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36,688 Abstracts & Growing Daily. Sourced from the US National Library of Medicine.


Curcumin exposure reduced BPA-induced apoptosis evasion and rapid growth kinetics in all cell lines to varying degrees.

Widespread distribution of bisphenol-A (BPA) complicates epidemiological studies of possible carcinogenic effects on the breast because there are few unexposed controls. To address this challenge, we previously developed non-cancerous human high-risk donor breast epithelial cell (HRBEC) cultures, wherein BPA exposure could be controlled experimentally. BPA consistently induced activation of the mammalian target of rapamycin (mTOR) pathway--accompanied by dose-dependent evasion of apoptosis and increased proliferation--in HRBECs from multiple donors. Here, we demonstrate key molecular changes underlying BPA-induced cellular reprogramming. In 3/3 BPA-exposed HRBEC cell lines, and in T47D breast cancer cells, proapoptotic negative regulators of the cell cycle (p53, p21(WAF1) and BAX) were markedly reduced, with concomitant increases in proliferation-initiating gene products (proliferating cell nuclear antigen, cyclins, CDKs and phosphorylated pRb). However, simultaneous exposure to BPA and the polyphenol, curcumin, partially or fully reduced the spectrum of effects associated with BPA alone, including mTOR pathway proteins (AKT1, RPS6, pRPS6 and 4EBP1). BPA exposure induced an increase in the ERα (Estrogen Receptor): ERβ ratio--an effect also reversed by curcumin (analysis of variance, P

Carcinogenesis. 2013 Mar ;34(3):703-12. Epub 2012 Dec 7. PMID: 23222814


H. rosa-sinesis flower extract contains compounds that inhibit melanoma cell growth.

Skin cancer is extremely common, and melanoma causes about 80% of skin cancer deaths. In fact, melanoma kills over 50 thousand people around the world each year, and these numbers are rising. Clearly, standard treatments are not effectively treating melanoma, and alternative therapies are needed to address this problem. Hibiscus tea has been noted to have medicinal properties, including anticancer effects. Extracts from Hibiscus have been shown to inhibit the growth of a variety of cancer cells. In particular, recent studies found that polyphenols extracted from Hibiscus sabdariffa by organic solvents can inhibit melanoma cell growth. However, effects of aqueous extracts from Hibiscus rosa-sinesis flowers, which are commonly used to make traditional medicinal beverages, have not been examined on melanoma cells. Here, we report that aqueous H. rosa-sinesis flower extract contains compounds that inhibit melanoma cell growth in a dose dependent manner at concentrations that did not affect the growth of nontransformed cells. In addition, these extracts contain low molecular weight growth inhibitory compounds below 3 kD in size that combine with larger compounds to more effectively inhibit melanoma cell growth. Future work should identify these compounds, and evaluate their potential to prevent and treat melanoma and other cancers.

J Tradit Complement Med. 2017 Jan ;7(1):45-49. Epub 2016 Feb 23. PMID: 28053887


Carvacrol could be a novel and strong anticancer agent against the human gastric adenocarcinoma.

Gastric cancer (GC) is the most common cause of morbidity and mortality because of cancer. Medicinal plants containing polyphenolic compounds have gained importance in anticancer treatment. In this context, carvacrol is a main component of many plants in the family Lamiaceae that are frequently used in folk medicine and a good candidate to investigate for GC treatment. The present study aimed to explore the cytotoxic, genotoxic, apoptotic, and reactive oxygen species (ROS)-generating effects of carvacrol on gastric adenocarcinoma in vitro. For these purposes, human gastric adenocarcinoma (AGS) cells were used and analyzed after 24 h of exposure to carvacrol with different concentrations. The cytotoxicity, ROS generation, glutathione (GSH) level, and genotoxicity were investigated by the ATP cell viability assay, 2',7'-dichlorodihydrofluorescein-diacetate assay, GSH/GSSG-Glo assay, and comet assay, respectively. Apoptosis induction was detected by acridine orange/ethidium bromide staining and western blotting at below the half-maximal growth inhibitory concentration value. Carvacrol showed cytotoxic, genotoxic, apoptotic, ROS generating, and GSH-reducing effects on AGS cells in a dose-dependent manner. There was a close negative relationship between cell viability and ROS level. Carvacrol inhibited the proliferation of AGS cells, suggesting that it could be a novel and strong anticancer agent against the human gastric adenocarcinoma. These results support the interest of natural diet components in the development of therapeutic products for diseases.

Anticancer Drugs. 2017 Feb 27. Epub 2017 Feb 27. PMID: 28244942


This evaluated the antioxidant and antiproliferative effects of polyphenolic extracts obtained from old twelve varieties of endemic bean.

Beans are important dietary components with versatile health benefits. We analysed the extracts of twelve ecotypes of Phaseolus vulgaris in order to determine their phenolic profiles, antioxidant activity, and the in vitro antiproliferative activity. Ultra-performance liquid chromatography with diode array detector (UPLC-DAD) admitted us to detect and quantify some known polyphenols, such as gallic acid, chlorogenic acid, epicatechin, myricetin, formononetin, caffeic acid, and kaempferol. The antioxidant activity (AA) ranged from 1.568± 0.041 to 66.572 ± 3.197 mg necessary to inhibit the activity of the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical by 50% (EC50). The extracts, except those obtained from the nonpigmented samples, were capable of inhibiting the proliferation of the human epithelial colorectal adenocarcinoma (Caco-2) cells, human breast cancer cells MCF-7, and A549 NSCLC cell line. Cultivars differed in composition and concentration of polyphenols including anthocyanins; cooking affected the antioxidant activity only marginally. Qualitative and quantitative differences in phenolic composition between the groups of beans influenced the biological activities; on the other hand, we did not find significant differences on the biological activities within the same variety, before and after cooking.

Oxid Med Cell Longev. 2016 ;2016:1398298. Epub 2016 Dec 25. PMID: 28105248


Phenolic fractions from Muscadine grape "Noble" pomace can inhibit breast cancer cell MDA-MB-231 better than those from European grape.

Tons of grape pomace which still contained a rich amount of plant polyphenols, is discarded after winemaking. Plant polyphenols have multi-functional activities for human body. In this study, polyphenols of pomaces from Muscadinia rotundifolia"Noble"and Vitis vinifera"Cabernet Sauvignon"were extracted and fractionated, and then they were analyzed with LC-MS and the inhibitory effects on breast cancer cells were compared. The inhibition on MDA-MB-231 cells of fractions from"Noble"was further evaluated. The results showed that polyphenols from 2 grape pomaces could be separated into 3 fractions, and ellagic acid and/or ellagitannins were only detected in fractions from"Noble"pomace. All 3 fractions from"Noble"pomace inhibited MDA-MB-231 better than MCF-7. But fraction 2 from"Cabernet Sauvignon"inhibited MCF-7 better while fraction 1 and fraction 3 inhibited both 2 cells similarly. Moreover, the fractions from"Noble"pomace rather than"Cabernet Sauvignon"can inhibit MDA-MB-231 better. Finally, fractions from"Noble"pomace can induce S-phase arrest and apoptosis on MDA-MB-231. These findings suggested the extracts from grape pomace especially those from"Noble,"are potential to be utilized as health beneficial products or even anti-breast cancer agents.

J Food Sci. 2017 Mar 22. Epub 2017 Mar 22. PMID: 28329437


Polyphenols of Pinus koraiensis pinecone could be a promising natural antitumor agents.

In this study, an efficient purification method for the polyphenols of Pinus koraiensis pinecone (PPP) has been developed. AB-8 resin was verified to offer good adsorption and desorption ratio for PPP. Response surface methodology (RSM) indicated that the optimized purification parameters for PPP were 1.70 mg GAE/mL phenolic sample concentration, 22.00 mL sample volume, and 63.00% ethanol concentration. Under these conditions, the experimental purity of PPP was 27.93± 0.14% (n = 3), which matched well with the predicted purity of 28.17%. Next, the antiproliferative effects of PPP on seven cancer cell lines, including A375 (human skin melanoma cancer cell line), A549 (human lung cancer cell line), SH-SY5Y (human neuroblastoma cell line), LOVO (human colon cancer stem cell line), MCF-7 (human breast cancer cell line), HeLa (human cervical cancer line), and HT29 (human colon cancer line), were examined by MTT assays. The results indicated that PPP had the highest capacity for inhibiting LOVO cells growth with an EC50 value of 0.317 ± 0.0476 mg/mL. Finally,Ultra-high performance liquid chromatography- tandem mass spectrometry (UPLC-MS) was used to tentatively identify twenty-four peaks in the purified PPP, of which five representative peaks were identified as catechin, methyl quercetin, o-vanillin, luteolin and coronaric acid. Our results demonstratethat Pinus koraiensis pinecone is a readily available source of polyphenols, and the purified PPP could be a promising natural antitumor agent for applications in functional foods.

Molecules. 2015 Jun 5 ;20(6):10450-67. Epub 2015 Jun 5. PMID: 26056816


Recent studies have documented that pharmacological effects of curcumin in lung cancer are also mediated by modulation of several miRNAs.

BACKGROUND: Lung cancer is one of the most common types of cancer worldwide and is characterized by a poor prognosis, related both to late diagnosis and lack of effective treatments. In the last years, microRNAs (miRNAs) have been demonstrated to have an important role in tumor microenvironment and immune regulation. These RNAs can be categorized into tumor-suppressor genes, such as let-7 family and miR-34, and oncogenes such as miR-221 and miR-222. Curcumin is a bioactive polyphenol that is documented to have promising anti-cancer activity, and to be well tolerated in humans.METHODS: The present review aims to gather available evidence on the involvement of mRNAs in the therapeutic effects of curcumin against lung cancer.RESULTS: The anti-cancer properties of curcumin against lung cancer have been shown in both cellular and experimental models and are mediated by modulation of several molecular targets that regulate the expression of transcription factors, inflammatory cytokines, enzymes, growth factors, receptors, adhesion molecules, antiapoptotic proteins, and cell cycle proteins, leading to cell apoptosis, inhibition of cell proliferation and migration, and also chemo- and radio-sensitization of lung cancer cells. Recent studies have documented that pharmacological effects of curcumin in lung cancer are also mediated by modulation of several miRNAs, such as downregulation of oncogenic miR-21 and upregulation of oncosuppressive miR-192-5p and miR-215.CONCLUSION: Further studies are necessary to explore this very promising field and the link between regulation of oncogenic and tumor-suppressive miRNAs and putative anti-cancer properties of curcumin.

Curr Pharm Des. 2017 Jan 9. Epub 2017 Jan 9. PMID: 28067164


Proliferation of hepatic and colon cancer cells, HepG2 and Caco-2, were shown to be sensitive to olive leaf extract.

Olea europaea L. has been widely used as an advantageous rich source of bioactive compounds of high economic value leading to its use in pharmaceutical, cosmetic, and agriculture industries. Ethanolic extracts of olive fruits from three different cultivars (OFE) were studied for their phytochemical contents and were investigated for antioxidant activities and anticancer potential. Major polyphenols detected in these extracts were tyrosol, hydroxytyrosol, oleuropein, rutin, quercetin and glucoside forms of luteolin and apigenin. All these compounds have shown to significantly contribute to the antioxidant activity of OFE, which was evaluated by DPPH and ABTS assays. Proliferation of hepatic and colon cancer cells, HepG2 and Caco-2, were shown to be sensitive to OFE with IC50 less than 1.6mg/ml for all tested extracts. Moreover, flow cytometry analysis showed that OFE induced cell cycle arrest in the S-phase within both HepG2 and Caco-2 cells. This has triggered a cell death mechanism as shown by DNA fragmentation, expression of p53 and phosphorylation level of Akt and Erk proteins. Interestingly, these extracts could be further used as a potential source of natural compounds with both antioxidant and anticancer effects.

Biomed Pharmacother. 2017 Mar 27 ;90:179-186. Epub 2017 Mar 27. PMID: 28360012


New insights into therapeutic activity and anticancer properties of curcumin.

Natural compounds obtained from plants are capable of garnering considerable attention from the scientific community, primarily due to their ability to check and prevent the onset and progress of cancer. These natural compounds are primarily used due to their nontoxic nature and the fewer side effects they cause compared to chemotherapeutic drugs. Furthermore, such natural products perform even better when given as an adjuvant along with traditional chemotherapeutic drugs, thereby enhancing the potential of chemotherapeutics and simultaneously reducing their undesired side effects. Curcumin, a naturally occurring polyphenol compound found in the plant Curcuma longa, is used as an Indian spice. It regulates not only the various pathways of the immune system, cell cycle checkpoints, apoptosis, and antioxidant response but also numerous intracellular targets, including pathways and protein molecules controlling tumor progression. Many recent studies conducted by major research groups around the globe suggest the use of curcumin as a chemopreventive adjuvant molecule to maximize and minimize the desired effects and side effects of chemotherapeutic drugs. However, low bioavailability of a curcumin molecule is the primary challenge encountered in adjuvant therapy. This review explores different therapeutic interactions of curcumin along with its targeted pathways and molecules that are involved in the regulation of onset and progression of different types of cancers, cancer treatment, and the strategies to overcome bioavailability issues and new targets of curcumin in the ever-growing field of cancer.

J Exp Pharmacol. 2017 ;9:31-45. Epub 2017 Mar 31. PMID: 28435333


The results support a role for dietary polyphenols in protecting against benzo[a]pyrene induced carcinogenesis.

While dietary polyphenols are widely recognized for cancer-preventing characteristics, the relative effectiveness and mechanisms of action of different polyphenols is not clear. In the present study, we investigated the protective effects of six different polyphenols against benzo[a]pyrene (B[a]P)-induced oxidative stress and neoplastic transformation in the Bhas 42 cell carcinogenesis assay. All of the polyphenols completely prevented the increased intracellular ROS generation by B[a]P at 12 h, and most inhibited after 3 days. B[a]P increased mitochondrial superoxide generation at 12 h, which was inhibited by the anthocyanins and berberine. B[a]P increasedexpression of genes related to oxidative stress and inflammation (Nrf2, UCP2, and TNF-α) after 24 h. Polyphenols strongly inhibited the increase in TNF-α and also several polyphenols inhibited the increase in UCP2. At 21 days after 72 h treatment, B[a]P produced a large increase in the number of neoplastic colonies. This transformation was inhibited by most polyphenols, and strongly by resveratrol. In summary, all tested polyphenols were able to inhibit B[a]P-induced increases in markers of oxidative stress and inflammation, and to inhibit cellular transformation, with resveratrol being notable for the strongest preventive effect on cell transformation. The results support a role for dietary polyphenols in protecting against B[a]P-induced carcinogenesis.

Food Chem Toxicol. 2017 May 19. Epub 2017 May 19. PMID: 28533128


Rosmarinus officinalis L. extracts markedly inhibited the proliferation of two tested cancer cells.

Rosmarinus officinalis L., a medicinal herb from the labiates family, has been reported to have potential benefit in the treatment and prevention of several diseases. In particular its phenolics have demonstrated protective effects on various types of cancer through several mechanisms. The present study aimed to determine the effects of rosemary phenolic extracts on human cell functions, with particular regard to their anti-proliferative properties in three cell types U937, CaCo-2 and the peripheral blood mononuclear cells (PBMCs). The radical scavenging and Ferric reducing abilities of the extracts have been assessed as well as their cyto-toxicity and effects on cell cycle distribution and apoptosis. About 13 compounds were identified with dominance of rosmarinic acid in the methanolic extract and phenolic diterpens in the ethyl acetate fraction (Carnosol, Carnosic acid and methyl Carnosate). The total polyphenolic content was important in the first extract with 2.589± 0.005 g/100 g in gallic acid equivalent compared to 0.763 ± 0.005 g/100 g. The methanolic fraction displayed higher antioxidant activity (DPPHIC50: 0.510 mg/mL and FRAP: 1.714 ± 0.068 mmol Fe(2+)/g) while ethyl acetate showed pronounced antiproliferative effects (IC50: 14.85 ± 0.20µg/mL and 14.95 ± 2.32 µg/mL respectively for U937 and CaCo-2 cells). The anti-proliferative effect was associated with a cell cycle arrest in S phase for U937 (62% of the population at 5 µg/mL) with a concomitant decrease in G1 and G2/M phases. Tested extracts displayed in addition early apoptotic effectsin U937 and late apoptosis in CaCo-2 cells. The obtained data indicate that the identified phenolics are at least partially responsible for the observed cytotoxicity.

Iran J Pharm Res. 2017 ;16(1):315-327. PMID: 28496485


The aim of this review is to collect and present recent evidence from the literature regarding resveratrol and its effects on cancer prevention.

Increasing epidemiological and experimental evidence has demonstrated an inverse relationship between the consumption of plant foods and the incidence of chronic diseases, including cancer. Microcomponents that are naturally present in such foods, especially polyphenols, are responsible for the benefits to human health. Resveratrol is a diet-derived cancer chemopreventive agent with high therapeutic potential, as demonstrated by different authors. The aim of this review is to collect and present recent evidence from the literature regarding resveratrol and its effects on cancer prevention, molecular signaling (especially regarding the involvement of p53 protein), and therapeutic perspectives with an emphasis on clinical trial results to date.

Molecules. 2017 Jun 18 ;22(6). Epub 2017 Jun 18. PMID: 28629161


Preliminary results indicate a selective cytotoxicity of an aqueous extract of Pterocarpus marsupium towards the cancer cells.

Pterocarpus marsupium is a well-known plant due to its healing properties, in particular, the use of its aqueous extract is able to reduce blood sugar levels and blood triglyceride concentrations. Although this plant has already been widely studied, a complete characterization of its aqueous extract has not been reported. The present study deals with the characterization of the aqueous extract of P. marsupium in order to obtain a full fingerprint of the volatile and nonvolatile constituents. The volatile constituents were identified by CG-MS, whereas the nonvolatile fraction was characterized by UHPLC-MS/MS using a nontarget approach. Several compounds were identified, in particular, polyphenolic species belonging to the class of proanthocyanidins. Cytotoxicity tests were carried out on four different cancer cell lines and three different non-tumoral cell lines. Preliminary results indicate a selective cytotoxicity of the aqueous extract towards the cancer cells. The potential cytotoxicity due to the presence of metals in the aqueous extract was ruled out by testing an aqueous mixture of the metals at the same concentration found in the P. marsupium extract.

Planta Med. 2016 Sep ;82(14):1295-301. Epub 2016 Apr 28. PMID: 27124243


These results may suggest that Annona muricata leaf extract had anticancer properties by enhancing caspase-3 activity

Annona muricata, commonly known as soursop, contains annonacin, acetogenin, and polyphenol which are known to have chemopreventive effects on cancer. In this study, we tend to evaluate the apoptosis-inducing effect of soursop (Annona muricata) leaf extract on the colorectal cancer cell line COLO-205 through the activities of caspase-3 which is a marker of cell apoptosis. Cell cultures were incubated with soursop leaf with a concentration of 10 μg/ml and then compared with those of the incubated positive control leucovorin 10 μg/ml and placebo as a negative control. The apoptotic activity of caspase-3 was measured with ELISA. After the administration of each treatment in the colorectal cancer cell line COLO-205, the expression of caspase-3 activity was 1422 ng/ml after incubation with the extract of Annona muricata leaves, 1373 ng/ml after the administration of leucovorin, and 1297 ng/ml in the one with placebo. Annona muricata leaf extract elevated caspase-3 by 1.09 times compared to that of the pure cell line. Annona muricata leaf extract had a higher value of caspase-3 activity than leucovorin and placebo in the COLO-205 colorectal cancer cell line. These results may suggest that Annona muricata leaf extract had anticancer properties by enhancing caspase-3 activity which is a proapoptotic marker.

Gastroenterol Res Pract. 2017 ;2017:4357165. Epub 2017 Apr 9. PMID: 28487731


Curcumin mediates anticancer effects by modulating multiple cell signaling pathways.

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.

Clin Sci (Lond). 2017 Aug 1 ;131(15):1781-1799. Epub 2017 Jul 5. PMID: 28679846


This article summarizes the existing in vitro and in vivo studies focusing on the anticancer effects of oleuropein.

Cancer cells exhibit enhanced proliferation rate and a resistance to apoptosis. Epidemiological studies suggest that olive oil intake is associated with a reduced risk of cancer. Olive oil, olives, and olive leaves contain many polyphenols, including oleuropein. Recently, several studies have demonstrated that oleuropein inhibits proliferation and induces apoptosis in different cancer cell lines. In addition, anticancer effects of oleuropein have been seen in animal studies. These effects are associated with oleuropein's ability to modulate gene expression and activity of a variety of different signaling proteins that play a role in proliferation and apoptosis. This article summarizes the existing in vitro and in vivo studies focusing on the anticancer effects of oleuropein and its effects on key signaling molecules.© 2017 BioFactors, 2017.

Biofactors. 2017 Jun 14. Epub 2017 Jun 14. PMID: 28612982


Curcumin prevents cisplatin-induced renal alterations in mitochondrial bioenergetics

Cisplatin is widely used as chemotherapeutic agent for treatment of diverse types of cancer, however, acute kidney injury (AKI) is an important side effect of this treatment. Diverse mechanisms have been involved in cisplatin-induced AKI, such as oxidative stress, apoptosis and mitochondrial damage. On the other hand, curcumin is a polyphenol extracted from the rhizome of Curcuma longa L. Previous studies have shown that curcumin protects against the cisplatin-induced AKI; however, it is unknown whether curcumin can reduce alterations in mitochondrial bioenergetics and dynamic in this model. It was found that curcumin prevents cisplatin-induced: (a) AKI and (b) alterations in the following mitochondrial parameters: bioenergetics, ultrastructure, hydrogen peroxide production and dynamic. In fact, curcumin prevented the increase of mitochondrial fission 1 protein (FIS1), the decrease of optic atrophy 1 protein (OPA1) and the decrease of NAD(+)-dependent deacetylase sirtuin-3 (SIRT3), a mitochondrial dynamic regulator as well as the increase in the mitophagy associated proteins parkin and phosphatase and tensin homologue (PTEN)-induced putative kinase protein 1 (PINK1). In conclusion, the protective effect of curcumin in cisplatin-induced AKI was associated with the prevention of the alterations in mitochondrial bioenergetics, ultrastructure, redox balance, dynamic, and SIRT3 levels.

Food Chem Toxicol. 2017 Jul 8. Epub 2017 Jul 8. PMID: 28698153


Honokiol induces apoptosis, G1 arrest, and autophagy in KRAS mutant lung cancer cells.

Aberrant signaling transduction induced by mutant KRAS proteins occurs in 20∼30% of non-small cell lung cancer (NSCLC), however, a direct and effective pharmacological inhibitor targeting KRAS has not yet reached the clinic to date. Honokiol, a small molecular polyphenol natural biophenolic compound derived from the bark of magnolia trees, exerts anticancer activity, however, its mechanism remains unknown. In this study, we sought to investigate the in vitro effects of honokiol on NSCLC cell lines harboring KRAS mutations. Honokiol was shown to induce G1 arrest and apoptosis to inhibit the growth of KRAS mutant lung cancer cells, which was weakened by an autophagy inhibitor 3-methyladenine (3-MA), suggesting a pro-apoptotic role of honokiol-induced autophagy that was dependent on AMPK-mTOR signaling pathway. In addition, we also discovered that Sirt3 was significantly up-regulated in honokiol treated KRAS mutant lung cancer cells, leading to destabilization ofits target gene Hif-1α, which indicated that the anticancer property of honokiol maybe regulated via a novel mechanism associated with the Sirt3/Hif-1α. Taken together, these results broaden our understanding of the mechanisms on honokiol effects in lung cancer, and reinforce the possibility of its potential anticancer benefit as a popular Chinese herbal medicine (CHM).

Front Pharmacol. 2017 ;8:199. Epub 2017 Apr 11. PMID: 28443025


Hazelnut shell extract has antioxidant effects, and cytotoxic activity in human cancer cell lines.

Hazelnut shells, a by-product of the kernel industry processing, are reported to contain high amount of polyphenols. However, studies on the chemical composition and potential effects on human health are lacking. A methanol hazelnut shells extract was prepared and dried. Our investigation allowed the isolation and characterization of different classes of phenolic compounds, including neolignans, and a diarylheptanoid, which contribute to a high total polyphenol content (193.8± 3.6 mg of gallic acid equivalents (GAE)/g of extract). Neolignans, lawsonicin and cedrusin, a cyclic diarylheptanoid, carpinontriol B, and two phenol derivatives, C-veratroylglycol, and β-hydroxypropiovanillone, were the main components of the extract (0.71%-2.93%, w/w). The biological assays suggested that the extract could be useful as a functional ingredient in food technology and pharmaceutical industry showing an in vitro scavenging activity against the radical 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) (EC50 = 31.7 μg/mL with respect to α-tocopherol EC50 = 10.1 μg/mL), and an inhibitory effect on the growth of human cancer cell lines A375, SK-Mel-28 and HeLa (IC50 = 584, 459, and 526 μg/mL, respectively). The expression of cleaved forms of caspase-3 and poly(ADP-ribose) polymerase-1 (PARP-1) suggested that the extract induced apoptosis through caspase-3 activation in bothhuman malignant melanoma (SK-Mel-28) and human cervical cancer (HeLa) cell lines. The cytotoxic activity relies on the presence of the neolignans (balanophonin), and phenol derivatives (gallic acid), showing a pro-apoptotic effect on the tested cell lines, and the neolignan, cedrusin, with a cytotoxic effect on A375 and HeLa cells.

Int J Mol Sci. 2017 Feb 13 ;18(2). Epub 2017 Feb 13. PMID: 28208804


Targeting STAT3 by polyphenols brings an opportunity to melanoma therapy.

Melanoma or malignant melanocytes appear with the low incidence rate, but very high mortality rate worldwide. Epidemiological studies suggest that polyphenolic compounds contribute for prevention or treatment of several cancers particularly melanoma. Such findings motivate to dig out novel therapeutic strategies against melanoma, including research toward the development of new chemotherapeutic and biologic agents that can target the tumor cells by different mechanisms. Recently, it has been found that signal transducer and activator of transcription 3 (STAT3) is activated in many cancer cases surprisingly. Different evidences supply the aspect that STAT3 activation plays a vital role in the metastasis, including proliferation of cells, survival, invasion, migration, and angiogenesis. This significant feature plays a vital role in various cellular processes, such as cell proliferation and survival. Here, we reviewed the mechanisms of the STAT3 pathway regulation and their role in promoting melanoma. Also, we have evaluated the emerging data on polyphenols (PPs) specifically their contribution in melanoma therapies with an emphasis on their regulatory/inhibitory actions in relation to STAT3 pathway and current progress in the development of phytochemical therapeutic techniques. An understanding of targeting STAT3 by PPs brings an opportunity to melanoma therapy.© 2016 BioFactors, 43(3):347-370, 2017.

Biofactors. 2017 May 6 ;43(3):347-370. Epub 2016 Nov 29. PMID: 27896891


This review explores the potential of quercetin as an anti-melanoma agent.

Replacing current refractory treatments for melanoma with new prevention and therapeutic approaches is crucial in order to successfully treat this aggressive cancer form. Melanoma develops from neural crest cells, which express tyrosinase - a key enzyme in the pigmentation pathway. The tyrosinase enzyme is highly active in melanoma cells and metabolizes polyphenolic compounds; tyrosinase expression thus makes feasible a target for polyphenol-based therapies. For example, quercetin (3,3',4',5,7-pentahydroxyflavone) is a highly ubiquitous and well-classified dietary polyphenol found in various fruits, vegetables, and other plant products including onions, broccoli, kale, oranges, blueberries, apples, and tea. Quercetin has demonstrated antiproliferative and proapoptotic activity in various cancer cell types. Quercetin is readily metabolized by tyrosinase into various compounds that promote anticancer activity; additionally, given that tyrosinase expression increases during tumorigenesis, and its activity is associated with pigmentation changes in both early- and late-stage melanocytic lesions, it suggests that quercetin can be used to target melanoma. In this review, we explore the potential of quercetin as an anti-melanoma agent utilizing and extrapolating on evidence from previous in vitro studies in various human malignant cell lines and propose a"four-focus area strategy"to develop quercetin as a targeted anti-melanoma compound for use as either a preventative or therapeutic agent. The four areas of focus include utilizing quercetin to (i) modulate cellular bioreduction potential and associated signaling cascades, (ii) affect transcription of relevant genes, (iii) regulate epigenetic processes, and (iv) develop effective combination therapies and delivery modalities/protocols. In general, quercetin could be used to exploit tyrosinase activity to prevent, and/or treat, melanoma with minimal additional side effects.

Front Nutr. 2016 ;3:48. Epub 2016 Oct 31. PMID: 27843913


In vitro and in vivo studies have demonstrated that curcumin and its analogues can be used as novel therapeutic agents in melanoma.

Melanoma remains among the most lethal cancers and, in spite of great attempts that have been made to increase the life span of patients with metastatic disease, durable and complete remissions are rare. Plants and plant extracts have long been used to treat a variety of human conditions; however, in many cases, effective doses of herbal remedies are associated with serious adverse effects. Curcumin is a natural polyphenol that shows a variety of pharmacological activities including anti-cancer effects, and only minimal adverse effects have been reported for this phytochemical. The anti-cancer effects of curcumin are the result of its anti-angiogenic, pro-apoptotic and immunomodulatory properties. At the molecular and cellular level, curcumin can blunt epithelial-to-mesenchymal transition and affect many targets that are involved in melanoma initiation and progression (e.g., BCl2, MAPKS, p21 and some microRNAs). However, curcumin has a low oral bioavailability that may limit its maximal benefits. The emergence of tailored formulations of curcumin and new delivery systems such as nanoparticles, liposomes, micelles and phospholipid complexes has led to the enhancement of curcumin bioavailability. Although in vitro and in vivo studies have demonstrated that curcumin and its analogues can be used as novel therapeutic agents in melanoma, curcumin has not yet been tested against melanoma in clinical practice. In this review, we summarized reported anti-melanoma effects of curcumin as well as studies on new curcumin formulations and delivery systems that show increased bioavailability. Such tailored delivery systems could pave the way for enhancement of the anti-melanoma effects of curcumin.

Int J Cancer. 2016 Oct 15 ;139(8):1683-95. Epub 2016 Jul 4. PMID: 27280688


Punicalagin exerts anti-proliferative activity in prostate cancer cells via induction of apoptosis and anti-angiogenic effects.

Prostate cancer (PCa) is an international health problem and search for its effective treatment is in progress. Punicalagin (PN), polyphenol from pomegranate fruit, is known to exhibit potent anticancer activity in lung, breast and cervical cells. However, there is paucity of information on its effect in PCa. This study evaluated anti-proliferative effects of PN and its effects on extrinsic pathway of apoptosis in PCa cells, and angiogenesis in chicken chorioallantoic membrane (CAM). Antioxidant activities of PN were determined by 2,2-diphenyl-1-picryhydrazyl (DPPH) radical scavenging and inhibition of lipid peroxidation (LPO) methods. PCa (PC-3 and LNCaP) and normal prostate (BPH-1) cells were cultured and treated with PN (10, 50 and 100 μM). Cytotoxicity and viability effects of PN were determined by lactate dehydrogenase (LDH) and XTT assays, respectively. Antiangiogenic effects were measured using CAM assay, while apoptosis was assessed by DNA fragmentation, enrichment factor by Cell Death Detection ELISA kit and expressions of caspases-3 and -8. Results showed that PN (10-200 μM) significantly scavenged DPPH and inhibited LPO in a concentration-dependent manner. Furthermore, PN (10-100 μM) concentration-dependently inhibited viability in PC-3 and LNCaP, while viability in BPH-1 was insignificantly affected. PN had low toxicity on cells in vitro at concentrations tested. Also, PN (100 μM) increased enrichment factor in PC-3 (2.34 ± 0.05) and LNCaP (2.31 ± 0.26) relative to control (1.00 ± 0.00). In addition, PN (50 μM) decreased the network of vessels in CAM, suggesting its anti-angiogenic effect.Moreso, PN increased the expressions of caspases-3 and -8 in PC-3. Overall, PN exerts anti-proliferative activity in PCa cells via induction of apoptosis and anti-angiogenic effect.

Chem Biol Interact. 2017 Jul 11. Epub 2017 Jul 11. PMID: 28709945


All the polyphenols exhibited a significant cytotoxicity against melanoma cells.

The Bcl-2 family includes 26 proteins involved in apoptosis. Cancer cells can develop the ability to avoid apoptosis through the upregulation and/or down regulation of such proteins Bax, Bcl-xL or Mcl-1, especially during chemoresistance progress. These proteins engaged in a network of dynamic interactions that control apoptosis triggering have become attractive therapeutic targets in cancers including melanoma. Among them, the Bax/Bcl-xL interaction appears critical in maintaining mitochondria integrity. Therefore a series of mixed polyphenol-heterocyclic molecules, were rationally designed by molecular docking as Bax/Bcl-xL inhibitors. It has been screened against B16-F10 melanoma cancer cells for a preliminary investigation of their cytotoxicity. All these compounds exhibited a significant cytotoxicity against these cancer cells, in the 0.3-6 .M range. A pyrazole-type molecule, which had a submicromolar IC50 value with an excellent selectivity index (14), is the most promising derivative for further development.

Med Chem. 2016 ;12(5):419-25. PMID: 26825069


Polyphenols from green tea inhibit the growth of melanoma cells.

Melanoma is the leading cause of skin cancer-related deaths. We have examined the effect of green tea polyphenols (GTPs), a natural mixture of epicatechin monomers, on melanoma cancer cell growth and the molecular mechanism underlying these effects using different human melanoma cell lines as an in vitro model. Treatment of melanoma cell lines (A375, Hs294t, SK-Mel28 and SK-Mel119) with GTPs significantly inhibited the cell viability as well as colony formation ability of melanoma cells in a dose-dependent manner. These effects of GTPs were associated with a significant inhibition of histone deacetylase (HDAC) activity, reduction in the levels of class I HDAC proteins, enhancement of histone acetyltransferase (HAT) activity and induction of DNA damage, as detected by Comet assay, in melanoma cells. GTPs-induced decrease in the levels of class I HDAC proteins is mediated through proteasomal degradation. Valproic acid, an inhibitor of HDACs, exhibited a similar pattern of reduced viability and induction of death of melanoma cells. Treatment of A375 and Hs294t cells with GTPs resulted in a decrease in the levels of cyclins and cyclin dependent kinases of G1 phase of cell cycle whereas upregulated the levels of tumor suppressor proteins (Cip1/WAF1/p21, p16 and p53).

Genes Cancer. 2015 Jan ;6(1-2):49-61. PMID: 25821561


Curcumin intake affects miRNA signature in murine melanoma.

Melanoma is the most aggressive form of skin cancer with estimated 48,000 deaths per year worldwide. The polyphenol curcumin derived from the plant Curcuma longa is well known for its anti-inflammatory and anti-cancerogenic properties. Accordingly, dietary intake of this compound may be suitable for melanoma prevention. However, how this compound affects basic cellular mechanisms in developing melanoma still remains elusive. Therefore, the aim of this study was to investigate for the first time the impact of oral curcumin administration on the miRNA signature of engrafting melanoma. For this purpose, the effects of a 4% curcumin diet were tested on melanoma, which were established by injection of murine B78H1 cells in the flank of C57BL/6 mice. Curcumin diet or standard chow (control) was administered two weeks prior to injection of tumor cells until termination of the experiment. High throughput chip-based array analysis was deployed to detect alterations in the miRNA signature of the tumors. Curcumin treatment significantly reduced the growth of the flank tumors. Furthermore the miRNA expression signature in tumors was substantially altered by curcumin intake with mmu-miR-205-5p over 100 times higher expressed when compared to controls. The expression levels of identified key miRNAs in the tumor samples were confirmed by quantitative real-time polymerase chain reaction (qRT-PCR). A comparable expression pattern of these miRNAs was also detected in other curcumin-treated melanoma cell lines under in vitro conditions. Putative targets of curcumin-induced up-regulated miRNAs were enriched in 'o-glycan biosynthesis', 'endoplasmatic reticulum protein processing' and different cancer-related pathways. Western Blot analyses revealed that of these targets anti-apoptotic B-cell CLL/lymphoma 2 (Bcl-2) and proliferating cell nuclear antigen (PCNA) were significantly down-regulated in curcumin-treated tumors. These findings demonstrate a profound alteration of the miRNA expression signature in engrafting curcumin-treated melanoma with mmu-miR-205-5p being up-regulated most significantly.

PLoS One. 2013 ;8(12):e81122. Epub 2013 Dec 12. PMID: 24349037


This data indicate that lysosomal membrane permeabilization is the main cell death pathway triggered by pterostilbene.

The phenolic phytoalexin resveratrol is well known for its health-promoting and anticancer properties. Its potential benefits are, however, limited due to its low bioavailability. Pterostilbene, a natural dimethoxylated analog of resveratrol, presents higher anticancer activity than resveratrol. The mechanisms by which this polyphenol acts against cancer cells are, however, unclear. Here, we show that pterostilbene effectively inhibits cancer cell growth and stimulates apoptosis and autophagosome accumulation in cancer cells of various origins. However, these mechanisms are not determinant in cell demise. Pterostilbene promotes cancer cell death via a mechanism involving lysosomal membrane permeabilization. Different grades of susceptibility were observed among the different cancer cells depending on their lysosomal heat shock protein 70 (HSP70) content, a known stabilizer of lysosomal membranes. A375 melanoma and A549 lung cancer cells with low levels of HSP70 showed high susceptibility to pterostilbene, whereas HT29 colon and MCF7 breast cancer cells with higher levels of HSP70 were more resistant. Inhibition of HSP70 expression increased susceptibility of HT29 colon and MCF7 breast cancer cells to pterostilbene. Our data indicate that lysosomal membrane permeabilization is the main cell death pathway triggered by pterostilbene.

PLoS One. 2012 ;7(9):e44524. Epub 2012 Sep 5. PMID: 22957077


The use of resveratrol and its analogs as an attractive miRNA-mediated chemopreventive and therapeutic strategy in prostate cancer.

Growing evidence indicates that deregulation of the epigenetic machinery comprising the microRNA (miRNA) network is a critical factor in the progression of various diseases, including cancer. Concurrently, dietary phytochemicals are being intensively studied for their miRNA-mediated health-beneficial properties, such as anti-inflammatory, cardioprotective, antioxidative, and anticancer properties. Available experimental data have suggested that dietary polyphenols may be effective miRNA-modulating chemopreventive and therapeutic agents. Moreover, noninvasive detection of changes in miRNA expression in liquid biopsies opens enormous possibilities for their clinical utilization as novel prognostic and predictive biomarkers. In our published studies, we identified resveratrol-regulated miRNA profiles in prostate cancer. Resveratrol downregulated the phosphatase and tensin homolog (PTEN)-targeting members of the oncogenic miR-17 family of miRNAs, which are overexpressed in prostate cancer. We have functionally validated the miRNA-mediated ability of resveratrol and its potent analog pterostilbene to rescue the tumor suppressor activity of PTEN in vitro and in vivo. Taken together, our findings implicate the use of resveratrol and its analogs as an attractive miRNA-mediated chemopreventive and therapeutic strategy in prostate cancer and the use of circulating miRNAs as potential predictive biomarkers for clinical development.

Ann N Y Acad Sci. 2017 Jun 29. Epub 2017 Jun 29. PMID: 28662290


Fisetin could be a useful chemotherapeutic agent for the management of prostate and other cancers.

Epidemiologic and case control population based studies over the past few decades have identified diet as an important determinant of cancer risk. This evidence has kindled interest into research on bioactive food components and has till date resulted in the identification of many compounds with cancer preventive and therapeutic potential. Among such compounds has been fisetin (3,7,3',4'-tetrahydroxyflavone), a flavonol and a member of the flavonoid polyphenols that also include quercetin, myricetin and kaempferol. Fisetin is commonly found in many fruits and vegetables such as apples, persimmons, grapes, kiwis, strawberries, onions and cucumbers. We evaluated the effects of fisetin against melanoma and cancers of the prostate, pancreas and the lungs. Using prostate and lung adenocarcinoma cells, we demonstrated that fisetin acts as a dual inhibitor of the PI3K/Akt and the mTOR pathways. This is a significant finding considering the fact that mTOR is phosphorylated and its activation is more frequent in tumors with overexpression of PI3K/Akt. Dual inhibitors of PI3K/Akt and mTOR signaling have been suggested as valuable agents for treating such cancers. Here, we summarize our findings on the dietary flavonoid fisetin and its effects on cancer with particular focus on prostate cancer. Our observations and findings from other laboratories suggest that fisetin could be a useful chemotherapeutic agent that could be used either alone or as an adjuvant with conventional chemotherapeutic drugs for the management of prostate and other cancers.

Biochem Pharmacol. 2012 Nov 15 ;84(10):1277-81. Epub 2012 Jul 25. PMID: 22842629


Resveratrol prevents endothelial cells injury in high-dose interleukin-2 therapy against melanoma.

Immunotherapy with high-dose interleukin-2 (HDIL-2) is an effective treatment for patients with metastatic melanoma and renal cell carcinoma. However, it is accompanied by severe toxicity involving endothelial cell injury and induction of vascular leak syndrome (VLS). In this study, we found that resveratrol, a plant polyphenol with anti-inflammatory and anti-cancer properties, was able to prevent the endothelial cell injury and inhibit the development of VLS while improving the efficacy of HDIL-2 therapy in the killing of metastasized melanoma. Specifically, C57BL/6 mice were injected with B16F10 cells followed by resveratrol by gavage the next day and continued treatment with resveratrol once a day. On day 9, mice received HDIL-2. On day 12, mice were evaluated for VLS and tumor metastasis. We found that resveratrol significantly inhibited the development of VLS in lung and liver by protecting endothelial cell integrity and preventing endothelial cells from undergoing apoptosis. The metastasis and growth of the tumor in lung were significantly inhibited by HDIL-2 and HDIL-2 + resveratrol treatment. Notably, HDIL-2 + resveratrol co-treatment was more effective in inhibiting tumor metastasis and growth than HDIL-2 treatment alone. We also analyzed the immune status of Gr-1(+)CD11b(+) myeloid-derived suppressor cells (MDSC) and FoxP3(+)CD4(+) regulatory T cells (Treg). We found that resveratrol induced expansion and suppressive function of MDSC which inhibited the development of VLS after adoptive transfer. However, resveratrol suppressed the HDIL-2-induced expansion of Treg cells. We also found that resveratrol enhanced the susceptibility of melanoma to the cytotoxicity of IL-2-activated killer cells, and induced the expression of the tumor suppressor gene FoxO1. Our results suggested the potential use of resveratrol in HDIL-2 treatment against melanoma. We also demonstrated, for the first time, that MDSC is the dominant suppressor cell than regulatory T cell in the development of VLS.

PLoS One. 2012 ;7(4):e35650. Epub 2012 Apr 20. PMID: 22532866


Anthocyanidins inhibit epithelial-mesenchymal transition in glioblastoma cells.

Epidemiological studies have convincingly demonstrated that diets rich in fruits and vegetables play an important role in preventing cancer due to their polyphenol content. Among polyphenols, the anthocyanidins are known to possess anti-inflammatory, cardioprotective, anti-angiogenic, and anti-carcinogenic properties. Despite the well-known role of transforming growth factor-β (TGF-β) in high grade gliomas, the impact of anthocyanidins on TGF-β-induced epithelial-mesenchymal transition (EMT), a process that allows benign tumor cells to infiltrate surrounding tissues, remains poorly understood. The objective of this study is to investigate the impact of anthocyanidinssuch as cyanidin (Cy), delphinidin (Dp), malvidin (Mv), pelargonidin (Pg), and petunidin (Pt) on TGF-β-induced EMT and to determine the mechanism(s) underlying such action. Human U-87 glioblastoma (U-87 MG) cells were treated with anthocyanidins prior to, along with or following the addition of TGF-β. We found that anthocyanidins differently affected TGF-β-induced EMT, depending on the treatment conditions. Dp was the most potent EMT inhibitor through its inhibitory effect on the TGF-β Smad and non-Smad signaling pathways. These effects altered expression of the EMT mesenchymal markers fibronectin and Snail, as well as markedly reducing U-87 MG cell migration. Our study highlights a new action of anthocyanidins against EMT that supports their beneficial health and chemopreventive effects in dietary-based strategies against cancer. © 2016 Wiley Periodicals, Inc.

Mol Carcinog. 2017 Mar ;56(3):1088-1099. Epub 2016 Oct 4. PMID: 27649384


Curcumin reduced the migration and invasive ability of T24 and 5637 bladder cancer cells.

Bladder cancer has a considerable morbidity and mortality impact with particularly poor prognosis. Curcumin has been recently noticed as a polyphenolic compound separated from turmeric to regulate tumor progression. However, the precise molecular mechanism by which curcumin inhibits the invasion and metastasis of bladder cancer cells is not fully elucidated. In this study, we investigate the effect of curcumin on the bladder cancer as well as possible mechanisms of curcumin. The expression ofβ-catenin was detected by quantitative real-time polymerase chain reaction and immunohistochemical analysis in a series of bladder cancer tissues. In addition, bladder cancer cell lines T24 and 5637 cells were treated with different concentrations of curcumin. The cytotoxic effect of curcumin on cell proliferation of T24 and 5637 cells was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The migration and invasion capacity of T24 and 5637 cells were measured by transwell assay. The effects of curcumin on expression levels of β-catenin and epithelial-mesenchymaltransition marker were determined by western blotting. The β-catenin expression was significantly upregulated in bladder cancer tissues when compared with corresponding peri-tumor tissues. Furthermore, curcumin inhibited the cell proliferation of T24 and 5637 cells, and curcumin reduced the migration and invasive ability of T24 and 5637 cells via regulating β-catenin expression and reversing epithelial-mesenchymal transition. Curcumin may be a new drug for bladder cancer.

Tumour Biol. 2017 Jul ;39(7):1010428317702548. PMID: 28705118


Annurca apple polyphenol extract strongly inhibits the proliferation of MCF-7 cells by inducing G2/M cell cycle arrest and apoptosis.

Among nutraceuticals, polyphenols represent the most intriguing and studied class of compounds that can be therapeutics for a large spectrum of the most common diseases, including cancer. Although polyphenols are well known as potent antioxidants, a pro-oxidant effect has been associated with a pro-apoptotic function of these compounds in various types of tumor cells. Annurca apple, a southern Italian variety, is characterized by an extremely high content of polyphenols and displays a stronger antioxidant activity compared with other varieties. In the present study we explored the antiproliferative effect of Annurca apple polyphenol extract (APE) in human breast cancer MCF-7 cells and we investigated the underlying mechanisms. Results showed that at 500 µM catechin equivalent (EqC) APE acts as a pro-oxidant increasing thiobarbituric acid-reactive species cell content of approximately 6-fold more than the untreated cells. We found that APE strongly inhibits the proliferation of MCF-7 cells by inducing G2/M cell cycle arrest and apoptosis. Immunoblot analysis demonstrated that APE treatment increases the levels of p53 and p21, downregulates the expression of the cell cycle regulatory protein cyclin D1, and inhibits ERK1/2 phosphorylation. Moreover, APE treatment caused a marked increase of pro-apoptotic Bax/Bcl-2 ratio paralleled by caspase-9, -6, -7, and poly(ADP ribose) polymerase cleavage. Altogether our data indicate that APE, at elevated concentrations, acts as a potent pro-oxidant and antiproliferative agent able to downregulate ERK1/2 pathway leading to cell cycle inhibition and apoptosis and provides a rationale for its potential use in the development of novel therapeutics towards breast cancer.

Int J Oncol. 2017 Sep ;51(3):939-948. Epub 2017 Jul 31. PMID: 28766690


There is good epidemiological evidence of a reduction in CRC risk from case-control and cohort studies assessing polyphenol intake.

Current focus in colorectal cancer (CRC) management is on reducing overall mortality by increasing the number of early-stage cancers diagnosed and treated with curative intent. Despite the success of screening programs in down-staging CRC, interval cancer rates are substantial and other strategies are desirable. Sporadic CRC is largely associated with lifestyle factors including diet. Polyphenols are phytochemicals ingested as part of a normal diet, which are abundant in plant foods including fruits/berries and vegetables. These may exert their anti-carcinogenic effects via the modulation of inflammatory pathways. Key signal transduction pathways are fundamental to the association of inflammation and disease progression including those mediated by NF-κB and STAT, PI3K and COX. Our aim was to examine the evidence for the effect of dietary polyphenols intake on tumor and host inflammatory responses to determine if polyphenols may be effective as part of a dietary intervention. There is good epidemiological evidence of a reduction in CRC risk fromcase-control and cohort studies assessing polyphenol intake. It would be premature to suggest a major public health intervention to promote their consumption; however, dietary change is safe and feasible, emphasizing the need for further investigation of polyphenols and CRC risk.

Crit Rev Food Sci Nutr. 2017 Jul 24 ;57(11):2310-2320. PMID: 26066365


Silibinin suppressed chemoresistance and bladder cancer malignancy in an NF-κB-dependent and independent manner.

Because bladder cancer (BCa) is the 9th most common malignant tumor and 13th leading cause of death due to cancer, therapeutic approaches have attracted a great deal of attention from both clinicians and BCa patients. Although the development of surgery and targeted drugs has brought new challenges for the traditional concept of BCa therapy, various types of chemotherapy remain the final treatment method for many BCa patients. However, chemoresistance inevitably appears, leading to the failure of chemotherapy. Silibinin, a polyphenolic flavonoid component isolated from the fruits or seeds of milk thistle, has been reported to play important roles in inhibiting tumor chemoresistance in breast cancer and head and neck squamous cell carcinomas. Our previous study indicated that silibinin inhibited BCa progression in some mechanisms but with no conclusion of chemoresistance inhibition. Therefore, in the present study, we dissected the role of silibinin in BCa progression and chemoresistance. Our results revealed that in BCa, chemodrug-induced chemoresistance was reversed in the presence of silibinin. Further mechanistic study indicated that silibinin suppressed chemoresistance and BCa malignancy in an NF-κB-dependent and -independent manner. In addition, all of the inhibitory effects were dose‑dependent. Thus, our results provide a potential use for silibinin in BCa therapeutics.

Int J Oncol. 2017 Aug 2. Epub 2017 Aug 2. PMID: 28791405


Phytochemicals may serve as novel therapeutic agents for breast cancer treatment.

Breast cancer is the most common form of cancer diagnosed in women worldwide and the second leading cause of cancer-related deaths in the USA. Despite the development of newer diagnostic methods, selective as well as targeted chemotherapies and their combinations, surgery, hormonal therapy, radiotherapy, breast cancer recurrence, metastasis and drug resistance are still the major problems for breast cancer. Emerging evidence suggest the existence of cancer stem cells (CSCs), a population of cells with the capacity to self-renew, differentiate and be capable of initiating and sustaining tumor growth. In addition, CSCs are believed to be responsible for cancer recurrence, anticancer drug resistance, and metastasis. Hence, compounds targeting breast CSCs may be better therapeutic agents for treating breast cancer and control recurrence and metastasis. Naturally occurring compounds, mainly phytochemicals have gained immense attention in recent times because of their wide safety profile, ability to target heterogeneous populations of cancer cells as well as CSCs, and their key signaling pathways. Therefore, in the present review article, we summarize our current understanding of breast CSCs and their signaling pathways, and the phytochemicals that affect these cells including curcumin, resveratrol, tea polyphenols (epigallocatechin-3-gallate, epigallocatechin), sulforaphane, genistein, indole-3-carbinol, 3, 3'-di-indolylmethane, vitamin E, retinoic acid, quercetin, parthenolide, triptolide, 6-shogaol, pterostilbene, isoliquiritigenin, celastrol, and koenimbin. These phytochemicals may serve as novel therapeutic agents for breast cancer treatment and future leads for drug development.

Semin Cancer Biol. 2016 Oct ;40-41:192-208. Epub 2016 Sep 5. PMID: 27609747


These results indicate that methoxylated stilbenes are efficient inhibitors of glioma cell proliferation and apoptosis inducers.

Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a potent chemopreventive and potentially cancer therapeutic agent. Since rapid metabolism limits resveratrol bioavailability, derivatives less prone to metabolic transformation are being sought and tested. We evaluated the effect of resveratrol, and its analogs (pterostilbene and 3,5,4'-trimethoxystilbene) along with tannic acid, on cell cycle and apoptosis in rat C6 and human T98G glioma cells. At concentration ranges both lower and higher than IC50 calculated based on MTT assay, all these polyphenols affected the cell cycle distribution. However, resveratrol and pterostilbene increased the percentage of the cells in S phase, while trimethoxystilbene (TMS) caused a massive accumulation of cells at the G2/M phase of the cell cycle. Tannic acid had no effect on cell cycle distribution in C6 cells, but increased the number of dead cells in both glioma cell lines. The ability to induce apoptosis by tannic acid and stilbenes was confirmed by phosphatidylserine externalization, the loss of mitochondrial membrane potential and the level of cleaved caspase-3. The apoptosis rate was most significantly increased by TMS and this was related to p53 induction. These results indicate that methoxylated stilbenes are efficient inhibitors of glioma cell proliferation and apoptosis inducers and might be considered adjuvants in glioma therapy.

Toxicol In Vitro. 2017 Sep ;43:69-75. Epub 2017 Jun 6. PMID: 28595835


Xanthohumol treatment can induce paraptosis of leukemia cells through activation of p38 MAPK signalling.

Xanthohumol as a natural polyphenol demonstrates an anticancer activity, but its underlying mechanism remains unclear. In this study, we showed that xanthohumol (XN) induces paraptosis of leukemia cells. The paraptosis is one cell death which is characterized by dilation of the endoplasmic reticulum and/or mitochondria. The results demonstrated that XN treatment significantly inhibited cell proliferation and triggered extensive cytoplasmic vacuolation of HL-60 leukemia cells, but it did not cause the cleavage of caspase-3 protein or apoptosis. In contrast, XN treatment resulted in LC3-II accumulation through blocking of autophagosome maturation. Interestingly, the induction of cytoplasmic vacuolization by XN is not associated with autophagy modulated by XN, therefore, XN-induced cell death of HL-60 leukemia cells is not the classical apoptotic cell death. Intriguingly, XN treatment triggered the dilatation of endoplasma reticulum (ER) and induced ER stress by upregulating C/EBP homologous protein and unfolded protein response regulator Grp78/Bip. Furthermore, XN treatment triggered p38 mitogen activated protein kinase and its specific inhibitor inhibited the paraptosis of HL-60 leukemia cells by XN. In conclusion, we for the first time demonstrated that XN treatment can induce paraptosis of leukemia cells through activation of p38 MAPK signaling.

Oncotarget. 2017 May 9 ;8(19):31297-31304. PMID: 28415750


Chlorogenic acid may contribute to the polyphenolic anti-cancer effect associated with consumption of vegetables and fruits.

Previous studies indicated that chlorogenic acid, a compound present in many fruits and vegetables, has anti-cancer activities. We report that chlorogenic acid regulates the expression of apoptosis-related genes and self-renewal-related stem cell markers in cancer cells. The lung cancer cell line A549 was cultured with or without chlorogenic acid. The presence of chlorogenic acid decreased cell proliferation as measured by MTT activity. Polymerase chain reaction (PCR) showed that treatment of cells with chlorogenic acid reduced the expression of BCL2 but increased that of both BAX and CASP3. Chlorogenic acid enhanced annexin V expression as measured using fluorescently labeled annexin V. Chlorogenic acid also induced p38 MAPK and JNK gene expression. Meanwhile, several agents, including SB203580 (p38 MAP kinase inhibitor), N-acetylcysteine (antioxidant inhibitor), dipyridamole (phosphodiesterase inhibitor), and apocynin (NADPH-oxidase inhibitor) blocked chlorogenic acid-induced BAX gene expression. Chlorogenic acid reduced gene expression levels of stem cell-associated markers NANOG, POU5F1, and SOX2. Together these results indicate that chlorogenic acid affects the expression of apoptosis-related genes that are part of oxidative stress and p38 MAP-dependent pathways, as well as genes encoding stem cell markers. In conclusion, chlorogenic acid may contribute to the polyphenolic anti-cancer effect associated with consumption of vegetables and fruits.

Mol Cell Biochem. 2017 Sep 5. Epub 2017 Sep 5. PMID: 28875417


There exists strong evidence from animal models suggesting pomegranate juice can be used to effectively treat IBD, and chronic inflammatory diseases.

Fruits rich in polyphenols, such as pomegranates, have been shown to have health benefits relating to their antioxidant and anti-inflammatory properties. Using data obtained from PubMed and Scopus, this article provides a brief overview of the therapeutic effects of pomegranate on chronic inflammatory diseases (CID) such as inflammatory bowel disease (IBD), rheumatoid arthritis (RA), metabolic and cardiovascular disorders, and other inflammatory-associated conditions, with an emphasis on fruit-derived juices. Most studies regarding the effects of pomegranate juice have focused on its ability to treat prostate cancer, diabetes, and atherosclerosis. However, pomegranate juice has shown therapeutic potential for many other illnesses. For instance, a small number of human clinical trials have highlighted the positive effects of pomegranate juice and extract consumption on cardiovascular health. The beneficial effects of pomegranate components have also been observed in animal models for respiratory diseases, RA, neurodegenerative disease, and hyperlipidaemia. Furthermore, there exists strong evidence from rodent models suggesting that pomegranate juice can be used to effectively treat IBD, and as an anti-inflammatory agent to treat CID. The effects of pomegranate intake should be further investigated by conducting larger and more well-defined human trials.

Nutrients. 2017 Aug 30 ;9(9). Epub 2017 Aug 30. PMID: 28867799


Health benefits of manuka honey as an essential constituent for tissue regeneration.

Honey is known for its therapeutic properties from ancient civilizations but only since last few decades its mechanism has been studied on how it causes epithelial regeneration leading to wound and ulcer healing.. In the present review the health perspectives of honey, its chemical composition with special reference to flavonoids, polyphenol composition and other bioactive trace compounds used in tissue regeneration have been highlighted. Honey can inhibit carcinogenesis by moderating with molecular processes of initiation, advancement and progression stage of cancer cells, therefore it is considered a promising anti-cancer agent. Several, well-intentioned characteristics have drawn the attention of researchers to check copious endowed-biological activities of Manuka honey, including antioxidant, antimicrobial and anti-proliferative capacities against cancer cells. Thus, scientists are trying to use Manuka honey in the area of biomedical and tissue engineering to design a template for regeneration. Naturally derived antibacterial agents, like Manuka honey, contain mixture of compounds, which can influence antibacterial potency. The non-peroxide bacteriostatic properties of Manuka honey have been formerly associated to the presence of methylglyoxal (MGO). The assimilation of MGO as a functional antibacterial additive during designing a tissue template production would explore its properties as a potential agent for manufacturing tissue regeneration template.The role of glyoxal (GO) and MGO in the bacterial growth inhibition, and in addition to immunomodulatory role, it also enhances wound healing and tissue regeneration. Researchers should step forward to explore the biomedical application, particularly integration into tissue regeneration templates. Therefore, further studies are fully needed to provide detailed information on active components of Manuka honey and their potential therapeutic efficacy in numerous models of human diseases.

Curr Drug Metab. 2017 Sep 11. Epub 2017 Sep 11. PMID: 28901255


Anticancer effects of seaweed compound fucoxanthin alone and in combination with 5-fluorouracil in colon cells.

Colorectal cancer therapy with 5-fluorouracil (5-Fu) frequently become ineffective due to resistance to this drug; and thus other effective compounds are essential for therapy. It is well-known marine brown seaweeds contain antioxidant compounds the carotenoid fucoxanthin (Fx) and polyphenolic compound phloroglucinol (Ph) which exerted diverse biological activities including antioxidant and anticancer. The aim of this study was to determine the anticancer activities of Fx or Ph alone as well as combination of each chemical with 5-Fu on two human colorectal cancer cell lines (HCT116 and HT29), with comparison to responses in a normal colon cell line (CCD-18Co). Effects of these compounds on cell viability, induction of DNA damage, and cell death were evaluated using MTT assay, comet assay, nuclear condensation assay, and Western blot. 5-Fu decreased cell viability in a concentration-dependent manner in HCT116 and HT29 cells but was not cytotoxic in CCD-18Co cells. 5-Fu induced DNA damage in HCT116 cells with induction of cell death, while no marked effects on DNA damage and cell death were observed in HT29 cells. Fx or Ph alone also reduced cell viability in both cancer cell lines but no apparent cytotoxic effect in CCD-18Co cells, except for Fx at 50 and 100µM. Diminished cell viability was accompanied by induction of DNA damage (by Fx) and induction of cell death (by Ph). In combination with 5-Fu, Fx at 10 µM (in HCT116 and HT29 cells), and Ph at 300 µM (in HT29 cells) enhanced the cytotoxic effect of 5-Fu; however, no marked cytotoxicity was notedin CCD-18Co cells. Since Fx and Ph alone reduced cancer cell line viability without an effect on normal cells and when in combination enhanced the cytotoxic effect of 5-Fu only in colon cancer cells, these compounds seem promising as anticancer agents.

J Toxicol Environ Health A. 2017 Aug 29:1-12. Epub 2017 Aug 29. PMID: 28850007


Genistein and tamoxifen can significantly inhibit growth of liver cancer cells and plays a significant role in apoptosis.

Introduction: The flavonoids comprise a diverse group of polyphenolic compounds with antioxidant activity that is present in edible plants like soybeans and soy products. In vivo studies have concentrated on the effects of flavonoids on cancer and genistein (GE), a soy-derived isoflavone, has been reported to reduce prostate, colon, hepatic and breast adenocarcinoma risk. Tamoxifen (TAM) is an important drug for cancer treatment worldwide, which can induce apoptosis in various cancers, including examples in the liver, breast and ovaries. The aim of the present study was to evaluate the effects of GE and TAM, alone and in combination, on proliferation and apoptosis in the human hepatocellular carcinoma (HCC) HepG2 cell line. Materials and Methods: HepG 2 cells were treated with GE, TAM and GE/TAM and then MTT and flow cytometry assays were conducted to determine effects on viability and apoptosis, respectively. Results: GE and TAM inhibited cell proliferation and induced apoptosis in the HepG 2 cell lines. Discussion: Our findings clearly indicated that GE and TAM may exert inhibitory and apoptotic effects in liver cancer cells. Conclusion: GE and TAM can significantly inhibit growth of HCC cells and play a significant role in apoptosis.

Asian Pac J Cancer Prev. 2017 09 27 ;18(9):2381-2385. Epub 2017 Sep 27. PMID: 28950682


This shows that genistein could be an important arsenal in the development of epigenetic based cancer therapy.

Introduction Epidemiological studies indicate that diet rich in fruits and vegetables are associated with decreased cancer risk thereby indicating that dietary polyphenols can be potential chemo-preventive agents. The reversible nature of epigenetic modifications makes them a favorable target for cancer prevention. Polyphenols have been shown to reverse aberrant epigenetic patterns by targeting the regulatory enzymes, DNA methyltransferases (DNMTs) and histone deacetylases (HDACs). In vitro and in silico studies of DNMTs and HDACs were planned to examine genistein's role as a natural epigenetic modifier in human cervical cancer cells, HeLa.Methods Expression of the tumour suppressor genes (TSGs) [MGMT, RARβ, p21, E-cadherin, DAPK1] as well the methylation status of their promoters were examined alongwith the activity levels of DNMT and HDAC enzymes after treatment with genistein. Expression of DNMTs and HDACs was also studied. In-silico studies were performed to determine the interaction of genistein with DNMTs and HDACs.Results Genistein treatment significantly reduced the expression and enzymatic activity of both DNMTs and HDACs in a time dependent way. Molecular modeling data suggests that genistein can interact with various members of DNMT and HDAC families and supports genistein mediated inhibition of their activity. Time dependent exposure of genistein reversed the promoter region methylation of the TSGs and re-established their expression.Conclusions In this study, we find that genistein is able to reinstate the expression of the TSGs studied by inhibiting the action of DNMTs and HDACs. This shows that genistein could be an important arsenal in the development of epigenetic based cancer therapy.

Anticancer Agents Med Chem. 2017 Sep 18. Epub 2017 Sep 18. PMID: 28925878


These findings demonstrate that Pro-EGCG is a novel angiogenesis inhibitor for endometrial cancer.

Anti-angiogenesis effect of a prodrug of green tea polyphenol (-)-epigallocatechin-3-gallate (Pro-EGCG) in malignant tumors is not well studied. Here, we investigated how the treatment with Pro-EGCG inhibited tumor angiogenesis in endometrial cancer. Tumor xenografts of human endometrial cancer were established and subjected to microarray analysis after Pro-EGCG treatment. First, we showed Pro-EGCG inhibited tumor angiogenesis in xenograft models through down-regulation of vascular endothelial growth factor A (VEGFA) and hypoxia inducible factor 1 alpha (HIF1α) in tumor cells and chemokine (C-X-C motif) ligand 12 (CXCL12) in host stroma by immunohistochemical staining. Next, we investigated how HIF1α/VEGFA was down-regulated and how the reduction of CXCL12 inhibited tumor angiogenesis. We found that VEGFA secretion from endometrial cancer cells was decreased by Pro-EGCG treatment through inhibiting PI3K/AKT/mTOR/HIF1α pathway. Furthermore, the down-regulation of CXCL12 in stromal cells by Pro-EGCG treatment restricted migration and differentiation of macrophages thereby inhibited infiltration of VEGFA-expressing tumor-associated macrophages (TAMs). Taken together, we demonstrated that treatment with Pro-EGCG not only decreases cancer cell-secreted VEGFA but also inhibits TAM-secreted VEGFA in endometrial cancer. These findings demonstrate that Pro-EGCG is a novel angiogenesis inhibitor for endometrial cancer.

Cancer Lett. 2017 Oct 9. Epub 2017 Oct 9. PMID: 29024813


Ellagic acid may be a potential drug adjuvant for improving cancer radiotherapy by increasing tumor toxicity.

Herbal polyphenols have gained increased significance because of the promises they hold in the prevention and treatment of cancer. There exists an enormous opportunity for the screening and valuation of natural dietary compounds in the development of an effective chemopreventive drug and radiosensitizer that may be of practical use for patients undergoing cancer therapy. This study describes the effect of the flavonoid ellagic acid (EA) on gamma-irradiated human breast cancer MCF-7 cells in vitro when administered alone or in combination with radiation. It was interesting to find the radioprotective effect of EA on NIH3T3, which is a normal cell line. Irradiation of breast tumor cells in the presence of EA (10 μM) to doses of 2 and 4-Gy gamma radiation produced a marked synergistic tumor cytotoxicity while it was found to aid recovery from the radiation damage to NIH3T3 cells. When cells were given a combined treatment of EA and radiation, the cell death increased to 21.7% and 20.7% in the 2 and 4-Gy-treated cells respectively, significantly (P

Nutr Cancer. 2017 Aug-Sep;69(6):904-910. Epub 2017 Jul 18. PMID: 28718725


Ellagic acid may provide benefit in reducing oxidative injury and cardiac dysfunction in cancer patients undergoing anthracycline treatment.

The Bcl-2 protein Bnip3 is crucial for provoking oxidative injury to mitochondria following anthracycline treatment or ischemia-reperfusion injury. Herein, we investigate the effects of the polyphenolic compound ellagic acid (EA) on Bnip3 mediated mitochondrial injury and necrotic cell death in cardiac myocytes. In contrast to vehicle treated cardiomyocytes, Bnip3 was highly enriched in mitochondrial fractions of cardiac myocytes treated with the anthracycline doxorubicin or in cells subjected to hypoxia (HPX). Mitochondrial associated Bnip3 was accompanied by mPTP opening and loss of∆Ψm. The dynamin related fission protein Drp-1 was phosphorylated (Drp1(616)) and coincided with excessive mitochondrial fragmentation, mitophagy and necrosis in cardiac myocytes treated with doxorubicin or subjected to hypoxia. Moreover, knock-down of Bnip3 was sufficient to prevent mitochondrial fission and doxorubicin-induced cell death supporting the involvement of Bnip3 in doxorubicin cardiotoxity. Interestingly, mitochondrial associated Bnip3 in cells treated with doxorubicin was markedly reduced by EA. This resulted in significantly less mitochondrial fission and cell death. Notably,EA similarly suppressed mitochondrial injury and cell death induced by hypoxia or Bnip3 over-expression. Herein, we identify a novel signaling axis that operationally links EA and Bnip3 for suppression of cardiac cell death. We provide compelling new evidence that EA suppresses mitochondrial injuryand necrotic cell death of cardiac myocytes by functionally abrogating Bnip3 activity. Hence, by suppressing mitochondrial injury induced by Bnip3, EA may provide a therapeutic advantage in reducing oxidative injury and cardiac dysfunction in cancer patients undergoing anthracycline treatment or individuals with ischemic cardiac stress.

Free Radic Biol Med. 2017 Nov ;112:411-422. Epub 2017 Aug 30. PMID: 28838842


Ellagic acid down-regulates expression and function of the Na+/H+ exchanger, decreases cytosolic acidification with subsequent impairment of glycolysis.

BACKGROUND/AIMS: Key properties of tumor cells include enhanced glycolytic flux with excessive consumption of glucose and formation of lactate. As glycolysis is highly sensitive to cytosolic pH, maintenance of glycolysis requires export of H+ ions, which is in part accomplished by Na+/H+ exchangers, such as NHE1. The carrier is sensitive to oxidative stress. Growth of tumor cells could be suppressed by the polyphenol Ellagic acid, which is found in various fruits and vegetables. An effect of Ellagic acid on transport processes has, however, never been reported. The present study thus elucidated an effect of Ellagic acid on cytosolic pH (pHi), NHE1 transcript levels, NHE1 protein abundance, Na+/H+ exchanger activity, and lactate release.METHODS: Experiments were performed in Ishikawa cells without or with prior Ellagic acid (20µM) treatment. NHE1 transcript levels were determined by qRT-PCR, NHE1 protein abundance by Western blotting, pHi utilizing (2',7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein [BCECF] fluorescence, Na+/H+ exchanger activity from Na+ dependent realkalinization after an ammonium pulse, cell volume from forward scatter in flow cytometry, reactive oxygen species (ROS) from 2',7'-dichlorodihydrofluorescein fluorescence, glucose uptake utilizing 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose, and lactate concentration in the supernatant utilizing a colorimetric (570 nm)/ fluorometric enzymatic assay.RESULTS: A 48 hour treatment with Ellagic acid (20µM) significantly decreased NHE1 transcript levels by 75%, NHE1 protein abundance by 95%, pHi from 7.24 ± 0.01 to 7.02 ± 0.01, Na+/H+ exchanger activity by 77%, forward scatter by 10%, ROS by 82%, glucose uptake by 58%, and lactate release by 15%.CONCLUSION: Ellagic acid (20µM) markedly down-regulates ROS formation and NHE1 expression leading to decreased Na+/H+ exchanger activity, pHi, glucose uptake and lactate release in endometrial cancer cells. Those effects presumably contribute to reprogramming and growth inhibition of tumor cells.

Cell Physiol Biochem. 2017 ;41(6):2374-2382. Epub 2017 Apr 27. PMID: 28467979


EGCG inhibits gastric cancer growth and reverses 5-FU resistance in gastric cancer cells.

The effect of 5-fluorouracil (5-FU) chemotherapy for gastric cancer (GC) is limited by drug-resistance. To conquer this drug-resistance, various treatments including combination therapy have been used, but the overall survival has not been improved yet. In our current study, 5-FU resistant GC cells, SGC7901/FU and MGC803/FU, were established by long term exposure to 5-FU, and the proliferation capability of these resistant cells was verified to be reduced. The drug related proteins, MDR1 and P-gp were up-regulated in resistant cells compared to the parental cells. We further found proliferation and tumor growth suppressed effects of epigallocatechin gallate (EGCG), which is the predominant polyphenolic catechin constituent in green tea, on both the 5-FU resistant cells and the SGC7901/FU xenograft. Furthermore, an interesting results showed that reversal of 5-FU resistance of GC cells by EGCG treatment in vivo and in vitro. In the molecular study, We also found that EGCG suppressed the expression of both MDR-1 and P-gp at mRNA and protein levels in vivo and in vitro. Western blot and ELISA assay revealed that EGCG was able to inhibit VEGF secretion and expression, and its up-stream signal regulator, transcription factor activator protein 2A (TFAP2A) was also down-regulated by EGCG, our results indicated that TFAP2A/VEGF axis is one of the critical pathway inhibited by EGCG for cell proliferation and 5-FU resistance. Taken together, our data suggested that EGCG inhibits GC growth and reverses 5-FU resistance of GC through inactivation of TFAP2A/VEGF pathway and down-regulation of MDR-1 and P-gp expression.

Oncotarget. 2017 Oct 10 ;8(47):82842-82853. Epub 2017 Sep 6. PMID: 29137307

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