A Novel Formononetin Derivative Promotes Anti-ischemic Effects on Acute Ischemic Injury in Mice

Abstract

Natural flavonoids, formononetin and ononin, possess antioxidant, antibacterial, anti-inflammatory and neuroprotective effects. Many complications caused by SARS-CoV-2 make patients difficult to recover. Flavonoids, especially formononetin and ononin, have the potential to treat SARS-CoV-2 and improve myocardial injury. However, their poor water solubility, poor oral absorption, high toxicity, and high-cost purification limit industrial practical application. Succinylation modification provides a solution for the above problems. Formononetin-7-O-β-(6″-O-succinyl)-D-glucoside (FMP), a new compound, was succinyl glycosylated from formononetin by the organic solvent tolerant bacteria Bacillus amyloliquefaciens FJ18 in a 10.0% DMSO (v/v) system. The water solubility of the new compound was improved by over 106 times compared with formononetin, which perfectly promoted the application of formononetin and ononin. The conversion rate of formononetin (0.5 g/L) was almost 94.2% at 24 h, while the yield of formononetin-7-O-β-(6″-O-succinyl)-D-glucoside could achieve 97.2%. In the isoproterenol (ISO)-induced acute ischemia mice model, the myocardial injury was significantly improved with a high dose (40 mg/kg) of formononetin-7-O-β-(6″-O-succinyl)-D-glucoside. The lactate dehydrogenase level was decreased, and the catalase and superoxide dismutase levels were increased after formononetin-7-O-β-(6″-O-succinyl)-D-glucoside treatment. Thus, formononetin-7-O-β-(6″-O-succinyl)-D-glucoside has high water solubility, low toxicity, and shows significant antimyocardial ischemia effects.

Efficient Synthesis and In Vitro Hypoglycemic Activity of Rare Apigenin Glycosylation Derivatives

“…B. amyloliquefaciens FJ18 [ 4 , 18 ] and B. licheniformis ZSP01 [ 13 ] are organic solvent-resistant strains that produce glycosyltransferase and can biotransform apigenin. Production of SAG by B. amyloliquefaciens FJ18 in a nonaqueous phase has been previously described [ 18 ].…”

“…In a previous laboratory study, we isolated functional strains with glycosylation and succinylation activity. In this study, we evaluated the biotransformation activity of B. licheniformis WNJ02, which was derived from B. amyloliquefaciens FJ18 [ 4 ]. Microbial biotransformation is simpler and more efficient than chemical synthesis [ 25 , 26 ].…”

“…However, its low solubility in water reduces its bioavailability and limits clinical application. Glycosylation improves water solubility and bioavailability [ 4 ], and glycosylated flavonoids that are found in many fruits and vegetables have anticancer activity, and activity against cardiovascular, and neurodegenerative diseases. Antimalarial phytochemicals, including apigenin-7-O-glucoside, luteolin-7-O-glucoside, and others have predicted high-binding energy for the 3C-like protease of COVID-19 [ 5 ], and are considered useful for developing candidate antiCOVID-19 drugs.…”

“…Our research group has screened extremophiles and developed a biosynthetic method of glycosylating and succinylating flavonoids by organic solvent-resistant bacteria. The method improves the bioavailability of flavonoids and facilitates the development of flavonoids with potential clinical application [ 4 , 13 ]. Succinylation has also been found to enhance the water solvency and bioavailability of compounds and can be accomplished by a strain of Bacillus amyloliquefaciens [ 13 ].…”

Molecular mechanism of the effect of Gegen Qinlian decoction on COVID-19 comorbid with diabetes mellitus based on network pharmacology and molecular docking: A review

“…[ 17 ] Also contained within GGQL, formononetin is a flavonoid that may be a promising inhibitor of SARS-CoV-2 [ 18 ] and has demonstrated its potential as a treatment against the infection. [ 19 ] Formononetin treatment has been found to reduce insulin resistance and protect against pancreatic β-cell apoptosis caused by IL-1β to attenuate hyperglycemia in type 2 diabetes. [ 20 , 21 ] These studies demonstrate the efficacy of GGQL’s active components in the treatment of COVID-19 comorbid with DM.…”