Design, synthesis and biological evaluation of new ß-carboline-bisindole compounds as DNA binding, photocleavage agents and topoisomerase I inhibitors.

A series of new ß-carboline-bisindole compounds were designed, synthesized and evaluated for their antiproliferative activity against human cancer cell lines, such as A549 (lung cancer), DU-145 (prostate cancer), HeLa (cervical cancer) and MCF-7 (breast cancer). All the compounds exhibited considerable antiproliferative activity. Among them, compounds 7g and 7r exhibited significant antiproliferative activity against DU-145 cells with IC50 values 1.86 and 1.80 µM respectively. Further, these compounds effectively inhibit DNA topoisomerase I activity and can also cleave the pBR322 plasmid upon irradiation with UV light. In addition, Annexin V-FITC assay suggested that these compounds induced apoptosis in DU- 145 cell line (prostate cancer). To know the binding mode of these compounds with DNA, spectroscopic studies were also carried out. These new compounds were showing a unique mode of binding with DNA, both biophysical studies such as UV-Visible, fluorescence, circular dichroism and molecular docking studies revealed that the ß-carboline-bisindole compounds exhibit combilexin type of interaction with DNA.

FOXN1 Italian founder mutation in Indian family: Implications in prenatal diagnosis.

The Forkhead box N1 (FOXN1) is a transcriptional factor regulating the development, differentiation and function of thymic epithelial cells; maintaining T-lineage progenitors in bone marrow; promoting terminal differentiation of epithelial cells of hair follicles. Mutation in FOXN1 was reported to cause a rare disorder characterized by rudimentary thymus gland, T-cell immunodeficiency, congenital alopecia and nail dystrophy within an Italian community. This is the first report of FOXN1 p.R255X mutation from India, outside this endogamous Italian community. Out of the two affected children, only one was alive during the genetic evaluation and had all the clinical manifestations such as alopecia totalis and nail dystrophy. The proband was homozygous for FOXN1 p.R255X Italian founder mutation. The carrier status of both the parents was established. Immunological study of the proband revealed total absence of T-cells confirming T-cell immunodeficiency. Prenatal diagnosis during third pregnancy revealed absence of FOXN1 mutation. To conclude, this is the first report of FOXN1 mutation from India highlighting that diseases once confined to certain geographical areas are spreading across the globe probably due to human migrations.

Pleiotropic consequences of Bruton tyrosine kinase deficiency in myeloid lineages lead to poor inflammatory responses.

Bruton tyrosine kinase (Btk), a non-receptor-associated tyrosine kinase of the Tec family, appears to participate in many myeloid cell functions. We show that macrophages from X-linked immunodeficient (XID) mice lacking functional Btk cannot generate efficient bursts of reactive oxygen intermediates (ROIs). The induction of apoptotic cell death by inflammatory stimuli is also enhanced in XID macrophages. Phagocytosis of bacterial particles is only marginally affected in them. In vivo, XID mice show reduced severity of inflammatory diseases in models of experimental autoimmune encephalomyelitis (EAE), dextran sulfate sodium (DSS)-induced colitis, and carrageenan-induced acute edema. Also, polymorphonuclear neutrophil granulocytes (PMNs) in XID mice show poor ROI and nitric oxide (NO) induction, along with a reduction in PMN recruitment to peritoneal inflammation. XID mice show reduction in PMN numbers in peripheral blood, and their bone marrow shows a reduction in the numbers of both monocytic and granulocytic lineages, extending to the earliest progenitor populations. Thus, Btk is likely to play a significant role at multiple points during the development and functioning of the myeloid lineages, affecting the outcome of many infectious as well as noninfectious inflammatory events in vivo.

Was elusive carnivore a panther? DNA typing of faeces reveals the mystery.

In this study, we report the findings of a recent case in which the officials of an Indian zoo claimed that an animal, possibly a carnivore, is periodically visiting the zoo from a nearby vast forest area and causing panic in zoo and nearby villages. They collected some elusive faecal material from the vicinity of an herbivore enclosure. Looking to the pugmarks found in that area and faecal matter ceased, the officials could not decide whether it was a lioness, a tiger or a panther. We resolved this mystery by DNA-based analysis of the faecal material, using our recently developed novel universal primers to amplify and sequence a specific fragment of mitochondrial cytochrome b gene. The findings of the DNA-based analyses were confirmed after few days when the zoo officials trapped the animal of same species as suggested in our report. The potential of our procedure to investigate the cases related to wildlife offence is discussed.