Novel acetamide derivatives of 2-aminobenzimidazole prevent inflammatory arthritis in rats via suppression of pro-inflammatory mediators.

Benzimidazole ring system is an important pharmacophore with diverse pharmacological activities. In this study, we explored the anti-arthritic effects of newly synthesized acetamide derivatives of 2-aminobenzimidazole (N1 and N2) in rats. FTIR and NMR spectroscopies were used to characterize these compounds. Carrageenan (CRG) induced paw edema model was used to test the acute anti-inflammatory activity of various doses (10, 20 and 30 mg/kg) of N1 and N2 compounds. Based on acute anti-inflammatory effects, the most potent dose of each compound was selected and investigated in complete freund's adjuvant (CFA) induced inflammatory arthritis (RA) model (n = 4 in each group). Histopathological, hematological, radiographic, and RT-qPCR analyses were performed to assess the progression or resolution of inflammatory arthritis. The tested compounds produced a dose-dependent anti-inflammatory activity against CRG induced paw inflammation and similarly reduced edema in CFA induced inflammatory arthritis model. Histopathological and X-ray analyses of ankle joints revealed minimal inflammation and normal joint structures in N1 and N2 treated groups. The tested compounds also reduced the levels of autoantibodies and restored hematological parameters. Interestingly, the tested compounds did not elevate aspartate aminotransferase and alanine transaminase levels and displayed a better safety profile than methotrexate. N1 and N2 compounds also attenuated the transcript levels of IRAK1, NF-kB1, TNF-α, IL-1ß, IL17 and MMP1. In addition, N1 displayed a greater inhibition of mRNA levels of COX1, COX2, mPGES1 and PTGDS as compared to N2. Our findings demonstrate that N1 and N2 compounds possess strong anti-arthritic activity which can be attributed to the suppression of pro-inflammatory mediators.

Associations of transcription factor 7-Like 2 (TCF7L2) gene polymorphism in patients of type 2 diabetes mellitus from Khyber Pakhtunkhwa population of Pakistan.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is the most prevalent component of metabolic syndrome. Environmental factors and various complex genes like transcription factor 7-like 2 (TCF7L2) gene have involved in the disease development. OBJECTIVE: To determine TCF7L2 genetic association (rs7903146C/T and rs12255372G/T) in T2DM patients of Khyber Pakhtunkhwa population of Pakistan. SUBJECTS AND METHODS: This study comprised of 176 subjects including 118 T2DM patients and 58 healthy controls. Genomic DNA was extracted and genotype of common variants (rs7903146 C/T and rs12255372 G/T) was carried out by amplification-refractory mutation system (ARMS)-PCR of sequence specific oligonucleotides. RESULTS: The distribution of genotype of TCF7L2 SNPs (rs7903146 C/T and rs12255372 G/T) was significantly associated with T2DM as compared to the controls (p <0.0001). The genetic models of the rs7903146 (C/T) and rs12255372 (G/T) SNPs were significantly associated between cases and controls (p <0.0001). On the other hand, the significant association was observed between the two SNPs and different biochemical parameters like serum fasting glucose, lipid profile, creatinine and blood HbA1c levels (p <0.05). CONCLUSION: It is concluded that the SNPs of the TCF7L2 gene are significantly associated with T2DM disease susceptibility in the population of Khyber Pakhtunkhwa of Pakistan.

Genetic association of insulin receptor substrate-1 (IRS-1, rs1801278) gene with insulin resistant of type 2 diabetes mellitus in a Pakistani population.

Insulin resistance (IR), a pathological condition of type 2 diabetes mellitus (T2DM) is characterized by an inability of body's tissue to respond the secreted or administered insulin, a necessary step for cellular glucose transportation. The prevalence of insulin resistance progresses with age, especially in overweight people with central obesity. Insulin receptor substrates (IRS) are important molecular proteins in the insulin signalling pathway, where IRS-1 plays a key function in cells insulin sensitivity. The common mutation (rs1801278; r.2963G > A: Gly972Arg) of the IRS-1 gene occurs when residue glycine changes to arginine at codon 972. The objective of this study was to detect the genetic association of rs1801278 polymorphism of the IRS-1 gene with insulin resistance in type 2 diabetes from the Lahore region of Pakistan. A total of 322 subjects (161 cases and 161 healthy individuals) were included. DNA was isolated for detection of the genotype distribution and allele frequencies by PCR-RFLP. The results showed a significant difference in the genotype distribution and allele frequency between the T2DM cases and controls for single nucleotide polymorphism (SNP) rs1801278 (OR 17.61, 95% CI 8.06-38.4, p < 0.001). In conclusion, association between rs1801278 polymorphism of the IRS-1 gene and insulin resistance in T2DM has been established in a Pakistani population.

Association of genetic polymorphism of PC-1 gene (rs1044498 Lys121Gln) with insulin-resistant type 2 diabetes mellitus in Punjabi Population of Pakistan.

BACKGROUND: Insulin resistance (IR), known to reduce the response to insulin action, develops with obesity leading to type 2 diabetes mellitus (T2DM). The PC-1 gene has been associated with dyslipidemia, polycystic ovarian disease and T2DM in different regions of the world. The objective of the present study was to investigate the genetic association of PC-1 rs1044498 polymorphism with insulin resistance in type 2 diabetes in the Punjabi population of Pakistan. METHODS: This study was carried out on 161 healthy controls and 161 patients of T2DM with insulin resistance. Whole blood was collected for DNA extraction and molecular studies. PCR-RFLP with AvaII was performed to determine the genotype in cases and controls. Chi-square and Hardy Weinberg analyses were carried out. Statistical analysis was performed by SPSS software. RESULTS: The demographic data of cases and controls showed significant differences for different parameters like glucose, insulin, Homeostatic model assessment-insulin resistance (HOMA-IR) and lipid profiles (p < 0.000). Different statistical models revealed that all the dominant models were found associated in between alleles for disease risk (p < 0.001) while no association of PC-1 rs1044498 (K121Q) polymorphism was found with insulin-resistant parameters in T2DM cases. CONCLUSION: Overall, the results indicate that the K121Q polymorphism was not found associated with insulin resistance in type 2 diabetes in a Pakistani Punjabi population. This is the first-ever report about the genotype of PC-1 gene in this population.