Background and Aim: Helicobacter pylori (H. pylori) infection has been known to influence the gastric leptin and ghrelin secretion, for which the exact pathogenic role has not been documented yet. ...This study was designed to investigate the influence of H. pylori eradication on plasma or gastric levels of ghrelin, body mass index (BMI), and resultant levels of appetite in patients with peptic ulcer disease.
Methods: Twenty‐two patients with H. pylori‐associated active duodenal or gastric ulcer were treated with 7 weeks of antisecretory medication followed with 7 days of eradication regimen. The plasma and tissue ghrelin levels, tumor necrosis factor‐alpha (TNF‐α) mRNA, BMI, and appetite scale were checked before and after treatment. An additional endoscopic examination was conducted in 10 patients taking both ulcer treatment and H. pylori eradication.
Results: Gastric ghrelin mRNA expression was significantly increased after either ulcer healing or H. pylori eradication, whereas gastric TNF‐α mRNA expression was decreased after ulcer treatment and H. pylori eradication. In parallel with these changes, the visual analog scales for hunger and prospective food consumption were significantly increased after ulcer healing and H. pylori eradication. An increase in BMI was not statistically related to ulcer healing and H. pylori eradication therapy. In the subgroup analysis of 10 patients performed with additional endoscopic examination, ulcer treatment was associated with increased plasma ghrelin level and tissue ghrelin expression irrelevant to H. pylori eradication.
Conclusion: Restored tissue levels of ghrelin and improved status of appetite was achieved with gastric ulcer healing and H. pylori eradication.
A 60-year-old woman with end stage liver cirrhosis caused by genotype 2 hepatitis C virus (HCV) infection received an orthotopic liver transplantation (OLT). The patient was negative for the ...hepatitis B surface antigen (HBsAg) and positive for the anti-hepatitis B surface antibody (anti-HBs) prior to and one and a half months following the OLT. Due to reactivation of hepatitis C, treatment with interferon-alpha and Ribavirin started two months following the OLT and resulted in a sustained virological response. We performed a liver biopsy because a biochemical response was not achieved. Surprisingly, liver pathology showed HBsAg-positive hepatocytes with a lobular hepatitis feature, which had been negative in the liver biopsy specimen obtained one and a half months post-OLT. High titers of both HBsAg and HBeAg were detected, while anti-HBs antibodies were not found. Tests for IgM anti-hepatitis B core antibody and anti-delta virus antibodies were negative. The serum HBV DNA titer was over 1×10(7) copies/mL. A sequencing analysis showed no mutation in the "a" determinant region, but revealed a mixture of wild and mutant strains at an overlapping region of the S and P genes (S codon 213 (Leu/Ile); P codons 221 (Phe/Tyr) and 222 (Ala/Thr)). These findings suggest that de novo hepatitis B can develop in patients with HCV infection during the post-OLT period despite the presence of protective anti-HBs.
Recently, dual-specificity phosphatase 16 (DUSP16) emerged as a promising therapeutic target protein for the development of anti-atherosclerosis and anticancer medicines. The present study was ...undertaken to identify the novel inhibitors of DUSP16 based on the structure-based virtual screening. We have been able to find seven novel inhibitors of DUSP16 through the drug design protocol involving homology modeling of the target protein, docking simulations between DUSP16 and its putative inhibitors with the modified scoring function, and in vitro enzyme assay. These inhibitors revealed good potency, with IC50 values ranging from 1 to 22 µM, and they were also screened computationally for having desirable physicochemical properties as drug candidates. Therefore, they deserve consideration for further development by structure-activity relationship studies to optimize the inhibitory activity against DUSP16. Structural features relevant to the stabilization of the newly identified inhibitors in the active site of DUSP16 are addressed in detail.
Dual‐specificity protein phosphatases (DUSPs), which dephosphorylate both phosphoserine/threonine and phosphotyrosine, play vital roles in immune activation, brain function and cell‐growth ...signalling. A family‐wide structural library of human DUSPs was constructed based on experimental structure determination supplemented with homology modelling. The catalytic domain of each individual DUSP has characteristic features in the active site and in surface‐charge distribution, indicating substrate‐interaction specificity. The active‐site loop‐to‐strand switch occurs in a subtype‐specific manner, indicating that the switch process is necessary for characteristic substrate interactions in the corresponding DUSPs. A comprehensive analysis of the activity–inhibition profile and active‐site geometry of DUSPs revealed a novel role of the active‐pocket structure in the substrate specificity of DUSPs. A structure‐based analysis of redox responses indicated that the additional cysteine residues are important for the protection of enzyme activity. The family‐wide structures of DUSPs form a basis for the understanding of phosphorylation‐mediated signal transduction and the development of therapeutics.
We have identified eight novel inhibitors of SSH1 phosphatase based on the virtual screening with the homology-modeled protein structure. Display omitted
► We performed the virtual screening of SSH1 ...phosphatase inhibitors with docking simulations using the homology-modeled protein structure. ► Eight new inhibitors of SSH1 phosphatase were identified with IC50 values ranging from 2.8 to 12.7μM. ► Potent inhibitors were found to be capable of simultaneously establishing the strong multiple hydrogen bonds and hydrophobic interactions in the active site.
Although slingshot phosphatase 1 (SSH1) proved to be a promising target for the development of therapeutics for the treatment of vascular diseases and cancers, no small-molecule inhibitor has been reported so far. We have been able to identify eight novel inhibitors of SSH1 through the computer-aided drug design protocol involving homology modeling of SSH1 structure, virtual screening of a large chemical library with docking simulations, and in vitro enzyme assays. The identified inhibitors revealed high potencies with the associated IC50 values ranging from 2.8 to 12.7μM and were also screened for having desirable physicochemical properties as a drug candidate. Therefore, they deserve consideration for further development by structure–activity relationship studies to optimize the inhibitory activities. Structural features relevant to the stabilization of the inhibitors in the active site of SSH1 are discussed in detail.
VH1-like phosphatase Z (VHZ) has proved to be a promising target for the development of therapeutics for the treatment of human cancers. Here, we report the first example for a successful application ...of structure-based virtual screening to identify the novel small-molecule inhibitors of VHZ. These inhibitors revealed high potencies with the associated IC(50) values ranging from 3 to 20 µM and were also screened for having desirable physicochemical properties as a drug candidate. Therefore, they deserve consideration for further development by structure-activity relationship studies to optimize inhibitory and anticancer activities. Structural features relevant to the stabilization of the newly identified inhibitors in the active site of VHZ are discussed in detail.
PDF
