Emerging Roles of Glycogen Synthase Kinase 3 in the Treatment of Brain Tumors

The constitutively active protein glycogen synthase kinase 3 (GSK3), a serine/threonine kinase, acts paradoxically as a tumor suppressor in some cancers while potentiates growth in others. Deciphering what governs its actions is vital for understanding many pathological conditions, including brain cancer. What are seemingly disparate roles of GSK3 stems from the complex regulation of many cellular functions by GSK3. This review focuses on the regulation of GSK3, its role in survival, apoptosis and DNA damage, and finally its potential therapeutic impact in brain cancer. A thorough understanding of this versatile protein is critical for improving the outcome of various diseases, especially cancer

Antimicrobial and Antioxidant activities of Arnebia benthamii (Wall ex. G. Don Johnston) - A Critically Endangered Medicinal plant of Kashmir

Plants used in traditional medicines contain a vast array of substances that can be used to treat chronic and infectious diseases and the present study was carried out with the same intentto appraisethe possible medicinal value of Arnebia benthamii L. (Wall. ex G. Don) Johnston [Syn Macrotomia benthamii (Wall.) DC.] a threatened medicinal plant of Kashmir valley by examining its phyto-chemical constituents and evaluating the antimicrobial and antioxidant activity. Preliminary phytochemical screening was carried out to detect the presence of phyto-chemicals that add to the medicinal value of the plant. The antimicrobial assay was carried out by Disc diffusion and Micro-broth dilution methods. The crude plant extracts (both root as well as aerial parts) exhibited significant antimicrobial activity on majority of test organisms tested. The highest occurrence of secondary metabolites was of alkaloids and phenolic substances. The tannins and saponins were absent in all plant extracts. The total phenolic content that was quantitatively estimated showed highest presence in methanol extracts of the aerial parts. The antibacterial results revealed that methanol extracts of aerial parts were found to exhibit significant antibacterial activities against all tested bacterial strains except Staphylococcus aureus which was found resistant. The highest inhibition zone diameter (30mm) was recorded for Pseudomonas aeruginosa and Escherichia coli with respect to control i.e. Gentamycin (16 and21mm) followed by Salmonella typhimurium (28 mm). Chloroform extract also showed good inhibitory activity against all the tested bacterial strains likeE. coli (22mm) followed by Klebsella pnuemonie (20 mm) and P. aeruginosa (17mm). The aqueous extract didn’t show any inhibitory activity against the tested bacterial strains. The root extracts were separately tested for antibacterial activity against pathogenic strains and it was apparent from the results that they were less active than aerial part extracts. Among the strains tested, S. aureus was found susceptible to chloroform, ethyl acetate and methanol root extracts with an average inhibition zone diameter (10 mm) with respect to control and rest of extracts showed no activity against it. The Shigella flexneri was found susceptible to all the root extracts and the highest inhibition zone diameter was recorded for methanol (20mm) followed by ethanol (15 mm)against the control (Erythromicin 30 mm). Among all the strains, E. coli was highly susceptible towards the methanol root extracts followed by chloroform and ethyl acetate extract while the rest of the extracts did not exhibit any inhibitory activity. Most of the root extracts exhibit highest antibacterial activity against S. typhimurium compared to aerial parts. The screening served a s an indicator f or the selection of bacterial strains that displayed antibacterial activity for further testing to determine the MIC’s of plant extracts. Four bacterial strains S. fle xnerii, K. pneumonia, E. coli and P. aeruginosa were found viable for testing with the specific plant extracts. S. flexnerii was found highly susceptible towards methanol aerial part extract with MIC and MBC value of 200μg/ml and 750 μg/ml respectively as compared to reference (Erythromycin75 and 100 μg/ml) followed by methanol root extract { MIC 300 μg/ml and500 MBC μg/ml}. Methanol aerial part extract exhibited the MIC value 500 μg/ml and MBC 750 μg/ml against K. pneumonia. However the root extracts showed co mparatively higher value of MIC against the tested organism ranging f rom400-500μg/ml with respect to positive control (MIC-150 μg/ml).The MIC value for E . coli ranged between 150 to 500 μg/ml towards aerial part extracts w ith lowest MIC observed for methanol aerial part extract with respect to Erythromycin (175 μg/ml), and for root extract MIC value ranged between 225 -425 μg/ml. P. aeruginosa was found to be most susceptible towards all aerial part extracts with MIC value ranged between 75 μg/ml and 425 μg/ml and MBC value from 100 to750 μg/ml. All the fungal strains except Candida parapsilosis were more or less inhibited b y both aerial and root part extracts of the plant. The aqueous extract of both root as well as aerial parts did not show any antifungal activity. Asperigillus flavus was found to be highly susceptible to butanol aerial part extract with inhibition zone diameter (25mm) followed by ethyl acetate extract(22 mm) and chlorof orm extract (14 mm) compared to the control (Nystatin 35mm) used. The methanol aerial part extract showed highest inhibitory activity against Asperigill us versicolor with inhibition zone diameter (22 mm) and Acremonium spp (25 mm). The petroleum ether, ethyl acetate and chloroform extracts of aerial part did not exhibit any inhibitory activity against Candida spp . Only methanol extract followed by ethanol and butanol extract exhibited antif ungal activity against Candida spp. Among the Candida spp, the highest inhibition zone diameter (14 mm) of methanol extract was seen against C. albicans whereas C. parapsalosis was found completely resistant against the all aerial part extra cts. The ethanol and aqueous root extracts didn’t exhibit any inhibitory activity against any tested fungal strains. Meanwhile the ethyl acetate extract sho wed highest inhibition zone diameter(33mm) against C. albicans f ollowed by Acremonium spp (18mm).The methanol root extract showed good inhibitory activity with an average inhibition zone diameter (12mm) against A. versicolor, C. albicans and C. kruesie with respect to reference used. The four in-vitro tests i.e. DPPH radical scavenging action, riboflavin photo- oxidation method, hydroxyl scavenging and the lipid peroxidation assay for antioxidant activity were used. Together all the methods provide a better assessment of antioxidant properties and results revealed that inhibitory activity was concentration dependent. Free radical scavenging potential of aerial and root part extracts at different concentrations was tested by the DPPH method. Highest inhibition of 86% and 94% was recorded for both methanol extracts of aerial as well as root parts with respect to reference (Ascorbic acid 90%) at the higher concentration (300 μg/ml) followed by ethyl acetate (60%) and chloroform extract (63 %) of aerial parts. The superoxide radical scavenging activity of aerial parts was observed in the following order butanol extract (85%) >ethyl acetate (79%)> methanol extract (70%) however Petroleum ether, ethanol and aqueous extracts didn't exhibit any scavenging activity. The root extracts were also effective in scavenging the superoxide radicals and the order of scavenging was as butanol (91%)> methanol (88%)>aqueous (79%) extracts. As far as the protective effect of deoxyribose was concerned, the highest inhibition of radicals was observed for methanol extract of root part and aerial part (~85% inhibition). The ethanol extracts of both parts were found to be ineffective. The overall inhibition of FeSO4 induced lipid peroxidation was high in presence of positive control (ascorbic acid 95.78±1.0%) compared to the plant extracts of A. benthamii. However, the ethyl acetate extract of aerial parts (95 %) showed almost the same activity as compared to the reference antioxidant. The ethyl acetate (87%) of root parts also exhibited significant inhibitory activity followed by ethanol extracts (78%)

Evasion of anti-growth signaling: a key step in tumorigenesis and potential target for treatment and prophylaxis by natural compounds

The evasion of anti-growth signaling is an important characteristic of cancer cells. In order to continue to proliferate, cancer cells must somehow uncouple themselves from the many signals that exist to slow down cell growth. Here, we define the anti-growth signaling process, and review several important pathways involved in growth signaling: p53, phosphatase and tensin homolog (PTEN), retinoblastoma protein (Rb), Hippo, growth differentiation factor 15 (GDF15), AT-rich interactive domain 1A (ARID1A), Notch, insulin-like growth factor (IGF), and Krüppel-like factor 5 (KLF5) pathways. Aberrations in these processes in cancer cells involve mutations and thus the suppression of genes that prevent growth, as well as mutation and activation of genes involved in driving cell growth. Using these pathways as examples, we prioritize molecular targets that might be leveraged to promote anti-growth signaling in cancer cells. Interestingly, naturally-occurring phytochemicals found in human diets (either singly or as mixtures) may promote anti-growth signaling, and do so without the potentially adverse effects associated with synthetic chemicals. We review examples of naturally-occurring phytochemicals that may be applied to prevent cancer by antagonizing growth signaling, and propose one phytochemical for each pathway. These are: epigallocatechin-3-gallate (EGCG) for the Rb pathway, luteolin for p53, curcumin for PTEN, porphyrins for Hippo, genistein for GDF15, resveratrol for ARID1A, withaferin A for Notch and diguelin for the IGF1-receptor pathway. The coordination of anti-growth signaling and natural compound studies will provide insight into the future application of these compounds in the clinical setting

Predictions for the future of kallikrein-related peptidases in molecular diagnostics

Kallikrein-related peptidases (KLKs) form a cancer-related ensemble of serine proteases. This multigene family hosts the most widely used cancer biomarker that is PSA-KLK3, with millions of tests performed annually worldwide. The present report provides an overview of the biomarker potential of the extended KLK family (KLK1-KLK15) in various disease settings and envisages approaches that could lead to additional KLK-driven applications in future molecular diagnostics. Particular focus is given on the inclusion of KLKs into multifaceted cancer biomarker panels that provide enhanced diagnostic, prognostic and/or predictive accuracy in several human malignancies. Such panels have been described so far for prostate, ovarian, lung and colorectal cancers. The role of KLKs as biomarkers in non-malignant disease settings, such as Alzheimer’s disease and multiple sclerosis, is also commented upon. Predictions are given on the challenges and future directions regarding clinically oriented KLK research

Designing a broad-spectrum integrative approach for cancer prevention and treatment

Targeted therapies and the consequent adoption of "personalized" oncology have achieved notablesuccesses in some cancers; however, significant problems remain with this approach. Many targetedtherapies are highly toxic, costs are extremely high, and most patients experience relapse after a fewdisease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistantimmortalized cells that have adopted alternate and compensatory pathways (i.e., pathways that are notreliant upon the same mechanisms as those which have been targeted). To address these limitations, aninternational task force of 180 scientists was assembled to explore the concept of a low-toxicity "broad-spectrum" therapeutic approach that could simultaneously target many key pathways and mechanisms. Using cancer hallmark phenotypes and the tumor microenvironment to account for the various aspectsof relevant cancer biology, interdisciplinary teams reviewed each hallmark area and nominated a widerange of high-priority targets (74 in total) that could be modified to improve patient outcomes. For thesetargets, corresponding low-toxicity therapeutic approaches were then suggested, many of which werephytochemicals. Proposed actions on each target and all of the approaches were further reviewed forknown effects on other hallmark areas and the tumor microenvironment. Potential contrary or procar-cinogenic effects were found for 3.9% of the relationships between targets and hallmarks, and mixedevidence of complementary and contrary relationships was found for 7.1%. Approximately 67% of therelationships revealed potentially complementary effects, and the remainder had no known relationship. Among the approaches, 1.1% had contrary, 2.8% had mixed and 62.1% had complementary relationships. These results suggest that a broad-spectrum approach should be feasible from a safety standpoint. Thisnovel approach has potential to be relatively inexpensive, it should help us address stages and types ofcancer that lack conventional treatment, and it may reduce relapse risks. A proposed agenda for futureresearch is offered

Radical scavenging potential and DNA damage protection of wild edible mushrooms of Kashmir Himalaya

The edible mushrooms Verpa bohemica and Morchella esculenta are locally used for dietary and antioxidant in tribal areas of Kashmir Himalaya. In the present study, sequences of solvents on the basis of their polarity were used for the extraction from selected mushrooms. The comprehensive antioxidant activity of all edible mushroom extracts was evaluated by seven different methods. V. bohemica exhibited significant inhibitory activity of radicals among all the mushrooms while Morchella extracts protected the DNA damage from OH· radicals. This study provides us the substantiation for the use of these mushrooms as antioxidants besides being already eaten as food

Cloning and Expression of the Organophosphate Pesticide-Degrading α-β Hydrolase Gene in Plasmid pMK-07 to Confer Cross-Resistance to Antibiotics

Pesticide residual persistence in agriculture soil selectively increases the pesticide-degrading population and transfers the pesticide-degrading gene to other populations, leading to cross-resistance to a wide range of antibiotics. The enzymes that degrade pesticides can also catabolize the antibiotics by inducing changes in the gene or protein structure through induced mutations. The present work focuses on the pesticide-degrading bacteria isolated from an agricultural field that develop cross-resistance to antibiotics. This cross-resistance is developed through catabolic gene clusters present in an extrachromosomal plasmid. A larger plasmid (236.7 Kbp) isolated from Bacillus sp. was sequenced by next-generation sequencing, and important features such as α-β hydrolase, DNA topoisomerase, DNA polymerase III subunit beta, reverse transcriptase, plasmid replication rep X, recombination U, transposase, and S-formylglutathione hydrolase were found in this plasmid. Among these, the α-β hydrolase enzyme is known for the degradation of organophosphate pesticides. The cloning and expression of the α-β hydrolase gene imply nonspecific cleavage of antibiotics through a cross-resistance phenomenon in the host. The docking of α-β hydrolase with a spectrum of antibiotics showed a high G-score against chloramphenicol (−3.793), streptomycin (−2.865), cefotaxime (−5.885), ampicillin (−4.316), and tetracycline (−3.972). This study concludes that continuous exposure to pesticide residues may lead to the emergence of multidrug-resistant strains among the wild microbial flora