Shuo Gao

Diabetes is a complex and refractory metabolic disease severely threatening human health. A common feature of both type 1 and advanced type 2 diabetes is the failure and loss of functional β‐cells. Stimulating pancreatic β cell proliferation for endogenous regeneration represents the most direct therapeutic approach.Through screening of secondary metabolites from the endophytic fungus of Ajuga decumbens Thunb using a zebrafish model, we identified Arenarine D promoting β cell regeneration. In a low‐dose STZ‐induced T1DM mouse model, Arenarine D treatment lowered blood glucose and improved insulin resistance. Importantly, we found it promotes mouse β cell proliferation by inhibiting DYRK1A. To our knowledge, we are the first to report that Arenarine D can promote the proliferation of pancreatic β cells by inhibiting DYRK1A, and this effect stems from the replication of existing β cells rather than other pathways. This demonstrates the great potential of Arenarine D in the treatment of T1DM.

A new prenylated indole alkaloid—Penicimutamide C N-oxide (1), a new alkaloid penicimutamine A (2), along with six known alkaloids were isolated from an endophytic fungus Pallidocercospora crystallina. A simple and accurate method was used to determine the N-O bond in the N-oxide group of 1. By using a β-cell ablation diabetic zebrafish model, compounds 1, 3, 5, 6 and 8 showed significantly hypoglycemic activities under the concentration of 10 μM. Further studies revealed that compounds 1 and 8 lowered the glucose level through promoting glucose uptake in zebrafish. In addition, all eight compounds showed no acute toxicity, teratogenicity, nor vascular toxicity in zebrafish under the concentrations range from 2.5 μΜ to 40 μM. Importantly, these results provide new lead compounds for the development of antidiabetes strategies.

The pathogenesis of nonalcoholic fatty liver disease (NAFLD) is closely linked to the imbalance of lipid and glucose metabolism, in which peroxisome proliferator-activated receptors (PPARs) play essential roles. The clinical trials have shown the beneficial effects of the PPARs' ligands on NAFLD. In this study, we screen the extracts from the marine fungus Acremonium citrinum and identify the natural compounds dihydrotrichodimerol (L1A) and trichodimerol (L1B) as the ligands of PPARs, of which L1A is a dual PPARα/γ agonist, whereas L1B is a selective PPARγ agonist. L1A but not L1B significantly prevents hepatic lipid accumulation in an oleic acid-induced NAFLD cell model as well as in a high-fat-diet-induced NAFLD mouse model. Moreover, L1A potently inhibits hepatic steatosis in a PPARα-dependent manner in another NAFLD mouse model constructed by using a choline-deficient and amino acid-defined diet. Mechanistically, L1A transcriptionally up-regulates the expression of SIRT1 in a PPARα-dependent manner, followed by the activation of AMPK and inactivation of ACC, resulting in the inhibition of lipid anabolism and the increase of lipid catabolism. Taken together, our study reveals a dual ligand of PPARα/γ with a distinct structure and therapeutic effect on NAFLD, providing a potential drug candidate bridging the currently urgent need for the management of NAFLD.

The chemical investigation on endophytic fungus Annulohypoxylon cf. stygium in leaves of Anoectochilus roxburghii (Wall.) Lindl. has been performed. Sixteen compounds were isolated and their structures were identified as (−)‐notoamide A, (−)‐notoamide B, (+)‐versicolamide B, notoamide C, notoamide D, stephacidin A, sterigmatocystin, dihydrosterigmatocystin, secosterigmatocystin, versiconol, averufanin, kipukasin D, kipukasin E, diorcinal, palmarumycin CP2 and (−)‐(3R)‐mellein methyl ether, respectively, by spectroscopic analysis and comparison with literature data. All the compounds were isolated from Annulohypoxylon genus for the first time. Sterigmatocystin and palmarumycin CP2 showed selective cytotoxic activities against HepG2, HeLa, MCF‐7 and HT‐29.