RESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Qinghao-Biejia herb pair (QB) is the core herb pair of "Jieduquyuziyin prescription" and is one of the commonly used herb pairs for the clinical treatment of systemic lupus erythematosus (SLE). Previous studies have shown that QB reduces the expression of inflammatory cytokines like IL-6 and TNF-α in the serum and kidney of MRL/lpr mice. Additionally, it inhibits the expression of TLR4 and MyD88 in the kidney and aorta and reduces the deposition of renal complement C3 and aortic plaque after treatment. These findings suggest that QB has a preventive and therapeutic effect on lupus rats. AIM OF THE STUDY: This study sought to investigate the mechanisms underlying the anti-SLE combined with atherosclerosis activity of the Qinghao-Biejia herb pair. MATERIALS AND METHODS: Drug targets for QB were identified using the HERB database, while targets associated with SLE and atherosclerosis were retrieved from the GeneCards database. The intersection of these drug and disease targets was then analyzed using a protein-protein interaction (PPI) network with GO and KEGG pathway enrichment analysis. In vivo, apolipoprotein E-deficient (ApoE-/-) mice were induced to develop SLE-AS by intraperitoneal injection of pristane and continued feeding of a high-fat diet. The changes in relevant indexes were observed after 12 weeks of gavage treatment with hydroxychloroquine, QB, Q (Qinghao alone), and B (Biejia alone). Bone marrow-derived macrophages from ApoE-/- mice and Raw 264.7 macrophages were used to explore the mechanisms of QB treatment. RESULTS: The levels of inflammatory cytokines in serum and pathological liver changes in mice were improved to varying degrees in the treatment groups. Additionally, there was a reduction in aortic atheromatous plaque formation and some improvement in cholesterol efflux. Furthermore, QB suppressed the expression of inflammatory cytokines in M1 macrophages, suggesting a role in regulating macrophage polarization. CONCLUSION: QB demonstrates clear efficacy for treating SLE-AS, and its therapeutic mechanism may involve the regulation of macrophage phenotypes by promoting cholesterol efflux.
Assuntos
Transportador 1 de Cassete de Ligação de ATP , Aterosclerose , Colesterol , Medicamentos de Ervas Chinesas , Lúpus Eritematoso Sistêmico , Macrófagos , Animais , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Aterosclerose/tratamento farmacológico , Camundongos , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Colesterol/sangue , Colesterol/metabolismo , Células RAW 264.7 , Camundongos Endogâmicos C57BL , Feminino , Camundongos Endogâmicos MRL lpr , Camundongos Knockout para ApoERESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Jieduquyuziyin prescription (JP), as a traditional Chinese medicine formula, is extensively applied to treat systemic lupus erythematosus (SLE). Its prescription is based on clinical practice and an evidence-based application of traditional medicines. It is approved by use in Chinese hospitals as a clinical prescription that can be directly used. AIM OF THE STUDY: The study aims to elucidate JP's efficacy on lupus-like disease combined with atherosclerosis and to explore its mechanism. MATERIALS AND METHODS: To conduct in vivo experiments, we established a model of lupus-like disease with atherosclerosis in ApoE-/- mice fed a high-fat diet and injected intraperitoneally with pristane. In addition, oxidized low-density lipoprotein (ox-LDL) and a TLR9 agonist (CpG-ODN2395) were utilized to examine the mechanism of JP on SLE combined with AS in RAW264.7 macrophages in vitro. RESULTS: Results indicated that JP reduced hair loss and levels of the spleen index, maintained stable body weight, alleviated kidney damage in mice, and reduced the expression levels of urinary protein, autoantibodies, and inflammatory factors in serum. Furthermore, JP is effective at alleviating the lupus-like symptoms observed in mice. In mice, JP inhibited aortic plaque deposition, stimulated lipid metabolism, and increased the expression of genes that regulate cholesterol efflux, including ATP-binding cassette transporter A1 (ABCA1), ATP-binding cassette subfamily G member 1 (ABCG1), scavenger receptor class B type I (SR-BI), and peroxisome proliferator-activated receptor γ (PPAR-γ). In vivo, JP inhibited the expression of the Toll-like receptor 9 (TLR9)-induced signaling pathway, which links TLR9/MyD88/NF-kB to the expression of subsequent inflammatory factors. Furthermore, JP inhibited the expression of TLR9 and MyD88 in vitro. In addition, the JP treatment effectively reduced foam cell formation in RAW264.7 macrophages by increasing the expression of ABCA1/G1, PPAR-γ and SR-BI. CONCLUSIONS: JP played a therapeutic role in ApoE-/- mice with pristane-induced lupus-like diseases and AS, possibly through inhibition of TLR9/MyD88 signaling and promotion of cholesterol efflux.
Assuntos
Aterosclerose , Lúpus Eritematoso Sistêmico , Camundongos , Animais , Receptor Toll-Like 9/metabolismo , Fator 88 de Diferenciação Mieloide/metabolismo , Colesterol/metabolismo , Lipoproteínas LDL/metabolismo , Células Espumosas , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Aterosclerose/genética , PPAR gama/metabolismo , Apolipoproteínas E/genética , Lúpus Eritematoso Sistêmico/tratamento farmacológicoRESUMO
Backgroud: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease involving multiple systems with a high prevalence of nephritis and atherosclerosis. Jieduquyuziyin prescription is a famous prescription with immune modulating and inflammation controlling effects, which is efficacious in the treatment of SLE. The most critical herbs in this prescription are Qinghao and Biejia. The aim of this study was to evaluate the therapeutic effect of Qinghao-Biejia herb hair (QB) on mice with SLE combined with atherosclerosis. Materials and Methods: The effect of QB (identification using UPLC-TOF-MS) was assessed in female ApoE-/- mice intraperitoneally injected with 0.5 ml of pristane. Serum autoantibodies and lipid metabolic parameters were tested every 4 weeks, and spleen index, serum inflammatory biomarkers, renal injury, and aortic injury were observed after 16 weeks. The expression of signaling pathway in kidney tissues was observed by RT-qPCR and Western blot. Results: The mice of QB-treated group exhibited a significant reduced serum autoantibodies level, urine protein, and renal immune complex deposition. QB treatment reduced the levels of inflammatory cytokines and improved the renal pathological changes. In addition, there was a reduction in aortic atheromatous plaque and some improvement in dyslipidemia. Moreover, QB suppressed the expression of HMGB1, TLR4, and MyD88 to some extent. Conclusion: The present study implied that QB has clear efficacy for the treatment of SLE combined with atherosclerosis, and that inhibition of the HMGB1/TLR4 signaling pathway may be one of the therapeutic targets of QB for SLE combined with atherosclerosis.