Synthesis and antihypertensive activity of novel 3-benzyl-2-substituted-3H-[1,2,4]triazolo[5,1-b]quinazolin-9-ones

A series of 3-benzyl-2-substituted-3H-[1,2,4]triazolo[5,1-b]quinazolin-9-ones have been synthesized by the cyclocondensation of 3-amino-2-benzylamino-3H-quinazolin-4-one with a variety of one-carbon donors. The starting material 3-amino-2-benzylamino-3H-quinazolin-4-one was synthesized from methyl anthranilate by a novel innovative route. The title compounds were evaluated for their in vivo antihypertensive activity using spontaneously hypertensive rats (SHR). While all the test compounds exhibited significant antihypertensive activity, 3-benzyl-2-methyl-3H-[1,2,4]triazolo[5,1-b] quinazolin-9-one exhibited antihypertensive activity more than the reference standard prazocin.     

Alzheimer's disease care and management: role of information technology

Alzheimer's disease (AD) an ailment that is supposed to affect people in old age. There are evidences that it might affect others also. The number of elders is increasing as the average life expectancy is increasing. AD afflicts its patients with the dementia and AD might increase in malignance over time. People with cognitive disabilities can be overwhelmed through cognitive prosthetics. With the help of information technology we can enhance the quality of life. Significant achievements are possible with an interdisciplinary approach that includes genomic, genetic, technological and therapeutic measures. The combination and coordination of Bioinformatics facilitates generation of various diagnostic tools for the people who are suffering from Alzheimer's disease. These tools help the care providers also. In this article, we emphasize the literature regarding the use of technology and its methodologies to improve the quality of care for the people with Alzheimer's disease.     

Induction of superficial zone protein (SZP)/lubricin/PRG 4 in muscle-derived mesenchymal stem/progenitor cells by transforming growth factor-β1 and bone morphogenetic protein-7

Introduction

Articular cartilage (AC) is an avascular tissue with precise polarity and organization. The three distinct zones are: surface, middle and deep. The production and accumulation of the superficial zone protein (SZP), also known as lubricin, by the surface zone is a characteristic feature of AC. To date, there is a wealth of evidence showing differentiation of AC from mesenchymal stem cells. Most studies that described chondrogenic differentiation did not focus on AC with characteristic surface marker SZP/lubricin. The present investigation was initiated to determine the induction of SZP/lubricin in skeletal muscle-derived mesenchymal stem/progenitor cells (MDMSCs) by transforming growth factor-β1 (TGF-β1) and bone morphogenetic protein-7 (BMP-7).

Methods

MDMSCs were cultured as a monolayer at a density of 1 × 10⁵ cells/well in 12-well tissue culture plates. Cell cultures were treated for 3, 7 and 10 days with TGF-β1 and BMP-7. The medium was analyzed for SZP. The cells were used to isolate RNA for RT-PCR assays for SZP expression.

Results

The SZP/lubricin increased in a time-dependent manner on Days 3, 7 and 10 in the medium. As early as Day 3, there was a three-fold increase in response to 3 ng/ml of TGF-β1 and 300 ng/ml of BMP-7. This was confirmed by immunochemical localization of SZP as early as Day 3 after treatment with TGF-β1. The expression of SZP mRNA was enhanced by TGF-β1.

Conclusions

The present investigation demonstrated the efficient and reproducible induction of SZP/lubricin accumulation by TGF-β1 and BMP-7 in skeletal MDMSCs. Optimization of the experimental conditions may permit the utility of MDMSCs in generating surface zone-like cells with phenotypic markers of AC and, therefore, constitute a promising cell source for tissue engineering approaches of superficial zone cartilage.     

Porphyromonas gingivalis regulates the RANKL-OPG system in bone marrow stromal cells

Porphyromonas gingivalis is a Gram-negative anaerobe implicated in chronic periodontitis, a bacterial-induced inflammatory condition that causes destruction of the periodontal connective tissues and underlying alveolar bone. The receptor activator of nuclear factor-kappaB ligand (RANKL) is a cytokine that directly stimulates osteoclastogenesis and bone resorption, whereas its decoy receptor osteoprotegerin (OPG) blocks this action. This study aimed to investigate the effects of P. gingivalis culture supernatants on RANKL and OPG expression in W20-17 bone marrow stromal cells, and evaluate the involvement of its virulence factors, particularly gingipains and lipopolysaccharide. P. gingivalis up-regulated RANKL and down-regulated OPG mRNA expression and protein production. These effects were blocked by indomethacin, suggesting mediation by prostaglandins. Furthermore, P gingivalis induced the production of prostaglandin E(2). Heat-inactivation, or chemical inhibition of P. gingivalis gingipains did not affect RANKL and OPG regulation. However, lipopolysaccharide depletion by polymyxin B abolished RANKL induction, and partly rescued the suppression of OPG. In conclusion, P. gingivalis regulates the RANKL-OPG system via prostaglandin E(2) in bone marrow stromal cells, in a manner that favours osteoclastogenesis. A non-proteolytic and non-proteinaceous P. gingivalis component is involved in these events, most probably its lipopolysaccharide. This activity may contribute to the bone loss characteristic of periodontitis.     

A comprehensive analysis of the naturally occurring polymorphisms in HIV-1 Vpr: Potential impact on CTL epitopes

In this report we test the hypothesis that long-term virus-induced alterations in CYP occur from changes initiated by the virus that may not be related to the immune response. Enzyme activity, protein expression and mRNA of CYP3A2, a correlate of human CYP3A4, and CYP2C11, responsive to inflammatory mediators, were assessed 0.25, 1, 4, and 14 days after administration of several different recombinant adenoviruses at a dose of 5.7 × 10¹² virus particles (vp)/kg to male Sprague Dawley rats. Wild type adenovirus, containing all viral genes, suppressed CYP3A2 and 2C11 activity by 37% and 39%, respectively within six hours. Levels fell to 67% (CYP3A2) and 79% (CYP2C11) of control by 14 days (p ≤ 0.01). Helper-dependent adenovirus, with all viral genes removed, suppressed CYP3A2 (43%) and CYP2C11 (55%) within six hours. CYP3A2 remained significantly suppressed (47%, 14 days, p ≤ 0.01) while CYP2C11 returned to baseline at this time. CYP3A2 and 2C11 were reduced by 45 and 42% respectively 6 hours after treatment with PEGylated adenovirus, which has a low immunological profile (p ≤ 0.05). CYP3A2 remained suppressed (34%, p ≤ 0.05) for 14 days while CYP2C11 recovered. Inactivated virus suppressed CYP3A2 activity by 25–50% for 14 days (p ≤ 0.05). CYP2C11 was affected similar manner but recovered by day 14. Microarray and in vitro studies suggest that changes in cellular signaling pathways initiated early in virus infection contribute to changes in CYP.     

Genetic studies on Gadaba: a tribal population of Andhra Pradesh, India.

Blood samples were collected from Gadaba, a tribal population of Andhra Pradesh, South India, in order to examine the distribution of blood groups, red cell enzymes and the gammaglobulin polymorphism. Out of 20 genetic markers studied seven protein loci exhibited monomorphism. Surprisingly a case of a rare homozygous variant and twenty-one heterozygous variants at the phosphogluconate dehydrogenase locus (6-PGD), six variants at the phosphohexose isomerase locus (PHI) and a single case of phosphoglucomutase locus 1 (PGM 1) variant were observed. Further, the tribal populations of South India reveal higher frequencies of rare variants than the caste populations. However, the presence of rare variants that are phenotypically neutral may be plausibly due to their high selective value.     

Comparison of two populations of Pseudophilothrips ichini (Thysanoptera: Phlaeothripidae) as candidates for biological control of the invasive weed Schinus terebinthifolia (Sapindales: Anacardiaceae)

Brazilian peppertree, Schinus terebinthifolia Raddi (Sapindales: Anacardiaceae) (hereafter Schinus), is one of the worst invasive species in Florida and Hawaii. The thrips Pseudophilothrips ichini Hood (Thysanoptera: Phlaeothripidae) is being considered as a potential biological control agent of Schinus. Two populations of this thrips were collected in the weed's native range; one from central-east Brazil (Ouro Preto thrips) and a second from north-east Brazil (Salvador thrips). Temperature requirements, adult fecundity and impact on different plant haplotypes by P. ichini were examined in the laboratory. Complete development of thrips from both populations occurred at temperatures ranging from 20 to 30°C. Two approaches were used to model the predicted distributions of the thrips populations in the USA: the physiological model (NAPPFAST) based on cold tolerance and the ecological niche model based on climatic variables (MaxEnt). The physiological model predicted that both populations of P. ichini may establish in similar areas of the USA, overlapping with the distribution of Schinus. However, the niche model predicted that only the Ouro Preto thrips could establish in the USA. The difference in model predictions suggests an apparent preadaptation of the Salvador thrips to lower temperatures than those experienced at the locations they were collected in Brazil. The Ouro Preto thrips had similar fecundity on two Florida Schinus haplotypes, whereas lower fecundity on haplotype A was found for the Salvador thrips. Based on these results, the Ouro Preto population may be better adapted to the climatic conditions and plant haplotypes found in Florida. Moreover, greenhouse studies indicated that Schinus growth was greatly reduced by thrips feeding, which may result in lower weed reproduction and densities in the field.