Kunxian capsule alleviates podocyte injury and proteinuria by inactivating ß-catenin in db/db mice.

Background: Diabetic kidney disease (DKD) remains the primary cause of end-stage renal disease (ESRD) globally, but treatment options are limited. Kunxian capsule (KXC) has been utilized for the treatment of autoimmune diseases and IgA nephropathy in China. However, its effect on DKD remains poorly investigated. Therefore, this study aimed to explore the protective effect of KXC in db/db mice and elucidate its underlying mechanism. Methods: The renoprotective effects of KXC were assessed in a DKD mouse model using male BKS db/db diabetic mice. After 8 weeks of treatment, the urinary albumin-to-creatinine ratio (UACR), blood biochemical parameters, renal histopathological manifestation, and podocyte ultrastructural changes were evaluated. Additionally, the expression of podocyte epithelial-to-mesenchymal transition (EMT) markers [WT1, ZO-1, and collogen I (Col1a1)] was quantitatively analyzed. Furthermore, we explored the role of KXC in the ß-catenin signaling pathway to elucidate the underlying mechanism of KXC's renoprotective effect. Results: KXC treatment effectively reduced albuminuria and attenuated renal structural abnormalities in db/db mice. Additionally, KXC restored the protein and mRNA expression of WT1 and ZO-1 while suppressing the expression of Col1a1 in db/db mice, indicating its ability to alleviate podocyte EMT. Mechanistically, KXC exerted a significant suppressive effect on the activation of ß-catenin signaling in diabetic kidneys. Conclusion: KXC has the potential to protect podocytes during DKD by alleviating podocyte EMT through inactivating ß-catenin signaling.

Pharmacological importance of Kunxian Capsule in clinical applications and its adverse effects: A review.

Kunxian Capsule (KX) is a popular Chinese patent medicine for the treatment of rheumatoid arthritis, nephrotic syndrome, systemic lupus erythematosus, Henoch-Schönlein purpura, ankylosing spondylitis, psoriatic arthritis and eczema. However, there is scarcity of comprehensive information on the significance of KX in the clinical application and its side effects. Hence, it is aimed to provide a review of the significance of KX, with a focus on the pharmacological effects, clinical applications, and its adverse reactions. This review was based on the published literatures in PubMed, China National Knowledge Infrastructure and WanFang database. The articles were collected by two independent authors with no time limits applied until November 30, 2022. The search term includes Kunxian Capsule and/or clinical effect, pharmacology, disease, therapy, adverse effects and quality control. KX has been shown to be effective in the treatment of autoimmune arthritis by inhibiting inflammatory responses and inducing apoptosis. Many studies suggest that KX has anti-inflammatory and analgesic properties that aid in the improvement of joint functions. KX dispels wind, removes dampness, invigorates the kidneys, and promotes blood circulation, thereby curing various diseases. However, studies also suggest KX-related adverse reactions in multiple systems. Overall, this review highlights the scientific basis of KX in curing or preventing various diseases and provides novel insights for further research and clinical applications.

Kunxian capsule alleviates renal damage by inhibiting the JAK1/STAT1 pathway in lupus nephritis.

ETHNOPHARMACOLOGICAL RELEVANCE: Kunxian capsule (KXC) is a new traditional Chinese medicine drug included in "The key science and technology achievements" in the Ninth Five Year Plan of China. KXC has been clinically used for more than 10 years in the treatment of lupus nephritis (LN). However, the underlying role and molecular mechanism of KXC in LN remain unclear. AIM OF THE STUDY: This study aimed to explore the efficacy and potential mechanisms of KXC through pharmacological network, in vitro and in vivo studies. MATERIALS AND METHODS: Pharmacological network analysis of KXC treatment in LN was performed using data acquired from the Traditional Chinese Medicine System Pharmacology Database and Analysis Platform (TCMSP, https://old.tcmsp-e.com/tcmsp.php) and NCBI Gene Expression Omnibus (GEO, https://www.ncbi.nlm.nih.gov/geo/database). HK-2 cells were chosen as an in vitro model of the tubular immune response by simulation with interferon γ (IFN-γ). MRL/lpr mice were used to explore the mechanism of KXC in vivo. Finally, the specific active molecules of KXC were further analyzed by molecular docking. RESULTS: The pharmacological network analysis showed that STAT1 is a key factor in the effects of KXC. In vitro and in vivo experiments confirmed the therapeutic effect of KXC on LN renal function and tubular inflammation. The protective effect of KXC is mediated by STAT1 blockade, which further reduces T-cell infiltration and improves the renal microenvironment in LN. Two main components of KXC, Tripterygium hypoglaucum (H.Lév.) Hutch (Shanhaitang) and Epimedium brevicornu Maxim (Yinyanghuo) could block JAK1-STAT1 activation. Furthermore, we found 8 molecules that could bind to the ATP pocket of JAK1 with high affinities by performing docking analysis. CONCLUSIONS: KXC inhibits renal damage and T-cell infiltration in LN by blocking the JAK1-STAT1 pathway.

Kunxian Capsule for Rheumatoid Arthritis: Inhibition of Inflammatory Network and Reducing Adverse Reactions Through Drug Matching.

Tripterygium wilfordii Hook.f and Tripterygium hypoglaucum (H.Lév.) Hutch is effective herbs to prevent aggravation of Rheumatoid arthritis (RA). However, both of them show severe side effects in the reproductive system and other systems. Kunxian Capsule (KX), a Traditional Chinese Medicine (TCM) patent prescription, comprised of 4 herbs, including H.Lév. Hutch, is reported to be an available prescription in treating RA with fewer side effects as compares to Tripterygium tablets. To reveal the pharmacological mechanism of KX in RA treatment and side effect alleviation, we collected related information of KX from open-access databases and performed various analyses. 1354 targets were identified in KX. These targets were enriched in the calcium signaling pathway, cAMP signaling pathway, cGMP-PKG signaling pathway and PI3K-AKT signaling pathway, forming biological functions, such as cofactor binding, coenzyme binding, etc. These pathways or functions mostly affect cell cycle, differentiation, and maturation of Th17 cells, macrophage, and synovial fibroblast. These targets also act on the IL-17 signaling pathway, Th17 cell differentiation signaling pathway and TNF signaling pathway, which is related to inflammation response inhibition. Next, a disease network was constructed, which indicated IMPDH2, MTHFD1 are the key genes answering for the side effects of H.Lév. Hutch. The side effect-related genes lead to the negative regulation of nucleic acid, which could be restored by the rest 3 herbs through some positive amino acid metabolism. In conclusion, KX is a relatively safe alternative approach in RA intervention.

Kunxian capsules in the treatment of patients with ankylosing spondylitis: a randomized placebo-controlled clinical trial.

BACKGROUND: Ankylosing spondylitis (AS) is a chronic inflammatory autoimmune disease. Kunxian capsule, a Chinese patent medicine which has been used in the treatment of immunologic diseases for many years in China, has anti-inflammatory and immunoregulatory effects. This study investigates the efficacy and safety of Kunxian capsules in the treatment of AS. METHOD: This was a randomized, double-blind, parallel control clinical trial involving 80 patients with AS who fulfilled the modified New York criteria (1984) and had active disease defined by a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ≥40 mm under background stable nonsteroidal anti-inflammatory drugs (NSAIDs) for more than 4 weeks. Patients were randomly divided into two groups, the Kunxian group and the placebo group, and Kunxian (0.6 g, three times per day) and the placebo were provided for 12 weeks. The primary endpoint was the Assessment of SpondyloArthritis international Society (ASAS) 20 response rate at week 12. The secondary endpoints were ASAS 40, BASDAI 50, the Bath Ankylosing Spondylitis Functional Index (BASFI), Bath Ankylosing Spondylitis Metrology Index (BASMI), and Ankylosing Spondylitis Disease Activity Score on the basis of C-reactive protein level (ASDAS-CRP) at weeks 2, 6, and 12. RESULTS: The primary endpoint of ASAS 20 at week 12 was achieved in 13 of 35 patients (37.1 %) among the Kunxian group, compared with 4 of 33 (12.1 %) in the placebo group (p < 0.05). Significant improvement (BASDAI 50) was also observed between the Kunxian group and the placebo group at week 6 (14 (40 %) and 5 (15.5 %), respectively, p < 0.05). At weeks 2, 6, and 12, the ASDAS-CRP level of the Kunxian group was significantly lower than that of the placebo group, especially at week 6 (p < 0.01). Kunxian obviously reduced CRP levels compared to placebo at weeks 2, 6, and 12 (p < 0.05). Compared with the placebo, Kunxian was associated with greater improvements in signs and symptoms of patients with AS from the baseline to week 12, and significant intergroup differences of additional composite indices of disease activity (i.e., erythrocyte sedimentation rate, patient global assessment of disease activity, total back pain, level of morning stiffness, tender joints, and BASFI scores) were also observed. CONCLUSION: Kunxian capsule significantly decreased the disease activity of patients with AS. TRIAL REGISTRATION: NCT00953979 . Registered on 5 August 2009.