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.

Study on the experience of nurses in the operating room of general hospitals / 中国实用护理杂志

Objective:To describe the experience of nurses in general hospital operating room for specialist management.Methods:A questionnaire survey was conducted among 226 operating room nurses using the questionnaire of specialist nurses' work obstruction factors. Eighteen of the operating room nurses were interviewed by phenomenological research methods in qualitative research.Results:The obstacles to the professional management of nurses in the operating room were mainly reflected in the difficulty of doing only the work of specialist nurses (96.46%,218/226), "there is no clear role positioning (93.81%, 212/226)", and "responsible for the work of several departments(89.82%, 203/226)." The refinement and analysis of the interview data showed that the management of specialist equipment could not be arranged and managed in a coordinated manner; the surgeons were over-reliant on the specialist nurses; the problem of setting up the positions of the senior nurses was outstanding; the nurses who were not the specialists have insufficient competence. With the sense of belonging; specialist nurses would have a slack situation.Conclusions:There are still many problems in the implementation of specialist management in the operating room of general hospitals. It is suggested that the rotation training of the operating room nurses should be carried out from the fixed professional group, the standardized training and the establishment of the mobile nurse database should be set up to promote the smooth implementation of the specialist management of the nurses in the operating room of the general hospital.

Interaction between human serum albumin and cholesterol-grafted polyglutamate as the potential carriers of protein drugs

Currently there is no successful platform technology for the sustained release of protein drugs. It seems inevitable to specifically develop new materials for such purpose, and hence the understanding of protein-material interactions is highly desirable. In this study, we synthesized cholesterol-grafted polyglutamate (PGA--Chol) as a hydrophobically-modified polypeptide, and thoroughly characterized its interaction with a model protein (human serum albumin) in the aqueous solution by using circular dichroism, fluorescence methods, and light scattering. With the protein concentration fixed at 5 μmol/L, adding PGA--Chol polymers into the solution resulted in continuous blue shift of the protein fluorescence (from 339 to 332 nm), until the polymer molar concentration reached the same value as the protein. In contrast, the un-modified polyglutamate polymers apparently neither affected the protein microenvironment nor formed aggregates. Based on the experimental data, we proposed a physical picture for such protein-polymer systems, where the polymer first bind with the protein in a 1:1 molar ratio a fraction of their hydrophobic pendant cholesterol resides along the polymer chain. In this protein/polymer complex, there are excess unbound cholesterol residues. As the polymer concentration increases, the polymers form multi-polymer aggregates around 200 nm in diameter the same hydrophobic cholesterol residues. The protein/polymer complex also participate in the aggregation their excess cholesterol residues, and consequently the proteins are encapsulated into the nanoparticles. The encapsulation was also found to increase the thermal stability of the model protein.