Targeting a cryptic allosteric site of SIRT6 with small-molecule inhibitors that inhibit the migration of pancreatic cancer cells

SIRT6 belongs to the conserved NAD+-dependent deacetylase superfamily and mediates multiple biological and pathological processes. Targeting SIRT6 by allosteric modulators represents a novel direction for therapeutics, which can overcome the selectivity problem caused by the structural similarity of orthosteric sites among deacetylases. Here, developing a reversed allosteric strategy AlloReverse, we identified a cryptic allosteric site, Pocket Z, which was only induced by the bi-directional allosteric signal triggered upon orthosteric binding of NAD+. Based on Pocket Z, we discovered an SIRT6 allosteric inhibitor named JYQ-42. JYQ-42 selectively targets SIRT6 among other histone deacetylases and effectively inhibits SIRT6 deacetylation, with an IC50 of 2.33 μmol/L. JYQ-42 significantly suppresses SIRT6-mediated cancer cell migration and pro-inflammatory cytokine production. JYQ-42, to our knowledge, is the most potent and selective allosteric SIRT6 inhibitor. This study provides a novel strategy for allosteric drug design and will help in the challenging development of therapeutic agents that can selectively bind SIRT6.

Mechanism of allosteric activation of SIRT6 revealed by the action of rationally designed activators

The recent discovery of activator compounds binding to an allosteric site on the NAD

Effect of intensive insulin treatment on healthcare-associated infection rate in acute stroke:A Meta-analysis / 中国感染控制杂志

Objective To evaluate effect of intensive insulin treatment(IIT)on healthcare-associated infection (HAI)rate in patients with acute stroke and stress hyperglycemia.Methods Databases,including PubMed,Em-base,Cochrane Library,WanFang,and China National Knowledge Infrastructure(CNKI)Data,were electronically searched,relevant journals and references of the included literatures were also searched manually,literatures were selected according to the uniform inclusion and exclusion criteria,incidence of HAI and mean blood glucose in patients who received IIT for acute stroke were assessed systematically.Results A total of 13 randomized controlled trials (RCT)involving 1 032 patients were included in this systematic review.Meta-analysis results showed that 10 studies involving 832 patients were finally enrolled for comparing HAI rate, HAI rates in IIT group and conventional insulin treatment group were 28.3% and 56.1 %,respectively(Z =4.50 ),difference between two groups was statistically significant (RR=0.53 [95 %CI :0.40 to 0.70],P <0.001 );A total of 328 patients in 5 studies were finally included in the comparison of blood glucose,difference in mean blood glucose between two groups was statistically significant(MD =-2.52 [95% CI :-4.30 to -0.74],P =0.006).Funnel plot of HAI rate revealed that there was publication bias.Conclusion IIT is used for the regulation of stress hyperglycemia in acute stroke,it can reduce the incidence of HAI and blood glucose in patients.

Determination of the localization of rupture aneurysms in patients with multiple cerebral aneurysms and spontaneous subarachnoid hemorrhage / 中国综合临床

Objective To discuss the reasons of false judgments of localization of the rupture aneurysms and find the way to fix this problem in patients with multiple intracranial aneurysms. Methods The clinical data of 25 consecutive patients, who presented with their first spontaneous subarachnoid hemorrhage and had multiple intracranial aneurysms from 2003 to 2009 in our hospital, were analyzed retrospectively. The rupture aneurysms were determined according to Nehls' method that reported before, and the supposed responsible rupture aneurysms w0ere clipped within 48 hours after hemorrhage in all patients. More aneurysms that could not be accessed in the same surgical session were surgically terated later. Results The location of the rupture aneurysm was verified at the time of surgery in all 25 patients. The concordance rate of the prediction and the reality of the rupture aneurysm was 80% (20/25). Four patients ( 16% ) ,in whom the ruptured aneurysm was not correctly identified,rebled after surgery,and 2 patients died as a result of the rebleeding One patients had no clear diagnosis at the end. Conclusion In the reported cases, about 80% rupture aneurysms could be correctly diagnosed before treatment according to the CT and DSA examinations. If clear diagnosis couldn't be made,additional examinations should be considered, such as CTA or MRI. Rupture aneurysms must be confirmed during the operation and the other aneurysms should be checked to exclude additional responsible aneurysms in all cases.

Clinical application of computer-aided design of composite materials with epoxide acrylate maleic and hydroxyapatite in cranioplasty / 中华创伤杂志

Objective To evaluate the effect of computer-aided design of composite materials with epoxide acrylate maleic (E) and hydroxyapatite (H) in cranioplasty. Methods A total of 45 patients with cranium defects were treated with cranioplasty by using skull bone flaps made of composite materials including epoxide acrylate maleic (E) and hydroxyapatite (H) ,which was designed with computer aid according to individual requirements. The patients were followed up for 6-36 months. Results After cranioplasty with composite EH, there occurred subcutaneous fluid in one patient and mild bone collapse in one. The composite EH showed good histocompatibility, with no infection or rejection. Conclusion During cranioplasty, use of computer-aided design of composite EH takes advantages of good accuracy, short operation time, good biocompatibility and good clinical efficiency.