Understanding the molecular principles that govern allosteric communication is an important goal in protein science. One way allostery could be transmitted is via sparse energetic networks of residues, and one such evolutionary conserved network was identified in the PDZ domain family of proteins by multiple sequence alignment [Lockless SW, Ranganathan R (1999) Science 286:295-299]. We have reassessed the energetic coupling of these residues by double mutant cycles together with ligand binding and stability experiments and found that coupling is not a special property of the coevolved network of residues in PDZ domains. The observed coupling for ligand binding is better explained by a distance relationship, where residues close in space are more likely to couple than distal residues. Our study demonstrates that statistical coupling from sequence analysis is not necessarily a reporter of energetic coupling and allostery.allostery ͉ coupling energy ͉ dynamics ͉ energetic network of residues ͉ PDZ domain P redicting allosteric mechanisms from protein sequence is an important goal, yet very difficult because the molecular basis for allostery in proteins is still not fully understood. Allosteric regulation is the alteration of protein function through the binding of an effector molecule elsewhere within the same protein. This definition can be expanded to include amino acid point mutations distal from the active site that can effectively alter protein function (1). Allosteric regulation is well established in multidomain proteins (2, 3), but allosteric behavior in single protein domains is less documented (for example, ref. 4), and its mechanisms unclear. Nevertheless, the idea of allostery without a (well defined) conformational change (5) has become popular, and it has even been proposed that all dynamic proteins are allosteric (6).Lockless and Ranganathan (7) set out to investigate whether allostery could be predicted from sequence conservation. They found a coevolved network of residues in the PDZ domain family of proteins, and these statistically coupled residues were confirmed by experiments on PSD95 PDZ3 to be energetically coupled (7). This study has served as a classic example of allostery in a single protein domain, with a ''sparse network'' of energetically linked positions that could affect function, in this case ligand binding. However, pathways of energetic connectivity inferred from statistical analysis have been questioned because the correlated mutation algorithm that was used finds pairs of residues that are close in physical space in the protein structure and it is therefore not surprising that the residues actually do couple (8). Furthermore, other issues regarding the validity of the statistical method used by Lockless and Ranganathan have been raised: the algorithm used is not symmetric (9), does not incorporate evolutionary noise (10), and performs less well than other algorithms (8,9,11). From an experimental point of view, previous work on PSD95 PDZ3 in our laboratory suggested that this PDZ ...
Objectives. Electroacupuncture (EA), an extension of acupuncture, which is based on traditional acupuncture combined with modern electrotherapy, is commonly used for poststroke dysphagia (PSD) in clinical treatment and research. However, there is still a lack of sufficient evidence to recommend the routine use of EA for PSD. The aim of this study was to assess the efficacy and safety of EA in the treatment of PSD. Methods. Randomized controlled trials (RCTs) evaluating the effects of EA on PSD were identified through a comprehensive literature search of the PubMed, Embase, Cochrane Library, Web of Science, Chinese National Knowledge Infrastructure, Chinese Biomedical Database, and VIP databases from their inception to July 2020. The quality assessment of the included trials was performed based on the guidance of the Cochrane Reviewers’ Handbook, and meta-analysis (MA) was performed by using the RevMan 5.3 software. Results. Sixteen trials were identified, and these included 1,216 patients with PSD. The results demonstrated that EA in combination with swallowing rehabilitation training (SRT) was significantly superior to SRT alone with regard to effective rate (OR 5.40, 95% CI [3.78, 7.72], P<0.00001, water swallow test (WST) (MD −0.78, 95% CI [−1.07, −0.50], P<0.00001), the video fluoroscopic swallowing study (VFSS) (MD 1.47, 95% CI [1.11, 1.84], P<0.00001), the Ichiro Fujishima Rating Scale (IFRS) (MD 1.94, 95% CI [1.67, 2.22], P<0.00001), and the incidence of aspiration pneumonia (IAP) (OR 0.20, 95% CI [0.06, 0.61], P=0.005). Conclusions. The results showed that EA was better than the control treatment in terms of the effective rate, WST, VFSS, IFRS, and IAP of dysphagia after stroke. Strict evaluation standards and high-quality RCT designs are necessary for further exploration.
BackgroundCurcumin is a major constituent of rhizomes of Curcuma longa that elicits beneficial effects for oxidative damage. The aim of this study was to investigate whether curcumin could attenuate hydrogen peroxide (H2O2)-induced apoptosis in H9c2 cardiomyoblasts and the underlying mechanisms.ResultsThe present study showed that exposure of H9c2 cells to H2O2 caused a significant increase in apoptosis as evaluated by flow cytometry analysis and the pretreatment of curcumin protected against H2O2-induced apoptosis. Exposure of cells with curcumin caused a dose-dependent induction of heme oxygenase-1 (HO-1) protein expression. Curcumin also decreased the cleaved caspase-3 (CC3) protein expression level and increased the Bcl-2/Bax ratio in H2O2-stimulated H9c2 cells. ZnPP-IX, a HO-1 inhibitor, partly reversed the anti-apoptotic effect of curcumin. Further, LY294002, an inhibitor of PI3K, partially reversed the effect of curcumin on HO-1 protein induction, leading to the attenuation of curcumin-mediated apoptosis resistance.ConclusionThese results demonstrated that the anti-apoptotic function of curcumin required the upregulation of HO-1 protein through the PI3K/Akt signaling pathway. Curcumin might be used as a preventive and therapeutic agent for treatment of cardiovascular diseases associated with oxidative stress.
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