Relationship between peroxisome proliferator-activated receptor-γ activation and the ameliorative effects of ascochlorin derivatives on type II diabetes

Abstract

Peroxisome proliferator-activated receptor-c (PPAR-c) is a crucial factor in the development of insulin resistance associated with type II diabetes. We previously found that 4-O-carboxymethyl ascochlorin, a derivative of ascochlorin, ameliorates diabetes and activates PPAR-c. Here, we compared the relationship between the amelioration of type II diabetes in db/db mice lacking leptin receptor, and PPAR-c activation by 4-O-carboxymethyl-ascochlorin, as well as by 4-O-methyl-ascochlorin, a derivative that does not activate PPAR-c. Administration of these compounds significantly reduces blood glucose in a dose-dependent manner, whereas blood cholesterol is significantly elevated in 4-O-carboxymethyl-ascochlorin-treated mice but is significantly decreased in 4-O-methyl-ascochlorin-treated mice. Pioglitazone, a potent PPAR-c agonist with a thiazolidinedione structure, reduces glucose but elevates cholesterol blood levels. These results suggest that ascochlorin derivatives ameliorate diabetes through a mechanism that is probably independent of PPAR-c activation, although PPAR-c activation could be partially involved in the ameliorative effect in certain derivatives.

Secondary metabolites from entomopathogenic Hypocrealean fungi

“…Junji et al proposed that ascochlorin derivatives ameliorate diabetes through a mechanism that is independent of the activation of the peroxisome proliferatoractivated receptor-g, a crucial factor in the development of insulin resistance associated with type II diabetes. 287 Compounds of the ascochlorin family were first isolated from Ascocyta viciae, 288 but since have been described from many fungi including Cylindrocladium ilicicola, 289 Nectria sp. 290 and a sponge-derived Acremonium sp.…”

Filamentous Fungi-Derived Orsellinic Acid-Sesquiterpene Meroterpenoids: Fungal Sources, Chemical Structures, Bioactivities, and Biosynthesis

“…33 was active against Pseudomonas syringae with IC 50 values of 28.5 µM [112] and against Aspergillus fumigatus with MIC values of 1.25 to 2.5 µg/mL [113,114]. Furthermore, 22 and 33 displayed anti-inflammatory activity [37,[115][116][117][118][119][120][121], as well as a potent agonist of peroxisome proliferator-activated receptor with IC 50 values of 3.2 and 1 μM, respectively [122].…”

“…Both compounds exhibited moderate fungicidal activity against plant pathogenic fungus Phytophthora infestans [43], as well as significant antimicrobial activity against S. aureus, MRSA, S. epidermidis, B. subtilis, and the human pathogenic fungus Candida albicans with MIC values of 0.25-32 µg/mL [22,47,111]; 33 was active against Pseudomonas syringae with an IC 50 value of 28.5 µM [112] and against Aspergillus fumigatus with MIC values of 1.25 to 2.5 µg/mL [113,114]. Furthermore, 22 and 33 displayed anti-inflammatory activity [37,[115][116][117][118][119][120][121], as well as a potent agonist of peroxisome proliferator-activated receptor with IC 50 values of 3.2 and 1 µM, respectively [122].…”

10′-Deoxy-10′ α-hydroxyascochlorin, a New Cell Migration Inhibitor and Other Metabolites from Acremonium sp., a Fungal Endophyte in Ephedra trifurca

“…Although ascochlorin-related fungal metabolites were originally isolated as antiviral antibiotics [17,18], they were found to exhibit a variety of physiological effects including hypolipidemic activity [19], suppression of hypertension [20], amelioration of type I and II diabetes [21,22], immunosuppressive activity [23], and antitumor activity [8,24]. Ascofuranone (2) was found to inhibit trypanosome alternative oxidase and is considered to be a promising chemotherapeutic candidate against African trypanosomiasis [25]. )…”