Synergistic Effect of Baculovirus-Mediated Endostatin and Angiostatin Combined with Gemcitabine in Hepatocellular Carcinoma.

Anti-angiogenic gene therapy is a promising strategy in treating cancer. Endostatin and angiostatin are widely used in tumor anti-angiogenesis therapy. Our previous studies have shown that the BDS-hEA, a baculovirus long-term expressing the fusion protein of human endostatin and angiostatin, has a favorable effect in inhibiting the growth and angiogenesis of hepatocellular carcinoma. The purpose of this study was to further investigate its synergistic antitumor efficiency in combination with low-dose chemotherapeutic gemcitabine (GEM) on the subcutaneous hepatocellular carcinoma xenograft model in nude mice. The results showed that the combined group significantly inhibited (p < 0.05 or p < 0.01 or p < 0.001) the growth of tumor weight and volume, reduced the expression of ki67 (cell proliferation marker), CD31 (angiogenic marker) and Matrix metalloproteinase 9 (MMP-9, tumor invasion and metastasis marker) and increased the apoptosis of tumor cells compared with the monotherapy and control groups, respectively. Synergistic index results showed that BDS-hEA combined with GEM had a synergistic effect in inhibiting tumor volume, proliferation, microvessel density, metastasis and promoting tumor apoptosis. Furthermore, there were no metastatic nodules and obvious pathological changes in liver tissue of the combined group, and the serum liver function indicators aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (T-BIL), alkaline phosphatase (ALP) and glutamyl transpeptidase (GGT) were significantly reduced (p < 0.05 or p < 0.01 or p < 0.001) in the BDS-hEA or GEM groups compared with the control group. Notably, the combined therapy showed lower levels of liver function indicators than the GEM group. These data support the view that the combination of BDS-hEA and GEM has a synergistic anti-tumor properties and can reduce the damage of liver to certain extent.

Anthocyanins from Lycium ruthenicum Murray Inhibit HepG2 Cells Growth, Metastasis and Promote Apoptosis and G2/M Phase Cycle Arrest by Activating the AMPK/mTOR Autophagy Pathway.

Among the most common malignancies in humans, liver cancer ranks third in terms of mortality in the world. Seeking new anticancer drugs or adjuvant chemotherapy drugs from natural products has attracted the attention of many researchers. Lycium ruthenicum Murray (LR), a health food and traditional Chinese medicine, exerts extensive pharmacological properties, of which anthocyanins are one of the key active components. In this research, we explored the antitumor activity and autophagy regulation mechanism of anthocyanins from Lycium ruthenicum Murray (ALR) in HepG2 cells. Our results found that ALR profoundly reduced the cell viability, clone formation, migration, and invasion and promoted apoptosis and G2/M phase arrest of HepG2 cells in a dose-dependent pattern. Further studies confirmed that ALR treatment significantly increased the number of autophagic vacuoles and autophagosomes, upregulated the expression of Beclin-1, p62, LC3-II/LC3-I, and p-AMPK, and concomitantly downregulated the expression of p-mTOR. When autophagy was inhibited by 3-methyladenine (3-MA), ALR-induced proliferation inhibition, invasion, and migration capabilities, as well as apoptosis rate and G2/M phase arrest, were all reversed, and the activities of key proteins in the AMPK/mTOR pathway were all constrained. In summary, the results presented here indicate that ALR may be effective as a natural antitumor agent by activating AMPK and inhibiting the mTOR autophagy pathway in HepG2 cells.

Development of a novel bivalent baculovirus vectors for complement resistance and sustained transgene expression and its application in anti-angiogenesis gene therapy.

Baculovirus (BV) is a potential gene delivery vector but only mediates transient transgene expression and easily inactivated by human complement. To this end, we intend to develop a novel bivalent BV vector for complement resistance and sustained transgene expression, and evaluate its effect in anti-angiogenesis gene therapy. The results showed that the hybrid bivalent BV significantly prolonged the expression of enhanced green fluorescent protein (eGFP) in vitro for at least 90 days at over 109 a.u. total fluorescence intensity, and exhibited significantly higher complement resistance. The control BV-mediated eGFP expression gradually declined within 15 days and showed lower transduction efficiency. In vivo studies confirmed that the hybrid bivalent BV exhibited longer duration of eGFP expression and higher transduction efficacy than the control BVs. Based on these findings, we further constructed a hybrid BV expressing the antiangiogenic fusion protein containing human endostatin and angiostatin (hEA). The hybrid BV-expressed hEA significantly prolonged the expression level of hEA with enhanced anti-angiogenic activities compared to the control groups, as evidenced by ELISA, cell proliferation, migration and tubular formation assays. With the stable expression of hEA, the hybrid BV conferred hEA more significant inhibitory effect on hepatocellular carcinoma tumor growth and significantly extended the life span of mice. These data implicate that the SB-based BV surface display system may have broad prospects as a novel platform for gene therapy of tumors.

Early onset of cardiometabolic risk factor profiles in drug naïve adolescents and young adults with first-episode schizophrenia.

OBJECTIVE AND METHOD: We performed a case-control study, which included antipsychotic-naïve first-episode schizophrenia (FES) of adolescents and young adults and general population controls, to investigate the early-onset cardiometabolic risk factors in FES. RESULTS: FES had more frequent lower HDL-C when compared to controls. However, the distribution of BMI and the frequency of hypercholesterolemia, elevated LDL-C, hypertriglyceridemia in FES were not significantly different to controls. CONCLUSIONS: The results indicated that abnormal HDL-C might be an early-onset event in drug-naïve FES of adolescents and young adults who are unlikely to have other cardiometabolic risks.