Pterostilbene-Isothiocyanate Conjugate Suppresses Growth of Prostate Cancer Cells Irrespective of Androgen Receptor Status

Chemotherapy and anti-hormonal therapies are the most common treatments for non-organ-confined prostate cancer (PCa). However, the effectiveness of these therapies is limited, thus necessitating the development of alternative approaches. The present study focused on analyzing the role of pterostilbene (PTER)-isothiocyanate (ITC) conjugate – a novel class of hybrid compound synthesized by appending an ITC moiety on PTER backbone – in regulating the functions of androgen receptor (AR), thereby causing apoptosis of PCa cells. The conjugate molecule caused 50% growth inhibition (IC₅₀) at 40±1.12 and 45±1.50 μM in AR positive (LNCaP) and negative (PC-3) cells, respectively. The reduced proliferation of PC-3 as well as LNCaP cells by conjugate correlated with accumulation of cells in G2/M phase and induction of caspase dependent apoptosis. Both PI3K/Akt and MAPK/ERK pathways played an important and differential role in conjugate-induced apoptosis of these PCa cells. While the inhibitor of Akt (A6730) or Akt-specific small interference RNA (siRNA) greatly sensitized PC-3 cells to conjugate-induced apoptosis, on the contrary, apoptosis was accelerated by inhibition of ERK (by PD98059 or ERK siRNA) in case of LNCaP cells, both ultimately culminating in the expression of cleaved caspase-3 protein. Moreover, anti-androgenic activity of the conjugate was mediated by decreased expression of AR and its co-activators (SRC-1, GRIP-1), thus interfering in their interactions with AR. All these data suggests that conjugate-induced inhibition of cell proliferation and induction of apoptosis are partly mediated by the down regulation of AR, Akt, and ERK signaling. These observations provide a rationale for devising novel therapeutic approaches for treating PCa by using conjugate alone or in combination with other therapeutics.     

Skeletal abnormalities in doubly heterozygous Bmp4 and Bmp7 mice

Analysis of the skeletal phenotypes caused by the genetic inactivation of individual Bmps, along with the study of their expression patterns, suggest possible functional redundancy of these molecules. To investigate the effect on skeleton development of the combined absence of some Bmp genes expressed in the same areas, we have intercrossed heterozygous Bmp7 mice with Bmp2^+/−, Bmp4^+/−, or Bmp5^+/− animals. Bmp2/7 and Bmp5/7 double heterozygous animals do not present with any abnormalities. In contrast, Bmp4/7 double heterozygotes develop minor defects in two restricted areas of the skeleton, the rib cage, and the distal part of the limbs. In the ribs, Bmp4 and Bmp7 seem to act in the same pathway to assure proper guidance of mesenchymal condensations of the ribs extending toward the sternum. In the limbs, these molecules appear to play a similar role in controlling digit number, possibly through induction of apoptosis in the interdigital and anterior mesenchyme. Dev. Genet. 22:340–348, 1998. © 1998 Wiley-Liss, Inc.     

Glutamate Receptor 6 Gene (<Emphasis Type="Italic">GluR6</Emphasis> or <Emphasis Type="Italic">GRIK2</Emphasis>) Polymorphisms in the Indian Population: A Genetic Association Study on Autism Spectrum Disorder

Autism is a neurodevelopmental disorder with early manifestation. It is a multifactorial disorder and several susceptible chromosomal regions for autism are identified through genome scan studies. The gene coding for glutamate receptor 6 (GluR6 or GRIK2) has been suggested as a candidate gene for autism based on its localization in the autism specific region on chromosome 6q21 and the involvement of receptor protein in cognitive functions like learning and memory. Despite its importance, so far no studies have been carried out on possible involvement of GluR6 with autism in the Indian population. Therefore in the present study, we have performed genetic analysis of three markers of GluR6 (SNP1: rs2227281, SNP2: rs2227283, SNP3: rs2235076) for possible association with autism through population, and family-based (TDT and HHRR) approaches. DSM-IV criteria and CARS/ADI-R have been utilized for diagnosis. Genotyping analysis for the SNPs has been carried out in 101 probands with autism spectrum disorder, 180 parents and 152 controls from different regions of India. Since the minor allele frequency of SNP3 was too low, the association studies have been carried out only for SNP1 and SNP2. Even though two earlier studies have shown association of these markers with autism, the present case–control and TDT, as well as HHRR analyses have not demonstrated any biased transmission of alleles or haplotypes to the affected offspring. Thus our results suggest that these markers of GluR6 are unlikely to be associated with autism in the Indian population.     

Crowd sourcing a new paradigm for interactome driven drug target identification in Mycobacterium tuberculosis

A decade since the availability of Mycobacterium tuberculosis (Mtb) genome sequence, no promising drug has seen the light of the day. This not only indicates the challenges in discovering new drugs but also suggests a gap in our current understanding of Mtb biology. We attempt to bridge this gap by carrying out extensive re-annotation and constructing a systems level protein interaction map of Mtb with an objective of finding novel drug target candidates. Towards this, we synergized crowd sourcing and social networking methods through an initiative 'Connect to Decode' (C2D) to generate the first and largest manually curated interactome of Mtb termed 'interactome pathway' (IPW), encompassing a total of 1434 proteins connected through 2575 functional relationships. Interactions leading to gene regulation, signal transduction, metabolism, structural complex formation have been catalogued. In the process, we have functionally annotated 87% of the Mtb genome in context of gene products. We further combine IPW with STRING based network to report central proteins, which may be assessed as potential drug targets for development of drugs with least possible side effects. The fact that five of the 17 predicted drug targets are already experimentally validated either genetically or biochemically lends credence to our unique approach.     

Maximizing EPS production from Pseudomonas aeruginosa and its application in Cr and Ni sequestration

Heavy metal contamination of water bodies has been a cause of grave concern around the globe. Analysis of various industrial effluents has revealed a perilous level of Cr (VI) and Ni (II). Pseudomonas aeruginosa is an extracellular polymeric substances (EPSs) producing bacterium. EPS has a great potential in the sequestration of heavy metal ions. In the present study efforts have been made to understand the effect of time, pH, and temperature on production of EPS by P. aeruginosa (MTCC 1688). The extracted EPS has been applied for removal of Ni (II) and Cr (VI) ions from aqueous system. The results revealed that highest EPS yield (26 mg/50 mL) can be obtained after 96 h of incubation at pH 6 and 32 °C temperature in 50 mL of culture. Treatment of 10 mg/L Cr (VI) and Ni (II) with 30 mg/L EPS resulted in the removal of 26% and 9% of Cr (VI) and Ni (II), respectively. Fourier-transform infrared spectral analysis revealed the involvement of –OH, –NH, C–O, diketone, and ester functional groups of EPS in the attachment of Cr (VI) ion while involvement of amide and –CO groups in Ni (II) binding with EPS. Scaling-up the production of EPS using bioreactor may further help in developing an efficient process for treatment of water polluted with Cr and Ni.     

Somatic Embryogenesis in Capparis decidua (Forsk) Edgew — A Multipurpose Agroforestry Plant

An efficient protocol for direct somatic embryogenesis in Capparis decidua has been developed. Mature zygotic embryos cultured in Murashige and Skoog (MS) liquid medium with 2,4-0 (0.1 mg l^?1) and BA (0.5 mg l^?1) produced somatic embryos directly without an intervening callus phase from the subepidermal cells. Treatment with ABA promoted maturation of somatic embryos and BA (1 mg l^?1)promoted germination. One zygotic embryo produced approximately 230 somatic embryos within 14 to 15 weeks. Embryos germinated in eight weeks and acclimatized plants were transferred to pots.