Insights into the Role of Defective Apoptosis in Cancer Pathogenesis and Therapy

One form of programmed cell death (PCD) is apoptosis. Defective apoptosis is an indispensable causative factor in the development of cancer that allows cancer cells to survive longer and favors the accumulation of oncogenic mutations. Further, upregulation of antiapoptotic proteins (e.g., Bcl-2, Mcl-1) and loss of pro-apoptotic proteins (e.g., Bid, Bad, Bax, Bak) strongly favors apoptosis evasion. The ability of cancer cells to evade apoptosis is critical for the progression and clonal expansion of malignantly transformed cells. Defective apoptosis imparts proliferative advantage to cancer cells or cells with the potential to become cancerous. The mechanisms employed by cancer cells to evade apoptosis can be used in the strategic design of therapeutic regimens aimed at exploiting apoptotic signaling networks to ensure tumor-specific cell death. Therefore, to ensure tumor-specific cell death, we may need to exploit the expression and/or function of different components of apoptotic signaling that are critical for maintaining cell survival and are regulated differently in tumor cells than normal cells. Both inhibitors of anti-apoptotic proteins and activators of pro-apoptotic proteins can be used for cancer therapy. In this chapter, we attempted to summarize the knowledge about the molecular mechanisms of defective apoptosis that could be translated into the development of novel therapeutic agents and therapeutic modalities for cancer treatment

Cell Cycle and Factors Involved in Inhibition or Progression of Breast Cancer

Cell cycle progression is driven by the sequential activation of a family of cyclin-dependent kinases (CDKs), which phosphorylate and activate proteins that execute events critical to cell cycle progression. Cell cycle checkpoints are scrutiny points that display the order, integrity, and fidelity of the major proceedings of the cell cycle. These comprise development to the correct cell size, the replication, integrity of the chromosomes, and their precise separation at mitosis. Many of these mechanisms are prehistoric in origin and highly preserved and hence have been deeply well versed by studies in model organisms such as the yeasts as well as in higher organisms. These molecular mechanisms switch alternative cell fates with substantial impact on tumor suppression. In the present study, we have explained different checkpoint pathways and the consequences of their dysfunction on cell fate in cancer

Trace elements and human health in the foot hill settlements of Pir Panjal range in Kashmir.

Geomedical study of essential trace elements and human health involves analysis of cause and effect relationship of human health and geographic environment by analyzing the geo-chemical status of soil, water, food items and air, assessing the dependence of people on local food items and their nutrient content, the prevalence of food preparation and cooking methodologies, incidence and prevalence of related disorders in the community, and mapping and modeling the spatial distribution and correlation of the human health with the physico-chemical and socio-economic factors. Both the physico-chemical (as nutrients in soil, water or food) and socioeconomic (as income levels, type of diet, cooking styles, and the like) determinants have a close relationship with the human health.Digital copy of Ph.D thesis.University of Kashmir

Cancer Chemoprevention and Piperine: Molecular Mechanisms and Therapeutic Opportunities

Cancer is a genetic disease characterized by unregulated growth and dissemination of malignantly transformed neoplastic cells. The process of cancer development goes through several stages of biochemical and genetic alterations in a target cell. Several dietary alkaloids have been found to inhibit the molecular events and signaling pathways associated with various stages of cancer development and therefore are useful in cancer chemoprevention. Cancer chemoprevention has long been recognized as an important prophylactic strategy to reduce the burden of cancer on health care system. Cancer chemoprevention assumes the use of one or more pharmacologically active agents to block, suppress, prevent, or reverse the development of invasive cancer. Piperine is an active alkaloid with an excellent spectrum of therapeutic activities such as anti-oxidant, anti-inflammatory, immunomodulatory, anti-asthmatic, anti-convulsant, anti-mutagenic, antimycobacterial, anti-amoebic, and anti-cancer activities. In this article, we made an attempt to sum up the current knowledge on piperine that supports the chemopreventive potential of this dietary phytochemical. Many mechanisms have been purported to understand the chemopreventive action of piperine. Piperine has been reported to inhibit the proliferation and survival of many types of cancer cells through its influence on activation of apoptotic signaling and inhibition of cell cycle progression. Piperine is known to affect cancer cells in variety of other ways such as influencing the redox homeostasis, inhibiting cancer stem cell (CSC) self-renewal and modulation of ER stress and autophagy. Piperine can modify activity of many enzymes and transcription factors to inhibit invasion, metastasis, and angiogenesis. Piperine is a potent inhibitor of p-glycoprotein (P-gp) and has a significant effect on the drug metabolizing enzyme (DME) system. Because of its inhibitory influence on P-gp activity, piperine can reverse multidrug resistance (MDR) in cancer cells and acts as bioavailability enhancer for many chemotherapeutic agents. In this article, we emphasize the potential of piperine as a promising cancer chemopreventive agent and the knowledge we collected in this review can be applied in the strategic design of future researches particularly human intervention trials with piperine

Precision and Recall of Five Search Engines for Retrieval of Scholarly Information in the Field of Biotechnology

This paper presents the results of a research conducted about five search engines- AltaVista, Google, HotBot, Scirus and Bioweb -for retrieving scholarly information using Biotechnology related search terms. The search engines are evaluated taking the first ten results pertaining to 'scholarly information' for estimation of precision and recall. It shows that Scirus is most comprehensive in retrieving 'scholarly information' followed by Google and HotBot. It also reveals that the search engines (except Bioweb) perform well on structured queries while Bioweb performs better on unstructured queries

Targeting Oncogene Addiction for Cancer Therapy

Oncogene addiction, a term first coined by Bernard Weinstein in 2000, refers to a condition where a tumor cell, despite harboring a multitude of genetic alterations, depends on a single oncogenic pathway or oncoprotein for sustained proliferation and survival. Several lines of evidence from mammalian cell culture models, genetically modified mice models, and human intervention trials of targeted drugs have revealed that many tumors, if not all, rely on oncogene addiction for sustained proliferation and survival. Oncogene addiction strongly impacts the therapeutic response of tumors to acute oncoprotein inhibition. An important implication of oncogene addiction is that inhibiting this critical pathway, on which cancer cells become dependent, can cause selective and specific cell death in cancer cells while sparing normal surrounding cells that are not oncogene addicted. However, the mechanism by which cancer cells become dependent on a single pathway or activated oncoprotein is not precisely understood in most cases. Thus, a better understanding of oncogene addiction may provide a rationale for improving current cancer therapies and help develop novel therapeutic strategies for the management of cancer

Inhibition of biofilm growth of Gram-positive and Gram-negative bacteria on tuned polyurethane nanofibers

112-121Biofilm formation is a process of bacterial attachment whereby they fasten irreversibly to a biomaterial surface and lead to unwanted phenotypic changes. The chief concern is its formation and to prevent the harmful changes that follow the accumulation of bacteria on implants, so the scientific community has made efforts. In this study, we attempted to fabricate a novel tissue engineering candidate to prevent the biofilm formation desired by ideal biomaterials. We prepared the micro/nanofibers of polyurethane (PU) incorporated with hydrophilic β-cyclodextrin (CD) by electrospinning technique. Further on, these as-spun fibers were in fused with an antibacterial agent. As an antibacterial agent, silver nanoparticles (Ag NPs) were adsorbed on scaffolds. Among the varied methods of its adsorption, adsorption by sonication and hydrothermal process were chosen. Characterization studies performed were scanning electron microscopy (SEM) and water contact angle analysis. The uniform morphology of nanofibers was seen in SEM micrographs which mimics the extracellular matrix. The hydrophilicity test showed the increased hydrophilicity of scaffolds with a decrease in contact angle in CD and Ag NPs incorporated fibre scaffolds. The Ag release assay showed slow release in the case of the fibers where Ag was adsorbed by hydrothermal treatment compared to adsorption by sonication. The antibacterial tests show inhibition of bacteria to different degrees by the fibers. The highest zones were seen in the case of samples with Ag NPs adsorption by sonication. The in vitro MTT assay presented that these scaffolds were non-toxic to the cells and could be employed in biological applications

A Potent Inhibitor of Phosphoinositide 3-Kinase (PI3K) and Mitogen Activated Protein (MAP) Kinase Signalling, Quercetin (3, 3', 4', 5, 7-Pentahydroxyflavone) Promotes Cell Death in Ultraviolet (UV)-B-Irradiated B16F10 Melanoma Cells.

Ultraviolet (UV) radiation-induced skin damage contributes strongly to the formation of melanoma, a highly lethal form of skin cancer. Quercetin (Qu), the most widely consumed dietary bioflavonoid and well known inhibitor of phosphoinositide 3-kinase (PI3K) and mitogen activated protein (MAP) kinase signalling, has been reported to be chemopreventive in several forms of non-melanoma skin cancers. Here, we report that the treatment of ultraviolet (UV)-B-irradiated B16F10 melanoma cells with quercetin resulted in a dose dependent reduction in cell viability and increased apoptosis. The present study has brought out that the pro-apoptotic effects of quercetin in UVB-irradiated B16F10 cells are mediated through the elevation of intracellular reactive oxygen species (ROS) formation, calcium homeostasis imbalance, modulation of anti-oxidant defence response and depolarization of mitochondrial membrane potential (ΔΨM). Promotion of UVB-induced cell death by quercetin was further revealed by cleavage of chromosomal DNA, caspase activation, poly (ADP) ribose polymerase (PARP) cleavage, and an increase in sub-G1 cells. Quercetin markedly attenuated MEK-ERK signalling, influenced PI3K/Akt pathway, and potentially enhanced the UVB-induced NF-κB nuclear translocation. Furthermore, combined UVB and quercetin treatment decreased the ratio of Bcl-2 to that of Bax, and upregulated the expression of Bim and apoptosis inducing factor (AIF). Overall, these results suggest the possibility of using quercetin in combination with UVB as a possible treatment option for melanoma in future

Quercetin attenuates PI3K-Akt pathway and MAPK signalling in UVB-irradiated B16F10 melanoma cells.

<p>A, western blot analysis of B-raf, p-MEK, MEK1/2, p-ERK, ERK1/2, phospho-p38, p-38, phospho-JNK and JNK in cells treated with Qu and/or UVB. β-actin was used as loading control. B, C, D, E and F represent the densitometric analysis of B-raf, p-MEK/MEK, p-ERK/ERK, phospho-p38/p-38, phospho-JNK/JNK respectively. G, immunoblot analysis of PI3K-α and p-Akt in B16F10 cells at 24 h post-UVB and/ or Qu treatment. Signals were quantified for PI3K (H) and p-Akt (I) using Image Lab Software (Bio Rad). *, P<0.05; **, P<0.01 for control versus treatments; #, P<0.05, ##, P<0.01 for control versus UVB-alone treatment versus UVB + Qu treatments.</p

Quercetin elevates UVB-induced reactive oxygen formation and intracellular calcium ion level.

<p>A, analysis of reactive oxygen species (ROS) formation immediately after UVB irradiation in B16F10 cells pre-treated with Qu for 24 hours. The generation of ROS was measured using BD FACS Calibur Aria. B, represents the fold increase in DCF fluorescence (a measure of ROS formation) relative to control. *, P<0.05; **, P<0.01 for control versus treatments; #, P<0.05, ##, P<0.01 for control versus UVB-alone treatment versus UVB + Qu treatments. C, effect of ascorbic acid (1 mM) on cell viability in response to treatment of UVB–irradiated B16F10 cells with Qu; UVB control cells were taken as 100% viable. D, analysis of intracellular free Ca²⁺ immediately after UVB exposure in B16F10 cells pre-treated with Qu for 24 hours. E, represents the effect of UVB (5 mJ/cm²) on calcium elevation in BAPTA-AM preloaded B16F10 cells. F, represents the fold increase in intracellular free calcium relative to control. *, P<0.05; **, P<0.01 for control versus treatments; #, P<0.05, ##, P<0.01 for control versus UVB-alone treatment versus UVB + Qu treatments.</p