Network pharmacology mechanism of Scutellarin to inhibit RGC pyroptosis in diabetic retinopathy

Abstract

To investigate the effect of scutellarin (SCU) in diabetic retinopathy (DR) and explore the associated molecular network mechanism. The animal model of DR was established from diabetic mellitus (DM) rats by intraperitoneally injected streptozotocin (STZ) at dosage 55 mg/kg. Meanwhile, SCU was intraperitoneally administrated to protect retina from cell pyroptosis induced by DM, and cell pyroptosis was detected by using HE, Nissl staining, and immunofluorescence recognition. Moreover, the hub gene involving in pyroptosis in DR was screened by bioinformatics and network pharmacology, designated as Venny intersection screen, GO and KEGG analysis, PPI protein interaction, and molecular docking. Lastly, the expressional change of hub genes were validated with experimental detection. Cell pyroptosis of the DR, specifically in retina ganglion cells (RGC), was induced in DM rats; SCU administration results in significant inhibition in the cell pyroptosis in DR. Mechanically, 4084 genes related to DR were screened from GeneCards and OMIM databases, and 120 SCU therapeutic targets were obtained, by using GeneCards, TCMSP with Swiss Target Prediction databases. Moreover, 357 targets related to pyroptosis were found using GenenCards database, and Drug, disease and phenotypic targets were analyzed online using the Draw Venn Diagram website, and 12 cross targets were obtained. Through GO function and KEGG pathway enrichment analysis, 659 BP related items, 7 CC related items, 30 MF related items, and 70 signal pathways were screened out; Of these, eleven proteins screened from cross-target PPI network were subsequently docked with the SCU, and their expressions including caspase-1, IL-1β, IL-18, GSDMD and NLRP3 in RGC indicated by immunofluorescence, and the mRNA expression for caspase-1 in DR indicated by quantitative PCR, were successfully validated. SCU can effectively protect RGC pyroptosis in DR, and underlying mechanisms are involved in the inhibition of caspase-1, GSDMD, NLRP3, IL-1β and IL-18. Our findings therefore provide crucial evidence to support the clinic practice of SCU for the treatment of DR, and explained the underlying molecular network mechanism.

Exploring the protective effects of herbal monomers against diabetic retinopathy based on the regulation of autophagy and apoptosis: A review

“…[ 107 , 108 ] Among all neurons, the RGC is most susceptible to damage, resulting in severe visual impairment. [ 109 ] The early stages of DR were closely associated with increased and decreased neurotransmitters, as evidenced by an increment in glutamate release and a decline in γ-aminobutyric acid release. [ 110 ] Fang found that Berberine potently defended against RGC apoptosis in the retina of rodent diabetic animals, and its defensive effect might be linked to the GABAARs/protein kinase C-α pathway activation.…”

Current advances on the therapeutic potential of scutellarin: an updated review

“…It is evident that scutellarin is a VEGF inhibitor and has the potential to be a therapeutic agent for diabetic microangiopathy. Li et al [ 67 ] found induced DR cell focussing in DM rats, particularly in retinal ganglion cells (RGCs), and found that scutellarin administration significantly inhibited cell focussing in DR and explained the molecular network mechanisms involved.…”

Diabetic Neuropathy of the Retina and Inflammation: Perspectives

“…Finally, excessive potassium efflux and caspase-1 activation lead to pyroptosis by cleavage of gasdermin D [110,120]. A recent study indicates that cell pyroptosis of diabetic retinopathy was found in specifically retinal ganglion cells and a flavonoid extracted from the traditional Chinese medicine, scutellarin protected retinal ganglion cell pyroptosis in diabetic retinopathy in vivo via inhibition of caspase-1, gasdermin D, NLRP3, IL-1β and IL-18 [121]. Ginsenosides are steroid-like saponins and are the main active components of ginseng, a well-known traditional Chinese medicine.…”