San-Huang-Yi-Shen capsule (SHYS) has been used in the treatment of diabetic nephropathy (DN) in clinic. However, the mechanisms of SHYS on DN remain unknown. In this study, we used a high-fat diet (HFD) combined with streptozotocin (STZ) injection to establish a DN rat model. Next, we used 16S rRNA sequencing and untargeted metabolomics to study the potential mechanisms of SHYS on DN. Our results showed that SHYS treatment alleviated the body weight loss, hyperglycemia, proteinuria, pathological changes in kidney in DN rats. SHYS could also inhibite the oxidative stress and inflammatory response in kidney. 16S rRNA sequencing analysis showed that SHYS affected the beta diversity of gut microbiota community in DN model rats. SHYX could also decrease the Firmicutes to Bacteroidetes (F to B) ratio in phylum level. In genus level, SHYX treatment affected the relative abundances of Lactobacillus, Ruminococcaceae UCG-005, Allobaculum, Anaerovibrio, Bacteroides and Candidatus_Saccharimonas. Untargeted metabolomics analysis showed that SHYX treatment altered the serum metabolic profile in DN model rats through affecting the levels of guanidineacetic acid, L-kynurenine, prostaglandin F1α, threonine, creatine, acetylcholine and other 21 kind of metabolites. These metabolites are mainly involved in glycerophospholipid metabolism, tryptophan metabolism, alanine, aspartate and glutamate metabolism, arginine biosynthesis, tricarboxylic acid (TCA) cycle, tyrosine metabolism, arginine and proline metabolism, arginine and proline metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, phenylalanine metabolism, and D-glutamine and D-glutamate metabolism pathways. Spearman correlation analysis showed that Lactobacillus, Candidatus_Saccharimonas, Ruminococcaceae UCG-005, Anaerovibrio, Bacteroides, and Christensenellaceae_R-7_group were closely correlated with most of physiological data and the differential metabolites following SHYS treatment. In conclusion, our study revealed multiple ameliorative effects of SHYS on DN including the alleviation of hyperglycemia and the improvement of renal function, pathological changes in kidney, oxidative stress, and the inflammatory response. The mechanism of SHYS on DN may be related to the improvement of gut microbiota which regulates arginine biosynthesis, TCA cycle, tyrosine metabolism, and arginine and proline metabolism.
Qingrequzhuo capsule (QRQZ), composed of Morus alba L., Coptis chinensis Franch., Anemarrhena asphodeloides Bunge, Alisma plantago-aquatica subsp. orientale (Sam.) Sam., Citrus × aurantium L., Carthamus tinctorius L., Rheum palmatum L., Smilax glabra Roxb., Dioscorea oppositifolia L., Cyathula officinalis K.C.Kuan, has been used to treat nonalcoholic steatohepatitis (NASH) in clinic. However, the mechanism of QRQZ on NASH remains unclear. Recent studies have found that the dysfunction of gut microbiota could impair the gut barrier and induce the activation of TLR4/NF-kB signaling pathway, and further contribute to the inflammatory response in NASH. Modulating the gut microbiota to reduce inflammation could prevent the progression of NASH. In this study, a mouse model of NASH was generated by methionine and choline deficient diet (MCD) and treated with QRQZ. First, we evaluated the therapeutic effects of QRQZ on liver injury and inflammation in the NASH mice. Second, the changes in the gut microbiota diversity and abundance in each group of mice were measured through 16S rRNA sequencing. Finally, the effects of QRQZ on gut mucosal permeability, endotoxemia, and liver TLR4/NF-kB signaling pathway levels were examined. Our results showed that QRQZ significantly reduced the lipid accumulation in liver and the liver injury in NASH mice. In addition, QRQZ treatment decreased the levels of inflammatory cytokines in liver. 16S rRNA sequencing showed that QRQZ affected the diversity of gut microbiota and a f f e c t e d t h e r e l a t i v e a b u n d a n c e s o f D u b o s i e l l a , Lachnospiraceae_NK4A136_group, and Blautiain NASH mice. Besides, QRQZ could increase the expression of tight junction proteins (zonula occludens-1 and occludin) in gut and decrease the lipopolysaccharide (LPS) level in serum. Western blot results also showed that QRQZ treatment decreased the protein expression ofTLR4, MyD88 and the phosphorylation of IkB and NF-kBp65 and qPCR results showed that QRQZ treatment down-regulated the gene expression of interleukin (IL)-1b, IL-6, and tumor necrosis factor (TNF)-a in liver. In conclusion, our study demonstrated that QRQZ could reduce the lipid accumulation and inflammatory response in NASH model mice. The mechanisms of QRQZ on NASH were associated with modulating gut microbiota, thereby inducing the tight junction of gut barrier, reducing the endotoxemia and inhibiting the activation of TLR4/NFkB signaling pathway in liver.
San-Huang-Yi-Shen capsule (SHYS) has been used in the treatment of diabetic kidney disease (DKD) in clinics. However, the mechanism of SHYS on DKD remains unclear. In this study, we used a high-fat diet combined with streptozocin (STZ) injection to establish a rat model of DKD, and different doses of SHYS were given by oral gavage to determine the therapeutic effects of SHYS on DKD. Then, we studied the effects of SHYS on PINK1/Parkin-mediated mitophagy and the activation of NLRP3 inflammasome to study the possible mechanisms of SHYS on DKD. Our result showed that SHYS could alleviate DKD through reducing the body weight loss, decreasing the levels of fasting blood glucose (FBG), and improving the renal function, insulin resistance (IR), and inhibiting inflammatory response and oxidative stress in the kidney. Moreover, transmission electron microscopy showed SHYS treatment improved the morphology of mitochondria in the kidney. In addition, western blot and immunoflourescence staining showed that SHYS treatment induced the PINK1/Parkin-mediated mitophagy and inhibited the activation of NLRP3 signaling pathway. In conclusion, our study demonstrated the therapeutic effects of SHYS on DKD. Additionally, our results indicated that SHYS promoted PINK1/Parkin-mediated mitophagy and inhibited NLRP3 inflammasome activation to improve mitochondrial injury and inflammatory responses.
Baihu Rensheng decoction (BHRS) can effectively improve insulin resistance (IR) and decrease blood glucose in diabetic patients. However, its specific mechanism of action remains unclear. In this study, a type 2 diabetes mellitus (T2DM) rat model was established using a high-fat diet combined with streptozotocin (STZ) injection and treated with BHRS. Firstly, the therapeutic and anti-inflammatory effects of BHRS on T2DM were evaluated. Secondly, the effects of BHRS on gut permeability were evaluated and western blot was used to detect the changes of TLR4/NF-κB pathway-related protein expressions in liver. Finally, 16S rRNA sequencing was used to detect alteration of gut microbiota diversity and abundance in rats after BHRS treatment. Our results showed that BHRS could alleviate the hyperglycemia, hyperlipidemia, IR, and pathological changes of liver, pancreas, and kidney in T2DM rats. BHRS could also decrease the levels of pro-inflammatory cytokines and inhibit the oxidative stress. Immunohistochemistry showed BHRS could increase the expression tight junction-related proteins (ZO-1 and occludin) in colon. Besides, the level of LPS in serum was decreased after BHRS treatment. Western blot results showed that the protein expression of TLR4, MyD88 and the phosphorylation IκB, and NF-κBp65 were lowered after BHRS treatment. 16S rRNA sequencing showed that BHRS treatment altered the diversity of gut microbiotra and decreases the Firmicutes/Bacteroidetes (F to B) ratio at the phylum level. At the genus level, BHRS could increase the relative abundances of Lactobacillus, Blautia, and Anaerostipes and decrease the relative abundances of Allobaculum, Candidatus Saccharimonas, and Ruminococcus. In conclusion, our study revealed the various ameliorative effects of BHRS on T2DM, including improving the liver and kidney functions and alleviating the hyperglycemia, hyperlipidemia, pathological changes, oxidative stress and inflammatory response. The mechanisms of BHRS on T2DM are likely linked to the repair of gut barrier and the inhibition of TLR4/NF-κB-mediated inflammatory response and the improvement in the dysbiosis of gut microbiota.
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