Bindings of PPARγ ligand-binding domain with 5-cholesten-3β, 25-diol, 3-sulfate: accurate prediction by molecular simulation

Abstract

Peroxisome proliferator-activated receptor gamma (PPAR_γ) has recently been identified as an attractive target for atherosclerosis intervention. Given potential relevance of 5-cholesten-3β, 25-diol, 3-sulphate (CHOS) and PPAR_γ, an integrated docking method was used to study their interaction mechanisms, with the full considerations to distinct CHOS conformations and dynamic ensembles of PPAR_γ ligand-binding domain (PPAR_γ-LBD). The results revealed that this novel platform is satisfactory to the accurate determination of binding profiles, and the binding pattern of CHOS is rather similar as those of current PPAR_γ full/partial agonists. CHOS contributes to the stabilization of the AF2 and β-sheet surfaces of PPAR_γ-LBD and promotes the configuration adjustment of Ω loop, in order to inhibit the Cdk5-mediated PPAR_γ phosphorylation. Nonetheless, there are clear differences in term of occupation of full or partial agonist-like binding models. The energetic and geometric analyses further revealed that CHOS may be fond of partial agonist-like binding, and its sulfonic group and carbon skeleton are helpful for the binding process. We hope that the results will aid our understanding of recognitions involving CHOS with PPAR_γ-LBD and warrant the further aspects to pharmacological experiments.

Communicated by Ramaswamy H. Sarma     

Structure-based methoxyflavone derivatives with potent inhibitory activity against various influenza neuraminidases

Communicated by Ramaswamy H. Sarma     

Baicalin suppresses the cell cycle progression and proliferation of prostate cancer cells through the CDK6/FOXM1 axis

Molecular and Cellular Biochemistry - Population data have consistently demonstrated a correlation between circulating branched-chain amino acids (BCAA) and insulin resistance. Most recently valine...     

Activation of PPAR-β/δ Attenuates Brain Injury by Suppressing Inflammation and Apoptosis in a Collagenase-Induced Intracerebral Hemorrhage Mouse Model

Neurochemical Research - Brain injury has been proposed as the major cause of the poor outcomes associated with intracerebral hemorrhage (ICH). Emerging evidence indicates that the nuclear...     

Integrated Bioinformatics Analysis for the Identification of Key Molecules and Pathways in the Hippocampus of Rats After Traumatic Brain Injury

Neurochemical Research - High-throughput and bioinformatics technology have been broadly applied to demonstrate the key molecules involved in traumatic brain injury (TBI), while no study has...     

C-reactive protein reduces protein S-nitrosylation in endothelial cells

Glycodelin A (GdA) is a dimeric glycoprotein synthesized by the human endometrium under progesterone regulation. Based on the high sequence similarity with β-lactoglobulin, it is placed under the lipocalin superfamily. The protein is one of the local immunomodulators present at the feto-maternal interface which affects both the innate as well as the acquired arms of the immune system, thereby bringing about successful establishment and progression of pregnancy. Our previous studies revealed that the domain responsible for the immunosuppressive activity of glycodelin lies on its protein backbone and the glycans modulate the same. This study attempts to further delineate the apoptosis inducing region of GdA. Our results demonstrate that the stretch of amino acid sequence between Met24 to Leu105 is necessary and sufficient to inhibit proliferation of T cells and induce apoptosis in them. Further, within this region the key residues involved in harboring the activity were shown to be present between Asp52 and Ser65.     

Immune responses induced in HHD mice by multiepitope HIV vaccine based on cryptic epitope modification

CD8+ T cells play an important role in early HIV infection. However, HIV has the capacity to avoid specific CTL responses due to a high rate of mutation under selection pressure. Although the HIV proteins, gag and pol, are relatively conserved, these sequences generate low-affinity MHC-associated epitopes that are poorly immunogenic. Here, we applied an approach that enhanced the immunogenicity of low-affinity HLA-A2.1-binding peptides. The first position with tyrosine (P1Y) substitution enhanced the affinity of HLA-A2.1-associated peptides without altering their antigenic specificity. More importantly, P1Y variants efficiently stimulated in vivo native peptide-specific CTL that also recognized the corresponding naturally processed epitope. The potential to generate CTL against any low-affinity HLA-A2.1-associated peptide provides us with the necessary technique for identification of virus cryptic epitopes for development of peptide-based immunotherapy. Therefore, identification and modification of the cryptic epitopes of gal and pol provides promising candidates for HIV immunotherapy dependent upon efficient presentation by virus cells. Furthermore, this may be a breakthrough that overcomes the obstacle of immune escape caused by high rates of mutation. In this study, bioinformatics analysis was used to predict six low-affinity cryptic HIV gag and pol epitopes presented by HLA-A*0201. A HIV compound multi-CTL epitope gene was constructed comprising the gene encoding the modified cryptic epitope and the HIV p24 antigen, which induced a strong CD8+ T cell immune response regardless of the mutation. This approach represents a novel strategy for the development of safe and effective HIV prophylactic and therapeutic vaccines.     

The Cdx-2 polymorphism in the VDR gene is associated with increased risk of cancer: a meta-analysis

The Cdx-2 polymorphism in VDR gene has been extensively investigated for association with cancer risk, however, results of different studies have been inconsistent. The objective of this study is to assess the relationship of the Cdx-2 polymorphism in VDR and cancer risk by meta-analysis. All eligible case–control studies were searched in Pubmed, Embase, CNKI and Wanfang databases. Odds ratios (OR) with the 95 % confidence intervals (CI) were used to assess the association. A total of 12,906 cases and 13,700 controls in 18 case–control studies were included. The results indicated that the AA homozygote carriers had a 16 % increased risk of cancer, when compared with the homozygote GG and heterozygote AG (OR = 1.16, 95 % CI 1.05–1.29 for AA vs. GG+AG). In the subgroup analysis by ethnicity, significant elevated risks were associated with AA homozygote carriers in Caucasians (OR = 1.16, 95 % CI 1.01–1.33, and P = 0.04) and African Americans (OR = 1.31, 95 % CI 1.07–1.61, and P = 0.01). In the subgroup analysis by cancer types, the polymorphism was associated with increased risk of breast cancer (OR = 1.23, 95 % CI 1.04–1.46, and P = 0.02). This meta-analysis suggested that the Cdx-2 polymorphism of VDR gene would be a risk factor for cancer. To further evaluate gene-to-gene and gene-to-environmental interactions between polymorphisms of VDR gene and cancer risk, more studies with large groups of patients are required.