Management of progressive exophthalmos

The present study reveals our experience in the medical management of 30 cases of progressive/malignant exophthalmos, employing costicosteroid, b-blocker, diuretic and a preparation containing proteolytic enzymes. There was encouraging improvement in terms of symptoms, proptosis and optic nerve compression, while reduction of ophthalmoplegia was not so satisfactory. However, none of the patients needed decompression surgery.     

Prevalence and geographic distribution of Hepatitis C Virus genotypes in Indian patient cohort

Viral hepatitis represents a major global health problem with 170 million Hepatitis C Virus (HCV) carriers worldwide, and 12–13 million HCV carriers in India. HCV genotypes are of clinical significance in indicating drug responsiveness and prognosis of the patient. The HCV genotypes are of epidemiologic significance as well, as they are indicative of transmission route of infection and have not been extensively studied in the Indian context. In the current study, HCV genotyping was examined in 2118 patients from different geographic regions of India. HCV was detected by PCR amplification of 5′ UTR and core-envelope1 regions, followed by genotyping using nucleotide sequencing and analysis with NCBI tool (http://www.ncbi.nlm.nih.gov/projects/genotyping/formpage.cgi). HCV genotype distribution in the 2118 Indian patients demonstrated prevalence of HCV3 (3a/3b primarily) in 62% and HCV1 (1a/1b primarily) in 31% patients. The predominance of HCV3 was significant in northern (p = 0.01) and eastern (p = 0.008) regions of India. HCV types 2, 4, 5, and 6 were detected in 0.05–4.5% of the patient group. Thus, our studies demonstrate HCV genotype prevalence in the cohort group in different regions of India.     

Scavenger receptors in innate immunity.

Scavenger receptors (SR) are expressed by myeloid cells (macrophages and dendritic cells) and certain endothelial cells. They play an important role in uptake and clearance of effete components, such as modified host molecules and apoptotic cells. They bind and internalise micro-organisms and their products including Gram-positive bacteria (lipoteichoic acid), Gram-negative bacteria (lipopolysaccharide), intracellular bacteria and CpG DNA. SR can alter cell morphology and their expression is affected by various cytokines. SR are involved in lipid metabolism and bind modified low-density lipoproteins.     

β-Cyclodextrin: a green supramolecular catalyst assisted eco-friendly one-pot three-component synthesis of biologically active substituted pyrrolidine-2-one

A green, novel and eco-efficient synthetic route towards the synthesis of highly substituted bio-active pyrrolidine-2-one derivatives was demonstrated using β-cyclodextrin, a water-soluble supramolecular solid as a green and eco-benign catalyst at room temperature under water–ethanol solvent medium. The exploration of the green catalyst β-cyclodextrin for the metal-free one-pot three-component synthesis of a wide range of highly functionalized bio-active heterocyclic pyrrolidine-2-one moieties from easily available aldehydes and amines explains the superiority and uniqueness of this protocol.

An eco-efficient protocol towards the synthesis of highly substituted bio-active pyrrolidine-2-one derivatives was demonstrated using β-cyclodextrin, a water-soluble supramolecular catalyst at room temperature under water–ethanol solvent medium.     

Two flares of Still’s disease after two doses of the ChAdOx1 vaccine

Clinical Rheumatology - We report the case of an 18-year-old male with Still’s disease for the last 3 years, in remission, who developed two flares of his disease after receiving two...     

Identifying a C-terminal ATP binding sites-based novel Hsp90-Inhibitor in silico: A plausible therapeutic approach in Alzheimer’s disease

Background

Alzheimer’s disease (AD) is a progressive brain disorder, which gradually and irreversibly destroys the intellectual and cognitive abilities of the brain. Heat shock protein 90 (Hsp90α) is a molecular chaperone which was found to regulate the function of number of client proteins including tau that is involved in the cause of the AD. Inhibition of Hsp90α by C-Terminal domain (CTD) ATP binding-site blockage might be used as an effective treatment strategy against the disease via degradation of tau proteins that are involved in the progression of the disease. Till date, a variety of drugs have been identified as Hsp90α inhibitors, which include Novobiocin, Clorobiocin, Epigallocatechingallate (EGCG) and Derrubone. However, which drug among the four binds to the CTD ATP binding site strongly and what are the specific residue responsible for such binding, have not been reported so far.

Hypothesis

We hypothesize that binding site for ATP of Hsp90α CTD contains multiple ATP binding sites. We also hypothesize that a drug which can bind to the ATP binding site of CTD strongly can inhibit Hsp90α function which is in turn redirects towards the proteasomal degradation of diseased client protein like tau in AD. Such inhibition will find a novel therapeutic approach in the treatment of AD.

Experimental design

The identification of ATP binding site of Hsp90α CTD was done using various software tools like Hex 6.3, CastP, protein Hydrophobicity plots, ATPint and LigPlot+ v.1.4.5. Docking experiments were conducted between Hsp90αCTD and its inhibitors at these ATP binding site using the Autodock 4.0. The docking energies were further compared to obtain the most effective Hsp90α inhibitor of CTD.

Results

From our experiments, Leucine (Leu) 665, Leu 666 and Leu 694 were predicted to be located in CTD ATP binding site. Furthermore, docking studies were performed of various Hsp90α inhibitors like Novobiocin, Clorobiocin, Epigallocatechingallate (EGCG) and Derrubone with the previously recognized ATP binding residues of CTD i.e. Leu 665, Leu 666 and Leu 694. The docking results of Derrubone showed the highest binding energy at all the three sites of ATP interaction. Additionally, Derrubone showed the best binding energy at Leu 666 (−7.53 kcal/mol) compared to Leu 665 (−7.20 kcal/mol) and Leu 694 (−6.67 kcal/mol).

Conclusion

Based on our findings, we propose that the recognized sites i.e. Leu665, Leu 666 and Leu694 could possibly be the binding sites of Hsp90α CTD for ATP and the Hsp90 inhibitors. It was predicted that Derrubone could bind with CTD of Hsp90α strongly and resulted tau protein degradation which might be considered to be a therapeutic approach in AD.