Sildenafil Reduces Insulin-Resistance in Human Endothelial Cells

The efficacy of Phosphodiesterase 5 (PDE5) inhibitors to re-establish endothelial function is reduced in diabetic patients. Recent evidences suggest that therapy with PDE5 inhibitors, i.e. sildenafil, may increase the expression of nitric oxide synthase (NOS) proteins in the heart and cardiomyocytes. In this study we analyzed the effect of sildenafil on endothelial cells in insulin resistance conditions in vitro

Huangqi Injection (a Traditional Chinese Patent Medicine) for Chronic Heart Failure: A Systematic Review

Chronic heart failure (CHF) is a global public health problem. Therefore, novel and effective drugs that show few side-effects are needed. Early literature studies indicated that Huangqi injection is one of the most commonly used traditional Chinese patent medicines for CHF in China. As a large number of clinical studies has been carried out and published, it is essential to evaluate the effectiveness and safety of Huangqi injection. Therefore, we carried out this systematic review under the support of the framework of the Joint Sino-Italian Laboratory (JoSIL).To evaluate the efficacy and safety of Huangqi injection for CHF according to the available scientific knowledge.An extensive search including PubMed, EMBASE, CBM, the Cochrane Library and Chinese literature databases was performed up to July 2008. Clinical trials regarding Huangqi injection for the treatment of CHF were searched for, irrespective of languages. The quality of each trial was assessed according to the Cochrane Reviewers' Handbook 5.0, and RevMan 5.0 provided by the Cochrane Collaboration and STATA 9.2 were used for data analysis.After selection of 1,205 articles, 62 RCTs and quasi-RCTs conducted in China and published in Chinese journals were included in the review. The methodological quality of the trials was low. In most trials inclusion and exclusion criteria were not specified. Furthermore, only one study evaluated the outcomes for drug efficacy after an adequate period of time. For these reasons and because of the different baseline characteristics we did not conduct a meta-analysis.Although available studies are not adequate to draw a conclusion on the efficacy and safety of Huangqi injection (a traditional Chinese patent medicine), we hope that our work could provide useful experience on further studies on Huangqi injections. The overall level of TCM clinical research needs to be improved so that the efficacy of TCM can be evaluated by the international community and possibly some TCM can enter into the international market

Serum- and Glucocorticoid-Inducible Kinase 1 Delay the Onset of Endothelial Senescence by Directly Interacting with Human Telomerase Reverse Transcriptase

Endothelial senescence is characteristic of vascular aging. Serum- and glucocorticoid-inducible kinase (SGK)1 belongs to a family of serine/threonine kinases regulated by various external stimuli. SGK1 has been shown to be protective against reactive oxygen species (ROS) production and to be involved in processes regulating aging. However, data on the direct relationship between SGK1 and senescence are sparse. In the present study, we sought to investigate the role of SGK1 in cellular aging by using human umbilical vein endothelial cells (HUVECs) infected with different constructs. Senescence was measured at different cellular stages by senescence-associated β-galactosidase (SA-β-gal) activity, human telomerase reverse transcriptase (hTERT) activity, p21 protein levels, and ROS production. HUVECs over-expressing full-length SGK1 (wild-type SGK1 [SGK1WT]) showed a decrease in SA-β-gal and p21 expression and a corresponding increase in hTERT activity in the early stages of aging. Moreover, SGK1WT presented lower levels of ROS production. A direct interaction between SGK1WT and hTERT was also shown by co-immunoprecipitation. The SGK1Δ60 isoform, lacking the amino-terminal 60 amino acids, did not show interaction with hTERT, suggesting a pivotal role of this protein site for the SGK1 anti-aging function. The results from this study may be of particular importance, because SGK1WT over-expression by activating telomerase and reducing ROS levels may delay the processes of endothelial senescence

Liver protein profiles in insulin receptor-knockout mice reveal novel molecules involved in the diabetes pathophysiology

Liver has a principal role in glucose regulation and lipids homeostasis. It is under a complex control by substrates such as hormones, nutrients, and neuronal impulses. Insulin promotes glycogen synthesis, lipogenesis, and lipoprotein synthesis and inhibits gluconeogenesis, glycogenolysis, and VLDL secretion by modifying the expression and enzymatic activity of specific molecules. To understand the pathophysiological mechanisms leading to metabolic liver disease, we analyzed liver protein patterns expressed in a mouse model of diabetes by proteomic approaches. We used insulin receptor-knockout (IR(-/-)) and heterozygous (IR(+/-)) mice as a murine model of liver metabolic dysfunction associated with diabetic ketoacidosis and insulin resistance. We evaluated liver fatty acid levels by microscopic examination and protein expression profiles by orthogonal experimental strategies using protein 2-DE MALDI-TOF/TOF and peptic nLC-MS/MS shotgun profiling. Identified proteins were then loaded into Ingenuity Pathways Analysis to find possible molecular networks. Twenty-eight proteins identified by 2-DE analysis and 24 identified by nLC-MS/MS shotgun were differentially expressed among the three genotypes. Bioinformatic analysis revealed a central role of high-mobility group box 1/2 and huntigtin never reported before in association with metabolic and related liver disease. A different modulation of these proteins in both blood and hepatic tissue further suggests their role in these processes. These results provide new insight into pathophysiology of insulin resistance and hepatic steatosis and could be useful in identifying novel biomarkers to predict risk for diabetes and its complications

NO production in insulin-resistance conditions after sildenafil treatment.

<p>Sildenafil treatment induces NO production in insulin resistance condition (HG and Gluc-N) in HUVEC (panel A) and HAEC (panel B). Full bars represent conditions without sildenafil, dashed bars represent sildenafil treatment. Means ± S.E. (n = 6). *<i>p</i><0.05 and **<i>p</i><0.01 <i>vs</i> Ctrl; ‡ <i>p</i><0.05 and ‡‡ <i>p</i><0.01 <i>vs</i> insulin; † <i>p</i><0.05 <i>vs</i> HG; $ <i>p<</i>0.05 <i>vs</i> sildenafil; # <i>p</i><0.05 <i>vs</i> sildenafil+HG; <b>∞ </b><i>p</i><0.05 <i>vs</i> Gluc-N.</p

eNOS Ser¹¹⁷⁷ phosphorylation after sildenafil treatment.

<p>Sildenafil chronic treatment (1 µM/72 h) enhances eNOS phosphorylation in basal condition and after HG treatment, but not significantly after Gluc-N treatment. Full bars represent conditions without sildenafil, dashed bars represent sildenafil treatment. Ctrl was expressed as 100%. Means ± S.E. (n = 5). *<i>p</i><0.05 <i>vs</i> Ctrl, ‡ <i>p</i><0.05 <i>vs</i> insulin; † <i>p</i><0.05 <i>vs</i> HG; †† <i>p</i><0.05 <i>vs</i> HG + insulin.</p

Schematic summary of sildenafil action in endothelial cells.

<p>Schematic summary of sildenafil action in endothelial cells.</p