The association of Human Leukocyte Antigens Complex with Type 1 Diabetes in Omanis

Background: Identifying the human leukocyte antigens (HLA) high risk alleles, genotypes and haplotypes in different populations is beneficial for understanding their roles in type 1 diabetes (T1D) pathogenesis and intervention practices. Objective: The aim of this study was to identify T1D associated HLA gene alleles in the Omani population. Methods: Our case-control study included 73 diabetic seropositive children (mean age 9.08±3.27 years) and 110 healthy controls. HLA–A, -B, -C, -DRB1, and -DQB1 genes were genotyped using sequence specific primer polymerase chain reaction (SSP-PCR). Results: Two HLA class I alleles (B*08, B*58) and three class II alleles (DQB1*02, DRB1*03 and DRB1*04) were associated with T1D susceptibility, while one class I (B*51) and three class II (DQB1*05, DQB1*06, and DRB1*16) alleles were associated with T1D protection. HLA- DRB1*03 and DQB1*02 alleles showed the strongest risk association among all alleles. Six DRB1 residues (E9, S11, S13, Y30, V70 and K71) were significantly associated with T1D susceptibility. Heterozygous genotypes, HLA-DRB1*03/*04 and DQB1*02/*03 were significantly associated with T1D susceptibility (P=4.29E-07, OR=63.2 and P=0.02, OR=3.6, respectively). Furthermore, we detected a significant combined action of DRB1*03-DQB1*02 haplotype in T1D risk (P=1.76E-05, OR=15), and DRB1*16-DQB1*05 haplotype in protection (P=3.12E-2, OR=0.48). Conclusion: Known HLA class II gene alleles are associated with T1D in Omani children

A new class of glycomimetic drugs to prevent free fatty acid-induced endothelial dysfunction

Background: Carbohydrates play a major role in cell signaling in many biological processes. We have developed a set of glycomimetic drugs that mimic the structure of carbohydrates and represent a novel source of therapeutics for endothelial dysfunction, a key initiating factor in cardiovascular complications. Purpose: Our objective was to determine the protective effects of small molecule glycomimetics against free fatty acid­induced endothelial dysfunction, focusing on nitric oxide (NO) and oxidative stress pathways. Methods: Four glycomimetics were synthesized by the stepwise transformation of 2,5­dihydroxybenzoic acid to a range of 2,5­substituted benzoic acid derivatives, incorporating the key sulfate groups to mimic the interactions of heparan sulfate. Endothelial function was assessed using acetylcholine­induced, endotheliumdependent relaxation in mouse thoracic aortic rings using wire myography. Human umbilical vein endothelial cell (HUVEC) behavior was evaluated in the presence or absence of the free fatty acid, palmitate, with or without glycomimetics (1µM). DAF­2 and H2DCF­DA assays were used to determine nitric oxide (NO) and reactive oxygen species (ROS) production, respectively. Lipid peroxidation colorimetric and antioxidant enzyme activity assays were also carried out. RT­PCR and western blotting were utilized to measure Akt, eNOS, Nrf­2, NQO­1 and HO­1 expression. Results: Ex vivo endothelium­dependent relaxation was significantly improved by the glycomimetics under palmitate­induced oxidative stress. In vitro studies showed that the glycomimetics protected HUVECs against the palmitate­induced oxidative stress and enhanced NO production. We demonstrate that the protective effects of pre­incubation with glycomimetics occurred via upregulation of Akt/eNOS signaling, activation of the Nrf2/ARE pathway, and suppression of ROS­induced lipid peroxidation. Conclusion: We have developed a novel set of small molecule glycomimetics that protect against free fatty acidinduced endothelial dysfunction and thus, represent a new category of therapeutic drugs to target endothelial damage, the first line of defense against cardiovascular disease

Single-chain technology using discrete synthetic macromolecules

International audienc