Sarandeep S.S. Boyanapalli

Bio: Sarandeep S.S. Boyanapalli is an academic researcher from Rutgers University. The author has contributed to research in topics: DNA methylation & Epigenetics. The author has an hindex of 9, co-authored 11 publications receiving 546 citations.

Epigenetic CpG demethylation of the promoter and reactivation of the expression of Neurog1 by curcumin in prostate LNCaP cells.

Abstract: Curcumin (CUR), a major bioactive polyphenolic component from turmeric curry, Curcuma longa, has been shown to be a potent anti-cancer phytochemical with well-established anti-inflammatory and anti-oxidative stress effects. Chromatin remodeling-related epigenetic regulation has emerged as an important mechanism of carcinogenesis, chemoprevention, and chemotherapy. CUR has been found to inhibit histone acetyltransferase activity, and it was also postulated to be a potential DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitor. In this study, we show that when human prostate LNCaP cells were treated with CUR, it led to demethylation of the first 14 CpG sites of the CpG island of the Neurog1 gene and restored the expression of this cancer-related CpG-methylation epigenome marker gene. At the protein level, CUR treatment had limited effects on the expression of epigenetic modifying proteins MBD2, MeCP2, DNMT1, and DNMT3a. Using ChIP assay, CUR decreased MeCP2 binding to the promoter of Neurog1 dramatically. CUR treatment showed different effects on the protein expression of HDACs, increasing the expression of HDAC1, 4, 5, and 8 but decreasing HDAC3. However, the total HDAC activity was decreased upon CUR treatment. Further analysis of the tri-methylation of histone 3 at lysine 27 (H3K27me3) showed that CUR decreased the enrichment of H3K27me3 at the Neurog1 promoter region as well as at the global level. Taken together, our present study provides evidence on the CpG demethylation ability of CUR on Neurog1 while activating its expression, suggesting a potential epigenetic modifying role for this phytochemical compound in human prostate cancer cells.

“Curcumin, the King of Spices”: Epigenetic Regulatory Mechanisms in the Prevention of Cancer, Neurological, and Inflammatory Diseases

Abstract: Curcumin (diferuloylmethane), a polyphenolic compound, is a component of Curcuma longa, commonly known as turmeric. It is a well-known anti-inflammatory, anti-oxidative, and anti-lipidemic agent and has recently been shown to modulate several diseases via epigenetic regulation. Many recent studies have demonstrated the role of epigenetic inactivation of pivotal genes that regulate human pathologies, such as neurocognitive disorders, inflammation, obesity, and cancers. Epigenetic changes involve changes in DNA methylation, histone modifications, or altered microRNA expression patterns which are known to be interconnected and play a key role in tumor progression and failure of conventional chemotherapy. The majority of epigenetic changes are influenced by lifestyle and diets. In this regard, dietary phytochemicals as dietary supplements have emerged as a promising source that are able to reverse these epigenetic alterations, to actively regulate gene expression and molecular targets that are known to promote tumorigenesis, and also to prevent age-related diseases through epigenetic modifications. There have been several studies which reported the role of curcumin as an epigenetic regulator in neurological disorders, inflammation, and in diabetes apart from cancers. The epigenetic regulatory roles of curcumin include (1) inhibition of DNA methyltransferases (DNMTs), which has been well defined from the recent studies on its function as a DNA hypomethylating agent; (2) regulation of histone modifications via regulation of histone acetyltransferases (HATs) and histone deacetylases (HDACs); and (3) regulation of micro RNAs (miRNA). This review summarizes the current knowledge on the effect of curcumin in the treatment and/or prevention of inflammation, neurodegenerative diseases, and cancers by regulating histone deacetylases, histone acetyltransferases, and DNA methyltransferases.

Nrf2 Knockout Attenuates the Anti-Inflammatory Effects of Phenethyl Isothiocyanate and Curcumin

Abstract: The role of phytochemicals in preventive and therapeutic medicine is a major area of scientific research. Several studies have illustrated the mechanistic roles of phytochemicals in Nrf2 transcriptional activation. The present study aims to examine the importance of the transcription factor Nrf2 by treating peritoneal macrophages from Nrf2(+/+) and Nrf2(-/-) mice ex vivo with phenethyl isothiocyanate (PEITC) and curcumin (CUR). The peritoneal macrophages were pretreated with the drugs and challenged with lipopolysaccharides (LPSs) alone and in combination with PEITC or CUR to assess their anti-inflammatory and antioxidative effects based on gene and protein expression in the treated cells. LPS treatment resulted in an increase in the expression of inflammatory markers such as cycloxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in both Nrf2(+/+) and Nrf2(-/-) macrophages, detected by quantitative polymerase chain reaction (qPCR). Nrf2(+/+) macrophages treated with PEITC and CUR exhibited a significant decrease in the expression of these anti-inflammatory genes along with an increase in the expression of hemeoxygenase-1 (HO-1), which is an antioxidative stress gene downstream of the Nrf2 transcription factor battery. Although there was no significant decrease in the expression of the anti-inflammatory genes or an increase in HO-1 expression in Nrf2(-/-) macrophages treated with either PEITC or CUR, there was a significant decrease in the protein expression of COX-2 and an increase in the expression of HO-1 in Nrf2(+/+) macrophages treated with PEITC compared to that with CUR treatment. No significant changes were observed in the macrophages from knockout animals. Additionally, there was a significant decrease in LPS-induced IL-6 and TNF-α production following PEITC treatment compared with that following CUR in Nrf2(+/+) macrophages, whereas no change was observed in the macrophages from knockout animals. The results from qPCR, western blot, and ELISA analyses in macrophages from Nrf2(+/+) and Nrf2 (-/-) mice indicate that Nrf2 plays an important role in the anti-inflammatory and antioxidative effects of PEITC and CUR, as observed by their decreased activities in Nrf2(-/-) macrophages.

Pharmacodynamics of Ginsenosides: Antioxidant Activities, Activation of Nrf2 and Potential Synergistic Effects of Combinations

Abstract: Ginseng has long been used in Asian countries for more than 2000 years. Currently, in the "Western World or Western Medicines", many reports have indicated that they have used herbal medicines, and ginseng is one of the most popular herbs. Several recent reports have indicated that the antioxidant/antioxidative stress activities of ginseng play a role in the benefits of ginseng; however, the precise mechanism is lacking. The antioxidant response element (ARE) is a critical regulatory element for the expression of many antioxidant enzymes and phase II/III drug metabolizing/transporter genes, mediated by the transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2). The aim of this study was to examine the potential activation and synergism of Nrf2-ARE-mediated transcriptional activity between three common ginsenosides present in ginseng, ginsenoside Rb1 (Rb1), ginsenoside Rg1 (Rg1), and ginsenoside 20(S)-protopanaxatriol (20S). We tested whether these ginsenosides and their combinations could induce Nrf2-ARE activities in HepG2-C8 cells with stably transfected ARE luciferase reporter gene. Cell proliferation, antioxidant and ARE activities, Western blotting of Nrf2 protein, and qPCR of mRNA of Nrf2 were conducted for Rb1, Rg1, and 20S as well as the combinations of 20S with Rb1 or Rg1. To determine the combination effects, the combination index (CI) was calculated. Rb1 and Rg1 are relatively nontoxic to the cells, while 20S at 50 μM or above significantly inhibited the cell proliferation. Rb1, Rg1, or 20S induced total antioxidant activity and ARE activity in a concentration-dependent manner. Furthermore, combinations of 20S with either Rb1 or Rg1 induced total antioxidant and ARE activity synergistically. The induction of Nrf2 protein and mRNA was also found to be synergistic with the combination treatments. In summary, in this study, we show that ginsenosides Rb1, Rg1, and 20S possess antioxidant activity, transcriptionally activating ARE as well as the potential of synergistic activities. The Nrf2-ARE-mediated antioxidant pathway could play a role for the overall antioxidative stress activities, which could be important for ginseng's health beneficial effects such as cancer chemopreventive activities.

In vivo pharmacodynamics of indole-3-carbinol in the inhibition of prostate cancer in transgenic adenocarcinoma of mouse prostate (TRAMP) mice: Involvement of Nrf2 and cell cycle/apoptosis signaling pathways†

Abstract: Indole-3-carbinol (I3C) found abundantly in crucifers has been shown to possess anti-cancer effects. The present study aims to examine the chemopreventive effects and the molecular mechanism of I3C, particularly the anti-oxidative stress pathway regulated by nuclear erythroid related factor 2 (Nrf2). HepG2-C8-ARE-luciferase cells were used for Nrf2-ARE activity. TRAMP C1 cells were used to investigate the effects of I3C on Nrf2-mediated genes. To test the chemopreventive efficacy of I3C, transgenic adenocarcinoma of mouse prostate (TRAMP) mice were fed with 1% I3C supplemented diet for 12 or 16 wk. The expression of Nrf2 and its downstream target genes, cell cycle and apoptosis genes were investigated using quantitative real-time polymerase chain reaction (qPCR). The protein expressions of these biomarkers were also investigated using Western blotting. I3C induced antioxidant response element (ARE)-luciferase activity in a dose-dependent manner. Treatments of TRAMP C1 cells with I3C also resulted in the induction of Nrf2-mediated genes. I3C significantly suppressed the incidence of palpable tumor and reduced the genitourinary weight in TRAMP mice. Western blots and qPCR analyses of prostate tissues showed that I3C induced the expression of Nrf2, NAD(P)H quinine oxidoreductase 1 (NQO-1) as well as cell cycle and apoptosis related biomarkers in I3C-fed TRAMP mice. This study demonstrated that the effectiveness of I3C as prostate cancer chemoprevention agent via up-regulation of a novel Nrf2-mediated anti-oxidative stress pathway. © 2011 Wiley Periodicals, Inc.

Curcumin, the golden nutraceutical: multitargeting for multiple chronic diseases

Abstract: Curcumin, a yellow pigment in the Indian spice Turmeric (Curcuma longa), which is chemically known as diferuloylmethane, was first isolated exactly two centuries ago in 1815 by two German Scientists, Vogel and Pelletier. However, according to the pubmed database, the first study on its biological activity as an antibacterial agent was published in 1949 in Nature and the first clinical trial was reported in The Lancet in 1937. Although the current database indicates almost 9000 publications on curcumin, until 1990 there were less than 100 papers published on this nutraceutical. At the molecular level, this multitargeted agent has been shown to exhibit anti-inflammatory activity through the suppression of numerous cell signalling pathways including NF-κB, STAT3, Nrf2, ROS and COX-2. Numerous studies have indicated that curcumin is a highly potent antimicrobial agent and has been shown to be active against various chronic diseases including various types of cancers, diabetes, obesity, cardiovascular, pulmonary, neurological and autoimmune diseases. Furthermore, this compound has also been shown to be synergistic with other nutraceuticals such as resveratrol, piperine, catechins, quercetin and genistein. To date, over 100 different clinical trials have been completed with curcumin, which clearly show its safety, tolerability and its effectiveness against various chronic diseases in humans. However, more clinical trials in different populations are necessary to prove its potential against different chronic diseases in humans. This review's primary focus is on lessons learnt about curcumin from clinical trials. Linked Articles This article is part of a themed section on Principles of Pharmacological Research of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.11/issuetoc

Plants vs. cancer: a review on natural phytochemicals in preventing and treating cancers and their druggability.

Abstract: Cancer remains to be one of the leading causes of death in the United States and around the world. The advent of modern drug-targeted therapies has undeniably improved cancer patients' cares. However, advanced metastasized cancer remains untreatable. Hence, continued searching for a safer and more effective chemoprevention and treatment is clearly needed for the improvement of the efficiency and to lower the treatment cost for cancer care. Cancer chemoprevention with natural phytochemical compounds is an emerging strategy to prevent, impede, delay, or cure cancer. This review summarizes the latest research in cancer chemoprevention and treatment using the bioactive components from natural plants. Relevant molecular mechanisms involved in the pharmacological effects of these phytochemicals are discussed. Pharmaceutical developmental challenges and opportunities in bringing the phytochemicals into the market are also explored. The authors wish to expand this research area not only for their scientific soundness, but also for their potential druggability.

An Overview of Nrf2 Signaling Pathway and Its Role in Inflammation

Abstract: Inflammation is a key driver in many pathological conditions such as allergy, cancer, Alzheimer’s disease, and many others, and the current state of available drugs prompted researchers to explore new therapeutic targets. In this context, accumulating evidence indicates that the transcription factor Nrf2 plays a pivotal role controlling the expression of antioxidant genes that ultimately exert anti-inflammatory functions. Nrf2 and its principal negative regulator, the E3 ligase adaptor Kelch-like ECH- associated protein 1 (Keap1), play a central role in the maintenance of intracellular redox homeostasis and regulation of inflammation. Interestingly, Nrf2 is proved to contribute to the regulation of the heme oxygenase-1 (HO-1) axis, which is a potent anti-inflammatory target. Recent studies showed a connection between the Nrf2/antioxidant response element (ARE) system and the expression of inflammatory mediators, NF-κB pathway and macrophage metabolism. This suggests a new strategy for designing chemical agents as modulators of Nrf2 dependent pathways to target the immune response. Therefore, the present review will examine the relationship between Nrf2 signaling and the inflammation as well as possible approaches for the therapeutic modulation of this pathway.

Curcumin mediates anticancer effects by modulating multiple cell signaling pathways.

Abstract: Curcumin, a component of a spice native to India, was first isolated in 1815 by Vogel and Pelletier from the rhizomes of Curcuma longa (turmeric) and, subsequently, the chemical structure of curcumin as diferuloylmethane was reported by Milobedzka et al. [(1910) 43., 2163-2170]. Since then, this polyphenol has been shown to exhibit antioxidant, anti-inflammatory, anticancer, antiviral, antibacterial, and antifungal activities. The current review primarily focuses on the anticancer potential of curcumin through the modulation of multiple cell signaling pathways. Curcumin modulates diverse transcription factors, inflammatory cytokines, enzymes, kinases, growth factors, receptors, and various other proteins with an affinity ranging from the pM to the mM range. Furthermore, curcumin effectively regulates tumor cell growth via modulation of numerous cell signaling pathways and potentiates the effect of chemotherapeutic agents and radiation against cancer. Curcumin can interact with most of the targets that are modulated by FDA-approved drugs for cancer therapy. The focus of this review is to discuss the molecular basis for the anticancer activities of curcumin based on preclinical and clinical findings.