Abstract
Diabetic nephropathy (DN) is one of the common and severe microvascular complications of diabetes mellitus (DM). The occurrence and development of DN are related to multiple factors in the human body, which makes DN a complex disease, and the pathogeneses of DN have not yet been fully illustrated. Furthermore, DN lacks effective drugs for treatment nowadays. Chinese herbal medicine (CHM) often shows the feature of multicomponents, multitargets, multipathways, and synergistic effects and shows a promising source of new therapeutic drugs for DN. As a CHM, Tangshen Formula (TSF) was used to treat DN patients in China. However, its bioactive compounds and holistic pharmacological mechanisms on DN are both unclear. A network pharmacology approach was firstly applied to explore multiple active compounds and multiple key pharmacological mechanisms for TSF treating DN by drug-targeted interaction databases, herb-compound-target network, protein-protein interaction network, compound-target-pathway network, and analysis methods. And the results showed that TSF have the characteristic of multicomponents, multitargets, multipathways, and synergistic effects for treating DN. The quercetin, naringenin, kaempferol, and isorhamnetin as key active compounds and the PI3K-Akt signaling pathway, TNF signaling pathway, nonalcoholic fatty liver disease (NAFLD), focal adhesion, rap1 signaling pathway, T cell receptor signaling pathway, MAPK signaling pathway, and insulin resistance as the key molecular mechanisms play important roles in TSF treating DN. Moreover, quercetin, naringenin, kaempferol, and isorhamnetin were successfully detected in TSF by the UHPLC-MS/MS analysis method. And their concentrations were 0.224, 8.295, 0.0564, and 0.0879 mg·kg-1, respectively. The present findings not only provide new insights for a deeper understanding of the constituent basis and pharmacology of TSF but also provide guidance for further pharmacological studies on TSF.
Highlights
Diabetic nephropathy (DN) is one of the common and severe microvascular complications of diabetes mellitus (DM) and the major substantial cause of end-stage renal disease (ESRD) which contributes to morbidity and mortality
The results suggested that these 11 components probably served as significant therapeutic compounds in Tangshen Formula (TSF)
The results indicated that TSF might be related to suppressing oxidative stress, restraining inflammatory reaction, regulating glucose and lipid metabolism disorders, and improving renal function by the HIF-1 signaling pathway, vascular endothelial growth factor (VEGF) signaling pathway, MAPK signaling pathway, TNF signaling pathway, PI3K-Akt signaling pathway, mTOR signaling pathway, NOD-like receptor signaling pathway, T cell receptor signaling pathway, lipopolysaccharide-mediated signaling pathway, insulin signaling pathway, adipocytokine signaling pathway, thyroid hormone signaling pathway, cysteine-type endopeptidase activity involved in apoptotic process, and other pathways
Summary
Diabetic nephropathy (DN) is one of the common and severe microvascular complications of diabetes mellitus (DM) and the major substantial cause of end-stage renal disease (ESRD) which contributes to morbidity and mortality. The standard agents involved drugs controlling hyperglycemia and high blood pressure such as angiotensin converting enzyme inhibitors or angiotensin receptor antagonist antiagents (ACEI/ARB), and renin angiotensin aldosterone system blockade and sodium glucose cotransporter 2 (SGLT2) inhibition are often used for the treatment of DN according to its pathological factors [6, 7]. These drugs cannot prevent the DM patients continuing to develop DN leading to glomerulosclerosis, tubulointerstitial fibrosis, and even cardiovascular comorbidities, because these drugs often tend to act on a single target or sole molecular mechanism.
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