Cell Transdifferentiation and Reprogramming in Disease Modeling: Insights into the Neuronal and Cardiac Disease Models and Current Translational Strategies.

Cell transdifferentiation and reprogramming approaches in recent times have enabled the manipulation of cell fate by enrolling exogenous/artificial controls. The chemical/small molecule and regulatory components of transcription machinery serve as potential tools to execute cell transdifferentiation and have thereby uncovered new avenues for disease modeling and drug discovery. At the advanced stage, one can believe these methods can pave the way to develop efficient and sensitive gene therapy and regenerative medicine approaches. As we are beginning to learn about the utility of cell transdifferentiation and reprogramming, speculations about its applications in translational therapeutics are being largely anticipated. Although clinicians and researchers are endeavoring to scale these processes, we lack a comprehensive understanding of their mechanism(s), and the promises these offer for targeted and personalized therapeutics are scarce. In the present report, we endeavored to provide a detailed review of the original concept, methods and modalities enrolled in the field of cellular transdifferentiation and reprogramming. A special focus is given to the neuronal and cardiac systems/diseases towards scaling their utility in disease modeling and drug discovery.

Cancer chemoprevention by natural products: how far have we come?

Since ancient times, natural products, herbs and spices have been used for preventing several diseases, including cancer. The term chemoprevention was coined in the late 1970s and referred to the prevention of cancer by selective use of phytochemicals or their analogs. The field utilizes experimental carcinogenesis models to examine the efficacy of chemopreventive agents in a stage-specific manner. The concept of using naturally derived chemicals as potential chemopreventive agents has advanced the field dramatically. Throughout the years, a vast number of chemopreventive agents present in natural products have been evaluated using various experimental models. A number of them have progressed to early clinical trials. More recently, the focus has been directed towards molecular targeting of chemopreventive agents to identify mechanism(s) of action of these newly discovered bioactive compounds. Moreover, it has been recognized that single agents may not always be sufficient to provide chemopreventive efficacy, and, therefore, the new concept of combination chemoprevention by multiple agents or by the consumption of "whole foods" has become an increasingly attractive area of study. Novel technologies, such as nanotechnology, along with a better understanding of cancer stem cells, are certain to continue the advancement of the field of cancer chemoprevention in years to come.

Efficacy of chemopreventive agents in mouse mammary gland organ culture (MMOC) model: a comprehensive review.

Currently, breast cancer is considered as one of the leading causes for death in women in the United States. Consumption of natural products has received considerable attention in recent years as a possible approach for cancer prevention in general population. There are numerous cancer preventive agents present in the natural products, which may contribute to their chemopreventive properties. During the past two decades, numerous chemopreventive agents have been isolated and/or synthesized and evaluated for their efficacy in a variety of biological assays. To this end, we have established and utilized mouse mammary gland organ culture model (MMOC) as a bioassay for identifying chemopreventive agents. Mammary glands respond to growth promoting hormones and the physiological differentiation can be reproduced in MMOC in chemically defined medium by altering hormonal milieu. Both estrogen and progesterone dependent (mammary ductal lesions, MDL) and independent (mammary alveolar lesions, MAL) precancerous lesions can be induced in response to a 24 hour exposure to DMBA in MMOC. Suppression of the incidence and multiplicity of these lesions by a possible chemopreventive agent can serve as a tool to evaluate efficacy of potential experimental agents. Using this approach, we have evaluated more than 200 synthetic and natural product-derived chemopreventive agents in this model as a part of the National Cancer Institute-supported projects. Many of these chemopreventive agents expressing significant activity have progressed to the in vivo experimental mammary carcinogenesis studies. Thus, this bioassay has proven to be a valuable tool for screening cancer chemopreventive agents for breast cancer prevention and for understanding molecular mechanism(s) of action of these agents. In this comprehensive review, we provide a complete list of chemopreventive agents evaluated for the efficacy against development of mammary alveolar lesions (MAL) in MMOC along with the recent developments in this area. The structure-activity relationships for many chemopreventive agents evaluated in the MMOC model have been discussed.

Antiviral activity of phytochemicals: a comprehensive review.

Numerous numbers of biologically active agents have been identified for their diverse therapeutic functions. Detailed investigations of phytochemicals for antiviral activities have assumed greater importance in the last few decades. A wide variety of active phytochemicals, including the flavonoids, terpenoids, organosulfur compounds, limonoids, lignans, sulphides, polyphenolics, coumarins, saponins, chlorophyllins, furyl compounds, alkaloids, polyines, thiophenes, proteins and peptides have been found to have therapeutic applications against different genetically and functionally diverse viruses. The antiviral mechanism of these agents may be explained on basis of their antioxidant activities, scavenging capacities, inhibiting DNA, RNA synthesis, inhibition of the viral entry, or inhibiting the viral reproduction etc. Large number candidate substances such as phytochemicals and their synthetic derivatives have been identified by a combination of in vitro and in vivo studies in different biological assays. In this article we have made attempts to extensively review and provide comprehensive description of different phyto-antiviral agents. We have examined the recent developments in the field of plant derived antiviral agents. The major advances in the field of viral interactions in various biological assays have been summarized. In addition sources of origin, major viral studies mechanistic action and phase trials of various phytoantiviral agents have been included in the review.

Organoselenium compounds in cancer chemoprevention.

Selenium is an important trace element involved in different physiological functions of human body. Knowledge of selenium in biology of cancer has increased at rapid rate especially during last two decades. Basic research and clinical studies involving animal models and more recently studies in human strongly support the protective role of selenium against various types of cancer. Selenium's role as an essential nutrient is as a result of its unique chemistry enabled by the presence of selenium in selenoproteins. Epidemiological findings have linked inadequate status of selenium to increased risk of cancer. The protective action of selenium is a combination of various mechanisms. Amongst all the diverse mechanism that have been proposed some important ones are (a) Protective role of selenoproteins/selenoenzymes (b) induction of apoptosis (c) immune system effects (d) detoxification of antagonistic metals (e) inactivation of nuclear transcription factor (f) regulation of lipoxygenases (g) effect on advanced cancer condition (h) reduction of oxidative stress (i) induction of Phase II enzymes (j) androgen receptor down regulation (k) inhibition of DNA adduct formation (l) cell cycle arrest. The purpose of this review is to focus the recent development in the field of cancer prevention utilizing selenium. The metabolism of selenium compounds , carcinogenesis studies, epidemiological data, and various proposed chemopreventive mechanisms of selenium compounds along with results of human intervention trials have been discussed.

Comprehensive review of cancer chemopreventive agents evaluated in experimental carcinogenesis models and clinical trials.

Cancer chemoprevention refers to the use of pharmacological agents to inhibit, delay or reverse the multi-step process of carcinogenesis. The last two decades in particular have witnessed explosive growth in this emerging field of cancer chemoprevention. Extensive efforts to evaluate possible application of various chemopreventive agents, in individuals at high risk of neoplastic development have been carried out. Epidemiological studies suggest a protective role of several agents in reducing the risk of cancer. The protective action of all these agents is explained as a combination of various proposed mechanisms involving anti-oxidant, anti-inflammatory, immunomodulatory action, apoptosis induction, molecular association with carcinogen, cell cycle arrest, cell differentiation induction, antimicrobial effect, and anti- angiogenesis etc. Large numbers of candidate substances such as phytochemicals and their synthetic derivatives have been identified by a combination of in vitro and in vivo studies in a wide range of biological assays. However, a comprehensive description of these chemopreventive agents has not been extensively reviewed. In this review we discuss cancer chemopreventive agents in relation to their source, efficacy in cancer chemopreventive action in vivo and epidemiological data. The experimental carcinogenesis studies in different biological models, in addition to the contribution from our laboratory are summarized.

Organosulfur compounds in cancer chemoprevention.

There has been a renewed interest to the application of natural products derived from cruciferous plants and members of Allium genus in chemoprevention of cancer. The potential chemopreventive properties of these vegetables have been attributed to the presence of high level of organosulfur compounds in these plants. Organosulfur compounds have been shown to exert diverse biological effects such as: (a) induction of carcinogen detoxification, (b) inhibition of tumor cell proliferation, (c) antimicrobial effect, (d) free radical scavenging, (e) inhibition of DNA adduct formation, (f) induction of cell cycle arrest and induction of apoptosis etc. It has been suggested that these compounds act as chemopreventive agents through a combination of above mechanisms. Epidemiological and experimental carcinogenesis provides overwhelming evidence to support the claim that individuals consuming diet rich in organosulfur are less susceptible to different types of cancers. The protective effects of OSCs against carcinogenesis have been shown in stomach, esophagus, mammary glands, breast, skin and lungs of experimental animals. Cumulatively all these studies show a strong correlation between cancer prevention and intake of organosulfur compounds in one form or the other. Since the protective effects of all these phytochemicals are as a result of additives and synergistic combination further studies are warranted for complete understanding of chemopreventive action of organosulfur compounds and define the effective dose that has no toxicity in humans. In this review an attempt has been made to summarize the different aspects of organosulfur compounds with relation to their source, chemopreventive mechanistic action, epidemiologic and experimental carcinogenesis.

Down-regulation of inhibitor of apoptosis proteins by deguelin selectively induces apoptosis in breast cancer cells.

The identification of differentially regulated apoptotic signals in normal and tumor cells allows the development of cancer cell-selective therapies. Increasing evidence shows that the inhibitor of apoptosis (IAP) proteins survivin and XIAP are highly expressed in tumor cells but are absent or have very low levels of expression in normal adult tissues. We found that inhibiting AKT activity with 10 to 100 nM deguelin, a small molecule derived from natural products, markedly reduced the levels of both survivin and XIAP, inducing apoptosis in human breast cancer cells but not in normal cells. It is noteworthy that we detected an elevated level of cleaved poly(ADP-ribose) polymerase, a signature of caspase activation, without a significant increase in caspase activity in deguelin-treated cancer cells. Our results suggest that severe down-regulation of the IAPs by deguelin releases their inhibitory activity over pre-existing active caspases present in cancer cells, inducing apoptosis without the need for further caspase activation. Because normal cells have very low levels of p-AKT, XIAP, survivin, and pre-existing caspase activity, deguelin had little effect on those cells. In addition, we found that combining deguelin with chemotherapy drugs enhanced drug-induced apoptosis selectively in human tumor cells, which suggests that deguelin has great potential for chemosensitization and could represent a new therapeutic agent for treatment of breast cancer.

Synthesis of Abyssinone II and related compounds as potential chemopreventive agents.

A facile and efficient approach to the synthesis of prenylated flavonoids as potential chemopreventive agents has been described. This features the synthesis of prenyl halide, prenylation of p-hydroxybenzaldehyde, formation of prenylated polyhydroxychalcone and cyclization of prenylated polyhydroxychalcone to flavanones (15) and (16), and flavonol (17) starting from isoprene (1). The structures of all three compounds have been characterized by NMR, IR and mass spectroscopy.

Cancer chemopreventive activity of sulforamate derivatives.

Chemoprevention can be defined as an intervention in the carcinogenic process by use of natural or synthetic substances. Induction of Phase II enzyme is an important mechanism of chemoprevention. In the present studies we have synthesized several derivatives of (+)(-) 4-methylsulfinyl-1-(S-methyldithiocarbamyl)-butane (sulforamate) and evaluated their effectiveness as monofunctional inducer of the NAD(P)H Quinone oxidoreductase [quinone reductase (QR)] a phase II enzyme in cultured Hepa1c1c7 murine hepatoma cells. The cytotoxicity of some of the derivatives was strongly reduced in comparison to [(-)-1-isothiocyanato-4(R)-(methylsulfinyl)butane] (sulforaphane). However, the induction potential of these compounds was comparable to sulforaphane. On the basis of these results sulforamate derivatives can be regarded as simple, inexpensive and readily available chemopreventive agents.