Hepatic STAMP2 alleviates high fat diet-induced hepatic steatosis and insulin resistance.

BACKGROUND & AIMS: Most studies on the role of STAMP2 in metabolism have used adipose tissue. Little knowledge exists concerning the role of STAMP2 in the liver, which is a metabolically central target. We hypothesized that STAMP2 is involved in non-alcoholic fatty liver disease (NAFLD) pathogenesis. METHODS: We examined our hypothesis using human NAFLD patient pathology samples and a high-fat diet (HFD)-induced NAFLD mouse model. The molecular mechanism underlying hepatic STAMP2-mediated lipid imbalance was explored using an oleic acid (OA)-induced NAFLD in vitro model. RESULTS: Noticeably, the expression level of STAMP2 protein was reduced in the livers obtained from NAFLD patients and HFD-induced NAFLD mice. In vivo knockdown of hepatic STAMP2 by siRNA accelerated hepatic steatosis and insulin resistance in mice fed a HFD. Conversely, the delivery of adenoviral STAMP2 (Ad-STAMP2) improved hepatic steatosis in HFD-induced NAFLD mice. The expression of lipogenic or adipogenic factors was increased in both in vitro and in vivo NAFLD models but was reversed by Ad-STAMP2. Adenoviral overexpression of STAMP2 improved insulin resistance in the HFD-induced NAFLD mice. In vivo and in vitro assays demonstrated that STAMP2 modulates insulin sensitivity and glucose metabolism and that STAMP2 counteracts OA-induced insulin resistance by modulating insulin receptor substrate-1 stability. CONCLUSIONS: The present study revealed that hepatic STAMP2 plays a pivotal role in preventing HFD-induced NAFLD and that STAMP2 overexpression improves hepatic steatosis and insulin resistance in NAFLD. Our findings indicate that STAMP2 may represent a suitable target for interventions targeting NAFLD.

Momilactone B, an allelochemical of rice hulls, induces apoptosis on human lymphoma cells (Jurkat) in a micromolar concentration.

Although momilactone B has been studied as an allelochemical of rice (Oryza sativa L.), to date we have no report showing the effect of momilactone B on mammalian cells. This study was undertaken to examine whether this allelochemical has anticancer activity on cancer cells. We show here that momilactone B at micromolar doses has antitumor efficacy by inducing apoptosis in several blood cancer cells including human leukemic T cells. In addition, our study elucidated that anticancer activity of momilactone B on human leukemic T cells resulted from the induction of apoptosis via caspase and mitochondria. From these results, momilactone B can be considered as a novel therapeutic strategy for human leukemic T cells from its direct apoptosis-inducing activity.

Clematis mandshurica protected to apoptosis of rat chondrocytes.

OBJECTIVE: To investigate the effect of SKI 306X, a purified extract from the mixture of three herbs, i.e. Clematis mandshurica, Trichosanthes kirilowii and Prunella vulgaris, on apoptosis in chondrocytes. DESIGN: Rat chondrocyte cell line RCJ3.1C.18 cells were incubated with 1 microM staurosporin and SKI 306X or each of its components. Cell viability was determined by trypan blue exclusion assay. Induction of apoptosis was determined by nuclear condensation or fragmentation after Hoechst staining. Amount of apoptosis was quantified both by nuclear morphology and flow cytometry. Expression level of Bcl-2, and caspase-3 and PARP activations were assayed by Western blot. RESULTS: SKI 306X significantly prevented staurosporin-induced apoptosis. Among its three components, only Clematis mandshurica significantly decreased the amount of staurosporin-induced apoptosis. Although the level of Bcl-2 expression was decreased after staurosporin treatment, it was sustained after the combination treatment with Clematis mandshurica. Whereas staurosporin induced the degradation of 32 kDa caspase-3 precursor and the production of 85-kDa cleavage products of PARP in a time-dependent fashion, Clematis mandshurica treatment prevented those manifestations. CONCLUSIONS: Pharmacological efficacy of SKI 306X protecting osteoarthritis in part may result from the inhibition of apoptosis in chondrocytes by Clematis mandshurica.

Genistein-induced apoptosis of p815 mastocytoma cells is mediated by Bax and augmented by a proteasome inhibitor, lactacystin.

Although genistein has been demonstrated to induce apoptosis of various cells, there is no report of its effect on mast cell proliferation. Here we show that genistein reduced the viability of mast cell tumor cell lines, p815 and RBL-2H, but not of a human mast cell line, HMC-1. Further investigation on its growth-inhibitory mechanism was undertaken on p815 mastocytoma cells. Genistein induced G2/M arrest and subsequent apoptotic death. p815 cells undergoing apoptosis showed many apoptotic manifestations, such as reduction of mitochondrial membrane potential, release of cytochrome c to cytosol, translocation of apoptosis-inducing factor to nucleus, activation of caspase-3, nuclear condensation, and generation of DNA fragmentation. Genistein treatment resulted in the increase of Bax expression and its translocation into mitochondria, whereas expression levels of Bcl-2 remained unchanged. Proteasome activity decreased at the early time points after genistein treatment, but thereafter it fluctuated at increased levels. A proteasome inhibitor, lactacystin, potentiated the induction of apoptosis. Taken together, genistein-induced apoptosis of p815 mastocytoma cells is at least in part mediated by proteasome, Bax, apoptosis-inducing factor, and caspase and augmented by cotreatment with a proteasome inhibitor, lactacystin.