QiDiTangShen Granules Activate Renal Nutrient-Sensing Associated Autophagy in db/db Mice

Abstract

QiDiTangShen granules (QDTS) have been proven to reduce the proteinuria in patients with diabetic nephropathy (DN) effectively. The present study was aimed to investigate the mechanism underlying QDTS’s renoprotection. The main components of QDTS were identified by ultra-high liquid chromatography-tandem mass spectrometry and pharmacological databases, among which active components were screened by oral bioavailability and drug-likeness. Their regulation on autophagy-related nutrient-sensing signal molecules (AMPK, SIRT1, and mTOR) was retrieved and analyzed through the Pubmed database. Then, db/db mice were randomly divided into three groups (model control, valsartan and QDTS), and given intragastric administration for 12 weeks, separately. Fasting and random blood glucose, body weight, urinary albumin excretion (UAE) and injury markers of liver and kidney were investigated to evaluate the effects and safety. Renal histological lesions were assessed, and the expressions of proteins related to nutrient-sensing signals and autophagy were investigated. Thirteen active components were screened from 78 components identified. Over half the components had already been reported to improve nutrient-sensing signals. QDTS significantly reduced UAE, ameliorated mesangial matrix deposition, alleviate the expression of protein and mRNA of TGF-β, α-SMA, and Col I, as well as improved the quality of mitochondria and the number of autophagic vesicles of renal tubular cells although the blood glucose was not decreased in db/db mice. Compared to the db/db group, the expression of the autophagy-inducible protein (Atg14 and Beclin1) and microtubule-associated protein 1 light chain 3-II (LC3-II) were up-regulated, autophagic substrate transporter p62 was down-regulated in QDTS group. It was also found that the expression of SIRT1 and the proportion of p-AMPK (thr172)/AMPK were increased, while the p-mTOR (ser2448)/mTOR ratio was decreased after QDTS treatment in db/db mice, which was consistent with the effect of its active ingredients on the nutrient-sensing signal pathway as reported previously. Therefore, QDTS may prevent the progression of DN by offering the anti-fibrotic effect. The renoprotection is probably attributable to the regulation of nutrient-sensing signal pathways, which activates autophagy.

Clinical efficacies, underlying mechanisms and molecular targets of Chinese medicines for diabetic nephropathy treatment and management

“…AMPK is another upstream regulator of mTOR, and it has been revealed that astragaloside IV (3, 6, and 12 mg/kg BW, daily, 8 weeks) could protect against albuminuria, glomerulosclerosis, and podocyte injury via AMPK α -mediated autophagy enhancement in STZ-induced DN mice 117 . Moreover, growing evidence has revealed that Sirtuin 1 (SIRT1) and HO-1 can promote autophagy through the activation of AMPK 118 , 124 , 153 . In a study, puerarin (5, 10, 20, and 40 mg/kg BW, daily, 12 weeks) was reported to protect podocytes from hyperglycaemia-induced injury through HO-1 and SIRT1-mediated upregulation of autophagy 124 .…”

SAKit: an all-in-one analysis pipeline for identifying novel protein caused by variant events at genomic and transcriptic level

“…After obtaining the FLNC, the cluster module of isoseq3 is further used to cluster FLNC reads using hierarchical n*log(n) alignment and iterative cluster merging. In the novel variant isoform (NVI) calling step following pre-processing step described above, we utilized the collapse_isoforms_by_sam.py of cDNAcupcake [17], which takes bam file as input obtained by mapping cluster.fasta files to the pre-defined reference using minimap2 [18], to collapse two or more identical transcript isoforms into a unique transcript isoform. [Fig2A] Simultaneously, the number of full-length reads corresponding to different unique isoforms was also obtained, which are important supporting evidence for the called isoforms, and will be used as the parameter in the following filter step.…”

“…Based on this principle, neoantigen-based immunotherapy has been developed by pharmaceutical companies or research institutions as a promising cancer treatment [4][5][6]. Additionally, novel proteins are also associated with other complex diseases, for instance, Alzheimer's [7], type II diabetes [8], liver disease [9][10][11][12][13][14], kidney disease [15][16][17][18][19][20], Obesity [21][22][23][24][25], and cardiovascular disease [26]. Therefore, effective identification of novel proteins is imperative for understanding human diseases and developing corresponding therapies.…”

The modulation of gut microbiota by herbal medicine to alleviate diabetic kidney disease – A review

“…R.J.Wang ( Gao et al, 2018 ). QDTS has been shown to be able to counteract kidney injuries and reduce proteinuria in DKD mice ( Wang et al, 2019 ). A study further investigated the mechanisms of action of QDTS and concluded that it could modulate the gut microbiota composition of db/db mice ( Wei et al, 2021 ).…”