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Early phase clinical trials have demonstrated good therapeutic index for oncolytic adenoviruses in patients with solid tumours when administered intratumorally, resulting in local tumour elimination. Entrapment and binding of adenovirus to erythrocytes, blood factors, and neutralising antibodies have prevented efficient systemic delivery and targeting of distant lesions in the clinic. We previously generated the novel replication-selective Ad-3∆-A20T to improve tumour targeting by increasing the viral dose at distant sites. Here, we developed a protocol to directly radiolabel the virus for rapid and sensitive detection by single-photon emitted computed tomography (SPECT/CT) providing a convenient method for determining biodistribution following intravenous administration in murine models. Longitudinal whole-body scans, demonstrated efficient viral uptake in pancreatic Suit-2 and Panc04.03 xenografts with trace amounts of 125I-Ad-3∆-A20T up to 48 h after tail vein delivery. Hepatic and splenic radioactivity decreased over time. Analysis of tissues harvested at the end of the study, confirmed potency and selectivity of mutant viruses. Ad-3∆-A20T-treated animals showed higher viral genome copy numbers and E1A gene expression in tumors than in liver and spleen compared to Ad5wt. Our direct radiolabeling approach, allows for immediate screening of novel oncolytic adenoviruses and selection of optimal viral genome alterations to generate improved mutants. [ABSTRACT FROM AUTHOR]

Hepatic steatosis is strongly linked to insulin resistance and type 2 diabetes. GPR40 is a G protein-coupled receptor mediating free fatty acid-induced insulin secretion and thus plays a beneficial role in the improvement of diabetes. However, the impact of GPR40 agonist on hepatic steatosis still remains to be elucidated. In the present study, we found that activation of GPR40 by its agonist GW9508 attenuated Liver X receptor (LXR)-induced hepatic lipid accumulation. Activation of LXR in the livers of C57BL/6 mice fed a high-cholesterol diet and in HepG2 cells stimulated by chemical agonist caused increased expression of its target lipogenic genes and subsequent lipid accumulation. All these effects of LXR were dramatically downregulated after GW9508 supplementation. Moreover, GPR40 activation was accompanied by upregulation of AMPK pathway, whereas the inhibitive effect of GPR40 on the lipogenic gene expression was largely abrogated by AMPK knockdown. Taken together, our results demonstrated that GW9508 exerts a beneficial effect to ameliorate LXR-induced hepatic steatosis through regulation of AMPK signaling pathway.

MiR-19a, a member of mir-17-92 microRNA clusters, has been demonstrated to promote cell proliferation and angiogenesis via regulating the PI3K/AKT pathway, the major insulin signaling pathway. However, whether miR-19a plays an important role in glycogen synthesis in hepatocytes remains unknown. Here, we define the impact of miR-19a on glycogen synthesis and IL-6-induced reduced glycogenesis in hepatocytes and its underlying mechanisms. Our studies indicate that miR-19a was down-regulated in the livers of db/db mice and mice injected with IL-6, as well as mouse NCTC 1469 hepatocytes and HEP 1-6 hepatocytes treated by IL-6. We found that over-expression of miR-19a in NCTC 1469 cells and HEP 1-6 cells led to increased activation of the AKT/GSK pathway and synthesis of glycogen, whereas down-regulation of miR-19a impaired AKT/GSK phosphorylation and glycogenesis. Over-expression of miR-19a ameliorated IL-6-induced reduced glycogen synthesis in hepatocytes. Moreover, we identified PTEN as the target of miR-19a by a luciferase assay. Down-regulation of PTEN rescued the effects of miR-19a suppression on the activation of the AKT/GSK pathway and improved glycogenesis in NTC 1469 cells. These findings show for the first time that miR-19a might activate the AKT/GSK pathway and glycogenesis via down-regulation of PTEN expression.

Common chemotherapeutic agents such as oxaliplatin often cause neuropathic pain during cancer treatment in patients. Such neuropathic pain is difficult to treat and responds poorly to common analgesics, which represents a challenging clinical issue. Corydalis yanhusuo is an old traditional Chinese medicine with demonstrated analgesic efficacy in humans. However, the potential analgesic effect of its active component, levo-tetrahydropalmatine (l-THP), has not been reported in conditions of neuropathic pain. This study found that l-THP (1-4 mg/kg, i.p.) produced a dose-dependent anti-hyperalgesic effect in a mouse model of chemotherapeutic agent oxaliplatin-induced neuropathic pain. In addition, we found that the anti-hyperalgesic effect of l-THP was significantly blocked by a dopamine D1 receptor antagonist SCH23390 (0.02 mg/kg), suggesting a dopamine D1 receptor mechanism. In contrast, l-THP did not significantly alter the general locomotor activity in mice at the dose that produced significant anti-hyperalgesic action. In summary, this study reported that l-THP possesses robust analgesic efficacy in mice with neuropathic pain and may be a useful analgesic in the management of neuropathic pain.