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Flavonoids: structure–function and mechanisms of action and opportunities for drug development
Safe Stephen,Jayaraman Arul,Chapkin Robert S.,Howard Marcell,Mohankumar Kumaravel,Shrestha Rupesh 한국독성학회 2021 Toxicological Research Vol.37 No.2
Flavonoids are polyphenolic phytochemicals produced in fruits, nuts and vegetables and dietary consumption of these structurally diverse compounds is associated with multiple health benefits including increased lifespan, decreased cardiovascular problems and low rates of metabolic diseases. Preclinical studies with individual flavonoids demonstrate that these compounds exhibit anti-inflammatory and anticancer activities and they enhance the immune system. Their effectiveness in both chemoprevention and chemotherapy is associated with their targeting of multiple genes/pathways including nuclear receptors, the aryl hydrocarbon receptor (AhR), kinases, receptor tyrosine kinases and G protein-coupled receptors. However, despite the remarkable preclinical activities of flavonoids, their clinical applications have been limited and this is due, in part, to problems in drug delivery and poor bioavailability and these problems are being addressed. Further improvements that will expand clinical applications of flavonoids include mechanism-based precision medicine approaches which will identify critical mechanisms of action of individual flavonoids with optimal activities that can be used in combination therapies.
A Newly Designed Fixed Bed Redox Flow Battery Based on Zinc/Nickel System
Mahmoud, Safe ELdeen M.E.,Youssef, Yehia M.,Hassan, I.,Nosier, Shaaban A. The Korean Electrochemical Society 2017 Journal of electrochemical science and technology Vol.8 No.3
A fixed-bed zinc/nickel redox flow battery (RFB) is designed and developed. The proposed cell has been established in the form of a fixed bed RFB. The zinc electrode is immersed in an aqueous NaOH solution (anolyte solution) and the nickel electrode is immersed in the catholyte solution which is a mixture of potassium ferrocyanide, potassium ferricyanide and sodium hydroxide as the supporting electrolyte. In the present work, the electrode area has been maximized to $1500cm^2$ to enforce an increase in the energy efficiency up to 77.02% at a current density $0.06mA/cm^2$ using a flow rate $35cm^3/s$, a concentration of the anolyte solution is $1.5mol\;L^{-1}$ NaOH and the catholyte solution is $1.5mol\;L^{-1}$ NaOH as a supporting electrolyte mixed with $0.2mol\;L^{-1}$ equimolar of potassium ferrocyanide and potassium ferricyanide. The outlined results from this study are described on the basis of battery performance with respect to the current density, velocity in different electrolytes conditions, energy efficiency, voltage efficiency and power of the battery.
Lee, H.S.,Safe, S.,Lee, S.O. Academic Press 2017 Toxicology and applied pharmacology Vol.332 No.-
Previous studies have demonstrated that the orphan nuclear receptor NR4A1 is overexpressed in human pancreatic cancer and antagonizing this receptor promotes apoptosis and inhibits pancreatic cancer cells and tumor growth. In the present study, we identified fangchinoline, a bisbenzyltetrahydroisoquinoline alkaloid from Stephania tetrandra, as a new inactivator of nuclear NR4A1 and demonstrated that fangchinoline inhibits cell proliferation and induces apoptosis, in part, via the NR4A1-dependent pro-apoptotic pathways in human pancreatic cancer cells. It decreased expression of the antiapoptotic protein survivin by inhibiting Sp1-mediated transcription and induced oxidative stress-mediated endoplasmic reticulum (ER) stress in pancreatic cancer cells. These results suggest that inhibition of NR4A1-mediated transcriptional activity was involved in the anticancer effects of fangchinoline, and fangchinoline represents a novel class of mechanism-based anticancer agents targeting NR4A1 that is overexpressed in pancreatic cancer.
Shin, Ji-Ae,Jung, Ji-Youn,Ryu, Mi Heon,Safe, Stephen,Cho, Sung-Dae American Society for Pharmacology and Experimental 2013 Molecular pharmacology Vol.83 No.1
<P>In several human malignancies, overexpression of myeloid cell leukemia-1 (Mcl-1) confers resistance to induction of apoptosis; however, Mcl-1-mediated inhibition of apoptosis in oral squamous cell carcinoma (OSCC) is not fully understood and has been investigated in this study. The Mcl-1 promoter activators (TPA) and epidermal growth factor (EGF) enhanced neoplastic transformation of JB6 cells and this response was accompanied by enhanced expression of Mcl-1, and knockdown of Mcl-1 by RNA interference (RNAi) decreased JB6 cell transformation. In the same cell line, we also demonstrated that mithramycin A (Mith) decreased TPA-induced JB6 cell transformation and Mcl-1 expression. Mcl-1 was overexpressed in human oral tumors compared with normal oral mucosa and also in several OSCC cell lines including HN22 and HSC-4 cells. Treatment of these cells with Mith also decreased Mcl-1 expression and neoplastic cell transformation, and this was accompanied by induction of several markers of apoptosis. Knockdown of Mcl-1 by RNAi also induced apoptotic cell death. The downregulation of Mcl-1 by Mith and RNAi increased pro-apoptotic protein Bax, resulting in the Bax translocation into mitochondria and its oligomerization. Mith also suppressed tumor growth in vivo and induced apoptosis in tumor by also regulating expression of Mcl-1 and Bax proteins. These indicate a critical role for Mcl-1 in the growth and survival of OSCC and demonstrate that Mith may be a potential anticancer drug candidate for clinical treatment of OSCC.</P>
Lee, Syng-Ook,Chintharlapalli, Sudhakar,Liu, Shengxi,Papineni, Sabitha,Cho, Sung Dae,Yoon, Kyungsil,Safe, Stephen American Association for Cancer Research 2009 Molecular cancer research Vol.7 No.7
<P>1,1-Bis(3'-indolyl)-1-(p-anisyl)methane (DIM-C-pPhOCH3) activates the orphan receptor nerve growth factor-induced Balpha (Nur77) in cancer cells, and in this study, DIM-C-pPhOCH3 decreased Panc1 pancreatic cancer cell survival and arrested cells in G0-G1. These responses were accompanied by induction of the cyclin-dependent kinase inhibitor p21 in pancreatic cancer cells. Mechanistic studies showed that induction of p21 mRNA and protein by DIM-C-pPhOCH3 was Nur77 dependent but did not depend on Krüppel-like factor 4, which was also induced by DIM-C-pPhOCH3. Activation of p21 promoter constructs by DIM-C-pPhOCH3 required the GC-rich proximal region of the promoter, and results of RNA interference studies showed that Nur77-dependent activation of the p21 promoter involved interactions with Sp1 and Sp4 but not Sp3. Interactions of Nur77 with the p21 promoter in Panc1 cells treated with DIM-C-pPhOCH3 were also confirmed in chromatin immunoprecipitation assays. These data show that activation of nuclear Nur77 results in a novel pathway for induction of p21, which is independent of Nur77 response elements but dependent on Sp proteins bound to the GC-rich proximal region of the p21 promoter.</P>
Shin, Ji-Ae,Shim, Jung-Hyun,Choi, Eun-Sun,Leem, Dae-Ho,Kwon, Ki Han,Lee, Syng-Ook,Safe, Stephen,Cho, Nam-Pyo,Cho, Sung-Dae Lippincott Williams Wilkins, Inc. 2011 EUROPEAN JOURNAL OF CANCER PREVENTION Vol.20 No.5
Diindolylmethane (DIM), an isothiocyanate found in cruciferous vegetables, has been shown to have cancer chemopreventive effects. A series of synthetic C-substituted DIMs (C-DIMs) analogs was developed, including DIM-C-pPhtBu and DIM-C-pPhC6H5, which exhibited better inhibitory activity in cancer cells than DIM. This study examined the effects of C-DIMs on the growth of human oral cancer cells. DIM-C-pPhtBu and DIM-C-pPhC6H5 decreased the number of viable KB cells and induced caspase-dependent apoptosis. The apoptotic cell death was accompanied by a change in Bax/Bcl-2 ratio and damage to mitochondrial membrane potential through the induction of death receptor 5 and the cleavage of Bid and caspase 8. Studies on the mechanism of action showed that the apoptotic cell death induced by DIM-C-pPhtBu and DIM-C-pPhC6H5 was mediated by endoplasmic reticulum stress. In addition, C-DIMs inhibited cell proliferation and induced PARP cleavage through death receptor 5 and CHOP in HEp-2 and HN22 cells. This provides the first evidence that synthetic C-DIMs originating from cruciferous vegetables induce apoptosis in human oral cancer cells through the endoplasmic reticulum stress pathway.
Chintharlapalli, Sudhakar,Papineni, Sabitha,Abdelrahim, Maen,Abudayyeh, Ala,Jutooru, Indira,Chadalapaka, Gayathri,Wu, Fei,Mertens-Talcott, Susanne,Vanderlaag, Kathy,Cho, Sung Dae,Smith III, Roger,Safe Wiley Subscription Services, Inc., A Wiley Company 2009 International journal of cancer: Journal internati Vol.125 No.8
<P>Methyl 2-cyano-3,11-dioxo-18β-olean-1,12-dien-30-oate (CDODA-Me) is a synthetic derivative of glycyrrhetinic acid, a triterpenoid phytochemical found in licorice extracts. CDODA-Me inhibited growth of RKO and SW480 colon cancer cells and this was accompanied by decreased expression of Sp1, Sp3 and Sp4 protein and mRNA and several Sp-dependent genes including survivin, vascular endothelial growth factor (VEGF), and VEGF receptor 1 (VEGFR1 or Flt-1). CDODA-Me also induced apoptosis, arrested RKO and SW480 cells at G<SUB>2</SUB>/M, and inhibited tumor growth in athymic nude mice bearing RKO cells as xenografts. CDODA-Me decreased expression of microRNA-27a (miR-27a), and this was accompanied by increased expression of 2 miR-27a-regulated mRNAs, namely ZBTB10 (an Sp repressor) and Myt-1 which catalyzes phosphorylation of cdc2 to inhibit progression of cells through G<SUB>2</SUB>/M. Both CDODA-Me and antisense miR-27a induced comparable responses in RKO and SW480 cells, suggesting that the potent anticarcinogenic activity of CDODA-Me is due to repression of oncogenic miR-27a. © 2009 UICC</P>
Choi, Kyeong-Hee,Kim, Hyung-Kook,Kim, Jun-Hee,Choi, Eun-Sun,Shin, Ji-Ae,Lee, Syng-Ook,Chintharlapalli, Sudhakar,Safe, Stephen,Abdelrahim, Maen,Kong, Gu,Choi, Hong Seok,Jung, Ji-Youn,Cho, Hyun-Tae,Cho, Lippincott Williams Wilkins, Inc. 2010 EUROPEAN JOURNAL OF CANCER PREVENTION Vol.19 No.2
Cruciferous vegetables contain isothiocyanates including diindolylmethane (DIM) that exhibit cancer chemopreventive effects. We developed a series of synthetic ring-substituted DIM analogs including 5,5&vprime;-dibromoDIM that exhibited better inhibitory activity in breast and colon cancer cells than DIM. In this study, we investigated whether 5,5&vprime;-dibromoDIM inhibits the proliferation of KB and YD-10B oral squamous carcinoma cell lines. 5,5&vprime;-dibromoDIM decreased the cell survival and inhibited the growth of oral cancer cells. Exposure of KB and YD-10B cells to 5,5&vprime;-dibromoDIM induced caspase-dependent apoptosis evidenced by poly-ADP ribose polymerase cleavage, accumulation of sub-G1 population, and nuclear condensation and fragmentation. In addition, apoptotic cell death was correlated with damage to the mitochondrial membrane potential through a decrease in the level of Bcl-2 protein expression. Mechanistic studies showed that mitochondria-dependent apoptosis induced by 5,5&vprime;-dibromoDIM was mediated by the p38 mitogen-activated protein kinase pathway but not the ERK1/2 and JNK pathway. These results highlight 5,5&vprime;-dibromoDIM as an important chemopreventive agent for the clinical treatment of oral cancer through the p38 mitogen-activated protein kinase pathway.