Structural optimization of a CXCR2-directed antagonist that indirectly inhibits γ-secretase and reduces Aβ

Amyloid β (Aβ), a key molecule in the pathogenesis of Alzheimer’s disease (AD), is derived from the amyloid precursor protein (APP) by sequential proteolysis via β- and γ-secretases. Because of their role in generation of Aβ, these enzymes have emerged as important therapeutic targets for AD. In the case of γ-secretase, progress has been made towards designing potent inhibitors with suitable pharmacological profiles. Direct γ-secretase inhibitors are being evaluated in clinical trials and new strategies are being explored to block γ-secretase activity indirectly as well. In this regard, we have previously reported an indirect regulation of γ-secretase through antagonism of CXCR2, a G-protein coupled receptor (GPCR). We demonstrated that N-(2-hydroxy-4-nitrophenyl)-N′-(2-bromophenyl)urea (SB225002), a selective inhibitor of CXCR2 also plays a role in an indirect inhibition of γ-secretase. Furthermore, we reported a ～5-fold difference in the selective inhibition of APP versus Notch processing via γ-secretase following treatment with SB225002. Herein we describe the synthesis and optimization of SB225002. By determination of the structure–activity relationship (SAR), we derived small molecules that inhibit Aβ40 production with IC₅₀ values in the sub-micromolar range in a cell-based assay and also validated the potential of CXCR2 as a new target for therapeutic intervention in AD.     

Polymorphisms of IL-6 174 G/C, IL-10 -592 C/A and risk of HIV/AIDS among North Indian population

A growing body of evidence suggests that host genetic factors play an important role both in susceptibility to HIV infection and progression to AIDS. The present study aimed at evaluating the role of IL-6 and IL-10 gene polymorphisms on the risk of HIV susceptibility and disease progression among North Indian patients. The polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) techniques were applied to genotype IL-6 and IL-10. 300 seropositive and an equal number of age- and sex-matched seronegative control subjects were recruited for this study. There was statistically no significant variation in the frequencies of IL-6 and IL-10 genotypes among cases and controls. However, statistically non-significant association for risk of rapid disease progression was observed due to the combined effect of the IL-6 homozygous CC genotype and CC of IL-10, OR = 1.62, 95% CI = 0.38–6.91. Therefore, combined effects of the CC of IL-6 and CC of IL-10 might reduce the hosts ability to hinder viral replication after infection.     

Significance of Tumor Necrosis factor α-308 (G/A) gene polymorphism in the development of prostate cancer

Prostate cancer (PCa) is the most common noncutaneous cancer among men, accounting for 10?% of male cancer-related deaths worldwide. The etiology of PCa is largely unknown, although multiple environmental and lifestyle factors such as ultraviolet irradiation, smoking, and diet might increase the risk of the disease. Risk of disease varies most prominently with age, ethnicity, family history, and diet. The multifunctional cytokine tumor necrosis factor alpha (TNF-α) has an important role in the pathogenesis of inflammatory, autoimmune and malignant diseases. In this case control study 150 Prostate cancer patients and 150 age matched benign prostate hyperplasia (BPH) and equal number of healthy control groups were involved. The aim of this study was to analyze the effect of TNF-α-308 (G/A) polymorphism on risk of prostate cancer on north Indian prostate cancer patients. The polymerase chain reaction (PCR) technique was utilized to genotype TNF-α-308 (G/A) polymorphism. The present study showed statistically significant increased risk of prostate cancer among individuals that carried the A allele of TNF-α-308 gene (OR?=?1.81, 95?% CI 1.00–3.481, p?=?0.03).     

Seasonal and life‐phase related differences in growth in Scarus ferrugineus on a southern Red Sea fringing reef

Temporal trends in growth of the rusty parrotfish Scarus ferrugineus were studied on a southern Red Sea fringing reef that experiences seasonal changes in environmental conditions and benthic algal resources. Length increment data from tagging and recapture were compared among periods and sexes and modelled using GROTAG, a von Bertalanffy growth model. The growth pattern of S. ferrugineus was highly seasonal with a maximum occurring between April and June and a minimum between December and March. Body condition followed the seasonal variation in growth, increasing from April to June and decreasing from December to March. The season of maximum growth coincided with high irradiation, temperature increases and peak abundance of the primary food source, the epilithic algal community. There was a decline in growth rate during summer (July to October) associated with a combination of extreme temperatures and lowered food availability. There were strong sexual size dimorphism (SSD) and life‐history traits. Terminal‐phase (TP) males achieved larger asymptotic lengths than initial‐phase individuals (IP) (L_∞ 34·55 v. 25·12 cm) with growth coefficients (K) of 0·26 and 0·38. The TPs were growing four times as fast as IPs of similar size. Three individuals changed from IP to TP while at liberty and grew eight times faster than IPs of similar size, suggesting that sex change in S. ferrugineus is accompanied by a surge in growth rate. The SSD in S. ferrugineus thus coincided with fast growth that started during sex change and continued into the TP. Faster growth during sex change suggests that the cost associated with sex change is limited.