Aneuploidy as a cause of impaired chromatin silencing and mating-type specification in budding yeast.

Aneuploidy and epigenetic alterations have long been associated with carcinogenesis, but it was unknown whether aneuploidy could disrupt the epigenetic states required for cellular differentiation. In this study, we found that ~3% of random aneuploid karyotypes in yeast disrupt the stable inheritance of silenced chromatin during cell proliferation. Karyotype analysis revealed that this phenotype was significantly correlated with gains of chromosomes III and X. Chromosome X disomy alone was sufficient to disrupt chromatin silencing and yeast mating-type identity as indicated by a lack of growth response to pheromone. The silencing defect was not limited to cryptic mating type loci and was associated with broad changes in histone modifications and chromatin localization of Sir2 histone deacetylase. The chromatin-silencing defect of disome X can be partially recapitulated by an extra copy of several genes on chromosome X. These results suggest that aneuploidy can directly cause epigenetic instability and disrupt cellular differentiation.

Single-Cell Based Quantitative Assay of Chromosome Transmission Fidelity.

Errors in mitosis are a primary cause of chromosome instability (CIN), generating aneuploid progeny cells. Whereas a variety of factors can influence CIN, under most conditions mitotic errors are rare events that have been difficult to measure accurately. Here we report a green fluorescent protein-based quantitative chromosome transmission fidelity (qCTF) assay in budding yeast that allows sensitive and quantitative detection of CIN and can be easily adapted to high-throughput analysis. Using the qCTF assay, we performed genome-wide quantitative profiling of genes that affect CIN in a dosage-dependent manner and identified genes that elevate CIN when either increased (icCIN) or decreased in copy number (dcCIN). Unexpectedly, qCTF screening also revealed genes whose change in copy number quantitatively suppress CIN, suggesting that the basal error rate of the wild-type genome is not minimized, but rather, may have evolved toward an optimal level that balances both stability and low-level karyotype variation for evolutionary adaptation.

Targeting the adaptability of heterogeneous aneuploids.

Aneuploid genomes, characterized by unbalanced chromosome stoichiometry (karyotype), are associated with cancer malignancy and drug resistance of pathogenic fungi. The phenotypic diversity resulting from karyotypic diversity endows the cell population with superior adaptability. We show here, using a combination of experimental data and a general stochastic model, that the degree of phenotypic variation, thus evolvability, escalates with the degree of overall growth suppression. Such scaling likely explains the challenge of treating aneuploidy diseases with a single stress-inducing agent. Instead, we propose the design of an "evolutionary trap" (ET) targeting both karyotypic diversity and fitness. This strategy entails a selective condition "channeling" a karyotypically divergent population into one with a predominant and predictably drugable karyotypic feature. We provide a proof-of-principle case in budding yeast and demonstrate the potential efficacy of this strategy toward aneuploidy-based azole resistance in Candida albicans. By analyzing existing pharmacogenomics data, we propose the potential design of an ET against glioblastoma.

Evaluation of antidiarrheal and in vitro antiprotozoal activities of extracts of leaves of Alocasia indica.

CONTEXT: Alocasia indica Schott (Araceae) is used in several regions of India, especially in rural communities, by traditional medicine practitioners to treat diarrhea. However, no scientific data are available to justify the traditional potentials of the plant species in gastrointestinal disorders. OBJECTIVE: To evaluate the antidiarrheal and in vitro antiprotozoal activities of extracts of leaves of Alocasia indica using various pharmacological models. MATERIALS AND METHODS: In vitro antidiarrheal activity of aqueous and ethanol extracts of Alocasia indica was evaluated against Escherichia coli, Salmonella typhimurium, Shigella flexneri and Staphylococcus aureus by agar well diffusion method. In vivo antidiarrheal activity of the extracts was studied against recinolic acid-induced diarrhea and magnesium sulfate-induced diarrhea. The effect of the extracts on normal intestinal transit, recinolic acid-induced intestinal transit, recinolic acid-induced intestinal fluid accumulation (enteropooling) and gastric emptying was assessed. In vitro antiprotozoal activity of aqueous and ethanol extracts of Alocasia indica was studied against Entamoeba histolytica and Giardia intestinalis. RESULTS: The aqueous and ethanol extracts exhibited significant in vitro antidiarrheal activity compared to the standard drug ciprofloxacine (10 µg/mL). The plant extracts showed significant (P <0.05) and dose-dependent antidiarrheal activity comparable to that of the reference drug, loperamide (10 mg/kg). The plant extracts exhibited significant in vitro antiprotozoal activity against both protozoa compared to the standard amebicidal and giardicidal drugs, metronidazole and emetine. DISCUSSION AND CONCLUSION: The results showed that the extracts of Alocasia indica have significant antidiarrheal and in vitro antiprotozoal activities which support its use in traditional herbal medicine practice.

Novel strategies for the treatment of inflammatory hyperalgesia.

There is a large unmet medical need in the area of treatment of inflammatory pain initiated by tissue damage or inflammation that manifests as spontaneous pain and pain hypersensitivity (hyperalgesia).The current review focuses on the key mechanisms that produce hyperalgesia that accompanies inflammation. Also, the inflammatory mediators that interact with neurons to produce hyperalgesia are explored. As the dominant classes of analgesic drugs such as the NSAIDs and the opiates are limited by their side effects and tolerability, elucidation of the molecular mechanisms responsible for inflammatory pain provides novel opportunities for therapeutic approaches for managing inflammatory pain, with improved specificity, efficacy, and possibly with fewer toxic effects.

Hepatoprotective activity of hydroalcoholic extract of leaves of Alocasia indica (Linn.).

Oral administration of hydroalcoholic extract of A. indica (250 and 500 mg/kg) effectively inhibited CCl4 and paracetamol induced changes in the serum marker enzymes, cholesterol, serum protein and albumin in a dose-dependent manner as compared to the normal and the standard drug silymarin-treated groups. Hepatic steatosis, fatty infiltration, hydropic degeneration and necrosis observed in CCl4 and paracetamol-treated groups were completely absent in histology of the liver sections of the animals treated with the extracts. The results suggests that the hydroalcoholic extract of leaves of A. indica possess significant potential as hepatoprotective agent.