Inhibition of breast cancer xenografts in a mouse model and the induction of apoptosis in multiple breast cancer cell lines by lactoferricin B peptide

Breast cancer has a diverse aetiology characterized by the heterogeneous expression of hormone receptors and signalling molecules, resulting in varied sensitivity to chemotherapy. The adverse side effects of chemotherapy coupled with the development of drug resistance have prompted the exploration of natural products to combat cancer. Lactoferricin B (LfcinB) is a natural peptide derived from bovine lactoferrin that exhibits anticancer properties. LfcinB was evaluated in vitro for its inhibitory effects on cell lines representing different categories of breast cancer and in vivo for its suppressive effects on tumour xenografts in NOD-SCID mice. The different breast cancer cell lines exhibited varied levels of sensitivity to apoptosis induced by LfcinB in the order of SKBR3>MDA-MB-231>MDA-MB-468>MCF7, while the normal breast epithelial cells MCF-10A were not sensitive to LfcinB. The peptide also inhibited the invasion of the MDA-MB-231 and MDA-MB-468 cell lines. In the mouse xenograft model, intratumoural injections of LfcinB significantly reduced tumour growth rate and tumour size, as depicted by live imaging of the mice using in vivo imaging systems (IVIS). Harvested tumour volume and weight were significantly reduced by LfcinB treatment. LfcinB, therefore, is a promising and safe candidate that can be considered for the treatment of breast cancer.     

Therapeutic effects of Semecarpus anacardium Linn. nut milk extract on the changes associated with collagen and glycosaminoglycan metabolism in adjuvant arthritic Wistar rats

The effect of milk extract of Semecarpus anacardium Linn. nut milk extract (SA) was studied to gain some insight into this intriguing disease with reference to collagen metabolism. Arthritis was induced in rats by injecting Freund's complete adjuvant containing 10mg of heat killed mycobacterium tuberculosis in 1 ml paraffin oil (0.1 ml) into the left hind paw of the rat intradermally. After 14 days of induction, SA (150 mg/kg body weight/day) was administered orally by gastric intubations for 14 days. Decreased levels of collagen and glycosaminoglycans (GAGS) components (chondroitin sulphate, heparan sulphate, hyaluronic acid) and increase in the levels of connective tissue degrading lysosomal glycohydrolases such as acid phosphatase, beta-glucuronidase, beta-N-acetyl glucosaminidase and cathepsin-D observed in arthritic animals were reverted back to near normal levels upon treatment with SA. The drug effectively regulated the uriniray markers of collagen metabolism namely hexosamine, hexuronic acid, hydroxyproline and total GAGS. Electron microscopic studies also revealed the protective effect of SA. Hence, it can be suggested that SA very effectively regulate the collagen metabolism that derange during arthritic condition.     

Synthesis,spectral, crystal and antimicrobial studies of biologically potent oxime ethers of nitrogen,oxygen and sulfur heterocycles

Three series of oxime ethers viz, 2,6-diarylpiperidin-4-one O-benzyloximes 5a–o, 2,6-diaryltetrahydropyran-4-one O-benzyloximes 7a–e and 2,6-diaryltetrahydrothiopyran-4-one O-benzyloximes 11a–b and 12a–c were synthesized and stereochemistry is established by their spectral and single crystal analysis. A SAR study has been carried out for the above oxime ethers against a panel of antibacterial (Pseudomonas aeruginosa, Staphylococcus aureus, Salmonella typhi and Escherichia coli) and antifungal agents (Candida albicans, Candida-51, Rhizopus sp., Aspergillus niger, Aspergillus flavus and Cryptococcus neoformans), respectively, using Ciprofloxacin and Amphotericin B as standards. Most of the chloro/methyl/methoxy substituted compounds exerted moderate to good activity against all the tested organisms; moreover, some compounds (5i, 5l, 5n, 5o, 7c2, 7d1, 7d2, 7e, 11b and 12c) exhibited promising activity than standard drugs.     

Racial disparity in pathophysiologic pathways of preterm birth based on genetic variants

Objective  

To study pathophysiologic pathways in spontaneous preterm birth and possibly the racial disparity associating with maternal and fetal genetic variations, using bioinformatics tools.     

Detection of α_(2u)-globulin in rat pup preputial gland by MALDI-TOF mass spectrometry

The α_ 2u-globulin,a soluble protein identified in the urine and preputial gland of adult male rat is reported to be pheromone carrier.The pup preputial gland plays a significant role in chemical communication for mother-young interaction;however,the presence of a pheromone-carrying protein in the pup preputial gland has not been confirmed.Therefore,the present study was carried out to identify the α_ 2u-globulin in the pup preputial gland by Matrix Assisted Laser Desorption Ionization Time of Flight mass s...     

Stereocontrolled facile synthesis and antimicrobial activity of oximes and oxime ethers of diversely substituted bispidines

A small library of diversely substituted 2,4,6,8-tetraaryl-3,7-diazabicyco[3.3.1]nonan-9-ones, their oximes and O-methyloximes were achieved in a stereocontrolled manner by an easiest synthetic strategy as single isomers with high yields. Stereochemistry of all the synthesized compounds was established by their 1D/2D NMR spectral studies, further, witnessed by single-crystal XRD analysis. Accordingly, the compounds exist in a chair-boat conformation with equatorial orientation of the substituents in the chair part and boat-axial orientation in the boat part. Finally, all the synthesized oximes and oxime ethers were evaluated for their in vitro antimicrobial activity against a panel of pathogenic bacteria and fungi, and as a result of the structure-activity correlations, some lead molecules were known for further optimization.     

Mitochondrial DNA variant A4917G, smoking and spontaneous preterm birth

Spontaneous preterm birth (PTB; <37 weeks gestation) is a major risk factor for neonatal morbidity and mortality. The exact cause of PTB is unknown but oxidative stress may play an important role. Genetic studies have recently begun to elucidate the role of genetic variation in PTB but these studies have overlooked the mitochondrial genome/gene(s) as a plausible PTB candidate. In the present study, we sought to document association between nonsynonymous mitochondrial DNA (mtDNA) variants A4917G, G10398A and T4216C and PTB. We performed a case (PTB; <36 weeks gestation)-control (normal term) analysis of these mtDNA markers and examined their potential interaction with smoking in PTB. A sample of 422 pregnant Caucasian women (220 preterm and 202 terms) was examined for association. Haplogroup T marker A4917G was identified as a possible candidate for association with PTB after adjusting for smoking (OR=1.99 [95% CI 0.93-4.24]) as was T4216C (OR=1.63 [95% CI 0.93-2.83]). No significant multi-locus interactions or interactions with other environmental variables were observed. Our data, although preliminary, support the hypothesis that mitochondrial genome polymorphisms may play a significant role in PTB through an interaction with smoking.     

Discovery of 3-acetyl-4-hydroxy-2-pyranone derivatives and their difluoridoborate complexes as a novel class of HIV-1 integrase inhibitors

HIV-1 integrase (IN) has emerged as an important therapeutic target for anti-HIV drug development. Its uniqueness to the virus and its critical role in the viral life cycle makes IN suitable for selective inhibition. The recent approval of Raltegravir (MK-0518) has created a surge in interest and great optimism in the field. In our ongoing IN drug design research, we herein report the discovery of substituted analogs of 3-acetyl-4-hydroxy-2-pyranones and their difluoridoborate complexes as novel IN inhibitors. In many of these compounds, complexation with boron difluoride increased the potency and selectivity of IN inhibition. Compound 9 was most active with an IC(50) value of 9 microM and 3 microM for 3'-processing and strand transfer inhibition, respectively.     

DNA methyltransferase homologue TRDMT1 in Plasmodium falciparum specifically methylates endogenous aspartic acid tRNA

In eukaryotes, cytosine methylation regulates diverse biological processes such as gene expression, development and maintenance of genomic integrity. However, cytosine methylation and its functions in pathogenic apicomplexan protozoans remain enigmatic. To address this, here we investigated the presence of cytosine methylation in the nucleic acids of the protozoan Plasmodium falciparum. Interestingly, P. falciparum has TRDMT1, a conserved homologue of DNA methyltransferase DNMT2. However, we found that TRDMT1 did not methylate DNA, in vitro. We demonstrate that TRDMT1 methylates cytosine in the endogenous aspartic acid tRNA of P. falciparum. Through RNA bisulfite sequencing, we mapped the position of 5-methyl cytosine in aspartic acid tRNA and found methylation only at C38 position. P. falciparum proteome has significantly higher aspartic acid content and a higher proportion of proteins with poly aspartic acid repeats than other apicomplexan pathogenic protozoans. Proteins with such repeats are functionally important, with significant roles in host-pathogen interactions. Therefore, TRDMT1 mediated C38 methylation of aspartic acid tRNA might play a critical role by translational regulation of important proteins and modulate the pathogenicity of the malarial parasite.     

Classical autophagy proteins LC3B and ATG4B facilitate melanosome movement on cytoskeletal tracks

Macroautophagy/autophagy is a dynamic and inducible catabolic process that responds to a variety of hormonal and environmental cues. Recent studies highlight the interplay of this central pathway in a variety of pathophysiological diseases. Although defective autophagy is implicated in melanocyte proliferation and pigmentary disorders, the mechanistic relationship between the 2 pathways has not been elucidated. In this study, we show that autophagic proteins LC3B and ATG4B mediate melanosome trafficking on cytoskeletal tracks. While studying melanogenesis, we observed spatial segregation of LC3B-labeled melanosomes with preferential absence at the dendritic ends of melanocytes. This LC3B labeling of melanosomes did not impact the steady-state levels of these organelles but instead facilitated their intracellular positioning. Melanosomes primarily traverse on microtubule and actin cytoskeletal tracks and our studies reveal that LC3B enables the assembly of microtubule translocon complex. At the microtubule-actin crossover junction, ATG4B detaches LC3B from melanosomal membranes by enzymatic delipidation. Further, by live-imaging we show that melanosomes transferred to keratinocytes lack melanocyte-specific LC3B. Our study thus elucidates a new role for autophagy proteins in directing melanosome movement and reveal the unconventional use of these proteins in cellular trafficking pathways. Such crosstalk between the central cellular function and housekeeping pathway may be a crucial mechanism to balance melanocyte bioenergetics and homeostasis.