Repurposing a clinically approved prescription Colquhounia root tablet to treat diabetic kidney disease via suppressing PI3K/AKT/NF-kB activation

Abstract

Background Growing clinical evidences show the potentials of Colquhounia root tablet (CRT) in alleviating diabetic kidney disease (DKD). However, its pharmacological properties and underlying mechanisms remain unclear. Methods ‘Drug target-Disease gene’ interaction network was constructed and the candidate network targets were screened through evaluating node genes' topological importance. Then, a DKD rat model induced by high-fat diet/streptozotocin was established and used to determine pharmacological effects and network regulatory mechanisms of CRT against DKD, which were also verified using HK2 cell model induced by high glucose. Results The candidate network targets of CRT against DKD were involved into various type II diabetes-related and nephropathy-related pathways. Due to the topological importance of the candidate network targets and the important role of the imbalance between immunity and inflammation in the pathogenesis of DKD, PI3K/AKT/NF-кB signaling-mediated immune-modulatory and anti-inflammatory actions of CRT were selected to be experimentally verified. On the basis of high-fat diet (HFD) / streptozotocin (STZ)-induced DKD rat model, CRT effectively reduced the elevated level of blood glucose, decreased the accumulation of renal lipid, suppressed inflammation and the generation of ECM proteins, and ameliorated kidney function and the renal histopathology through inhibiting the activation of PI3K, AKT and NF-кB proteins, reducing the nuclear accumulation of NF-кB protein and the serum levels of downstream cytokines, which were in line with the in vitro findings. Conclusions Our data suggest that CRT may be the promising candidate drug for treating DKD via reversing the imbalance of immune-inflammation system mediated by the PI3K/AKT/NF-кB/IL-1β/TNF-α signaling.

Integrated Network Pharmacology Analysis and Experimental Validation to Investigate the Molecular Mechanism of Triptolide in the Treatment of Membranous Nephropathy

“…In addition, triptolide and its corresponding patent medicines such as Colquhounia root tablets and Kunxian capsules have been applied for the treatment of kidney disease, including MN, diabetic kidney disease and lupus nephritis, which can restore the imbalance of the immune-inflammation system by modulating the PI3K/AKT/NF-κB/TNF-α pathway to exert beneficial effects. [36][37][38] These basic and clinical studies on the relationship between PI3K/AKT/ mTOR and MN, and the results of our study support the use of pharmacological network prediction.…”

Analysis of the Clinical Efficacy and Molecular Mechanism of Xuefu Zhuyu Decoction in the Treatment of COPD Based on Meta-Analysis and Network Pharmacology

“…Therefore, the ingredients with moderate to good-likeness (QED > 0.49) were considered as bioactive ingredients. Then, the targets of bioactive components, which were predicted by the MedChem Studio (version 3.0; Simulations Plus, Lancaster, CA, 2012) according to the structural and functional similarities of drugs, were also collected from ETCM database [ 33 ]. The targets with high similarity (structural similarity score > 0.80) were obtained for further analysis.…”

Computational repurposing and preclinical validation of colquhounia root tablets for membranous nephropathy

“…Our previous study revealed that CRT effectively ameliorated kidney functions and renal histopathology in diabetic kidney disease through recovering the balance of immune‐inflammation system. 8 To verify its potentials against MN in a further level, we herein identified chemical and target profilings of CRT and investigated the ‘disease genes‐drug target’ interaction network combined with the in vivo and in vitro experiment validations.…”