CREPT Disarms the Inhibitory Activity of HDAC1 on Oncogene Expression to Promote Tumorigenesis.

Histone deacetylases 1 (HDAC1), an enzyme that functions to remove acetyl molecules from ε-NH3 groups of lysine in histones, eliminates the histone acetylation at the promoter regions of tumor suppressor genes to block their expression during tumorigenesis. However, it remains unclear why HDAC1 fails to impair oncogene expression. Here we report that HDAC1 is unable to occupy at the promoters of oncogenes but maintains its occupancy with the tumor suppressors due to its interaction with CREPT (cell cycle-related and expression-elevated protein in tumor, also named RPRD1B), an oncoprotein highly expressed in tumors. We observed that CREPT competed with HDAC1 for binding to oncogene (such as CCND1, CLDN1, VEGFA, PPARD and BMP4) promoters but not the tumor suppressor gene (such as p21 and p27) promoters by a chromatin immunoprecipitation (ChIP) qPCR experiment. Using immunoprecipitation experiments, we deciphered that CREPT specifically occupied at the oncogene promoter via TCF4, a transcription factor activated by Wnt signaling. In addition, we performed a real-time quantitative PCR (qRT-PCR) analysis on cells that stably over-expressed CREPT and/or HDAC1, and we propose that HDAC1 inhibits CREPT to activate oncogene expression under Wnt signaling activation. Our findings revealed that HDAC1 functions differentially on tumor suppressors and oncogenes due to its interaction with the oncoprotein CREPT.

Myricetin, a naturally occurring flavonol, ameliorates insulin resistance induced by a high-fructose diet in rats.

The present study was conducted to explore the effects of myricetin on insulin resistance in rats fed for 6 weeks with a diet containing 60% fructose. Repeated intravenous (i.v.) injection of myricetin (1 mg/kg per injection, 3 times daily) for 14 days was found to significantly decrease the high glucose and triglyceride levels in plasma of fructose chow-fed rats. Also, the higher degree of insulin resistance in fructose chow-fed rats as measured by homeostasis model assessment of basal insulin resistance was significantly decreased by myricetin treatment. Myricetin increased the whole-body insulin sensitivity in fructose chow-fed rats, as evidenced by the marked elevation of composite whole-body insulin sensitivity index during the oral glucose tolerance test. Myricetin was found to reverse the defect in expression of insulin receptor substrate-1 (IRS-1) and the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI 3-kinase) in soleus muscle of fructose chow-fed rats under the basal state, despite the protein expression of insulin receptor (IR). Increased basal phosphorylation of IR and IRS-1 as well as Akt was observed in parallel. The reduced level of insulin action on phosphorylation of IR, IRS-1 and Akt in soleus muscle of fructose chow-fed rats was reversed by myricetin treatment. Furthermore, myricetin treatment improved the defective insulin action on the translocation of glucose transporter subtype 4 (GLUT 4) in insulin-resistant soleus muscle. These findings indicate that myricetin improves insulin sensitivity through the enhancement of insulin action on IRS-1-associated PI 3-kinase and GLUT 4 activity in soleus muscles of animals exhibiting insulin resistance.

Improvement of insulin sensitivity in obese Zucker rats by myricetin extracted from Abelmoschus moschatus.

In an attempt to develop new substances for treating insulin resistance, obese Zucker rats were employed to screen the effect of myricetin, an active principle of Abelmoschus moschatus (Malvaceae), on insulin resistance. Myricetin purified from the aerial portion of the plant was administered intravenously ( I. V.) into animals. A dose-dependent decrease in the plasma glucose concentration of obese Zucker rats was observed 30 min following an I. V. injection. Moreover, repeated I. V. injection of myricetin (1 mg/kg) into obese Zucker rats 3 times daily for 1 week reduced the value of the glucose-insulin index, an index of insulin resistance calculated from the areas under the curve of glucose and insulin during the intraperitoneal glucose tolerance test. Additionally, repeated myricetin treatments overturned the inability of insulin to increase the expression of glucose transporter subtype 4 (GLUT 4) and to increase the protein levels and phosphorylation of insulin receptor substrate-1 (IRS-1) in soleus muscle of these obese rats. The inability of insulin to increase expression of the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3-kinase) and to promote Akt serine phosphorylation in soleus muscle of these rats were also overturned by repeated myricetin treatments. These findings indicate that myricetin improves insulin sensitivity through increased post-receptor insulin signaling mediated by enhancements in IRS-1-associated PI3-kinase and GLUT 4 activity in muscles of obese Zucker rats. Myricetin might be used as a model substance for the development of antidiabetic compounds.

Kadsuphilols A-H, oxygenated lignans from Kadsura philippinensis.

Eight new oxygenated lignans, kadsuphilols A-H (1-8), were isolated from the leaves and stems of Kadsura philippinensis. Four of the isolated lignans (1-4) possess the normal C18-dibenzocyclooctadiene skeleton, while the other four lignans (5-8) are C19-homolignans possessing a substituted cyclohexadienone ring with a spiro-benzofuranoid moiety. The structures of the isolated metabolites were elucidated through spectroscopic analyses, including 2D NMR experiments. Compounds 1 and 4 are the first report of an R-biphenyl configuration with a beta-oxygenated substituent at the C-9 position. The in vitro radical-scavenging activities of these compounds using DPPH were tested and evaluated. Compound 3 exhibited more potent activity than vitamins C and E.

Myricetin as the active principle of Abelmoschus moschatus to lower plasma glucose in streptozotocin-induced diabetic rats.

The antihyperglycemic action of myricetin, purified from the aerial part of Abelmoschus moschatus (Malvaceae), was investigated in streptozotocin-induced diabetic rats (STZ-diabetic rats). Bolus intravenous injection of myricetin decreased the plasma glucose concentrations in a dose-dependent manner in STZ-diabetic rats. Myricetin at the effective dose (1.0 mg/kg) significantly attenuated the increase of plasma glucose induced by an intravenous glucose challenge test in normal rats. A stimulatory effect of myricetin on glucose uptake of the soleus muscles isolated from STZ-diabetic rats was obtained in a concentration-dependent manner from 0.01 to 10.0 micromol/L. The increase of glucose utilization by myricetin was further characterized using the enhancement of glycogen synthesis in isolated hepatocytes of STZ-diabetic rats. These results suggest that myricetin has an ability to enhance glucose utilization to lower plasma glucose in diabetic rats lacking insulin.