Inhibition of the p53 Y220C Mutant by 1-Hydroxy-2- Methylanthraquinone Derivatives: A Novel Strategy for Cancer Therapy.

Y220C, a substitution mutation in p53, causes major structural changes in the protein and is known to form a new protein cavity. This cavity is reckoned to accommodate small drug candidates that may play a key role in cancer treatment. Present study was aimed at determining a drug candidate that could inhibit the mutant p53 based on structural drug rationale. Docking of mutated p53 was performed to determine the drug of choice from the derivatives of 1-hydroxy-2- methylanthraquinone exhibiting anti-cancer properties. The cavity had been tested for identification of an accurate position vector for molecular docking studies using structure based drug design. The docked structure was validated using discovery studio 3.5. The best choice of two molecules were obtained by docking in specific solvent for 6 nanoseconds at a temperature of 310 K. Out of a library of compounds, acetamido-2-carboxy-4-dimethylamino-2- hydroxybenzophenone satisfied the ADMET and was found to be a potential target for mutant p53. This ligand binds at the active site of the protein. Results of present study offer a rationale of the lead ligands that can rescue oncogenic p53 by targeting the mutation site. Therefore, it is suggestive that small molecules may serve as an effective and novel anti-cancer drug.

On the mechanism of cellular toxicity in breast cancer by ionizing radiation and chemotherapeutic drugs.

Breast cancer is the second leading cause of cancer mortality and the most frequent cancer found in women around the globe. The development of breast cancer is a multistep and complicated process that includes the development of ductal and lobular cells into atypical hyperplasia, carcinoma in situ, and invasive carcinoma, with an ability to metastasize. The efficacy of radiotherapy in breast cancer seems to be reduced because of a frequently observed lack of cellular sensitivity to apoptosis. Both Bcl-2 and p53 are linked to apoptosis pathways and are known to play a role in the outcome of radiotherapy. Resistance of tumor cells to therapeutic drugs and the undesirable cytotoxicity of normal cells are frequently observed in treatment outcomes in clinics. Research is, therefore, needed to develop strategies for improving the protocols of chemotherapy and radiotherapy in patients with breast cancer. This review focuses on understanding the molecular mechanisms of enhanced tumor cell killing by the combined action of certain anticancer drugs together with gamma radiation in vitro, with possible implications for practical applications in clinics.

On the change in bacterial size and magnetosome features for Magnetospirillum magnetotacticum (MS-1) under high concentrations of zinc and nickel.

The characteristic size, shape and specific alignment of magnetite crystals synthesized by magnetotactic bacteria is a highly coordinated process with precise control over magnetosome vesicle formation, uptake and transport of Fe, and magnetite biomineralization. Magnetosome membranes along with some specific membrane proteins regulate crystal nucleation and morphology of magnetite. Several previous works have indicated that the morphology of mature magnetite crystals is largely unaffected by environmental conditions, though some recent studies have shown the possibility of manipulation of the biomineralization process. In this study we have examined the effects of high concentrations of Zinc and Nickel on the growth of Magnetospirillum magnetotacticum (MS-1) and the corresponding magnetosome formation. Using various characterizations it is shown that the growth of the bacterial cells, as well as the size, shape and magnetosome chain alignment is significantly influenced in the presence of high concentrations of Zn or Ni.

Extracellular electrical activity from the photoreceptors of midge.

The ontogeny of photosensitivity has been studied in a holometabolous insect, the midge Chironomus ramosus. The life cycle of midges shifts from an aquatic environment to a non-aquatic environment. Extracellular electrical activity of photoreceptor organs was recorded at larval and adult stages. We found an increase in photosensitivity as the larva metamorphosed to the adult stage. This is the first report of changes in photosensitivity during the development of any insect described in an ecological context.

Stimulation of transcription and translation by aurin tricarboxylic acid in mitochondrial lysates from Ehrlich ascites cells.

We have prepared a submitochondrial fraction from Ehrlich ascites tumor cell mitochondria which shows transcription and translation activities. The antibiotic aurin tricarboxylic acid (ATA) at low concentrations induces both RNA and protein synthetic activities of the mitochondrial lysate by several fold. At high concentrations, however, ATA inhibits the translation activity but continues to stimulate the transcription activity in a dose dependent manner up to 0.5 mM concentration tested. The lysate system transcribes endogenous DNA yielding RNA species resembling control mitochondrial RNA and synthesizes authentic cytochrome oxydase I and cytochrome oxidase II subunits.

Expression of the cytochrome b-URF6-URF5 region of the mouse mitochondrial genome.

The nature of RNA coded by the only light-strand (L-strand) open-reading frame unidentified reading frame 6 (URF6) was studied by using a variety of single- and double-strand DNA subclones derived from the 3.6-kilobase (kb) cytochrome b (cyt b)-URF5 coding region of the mouse mitochondrial genome. Northern blot experiments using single-strand-specific M13 clones indicate that both the heavy (H) and L strands of this genomic region are symmetrically transcribed and processed into poly(adenylic acid) [poly(A)] RNAs of comparable size. The 1.2- and 2.4-kb RNAs coded by the H strand, putative mRNAs for cyt b and URF5 reading frames, respectively, are derived from a common precursor of 3.6-kb RNA. The L-strand-coded 1.15-kb RNA, on the other hand, is derived from a short-lived precursor of 3.6-kb RNA by a multiple-step processing involving a 2.4-kb intermediate RNA. The S1 nuclease protection experiments using both the 3'- or 5'-end-labeled DNA probes and also affinity-purified 32P-labeled RNA probes indicate that the 1.15-kb RNA maps between the start of the URF6 reading frame (3' end) and a region 590-600 nucleotides to the 5' end of this reading frame. The 1.15-kb RNA thus contains the entire URF6 coding sequence and an about 590-nucleotide-long 3' untranslated region. The molar abundance of the three mRNAs in the steady-state mitochondrial RNA varies markedly. The 1.15-kb URF6 mRNA is only one-tenth the level of 1.2-kb cyt b mRNA, although it is nearly as abundant as the 2.4-kb URF5 mRNA.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiac dysautonomia in lepromatous leprosy.

Cardiovascular autonomic functions were studied in 32 patients of lepromatous leprosy, including 12 patients of lepra reaction. Fifty age and sex matched healthy subjects served as controls. Variable degree of autonomic dysfunction was observed in the study group. The derangement of autonomic functions in patients of leprosy can be explained on the basis of neurotrophic action of lepra bacilli that infiltrate the sympathetic and the parasympathetic fibres.