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Acta Pharm Sin B ; 8(4): 687-697, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30109192


Epigenetic modifications have been proved to be a powerful way to activate silent gene clusters and lead to diverse secondary metabolites in fungi. Previously, inactivation of a histone H3 deacetylase in Calcarisporium arbuscula had led to pleiotropic activation and overexpression of more than 75% of the biosynthetic genes and isolation of ten compounds. Further investigation of the crude extract of C. arbuscula ΔhdaA strain resulted in the isolation of twelve new diterpenoids including three cassanes (1-3), one cleistanthane (4), six pimaranes (5-10), and two isopimaranes (11 and 12) along with two know cleistanthane analogues. Their structures were elucidated by extensive NMR spectroscopic data analysis. Compounds 2 and 4 showed potent inhibitory effects on the expression of MMP1 and MMP2 (matrix metalloproteinases family) in human breast cancer (MCF-7) cells.

Arterioscler Thromb Vasc Biol ; 38(9): 2103-2116, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30026270


Objective- Obesity-induced inflammation in white adipose tissue, characterized by increased macrophage infiltration and associated with macrophage population shift from anti-inflammatory M2 to proinflammatory M1 macrophages, largely contributes to obesity-induced insulin resistance and influences type 2 diabetes mellitus pathogenesis. GSK3 (glycogen synthase kinase 3), a serine/threonine kinase, has been reported to participate in various cellular processes. We sought to examine the potential mechanism by which GSK3, a serine/threonine kinase implicated in various cellular processes, modulates obesity-induced visceral adipose tissue (VAT) inflammation. Approach and Results- Male C57BL/6J mice were fed a high-fat diet for 10 weeks while being treated with vehicle control or GSK3 inhibitors SB216763 or CHIR99021. RNA-sequencing results using VAT demonstrated that GSK3 inhibitor treatment reversed obesity-specific expression of genes associated with inflammation. Consistently, GSK3 inhibition reduced obesity-induced VAT inflammation as characterized by decreased proinflammatory M1 macrophages but increased anti-inflammatory M2 macrophages in the VAT and reduced circulatory inflammatory monocytes. These anti-inflammatory effects of GSK3 inhibition were found to be driven, at least in part, by inhibiting production of apoptosis inhibitor of macrophage in macrophages via inactivating STAT3 to reduce free fatty acid and chemokine level produced from VAT to suppress the migration/chemotaxis of macrophages and monocytes. Conclusions- Our findings suggest that GSK3 may act as an important regulator of obesity-induced inflammation and characterize the novel role of GSK3 in shifting macrophage polarization and reinforce its therapeutic potential for obesity-induced inflammation and its associated diabetes mellitus.

Tecido Adiposo Branco/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Apoptose , Movimento Celular , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Macrófagos/metabolismo , Obesidade/metabolismo , Receptores Imunológicos/metabolismo , Animais , Peso Corporal , Células Cultivadas , Regulação para Baixo , Quinase 3 da Glicogênio Sintase/metabolismo , Inflamação/genética , Inflamação/metabolismo , Resistência à Insulina , Células Matadoras Naturais/metabolismo , Fatores Inibidores da Migração de Macrófagos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Fosforilação , Regulação para Cima
Fitoterapia ; 116: 93-98, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27894905


Seven pairs of new alkaloid enantiomers, ganocochlearines C-I (1, 3-8), and three pairs of known alkaloids were isolated from the fruiting bodies of Ganoderma cochlear. The chemical structures of new compounds were elucidated on the basis of 1D and 2D NMR data. The absolute configurations of compounds 1, 3-10 were assigned by ECD calculations. Biological activities of these isolates against renal fibrosis were accessed in rat normal or diseased renal interstitial fibroblast cells. Importantly, the plausible biosynthetic pathway for this class of alkaloids was originally proposed.

Alcaloides/farmacologia , Fibroblastos/efeitos dos fármacos , Ganoderma/química , Rim/patologia , Alcaloides/química , Alcaloides/isolamento & purificação , Animais , Linhagem Celular , Fibrose , Carpóforos/química , Rim/citologia , Estrutura Molecular , Ratos , Estereoisomerismo
Bioorg Med Chem Lett ; 26(22): 5507-5512, 2016 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-27765504


Ganoderma mushrooms are of great nutritious and medicinal values. This study was designed to characterize compounds from the fruiting bodies of Ganoderma cochlear and investigate their protective effects against kidney disorders. Six novel meroterpenoids cochlearoids F-K (1-6) were isolated by utilizing phytochemical approaches. Their structures were identified on the basis of extensive spectroscopic data and calculation methods. Biological evaluation shows that compounds 1-4 and 6 exhibit potent inhibitory activity on fibronectin overproduction in TGF-ß1-induced HKC-8 cells.

Carpóforos/química , Ganoderma/química , Rim/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Terpenos/química , Terpenos/farmacologia , Linhagem Celular , Fibronectinas/metabolismo , Humanos , Rim/metabolismo , Terpenos/isolamento & purificação , Fator de Crescimento Transformador beta1/metabolismo
Org Lett ; 16(23): 6064-7, 2014 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-25402560


(+)- and (-)-cochlearols A (1) and B (2), two meroterpenoids with novel polycyclic skeletons, were isolated from the fruiting bodies of the fungus Ganoderma cochlear. Their structures and stereochemistry were determined by using spectroscopic, computational and single-crystal X-ray diffraction methods. Cochlearol A is a new normeroterpenoid containing a naturally unusual dioxaspiro[4.5]decane motif. Biological studies showed that (-)-2 is a strong inhibitor of p-Smads, exhibiting renoprotective activities in TGF-ß1 induced rat renal proximal tubular cells.

Ganoderma/química , Rim/efeitos dos fármacos , Terpenos/isolamento & purificação , Terpenos/farmacologia , Animais , China , Cristalografia por Raios X , Conformação Molecular , Estrutura Molecular , Ratos , Estereoisomerismo , Terpenos/química , Fator de Crescimento Transformador beta1/efeitos dos fármacos