Euphorbia helioscopia L. exhibits promising therapeutic effects on hemangioendothelioma and melanoma through angiogenesis inhibition.

BACKGROUND: Euphorbia helioscopia L (EHL), a widely used medicinal plant in traditional Chinese medicine, has shown promising effects on certain cancers. However, previous studies on EHL did not elucidate the underlying molecular mechanisms. Herein, for the first time, we present the strong therapeutic potential of EHL extracts on malignant hemangioendothelioma, a rare type of vascular tumor. PURPOSE: To investigate the potential anti-tumor mechanism of extracts of EHL on hemangioendothelioma and melanoma. METHODS: The dried stems and leaves of EHL were extracted with Ethyl Acetate and n-Butyl alcohol, yielding two crude extracts Ethyl Acetate fraction (EA) and n-Butyl alcohol fraction (Bu). EA and Bu were prepared to assess the potential mechanism by assays for cell proliferation, cell cycle, apoptosis, colony formation, tube formation, cellular metabolic activity, reactive oxygen species (ROS), N-Acetylcysteine (NAC) antagonism, RNA expression and western blot. To further confirm the anti-tumor effect of EHL in vivo, we established hemangioendothelioma and melanoma tumor-bearing mouse model using node mice and administered with EA and Bu, tracked alterations in tumor volume and survival rate. Furthermore, tissue samples were obtained for histological, protein, and genetic investigations. RESULTS: We demonstrate that the injection of EA and Bu, significantly inhibits tumor growth and prolongs the lifespan of tumor-bearing mice. Bu treatment exhibited a remarkable 33 % healing effect on the primary hemangioendothelioma tumor, bringing the survival rate to a level comparable to that of healthy mice. Mechanically, both EA and Bu impair respiratory chain complexes, leading to mitochondrial dysfunction and accumulation of reactive oxygen species (ROS), resulting in DNA damage, cell apoptosis, and finally blocked angiogenesis. While EA demonstrates robust inhibitory effects on cancer cell growth and a broader impact on metabolism in vitro, the in vivo effect of Bu surpasses that of EA in terms of strength. EA and Bu also exhibit potent anti-tumor effects on a primary melanoma model by inhibiting angiogenesis. Importantly, when compared to other compounds used in the treatment of hemangioendothelioma, EA and Bu demonstrate more profound anti-tumor effects. CONCLUSION: For the first time, our findings reveal that EHL extracts, especially the high polarity compounds, exhibit potent anti-tumor effects by targeting cellular metabolism, specifically through the inhibition of mitochondria-related metabolic activities. This leads to the accumulation of ROS and effectively suppresses abnormal angiogenesis.

Epigenetic modification in histone deacetylase deletion strain of Calcarisporium arbuscula leads to diverse diterpenoids.

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.

Inhibiting Glycogen Synthase Kinase 3 Reverses Obesity-Induced White Adipose Tissue Inflammation by Regulating Apoptosis Inhibitor of Macrophage/CD5L-Mediated Macrophage Migration.

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.

Racemic alkaloids from the fungus Ganoderma cochlear.

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.

Cochlearoids F-K: Phenolic meroterpenoids from the fungus Ganoderma cochlear and their renoprotective activity.

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.

Cochlearols A and B, polycyclic meroterpenoids from the fungus Ganoderma cochlear that have renoprotective activities.

(+)- 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.