TLR7 in B cells promotes renal inflammation and Gd-IgA1 synthesis in IgA nephropathy.

TLR7 has been linked to the pathogenesis of glomerulonephritis, but its precise roles are not clear. In this study, we evaluated the roles of TLR7 in IgA nephropathy (IgAN). TLR7 proteins were abundant in CD19+ B cells infiltrated in the kidneys of patients with IgAN. The intensities of both intrarenal TLR7 and CD19 proteins were closely associated with kidney function (estimated glomerular filtration rate [eGFR] and serum creatinine concentration) and renal histopathology (tubular atrophy, leukocyte infiltration, tubulointerstitial fibrosis, and global glomerulosclerosis) in patients with IgAN. Meanwhile, TLR7 mRNA levels were significantly increased in peripheral blood B cells of patients with IgAN. TLR7+CD19+ B cells expressed inflammatory cytokines (IL-6 and IL-12) in kidneys and produced high levels of IgA1 and galactose deficient-IgA1 (Gd-IgA1) in peripheral blood of patients with IgAN. Mechanistically, TLR7 activated B cells to produce high levels of Gd-IgA1 via the TLR7-GALNT2 axis in IgAN. Protein levels of GALNT2 were increased by overexpression of TLR7, while they were reduced by TLR7 knockdown in B cells. GALNT2 overexpression augmented Gd-IgA1 production in B cells derived from patients with IgAN. Taken together, high TLR7 expression in B cells has dual roles in the development and progression of IgAN, by facilitating renal inflammation and Gd-IgA1 antibody synthesis.

Tanshinol A Ameliorates Triton-1339W-Induced Hyperlipidemia and Liver Injury in C57BL/6J Mice by Regulating mRNA Expression of Lipemic-Oxidative Injury Genes.

Tanshinol A, which is derived from a traditional Chinese herbal Radix Salviae Miltiorrhizae is indicative of a hypolipidemic candidate. Therefore, we aim to validate its hypolipidemic activity of tanshinol A and explore its mechanism in triton-1339W-induced hyperlipidemic mice model, which possess multiply pathogenesis for endogenous lipid metabolism disorder. Experimental hyperlipidemia mice are treated with or without tanshinol A (i.g. 40, 20, 10 mg/kg), and blood and liver tissue were collected for validating its hypolipidemic and hepatic protective effect, and hepatic mRNA expression profile, which was associated with lipid metabolism dysfunction and liver injury, was detected by RT-qPCR. As results show, triton-1339W-induced abnormal of serum TC, TAG, HDL-C, LDL-C, SOD, MDA, GOT, and GPT is remarkably attenuated by tanshinol A. In pathological experiment, triton-1339W-induced hepatocellular ballooning degeneration, irregular central vein congestion, and inflammation infiltration are alleviated by tanshinol A. Correspondingly, hepatic mRNA expression of Atf4, Fgf21, Vldlr, Nqo1, Pdk4, and Angptl4, which are genes regulating lipemic-oxidative injury, are significantly increased by tanshinol A by 2~6 fold. Abcg5, Cd36, and Apob, which are responsible for cholesterol metabolism, are mildly upregulated. Noticeably, triton-1339W-suppressed expressions of Ptgs2/Il10, which are genes responsible for acute inflammation resolution in liver injury, are remarkably increased by tanshinol A. Conclusively, tanshinol A exerted hypolipidemic effect and hepatoprotective effect through restoring triton-1339W-suppressed mRNA expression, which may be involved in Atf4/Fgf21/Vldlr and Ptgs2/Il-10 signaling pathways.

Roles of Inflammasomes in Inflammatory Kidney Diseases.

The immune system has a central role in eliminating detrimental factors, by frequently launching inflammatory responses towards pathogen infection and inner danger signal outbreak. Acute and chronic inflammatory responses are critical determinants for consequences of kidney diseases, in which inflammasomes were inevitably involved. Inflammasomes are closely linked to many kidney diseases such as acute kidney injury and chronic kidney diseases. Inflammasomes are macromolecules consisting of multiple proteins, and their formation initiates the cleavage of procaspase-1, resulting in the activation of gasdermin D as well as the maturation and release of interleukin-1ß and IL-18, leading to pyroptosis. Here, we discuss the mechanism in which inflammasomes occur, as well as their roles in inflammatory kidney diseases, in order to shed light for discovering new therapeutical targets for the prevention and treatment of inflammatory kidney diseases and consequent end-stage renal disease.

Mechanism of YLTZ on glycolipid metabolism based on UPLC/TOF/MS metabolomics.

Type 2 diabetes mellitus (T2DM) is a metabolic disease characterized by dysfunction of glycolipid metabolism. YLTZ is used to treat hyperlipidemia, yet its hypolipidemic and hypoglycemic mechanism on T2DM are unknown. Thus, UPLC/TOF/MS was applied in this study to identify the potential bio-markers, and deduce the possible metabolic pathways. According to bio-indexes, the increased blood lipid levels, including TC, TG, LDL and FA, and the decreased HDL, the elevated glucose, reduced insulin level and impaired OGTT were observed in diabetic rat model. While YLTZ can decrease the lipid levels and glucose content, as well as increased insulin standards and improve OGTT. After data from UPLC/TOF/MS processed, 17 metabolites were obtained, including phospholipids (LPCs, PCs and PGP (18:1)), beta-oxidation production (HAA, VAG and CNE) and precursors (THA), bile acid (CA, CDCA and IDCA), hydrolysate of TG (MG (22:4)), glycometabolism (G6P), cholesterol-driven synthetics (ADO) and production of arachidonate acid (THETA). As a result, YLTZ was able to reduce LPCs, PCs, PGP (18:1), HAA, VAG, CNE, CA, ADO and THETA, as well as enhance MG (22:4) and G6P. After analyzing results, several metabolic pathways were deduced, which containing, cholesterol synthesis and elimination, FA beta-oxidation, TG hydrolysis, phospholipids synthesis, glycolysis, gluconeogenesis and inflammation. Consequently, YLTZ performed to prohibit the FA beta-oxidation, synthesis of cholesterol and phospholipids, gluconeogenesis and inflammation level, as well as promote TG hydrolysis, glycolysis and blood circulation. Hence, applying metabonomics in TCM research can uncover its pharmacological edges, elucidating comprehensively that YLTZ has capacity of hypolipidemic, hypoglycemic and promoting blood circulation, matching the effect of removing blood stasis, eliminating phlegm and dampness.

The gastric mucosal protective effects of astragaloside IV in mnng-induced GPL rats.

Gastric Cancer is one of the most common types of cancer. And the occurrence of gastric carcinoma is an evolutionary histopathological stage. As a result, further research of GPL, which is a borderline of gastric cancer, is indispensable for preventing the formation and development of gastric carcinoma. Several studies have demonstrated a correlation between the expression of autophagy, apoptosis and Gastric cancer (GC). However, the effects of autophagy and apoptosis on human gastric cancer progression, particularly on gastric precancerous lesions (GPL), have not totally been investigated. At present, Astragaloside IV(AS-IV) is a saponin purified from Astragalus membranaceous Bge, a traditional Chinese herb that has been widely used for more than 2000 y in the treatment of cancer, cardiovascular and immune disorders. This study was designed to investigate the mechanism of AS-IV protecting gastric mucosa in N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced GPL rats. The lesions of GIM and GED were significantly ameliorated compared with the model rats, especially crowded tubular glandular and back-to-back tubular structure, which were the dangerous borderline between GPL and GC. Western Blot analysis showed that the ratio of Bcl-2/Bax and the protein expression of Bcl-XL, p53, Beclin1, p62, ATG5 and ATG12 were decreased and the level of Caspase3 was increased in the group of AS-IV compared with the model group; RT-PCR analysis showed that the gene expression Ambra1, Beclin1, ATG5, LC3 and p62 were decreased in the group of AS-IV compared with the model group. This research manifested that the occurrence of gastric cancer was preceded by a prolonged precancerous stage, which could be ameliorated by the AS-IV. Meanwhile, the mild and moderate stage of precancerous lesions is similar with gastric adenocarcinoma in critical biological processes, including inflammation, cell proliferation, differentiation. But this lesion is very different from cancer, because it does not appear obvious invasion and malignant lesions in this pathologic stag. Further, AS-IV could regulate p53 expression to activate the Ambra1/Beclin1 complex in GPL, and it will protect the gastric mucosal injury, prevent and cure gastric mucosal atrophy, intestinal metaplasia and atypical hyperplastic lesions. It provided a potential therapeutic strategy in reversing intestinal metaplasia and dysplasia of gastric precancerous lesions and protecting the gastric mucosa in GPL rats.