM, respectively. A rat model of HN was established using a combination of potassium oxonate and adenine. The potential mechanism of action of VCP in alleviating HN was verified using Elisa kit, histopathological examination, Western blot, and immunofluorescence. Additionally, 16S rRNA gene sequencing was employed to detect the regulatory effect of VCP on the gut microbiota in HN rats. An in vitro model of HN was also constructed by stimulating HK-2 cells with uric acid. Finally, the underlying mechanism was further validated using small interfering RNA to silence the expression of Nrf2 in HK-2 cells. RESULTS:VCP is a neutral homogeneous polysaccharide with a molecular weight of 8.91 × 104 Da and is composed of Glc and Man. VCP enhanced the ability of the kidney to metabolize UA by inhibiting the expression of URAT1 and increasing that of ABCG2. It also increased species richness and diversity, enriched the abundance of Lactobacillus, Peptostreptococcaceae, and Ruminococcus, regulated gut microbiota imbalance, improved the intestinal capacity to metabolize uric acid, and reduced UA levels in HN rats. VCP activated the Nrf2/HO-1 pathway by upregulating Nrf2 expression, increased the activity of kidney antioxidant, attenuated kidney oxidative damage, and inhibited the downstream NLRP3/ASC/Caspase-1 and TGF-β1/Smad3 pathways to alleviate the symptoms of kidney tubular inflammation and fibrosis, while exerting a protective effect against kidney injury in HN rats. CONCLUSIONS:VCP decreased uric acid levels in HN rats by regulating the pathways related to urate transporters and gut microbiota. It also upregulated Nrf2 expression to inhibit the NLRP3/ASC/Caspase-1 and TGF-β1/Smad3 signaling pathways, and protecting against HN kidney injury.

Accumulating evidence supports the association between endocrine disrupting chemicals (EDCs) exposure and cardiovascular disease (CVD). However, the link between EDCs and cardiovascular health (CVH) prior to CVD onset remains unclear. This study investigates the relationship between individual and combined EDC exposure and Life’s Essential 8 (LE8). We included 9,940 participants from the National Health and Nutrition Examination Survey (NHANES) conducted between 2003 and 2016, excluding adults with known CVD. Twenty-two types of EDCs were detected in urine samples, including three phenols, two phenolic pesticides, eleven phthalates, and six polycyclic aromatic hydrocarbons (PAHs). Weighted generalized linear models (GLM) and weighted quantile sum (WQS) regression to explore the relationship between single/mixed exposure to EDCs and CVH. Overall, 9,940 individuals (weighted mean [SE] age, 42.53 [0.26] years; 5,313 women [weighted 53.7

Purpose To explore the protective effects of cassia polysaccharides on myopia by examining their influence on ARPE-19 cells with reduced PAX6 expression. Methods The ARPE-19 cell line with diminished PAX6 expression was established using a lentiviral approach and the addition of XAV-939, an inhibitor of Wnt/β-catenin. We assessed the expression of genes and proteins involved in Wnt/β-catenin, scleral remodeling, and cell cycle regulation following treatment with cassia polysaccharides. Gene and protein expression were quantified using reverse transcription PCR and western blot analyses, respectively. Additionally, the migratory capabilities of these cells were evaluated using a scratch assay. Results Optimal transduction was achieved with a multiplicity of infection of 20, successfully generating a stable ARPE-19 cell line with low PAX6 expression. Cassia polysaccharides did not significantly alter the expression of Wnt2 compared to control groups. Similarly, when treated with XAV-939, β-catenin levels were modified in PAX6-shRNA and XAV-939 but remained unchanged in the cassia polysaccharides. Scleral remodeling markers, including MMP-2 and TGF-β, were elevated, and COL1A1 was decreased in PAX6-shRNA, with no significant changes observed in the cassia polysaccharides. Cell cycle analysis indicated reduced cyclin-dependent kinase 1 and proliferating cell nuclear antigen levels in PAX6-shRNA, with cassia polysaccharides showing no significant effect. Scratch assay results demonstrated slower wound healing in PAX6-shRNA compared to controls over 72 h, with no significant differences observed in the cassia polysaccharides. Conclusions Cassia polysaccharides may mitigate ARPE-19 cell damage induced by low PAX6 expression through modulation of Wnt/β-catenin, potentially slowing the progression of myopia and offering a protective effect on vision.

Objective To explore the effect and mechanism of uric acid (UA) in regulating the larval growth and development of Drosophila melanogaster. Methods A total of 1350 newly hatched first-instar larvae of wild-type Drosophila melanogaster (W1118) were collected,and the Drosophila melanogaster model of hyperuricemia was constructed with a high purine diet.The larvae were assigned into three groups (n=150):control (standard corn meal medium),low-dose adenine (corn meal medium containing 0.05% adenine),and high-dose adenine (corn meal medium containing 0.10% adenine),and two parallel groups were set up.The growth and development of larvae in each group was observed,and the UA and hormone levels were measured.In addition,the expression levels of genes involved in growth and development were determined. Results Compared with the control group,the low- and high-dose adenine groups showed elevated UA levels (both P<0.001) and prolonged developmental period (P=0.024,P<0.001).The high-dose adenine group showed decreased survival rate,pupation rate,and eclosion rate and elevated levels of juvenile hormone (JH) and 20-hydroxyecdysone (20E) (all P<0.001).The PCR results showed that compared with the control group,high-dose adenine upregulated the mRNA levels of reactive oxygen species (ROS),forkhead box O (FOXO),and mammalian target of rapamycin (mTOR) while downregulating the mRNA levels of Sestrin,mTOR complex 1(mTORC1),and AMP-activated protein kinase (all P<0.001). Conclusion High concentrations of UA may promote the expression of ROS/FOXO/mTORC1/mTOR signaling pathway by regulating the levels of JH and 20E,thereby inhibiting the larval growth and development of Drosophila melanogaster.

The association between statin use and skeletal muscle-related side effects is always controversial. This study aimed to comprehensively investigate the associations between statin use and muscle-related phenotypes ).This cross-sectional study included 22,549 patients aged ≥20 years with cardiovascular disease, diabetes, or hyperlipidemia. Weighted generalized linear regression analysis and propensity score matching methods were used to estimate the associations between the use of statins or other lipid-lowering agents and skeletal muscle-related phenotypes. Mendelian randomization (MR) analysis was additionally used to verify the causal relationship between statin use and skeletal muscle-related phenotypes.The weighted mean age was 59 years, 50.3% were male, and 37.6% (n=8,481) received statin treatment. In the unadjusted model, compared with adults without any lipid-lowering drugs, statin use was associated with a higher likelihood of sarcopenia (appendicular skeletal muscle mass [ASM]/Body mass index [BMI] OR 1.35 (95%CI 1.12 to 1.62, p < 0.001) ASM/weight [Wt] OR 1.86 (95%CI 1.62 to 2.13, p < 0.001), max HGS β -3.01 (95% CI -3.97 to -2.06, p < 0.001), relative HGS β -0.23 (95% CI -0.30 to -0.17, p < 0.001) and combined HGS β -5.90 (95% CI -7.86 to -3.93, p < 0.001)), sarcopenic obesity and body fat percentage definition [OR 1.36 (95% CI 1.13 to 1.63, p < 0.001]). After multivariable adjustment or propensity score match, the independent associations of statin use with sarcopenia, sarcopenic obesity, HGS, LDH, and musculoskeletal pain became nonsignificant. Stepwise regression suggested that age was the predominant confounding factor for the associations. MR analysis also revealed no significant causality between statin use and skeletal muscle-related phenotypes. Our epidemiological and MR analyses found no causality between statin use and skeletal muscle-related phenotypes, suggesting age as a potential contributor to higher risk in statin users.Future studies should delve deeper into the biological factors influencing statin-related muscle phenotypes. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement SW was funded by the National Natural Science Foundation of China (82200396), Natural Science Foundation of Heilongjiang Province of China (YQ2022H006), New era Longjiang outstanding doctoral key project (LJYXL2022-013), Cultivation Project of Second Affiliated Hospital of Harbin Medical University (PYMS2023-3); YZ was funded by the Gout Etiology and Functional Food Research Innovation Team, the North Medicine and Functional Food Characteristic Subject Project in Heilongjiang Province (HLJTSXK-2022-03), Postdoctoral Science Foundation of Heilongjiang Province of China (LBH-Q21047), National Fund Cultivation Program of Jiamusi University (JMSUGPZR2022-022), Scientific and Technological Innovation Team of Jiamusi University (cxtd202101). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was conducted according to the guidelines laid down in the Declaration of Helsinki and all procedures involving research study participants were approved by the [NCHS]. Written informed consent was obtained from all subjects. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The datasets supporting the conclusions of this article are available in the National Health and Nutrition Examination Survey repository, unique persistent identifier and hyperlink to the dataset in https://wwwn.cdc.gov/nchs/nhanes/default.aspx.

BACKGROUND:The evidence on the association between cobalamin (Cbl) and aging or relevant outcomes is limited and controversial. We aimed to investigate the relationships between cobalamin intake- and function-related biomarkers and biological aging. METHODS:The study encompassed 22,812 participants aged 20 years and older from the National Health and Nutrition Examination Survey. A panel of biomarkers or algorithms was used to assess biological aging, including Klemera-Doubal Age Acceleration (KDMAccel), Phenotypic age acceleration (PhenoAgeAccel), telomere length, α-Klotho, and PhenoAge advancement. Weighted generalized linear regression analysis was used to assess the associations between cobalamin-intake biomarkers (serum cobalamin, cobalamin intake from food, cobalamin supplement use, serum methylmalonic acid [MMA], and homocysteine [Hcy]) and function-related biomarkers (functional cobalamin deficiency and cobalamin insensitivity index). RESULTS:Among the 22,812 individuals, the weighted mean (SE) age was 48.3 (0.2) years and 48.0% were males. Unexpectedly, serum and dietary cobalamin as well as serum MMA and Hcy levels were positively associated with most indicators of biological aging. Cobalamin sensitivity was assessed by the combination of binary Cbllow/high and MMAlow/high or Hcylow/high (cutoff values: 400 pg/mL for cobalamin, 250 nmol/L for MMA, and 12.1 μmol/l for Hcy) and a newly constructed cobalamin insensitivity index (based on the multiplicative term of serum cobalamin and serum MMA or Hcy). The multivariable-adjusted β (95%CIs) of KDMAccel in the MMAlowCbllow, MMAlowCblhigh, MMAhighCbllow, and MMAhighCblhigh groups were reference, 0.27 (0.03 to 0.51), 0.85 (0.41 to 1.29), and 7.97 years (5.77 to 10.17) respectively, which were consistent for the combination of serum Hcy and cobalamin. Both cobalamin insensitivity indices were robustly associated with biological aging acceleration in a dose-response pattern (each p < 0.001). CONCLUSIONS:Decreased cobalamin sensitivity but not cobalamin insufficiency might be associated with biological aging acceleration. Further studies would improve understanding of the underlying mechanisms between decreased cobalamin sensitivity and biological aging acceleration.