Ethnopharmacological relevance Despite its long history of use in traditional medicine for joint disorders, Wutou Decoction (WTD) has not been widely adopted as a complementary therapy for rheumatoid arthritis (RA) in modern practice. This is primarily due to a lack of robust pharmacological evidence and a clear understanding of its mechanisms of action. Further investigation into the mechanistic basis of WTD is essential to validate its efficacy and safety in the treatment of RA. Aim of the study Fibroblast-like synoviocytes in rheumatoid arthritis (RA-FLS) display a highly invasive phenotype, contributing to progressive bone and cartilage destruction. Evidence suggests that crosstalk between the hypoxic microenvironment and the Notch signaling pathway plays a central role in driving this pathological behavior, highlighting both as potential therapeutic targets. This study aimed to determine whether WTD exerts its therapeutic effect on RA by disrupting hypoxia-induced activation of the Notch signaling pathway. Materials and methods A collagen-induced arthritis (CIA) model in rats and hypoxia-treated RA-FLS were employed. WTD used in this study consist of Aconitum carmichaelii Debeaux. (processed root, 6 g), Astragalus mongholicus Bunge. (root, 9 g), Ephedra sinica Stapf. (herbaceous stem, 9 g), Paeonia lactiflora Pall. (root, 9 g) and Glycyrrhiza uralensis Fisch. (root, 9 g). The anti-arthritic effects of WTD were assessed through arthritis scoring, spleen index, and hematoxylin-eosin staining and Safranin O/Fast Green). The involvement of the Notch pathway and invasive RA-FLS phenotype was evaluated by immunostaining, RT-qPCR, and western blotting. Results WTD significantly attenuated synovial hyperplasia and cartilage degradation in CIA rats. In both CIA rat synovium and hypoxia-treated RA-FLS, WTD markedly inhibited activation of the HIF and Notch signaling pathways, along with the expression of their downstream target genes. Further analyses revealed that WTD suppressed hypoxia-induced RA-FLS invasiveness, including cartilage matrix degradation and pro-angiogenic activities, by blocking Notch signaling. Molecular docking suggested that active compounds in WTD may bind to the negative regulatory region domain of Notch receptors. Notably, WTD also reversed the hypoxia response induced by forced activation of the Notch pathway. Conclusions These findings elucidate the mechanism by which WTD alleviates RA, firstly demonstrating that it effectively inhibits the hypoxia-induced invasive phenotype of RA-FLS by targeting the Notch signaling pathway. However, this study has several limitations: the findings are based on a single batch of WTD, the predicted binding of active compounds to Notch receptors has not been experimentally validated, and the individual contributions of the candidate quality markers to the overall therapeutic effect remain to be systematically determined.

Background: Since its launch in China in 2019, camrelizumab has been widely used in various cancer treatments. Reactive cutaneous capillary endothelial proliferation (RCCEP) is the most common immunerelated adverse event of camrelizumab, typically occurring on the skin. However, RCCEP occurring in rare sites still requires special attention. Case Description: This case report describes a patient with hepatocellular carcinoma (HCC) who developed epistaxis and hemoptysis after treatment with camrelizumab combined with apatinib. After excluding multiple etiologies including lung metastasis of liver cancer, pulmonary diseases, infection, and coagulation dysfunction, nasal endoscopy revealed a polypoid vascular lesion in the right Little's area. Following nasal electrocoagulation for hemostasis and switching to regorafenib combined with atezolizumab, the epistaxis and hemoptysis resolved. During the follow-up process, the patient's positron emission tomography/computed tomography (PET/CT) and second nasal endoscopic examination showed no abnormalities in the nasal structure. It was inferred that the epistaxis and hemoptysis were secondary to an intranasal hemangioma induced by camrelizumab. Conclusions: This case highlights the need to monitor RCCEP in rare sites during camrelizumab therapy, especially when symptoms first appear in atypical locations. RCCEP can generally be relieved after discontinuation. The combination of camrelizumab and apatinib can reduce the occurrence of RCCEP, while thalidomide may be a low-cost drug for relieving RCCEP. There are many treatment options for HCC immunotherapy, but it is still necessary to carefully select the treatment options and monitor and manage adverse events in order to improve the prognosis of patients.

Rheumatoid arthritis belongs to arthralgia in the theory of traditional Chinese medicine, with cold dampness obstruction pattern (CDO) and damp heat obstruction pattern (DHO) as the main pattern types. Fine therapeutic effects have been obtained in clinical practice following the differentiation of CDO and DHO. However, suitable animal models are not available currently. For adapting to the clinical diagnosis, as well as carrying out basic research of integrated Chinese and Western medicine and preclinical study on new Chinese medicine in a better way, the “Guidelines for Establishing Animal Models of Rheumatoid Arthritis with Cold Dampness Obstruction Pattern and Damp Heat Obstruction Pattern” (referred to as “Guidelines”) were compiled by our research group in cooperation with renowned experts in clinical, pharmaceutical, zoological, and methodological research fields. According to the theory of disease and syndrome integration, experts standardized the establishment methods for animal models of rheumatoid arthritis with CDO and DHO. The Guidelines were compiled via the nominal group method according to the principle of evidence coming in main place, consensus as the auxiliary, and experience as the references. Contents such as animal species, arthritis induction methods, external stimulation conditions, and assessment indicators were specified in the Guidelines based on the comprehensive evaluation of pathogenesis homology, behavioral phenotypic consistency, and drug therapy predictability between animal models and human diseases. The Guidelines will be applicable to the research on syndromes in rheumatoid arthritis, elucidation of acting mechanism, and development of new medicine, and provide reference for standardizing other types of animal models with the integration of disease and syndrome, to promote the modernization of Chinese medicine research.

To investigate the association between insulin resistance (IR) and all-cause mortality among adults with rheumatoid arthritis (RA). In this cohort study, we included 1,427 adults with self-reported RA from the National Health and Nutrition Examination Survey (NHANES) 1999–2010 and 2015–2018. IR was assessed using the homeostatic model assessment of insulin resistance (HOMA-IR). Survey-weighted multivariable Cox proportional hazards models were used to evaluate the association between HOMA-IR and all-cause mortality. During a mean follow-up of 9.7 years, 491 deaths occurred. Compared with participants in the lowest tertile of HOMA-IR, the multivariable-adjusted hazard ratios (HRs) and 95

Autoimmune diseases are a group of disorders with multiple etiologies that disrupt normal immunological function, leading to the immune system mistakenly attacking the body’s own tissues. The Notch signaling pathway is a conserved pathway that is in part responsible for multiple cellular behaviors, including proliferation, differentiation, development, and death, through direct cell-to-cell communication. The expression and activation of Notch signaling pathway proteins are aberrantly regulated in autoimmune diseases in a manner that is closely related to their onset and development. We reviewed the functioning of the Notch signaling pathway in several autoimmune disorders, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), primary Sjögren’s syndrome (pSS), juvenile idiopathic arthritis (JIA), idiopathic thrombocytopenic purpura (ITP), multiple sclerosis (MS), autoimmune vasculitis, autoimmune hepatitis (AIH), autoimmune thyroid disease (AITD), autoimmune kidney diseases and type 1 diabetes mellitus (T1DM). We specifically sought to explore the involvement of the Notch signaling pathway in the occurrence and progression of RA to provide ideas and approaches for developing new therapeutic strategies for this autoimmune disease.

INTRODUCTION:As a new research technology, pulsed high magnetic fields (PHMF) have been gradually used in many fields such as industry, communication, and medical treatment. However, there is still a lack of studies on the safety of PHMF and their effects on autoimmune inflammation. Our work aims to expand the possibilities of PHMF application in autoimmune disease therapy and provide a foundation for further refined research into the safety of PHMF. MATERIALS AND METHODS:We used 30 DBA/1J mice to investigate the effects of 7.25 T PHMF exposure for 10 days on normal mice and collagen-induced arthritis (CIA) mice, a kind of autoimmune inflammation model. RESULTS:White blood cell counts, neutrophil counts, eosinophil counts, basophil counts, neutrophil percentage, the variable coefficient of red blood cell distribution width, and the standard deviation of red blood cell distribution width of normal mice were significantly up-regulated and lymphocyte percentage was significantly down-regulated by twice-daily 7.25 T PHMF. The body weight, other blood routine indexes, and organ pathological manifestations were not significantly affected by the PHMF. Moreover, different doses of PHMF exposure did not have significant effects on body weight, arthritis score, joint pathology, synovitis score, and the expression of inflammatory cytokines in CIA mice. CONCLUSION:In general, daily short-term exposure to 7.25 T PHMF does not have severe effects on normal mice and CIA model mice, and more studies are needed to verify its safety and efficacy.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovitis and progressive structural joint damage. Its pathology involves immune-cell infiltration, pannus formation, cartilage degradation, and bone destruction. Although autoantibodies, inflammatory cytokines, and aberrant immune activation are central to RA pathogenesis, they do not fully explain the persistence of synovitis, defective inflammation resolution, or structural joint damage in some patients. Emerging evidence indicates that fatty acid metabolic reprogramming may actively shape RA-related cellular dysfunction by linking lipid substrate availability, membrane remodeling, mitochondrial metabolism, oxidative stress, and lipid mediator generation. This review organizes current evidence within a cell-specific immune-synovial-bone destruction framework. In immune cells, alterations in fatty acid uptake and transport, de novo lipogenesis, fatty acid oxidation, and lipid mediator generation influence monocyte/macrophage-driven inflammatory amplification, T-cell effector responses and regulatory imbalance, and potential B-cell contributions to autoimmunity. In RA fibroblast-like synoviocytes, reprogrammed fatty acid metabolism supports proliferation, migration, invasion, inflammatory mediator production, and matrix degradation, thereby promoting synovial aggression. In osteoclast-lineage cells, fatty acid oxidation and related metabolic adaptations facilitate precursor fusion and bone resorption. In addition, an imbalance between arachidonic acid-derived pro-inflammatory mediators and eicosapentaenoic acid- and docosahexaenoic acid-derived specialized pro-resolving mediators may contribute to persistent inflammation and defective resolution. By integrating inflammatory amplification, defective resolution, synovial aggression, and bone destruction, this review highlights fatty acid metabolism as a context- and cell-dependent regulator of RA progression. Potential therapeutic approaches include limiting excessive fatty acid uptake and de novo lipogenesis, selectively modulating fatty acid oxidation, restoring pro-resolving lipid mediator balance, targeting relevant lipid-sensing receptors, and modulating microbiota-derived fatty acid metabolites. These strategies may complement existing anti-inflammatory and immunomodulatory therapies, although successful translation will require cell-selective targeting, disease-stage stratification, biomarker-guided patient selection, and careful safety evaluation.

It has been reported that individuals with type 1 diabetes (T1D) are at a higher risk of concomitant occurrence of other autoimmune diseases (AIDs). Currently, there is a lack of research investigating the causal relationship between T1D and other AIDs. A comprehensive Mendelian randomization (MR) study was conducted using debiased inverse-variance weighted (dIVW) and inverse-variance weighted (IVW) estimators to examine the bidirectional causal relationship between T1D and 12 AIDs. Genome-wide association study (GWAS) summary statistics datasets related to T1D or 12 AIDs were obtained from the FinnGen study or other published cohort studies. Pruned SNPs in linkage disequilibrium (LD)-clumped single-nucleotide polymorphisms (SNPs) were used as instrumental variables. For the dIVW analysis, no genome-wide significance threshold was applied for SNP selection. For each 1-unit increase in the log-transformed odds ratio (OR) of patients with primary biliary cholangitis (PBC) or rheumatoid arthritis (RA), the ORs of T1D were 1.123 (95% CI: 1.094–1.151) and 1.133 (95% CI: 1.100–1.167), respectively. Conversely, for each 1-unit increase in the log-transformed OR of T1D, the OR of RA was 1.383 (95% CI: 1.213–-1.578). No bidirectional associations were found between T1D and other AIDs. Patients with RA or PBC have a higher risk of developing T1D, and those with T1D also have an increased risk of developing RA. These findings highlight the importance of regular screening for individuals with T1D, RA, or PBC.

ETHNOPHARMACOLOGICAL RELEVANCE:Sepsis-associated encephalopathy (SAE) is a diffuse cerebral dysfunction caused by sepsis. Danshen (Salvia miltiorrhiza Bunge) is a traditional Chinese herb utilized to treat cardiovascular and neurological disorders. However, the therapeutic effects and underlying mechanisms of Danshen on sepsis-associated encephalopathy remain unclear. AIM OF THE STUDY:This study aims to investigate whether sodium tanshinone IIA sulfonate (STS), a lipid-soluble extract from Danshen, could alleviate neuroinflammatory-induced hippocampal neuronal injury and explore the mechanisms involved. METHODS:SAE model was generated by cecal ligation and puncture (CLP), along with HT22 cells treated with activated BV2-derived conditioned medium (Ac-BV2-CM). The effects of STS on SAE were assessed by behavioral tests, histopathology, immunostaining, RT-qPCR, western blotting, and RNA-seq. Mitochondria dysfunction was evaluated by detecting membrane potential, mitochondria reactive oxygen species (ROS) and ATP, and by mitochondria complex activity assays. RESULTS:STS significantly reduced the mortality rate of CLP mice over a 7-day period, ameliorated cognitive and emotional dysfunction, and prevented neuronal damage in the hippocampal CA1 region. STS effectively inhibited neuroinflammatory responses mediated by microglial activation and pyroptosis in the hippocampus of CLP mice. Ac-BV2-CM, mimicking neuroinflammatory responses in vivo, induced damage to HT22 cells, a mouse hippocampal neuronal cell line. RNA-seq and validation analysis demonstrated that STS improved mitochondria dysfunction induced by Ac-BV2-CM, thereby preventing neuroinflammatory response-induced hippocampal neuronal damage. In addition, STS enhanced the SIRT1/PGC-1α/NRF1/TFAM pathway in the hippocampus of CLP mice and Ac-BV2-CM treated HT22 cells. Finally, STS inhibited neuroinflammatory-induced hippocampal neuron apoptosis, leading to improved synaptic plasticity; these effects were achieved through the enhancement of SIRT1. CONCLUSIONS:The SIRT1/PGC-1α/NRF1/TFAM pathway regulates mitochondrial dysfunction and constitutes the underlying mechanism by which STS mitigates neuroinflammation-induced damage to hippocampal neurons in SAE.

BackgroundDisturbance of the blood‒brain barrier (BBB) and associated inflammatory responses are observed in patients with hepatic encephalopathy (HE) and can cause long-term complications. Dahuang-Wumei decoction (DWD) is a renowned traditional Chinese herbal medicine with a long history of clinical use and has been widely employed as an effective treatment for hepatic encephalopathy (HE). Despite its established efficacy, the precise mechanisms underlying the therapeutic effects of DWD have not been fully elucidated.PurposeThe present study aimed to comprehensively explore the potential effects and underlying molecular mechanisms of DWD on HE through an integrated investigation that included both in vivo and in vitro experiments.MethodsIn the present study, carbon tetrachloride (CCl4) and thioacetamide (TAA) were used to establish an HE model in mice. The therapeutic effects of DWD on liver injury, fibrosis, brain injury, behaviour, and consciousness disorders were evaluated in vivo. C8-D1A and bEnd.3 cells were used to construct a BBB model in vitro. The effects of DWD on proinflammatory factor expression, BBB damage and the Wnt/β-catenin pathway were detected in vivo and in vitro.ResultsOur results showed that DWD can improve liver injury and fibrosis and brain damage and inhibit neurofunctional and behavioural disorders in mice with HE. Afterwards, we found that DWD decreased the levels of proinflammatory factors and suppressed BBB disruption by increasing the levels of junction proteins in vivo and vitro. Further studies verified that the Wnt/β-catenin pathway may play a pivotal role in mediating the inhibitory effect of DWD on HE.ConclusionThese results demonstrated that DWD can treat HE by preventing BBB disruption, and the underlying mechanisms involved were associated with the activation of the Wnt/β-catenin pathway and the inhibition of inflammatory responses.

Male fertility and metabolic disorders, including obesity and diabetes, are closely connected. Since hyperuricemia and metabolic syndrome are strongly related, male fertility and hyperuricemia may, to some degree, be associated. According to recent studies, hyperuricemia imposes various effects on sex hormones, semen quality, and male erectile dysfunction. Some researchers claim that uric acid worsens male semen and raises the risk of erectile dysfunction (ED), while others state that it safeguards both penile erection and male semen. Additionally, it has been shown that gout and metabolic syndrome also raise the risk of ED. To clarify this controversy, the influence and potential mechanisms of hyperuricemia on ED, semen quality, sex hormone levels, and the effects of hyperuricemia-related disorders on ED will be comprehensively summarized.

ETHNOPHARMACOLOGICAL RELEVANCE:In traditional Chinese medicine (TCM), Wutou Decoction (WTD) has long been used to alleviate arthritis. Emerging studies have reported that WTD could improve the symptoms of rheumatoid arthritis (RA). However, the mechanism by which WTD is involved in the treatment of RA remains elusive, posing a challenge to the worldwide acceptance of WTD as an efficient RA therapy. AIM OF THE STUDY:This study investigated the antiarthritic efficacy of WTD in a collagen-induced arthritis (CIA) rat model and explored silent information regulator 1 (SIRT1)-mediated deacetylation of the high mobility group box 1 (HMGB1)/NF-κB pathway. MATERIALS AND METHODS:A rat CIA model was used to evaluate the antiarthritic activity of WTD. Clinical arthritis score assessment, left ankle thickness assessment, micro-CT, histopathological staining, immunofluorescence staining, and ELISA were conducted to elucidate the anti-inflammatory effects of WTD. The M1 macrophage polarization state, cell viability, and invasion were also determined to assess the effects of WTD on macrophage proliferation and invasion in vitro. Additionally, in vivo and in vitro HMGB1 nuclear translocation and NF-κB activation were analysed. Finally, deacetylase activity was assessed by Western blot, NAD+/NADH analysis, and co-immunoprecipitaion. RESULTS:WTD significantly alleviated arthritis in CIA rats and inhibited pathological changes in joint lesions while concurrently suppressing TNF-α, IL-6, and IL-1β release. Mechanistically, WTD suppressed M1 infiltration in ankle tissues and their invasion in vitro. Furthermore, WTD downregulated HMGB1/p65 nuclear translocation and acetylation, which may be associated with SIRT1 upregulation. CONCLUSIONS:Overall, WTD potentially alleviates RA through SIRT1-mediated downregulation of HMGB1 and NF-κB acetylation.

Introduction: Current anti-rheumatic drugs are primarily modulating immune cell activation, yet their effectiveness remained suboptimal. Therefore, novel therapeutics targeting alternative mechanisms, such as synovial activation, is urgently needed. Objectives: To explore the role of Midline-1 (Mid1) in synovial activation. Methods: NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice were used to establish a subcutaneous xenograft model. Wild-type C57BL/6, Mid1-/-, Dpp4-/-, and Mid1-/- Dpp4-/- mice were used to establish a collagen-induced arthritis model. Cell viability, cell cycle, qPCR and western blotting analysis were used to detect MH7A proliferation, dipeptidyl peptidase-4 (DPP4) and Mid1 levels. Co-immunoprecipitation and proteomic analysis identified the candidate protein of Mid1 substrates. Ubiquitination assays were used to determine DPP4 ubiquitination status. Results: An increase in Mid1, an E3 ubiquitin ligase, was observed in human RA synovial tissue by GEO dataset analysis, and this elevation was confirmed in a collagen-induced mouse arthritis model. Notably, deletion of Mid1 in a collagen-induced arthritis model completely protected mice from developing arthritis. Subsequent overexpression and knockdown experiments on MH7A, a human synoviocyte cell line, unveiled a previously unrecognized role of Mid1 in synoviocyte proliferation and migration, the key aspects of synovial activation. Co-immunoprecipitation and proteomic analysis identified DPP4 as the most significant candidate of Mid1 substrates. Mechanistically, Mid1 promoted synoviocyte proliferation and migration by inducing ubiquitin-mediated proteasomal degradation of DPP4. DPP4 deficiency led to increased proliferation, migration, and inflammatory cytokine production in MH7A, while reconstitution of DPP4 significantly abolished Mid1-induced augmentation of cell proliferation and activation. Additionally, double knockout model showed that DPP4 deficiency abolished the protective effect of Mid1 defect on arthritis. Conclusion: Overall, our findings suggest that the ubiquitination of DPP4 by Mid1 promotes synovial cell proliferation and invasion, exacerbating synovitis in RA. These results reveal a novel mechanism that controls synovial activation, positioning Mid1 as a promising target for therapeutic intervention in RA.

Background Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with multiorgan and tissue involvement. Lupus nephritis (LN), an inflammatory condition of the kidneys associated with SLE, represents a significant cause of morbidity and mortality in SLE patients. Current immunosuppressive therapies for LN have limited efficacy and can lead to significant side effects. Demethylzeylasteral (DML) has shown promise in the treatment of LN, but its precise mechanism of action remains unclear. Purpose To assess the therapeutic effects and potential molecular mechanisms of DML in LN Methods The study evaluated the renal protective effects of DML in MRL/lpr mice through assessments of immune complex levels, renal function, and pathological changes. Network pharmacology and transcriptomics approaches were used to elucidate the underlying mechanisms. Molecular docking, biacore assay, monoclonal antibody blocking experiments, and in vitro studies were conducted to verify the mechanisms of action. Results DML treatment reduced levels of anti-Sm and anti-dsDNA IgG antibodies, as well as serum creatinine and blood urea nitrogen levels. DML also mitigated glomerular damage and fibrosis. Mechanistically, DML alleviated podocyte damage by suppressing inflammation and enhancing autophagy through inhibition of the IL-17A/JAK2-STAT3 pathways. Additionally, DML exhibited high binding affinity with IL17A, JAK2, and STAT3. Conclusion These findings provide strong evidence for the beneficial effects of DML in LN, suggesting its potential as a novel therapeutic strategy for improving renal function in autoimmune kidney diseases.

ETHNOPHARMACOLOGICAL RELEVANCE:Wutou Decoction (WTD) is a classic traditional Chinese medicine formula, which has shown clinical efficacy in treating rheumatoid arthritis (RA). The Treg stability and Th17/Treg imbalance is an important immunological mechanism in RA progression. Whether WTD regulates CD4+ T cell subsets has not been thoroughly investigated yet. AIM OF THE STUDY:This study aimed to explore the potential role and mechanisms of WTD in regulating the diminished stability of Treg cells and the imbalance of CD4+ T cell subsets via in vivo and in vitro experiments. MATERIALS AND METHODS:Firstly, the therapeutic effects of WTD on the collagen-induced arthritis (CIA) mouse and its potential regulatory function on CD4+ T cell subsets were evaluated in vivo. Animal specimens were collected after 31 days of treatment with WTD. The anti-arthritic and anti-inflammatory effects of WTD were assessed through arthritis scoring, body weight, spleen index, serum IL-6 levels, and micro-PET/CT imaging. Gene enrichment analysis was performed to evaluate the activation T cell-related signaling pathway. Flow cytometry was used to determine the proportions of CD4+ T cell subsets in vitro and in vitro. Additionally, ELISA was used to assess the secretion of IL-10 and TGF-β by Treg cells under inflammatory conditions. The suppressive function of Treg cells on cell proliferation under inflammatory conditions was examined using CFSE labeling. Immunofluorescence staining was performed to detect the phosphorylation levels of STAT3 in CD4+ T cells from mouse spleen tissues. Western blotting was used to evaluate the phosphorylation levels of JAK2/STAT3 in Treg cells. RESULTS:WTD significantly alleviated joint inflammation in CIA mice. WTD reduced serum IL-6 levels in CIA mice, improved their body weight and spleen index. WTD treatment inhibited the activation of CD4+ T cell subgroup-related signaling in the joint tissues of CIA mice. In vitro and in vitro experiments showed that WTD increased the proportion of Treg cells and decreased the proportion of Th17 cells in CIA mice spleen. Furthermore, WTD promoted the secretion of IL-10 and TGF-β by Treg cells and enhanced the inhibitory capacity of Treg cells on cell proliferation under inflammatory conditions. Immunofluorescence detected decreased STAT3 phosphorylation levels in CD4+ T cells from CIA mice spleen, while western blotting revealed a decrease in JAK2/STAT3 phosphorylation levels in Treg cells in vitro. CONCLUSIONS:Inhibiting JAK2/STAT3 phosphorylation is a potential mechanism through which WTD improves Treg cell stability, balances CD4+ T cell subsets, and attenuates RA joint inflammation.

Hyperuricemia is a crucial feature of metabolic syndrome, characterized by elevated uric acid that causes urate crystal deposits in joints, kidneys, and subcutaneous tissues, resulting in gout and hyperuricemic nephropathy. The primary causes of uric acid metabolism disorder include overproduction and reduced excretion. The majority of uric acid in human body is derived from the breakdown of purine nucleotides. Overproduction of uric acid can result from increased concentration or activity of xanthine oxidase, the key enzyme responsible for uric acid synthesis. Alterations in the activity of proteins responsible for uric acid reabsorption and excretion can also affect serum uric acid. Many bioactive compounds derived from natural plants have been shown to inhibit xanthine oxidase activity to reduce uric acid production, modulate the activity of transport proteins to promote uric acid excretion, or alleviate oxidative stress and inflammation through various signaling pathways. These properties have garnered significant attention from researchers. In this paper, we first introduce the pathophysiological mechanisms of hyperuricemia, then summarize bioactive compounds with urate-lowering effects, and discuss their potential applications in treating hyperuricemia and its complications.

Controversy surrounds the role of serum uric acid and whether treatment intervention is favorable in retarding the progression of chronic kidney disease (CKD). The association of serum uric acid levels and CKD patient mortality risk needs to be further determined by large sample cohort studies. The National Health and Nutrition Examination Survey participants with CKD from 1998 to 2017 were enrolled in the study. Multivariable Cox regression models were used to reveal the association of serum uric acid concentrations and CKD mortality risks. A total of 9891 CKD patients were enrolled in the study, and 3698 individuals died during the follow-up. Increasing serum uric acid levels are independently relevant to higher mortality risks of CKD patients (HR per SD increase). A restricted cubic spline curve showed a nonlinear association between serum uric acid and CKD mortality risks (p for nonlinearity = 0.046). CKD patients with higher levels of serum uric acid (≥ 5.900 mg/dL) show a significant increase in mortality risks (HR = 1.102, 95% CI 1.043–1.165). Sensitivity analysis demonstrated that the results were stable and robust. High serum uric acid levels (≥ 5.900 mg/dL) may be associated with increased mortality risks in CKD patients.

Ethnopharmacological relevance: It has been widely reported that various anti-rheumatic traditional Chinese medicines (TCMs) ameliorate rheumatoid arthritis (RA) and osteoarthritis (OA) through regulating the abnormal production, assembly, and activation of the NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammasome. These TCMs include monomers isolated from Chinese herbs, extracts of Chinese herbs, and Chinese medical formulae with a lengthy application history. Aim of the study: This review aimed to summarize and analyze the published articles about the NLRP3 inflammasome and its role in the pathogenesis of RA and OA. We also reviewed existing knowledge on the therapeutic mechanism of TCMs in RA and OA via the regulation of the NLRP3 inflammasome. Materials and methods: We searched for relevant articles with the keywords "NLRP3 inflammasome", "traditional Chinese medicine," "Chinese herbal drugs," "rheumatoid arthritis," and "osteoarthritis." The information retrieval was conducted in medical Chinese and English databases from the date of construction to April 19, 2023, including PubMed, MEDLINE, Web of Science, Scopus, Ovid, China National Knowledge Infrastructure (CNKI), Chinese Biomedicine Literature Database (CBM), Chinese Science and Technology Periodicals Database (VIP), and China Online Journals (COJ). Results: According to retrieval results, 35 TCMs have been demonstrated to relieve RA by targeting the NLRP3 inflammasome, including six traditional Chinese prescriptions, seven extracts of Chinese herbs, and 22 monomers extracted from traditional Chinese herbs and formulae. Additionally, 23 TCMs have shown anti-OA effects with abilities to modulate the NLRP3 inflammasome, including five traditional Chinese prescriptions, one extract of Chinese herbs, and 17 monomers from Chinese herbs. Conclusions: We summarized mechanism research about the pivotal roles of the NLRP3 inflammasome in the pathogenesis of RA and OA. Moreover, a review of TCMs with targets of the NLRP3 inflammasome in RA and OA treatment was also conducted. Our work is conducive to a better application of TCMs in complementary and alternative therapies in RA and OA.

Objective To explore the mechanism and effect of Guishen pill on bone mineral density and microstructure of bone tissues in rats with premature ovarian failure（POF）, in order to provide experimental basis for the treatment of osteoporosis. Methods Twenty-four rats were randomly divided into 3 groups: normal group, model group, and the Guishen pill group. Eight rats were included in each group. POF rat model was established by peritoneal injection of cisplatin which was injected at 1st and 8 th days with a dose of 6.0 mg/kg. In the normal group and model group, the rats were given distilled water while the rats in Guishen pill group were given Guishen pill granule（9.45 g/kg/day）. At 30 th day, all the rats were killed. The arterial blood and humerus were collected. Micro CT was applied to detect bone mineral density（BMD） and parameters of microstructure. ELISA was applied to detect the expression of RANKL/OPG,IL-10, and TGF-β in the serum of each group. Immunohistochemical staining was applied to detect the expression of RANKL and OPG in bone tissue. Flow cytometry was used to detect the ratio of T regulatory cells in the peripheral blood. Results The scans in micro CT indicated that BMD, BV/TV, Tb.N, and Tb.Th in the Guishen pill group were higher than those in the POF group（P＜0.05）. Tb.Sp was lower than that in the POF group（P＜0.05）. Compared with the POF group, the expressions of serum OPG and IL-10 in the Guishen pill group obviously increased（P＜0.05）, while the expression of serum RANKL/OPG in the Guishen pill group obviously decreased（P＜0.05）. Serum RANKL and TGF-β in the Guishen pill group had no significant difference with the model group（P＞0.05）. The ratio of T regulatory cells in the peripheral blood was significantly higher than that in the model group（P＜0.05）. The expression of OPG in bone tissue was obviously higher than that of the model group（P＜0.05）. The expression of RANKL in bone tissue was obviously lower than that of the model group（P＜0.05）. Conclusion Guishen pill improves BMD and bone microstructure of POF rats. The mechanism may be associated with inhibition of the RANKL/OPG pathway by up-regulating T regulatory cells.

Background: Fibrotic extracellular matrix (ECM) remodeling characterized different types of pulmonary fibrosis, and its regulation could be a potential shared treatment strategy for pulmonary fibrosis. Purpose: We aimed to investigate the effect of triptolide on pulmonary fibrosis through the inhibition of several important aspects of fibrotic ECM remodeling. Methods: Bleomycin-induced pulmonary fibrosis mice and TGF-& beta;1-induced primary lung fibroblasts were used. The effect of triptolide on pulmonary fibrosis was detected using histopathology, immunostaining, RT-qPCR, western blotting, ELISA, and protein activity assay. Results: Triptolide significantly alleviated bleomycin-induced pulmonary fibrosis in mice. It inhibited the expression of fibrotic genes & alpha;-SMA, collagen I, fibronectin, and vimentin and blocked the TGF-& beta;-SMAD signaling pathway both in vivo and in vitro. In addition, triptolide regulated the expression and activity of MMPs during fibrosis. Interestingly, it suppressed the expression of lysyl oxidase, which was responsible for matrix cross linking and elevated ECM stiffness. Furthermore, triptolide blocked the biomechanical stress transduction pathway integrin-& beta;1-FAK-YAP signaling and attenuated the pro-fibrotic feedback of fibrotic ECM on fibroblasts via integrin inhibition. Conclusion: These findings show that triptolide prevents the key linkages of fibrotic ECM remodeling, including deposition, degradation, cross-linking, and pro-fibrotic feedback and, therefore, has potential therapeutic value for pulmonary fibrosis.