Effect of Ayurvedic mercury preparation Makaradhwaja on geriatric canine--a preliminary study

Makaradhwaja, an alchemical Ayurvedic mercury preparation is used as stimulant and vitalizer. Towards veterinary practices, the acceptability, tolerability and toxicity studies were undertaken in geriatric pet dogs aged more than 10 years irrespective of breed and sex for future use. Makaradhwaja (2.5 mg/kg) was used with honey once daily for 30 days. Before and after treatment, blood was collected for hematological studies as well as liver, kidney function and anti-oxidant activity. In control group, honey itself showed no appreciable change whereas, Makaradhwaja lowered neutrophil and total leucocyte count. Serum cholesterol, urea, glucose, alanine amino transferase, aspartate amino transferase, sodium, phosphorus and calcium were decreased. Haemoglobin and serum creatinine were significantly increased. There was appreciable physical, behavioral and body weight change including quality of life. The dose was used in replication of human dose (125 mg/50 kg). Anti-oxidant study showed significant increase of lipid per oxidation in experimental group while the values of ABTS radical cation decolorisation assay although decreased but did not show any significant changes. Decrease of serum urea and increase of serum creatinine could not be explained on single dose response. Different dose study could only explain the optimum dose to be required in canine practices.     

QSAR study on some pyridoacridine ascididemin analogues as anti-tumor agents

Pyridoacridine ascididemin analogues have been reported as anticancer agents for their interesting antitumor activity against human cancer cells. A quantitative structure–activity relationship (QSAR) analysis of ascididemin analogues was attempted using the physicochemical parameters and the electrotopological state atom (ETSA) indices. This study indicates that the electron withdrawing substituents with higher MR (molar refractivity) value at R₁ position favor the anti-tumor activity and the presence of NHR (R is hydrogen or alkyl group) at the R₃ position has contribution to the anti-tumor activity. ETSA indices have been incorporated as independent variable in the QSAR model with physicochemical parameters. It clearly suggests the importance of atoms 2, 3, 4, 5, 6 and 7 to the anti-tumor activity.     

Interface of apoptotic protein complexes has distinct properties

Apoptosis is a programmed mechanism of cell death that is a normal component of development and health of multi-cellular organisms. In this study, we ask if interface properties of apoptotic protein complexes are different from protein complexes in general. We find that although in apoptotic protein complexes the overall distribution of interface size, surface complementarity, hydrogen bonding, hydrophobicity are similar to general interface properties, apoptotic complexes tend to have more fragmented interfaces and different secondary structural preferences. The statistics on the number of interfaces where specific amino acid(s) occur with significantly enhanced frequency suggest that Arg, Met and Asp are most important functional residues. The role of Met is believed to be unique, as evidenced from the existing data on hot spot potential of residues. These findings together provide insight into the possible role of various physico-chemical attributes at the protein interface in regulation of the apoptosis process.     

Crystal Structures of HIV-1 gp120 Envelope Glycoprotein in Complex with NBD Analogues That Target the CD4-Binding Site

Efforts to develop therapeutic agents that inhibit HIV-1 entry have led to the identification of several small molecule leads. One of the most promising is the NBD series, which binds within a conserved gp120 cavity and possesses para-halogen substituted aromatic rings, a central oxalamide linker, and a tetramethylpiperidine moiety. In this study, we characterized structurally the interactions of four NBD analogues containing meta-fluoro substitution on the aromatic ring and various heterocyclic ring replacements of the tetramethylpiperidine group. The addition of a meta-fluorine to the aromatic ring improved surface complementarity and did not alter the position of the analogue relative to gp120. By contrast, heterocyclic ring replacements of the tetramethylpiperidine moiety exhibited diverse positioning and interactions with the vestibule of the gp120 cavity. Overall, the biological profile of NBD-congeners was modulated by ligand interactions with the gp120-cavity vestibule. Herein, six co-crystal structures of NBD-analogues with gp120 provide a structural framework for continued small molecule-entry inhibitor optimization.     

Exploring the potential of 3'-O-carboxy esters of thymidine as inhibitors of ribonuclease A and angiogenin

In this study, compounds with a carboxy ester in lieu of the phosphate ester at the 3'-position have been employed to inhibit the ribonucleolytic activity of ribonuclease A (RNase A). Phosphates at the 3'-position of pyrimidine bases are well-known inhibitors of the protein. We have investigated the inhibition of RNase A by 3'-O-carboxy esters of thymidine. The compounds behave as competitive inhibitors with inhibition constants ranging from 42 to 95 microM. The mode of inhibition has also been confirmed by (1)H NMR studies of the active site histidines of RNase A. Docking studies have further substantiated the experimental results. The compounds are also found to inhibit the ribonucleolytic activity of angiogenin, a homologous protein and potent inducer of blood vessel formation.     

Allosteric inhibition of the nonMyristoylated c-Abl tyrosine kinase by phosphopeptides derived from Abi1/Hssh3bp1

Here we report c-Abl kinase inhibition mediated by a phosphotyrosine located in trans in the c-Abl substrate, Abi1. The mechanism, which is pertinent to the nonmyristoylated c-Abl kinase, involves high affinity concurrent binding of the phosphotyrosine pY213 to the Abl SH2 domain and binding of a proximal PXXP motif to the Abl SH3 domain. Abi1 regulation of c-Abl in vivo appears to play a critical role, as demonstrated by inhibition of pY412 phosphorylation of the nonmyristoylated Abl by coexpression of Abi1. Pervanadate-induced c-Abl kinase activity was also reduced upon expression of the wild type Abi1 but not by expression of the Y213 to F213 mutant Abi1 in LNCaP cells, which are naturally deficient in the regulatory pY213. Our findings suggest a novel mechanism by which Abl kinase is regulated in cells.     

Uncharged thioflavin-T derivatives bind to amyloid-beta protein with high affinity and readily enter the brain

In vivo assessment of the beta-sheet proteins deposited in amyloid plaques (A beta peptide) or neurofibrillary tangles (tau protein) presents a target for the development of biological markers for Alzheimer's disease (AD). In an effort to develop in vivo beta-sheet imaging probes, derivatives of thioflavin-T (ThT) were synthesized and evaluated. These compounds lack the positively charged quaternary heterocyclic nitrogen of ThT and are therefore uncharged at physiological pH. They are 600-fold more lipophilic than ThT. These ThT derivatives bind to A beta(1-40) fibrils with higher affinity (Ki = 20.2 nM) than ThT (Ki = 890 nM). The uncharged ThT derivatives stained both plaques and neurofibrillary tangles in post-mortem AD brain, showing some preference for plaque staining. A carbon-11 labeled compound, [N-methyl-11C]6-Me-BTA-1, was prepared, and its brain entry and clearance were studied in Swiss-Webster mice. This compound entered the brain at levels comparable to commonly used neuroreceptor imaging agents (0.223 %ID-kg/g or 7.61 %ID/g at 2 min post-injection) and showed good clearance of free and non-specifically bound radioactivity in normal rodent brain tissue (brain clearance t(1,2) = 20 min). The combination of relatively high affinity for amyloid, specificity for staining plaques and neurofibrillary tangles in post-mortem AD brain, and good brain entry and clearance makes [N-methyl-11C]6-Me-BTA-1 a promising candidate as an in vivo positron emission tomography (PET) beta-sheet imaging agent.