Publications by authors named "Yulin Ren"

70 Publications

Spermidine alkaloid and glycosidic constituents of Vietnamese .

Phytochem Lett 2021 Jun 15;43:154-162. Epub 2021 Apr 15.

Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.

Phytochemical investigation of the aerial parts of led to the isolation of secondary metabolites belonging to the spermidine alkaloid, glycoside, depsidone and phenol classes. Of the eleven secondary metabolites isolated in this study, two spermidine alkaloids, dovyalicins H () and I (), which belong to a rare group among this class, and six glycosides () are previously undescribed. The structures of all new isolates were determined by interpretation of spectroscopic and spectrometric data. In this report, the structural elucidation of these unprecedented secondary metabolites () is described.
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http://dx.doi.org/10.1016/j.phytol.2021.04.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078847PMC
June 2021

Antitumor potential of the protein phosphatase inhibitor, cantharidin, and selected derivatives.

Bioorg Med Chem 2021 Feb 9;32:116012. Epub 2021 Jan 9.

Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, United States. Electronic address:

Cantharidin is a potent natural protein phosphatase monoterpene anhydride inhibitor secreted by several species of blister beetle, with its demethylated anhydride analogue, (S)-palasonin, occurring as a constituent of the higher plant Butea frondosa. Cantharidin shows both potent protein phosphatase inhibitory and cancer cell cytotoxic activities, but possible preclinical development of this anhydride has been limited thus far by its toxicity. Thus, several synthetic derivatives of cantharidin have been prepared, of which some compounds exhibit improved antitumor potential and may have use as lead compounds. In the present review, the potential antitumor activity, structure-activity relationships, and development of cantharidin-based anticancer drug conjugates are summarized, with protein phosphatase-related and other types of mechanisms of action discussed. Protein phosphatases play a key role in the tumor microenvironment, and thus described herein is also the potential for developing new tumor microenvironment-targeted cancer chemotherapeutic agents, based on cantharidin and its naturally occurring analogues and synthetic derivatives.
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http://dx.doi.org/10.1016/j.bmc.2021.116012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854516PMC
February 2021

Development of Potential Antitumor Agents from the Scaffolds of Plant-Derived Terpenoid Lactones.

J Med Chem 2020 12 8;63(24):15410-15448. Epub 2020 Dec 8.

Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, United States.

Naturally occurring terpenoid lactones and their synthetic derivatives have attracted increasing interest for their promising antitumor activity and potential utilization in the discovery and design of new antitumor agents. In the present perspective article, selected plant-derived five-membered γ-lactones and six-membered δ-lactones that occur with terpenoid scaffolds are reviewed, with their structures, cancer cell line cytotoxicity and in vivo antitumor activity, structure-activity relationships, mechanism of action, and the potential for developing cancer chemotherapeutic agents discussed in each case. The compounds presented include artemisinin (ART, ), parthenolide (PTL, ), thapsigargin (TPG, ), andrographolide (AGL, ), ginkgolide B (GKL B, ), jolkinolide B (JKL B, ), nagilactone E (NGL E, ), triptolide (TPL, ), bruceantin (BRC, ), dichapetalin A (DCT A, ), and limonin (LMN, ), and their naturally occurring analogues and synthetic derivatives. It is hoped that this contribution will be supportive of the future development of additional efficacious anticancer agents derived from natural products.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812702PMC
December 2020

Apoptosis Induced by (+)-Betulin Through NF-κB Inhibition in MDA-MB-231 Breast Cancer Cells.

Anticancer Res 2020 Dec 7;40(12):6637-6647. Epub 2020 Dec 7.

Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH, U.S.A.

Background/aim: This study aimed to uncover the effects of (+)-betulin on the NF-κB-apoptotic pathway in MDA-MB-231 cells, and determine its toxicity and protein expression in vivo.

Materials And Methods: Cell cytotoxicity and toxicity were determined using the SRB assay and a zebrafish model, respectively. Western blot, mitochondrial transmembrane potential (MTP), and computational modeling analysis were performed.

Results: (+)-betulin inhibited the growth of MDA-MB-231 cells, but did not induce toxicity in zebrafish. (+)-Betulin inhibited the activity of NF-κB p65 in silico and in vitro. In cells, (+)-betulin down-regulated NF-κB p50 and 65, IKKα and β, ICAM-1 and bcl-2 expressions. Cell co-treatment with (+)-betulin and TNFα increased the (+)-betulin cytotoxic potential. Moreover, (+)-betulin induced the loss of MTP. Furthermore, (+)-betulin, in zebrafish, down-regulated the expression of NF-κB p65, IKKα, ΙΚΚβ and procaspase-3.

Conclusion: The results contribute to the understanding of the mode of action on apoptosis induction by inhibiting NF-κB pathway in MDA-MB-231 cells.
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http://dx.doi.org/10.21873/anticanres.14688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849021PMC
December 2020

A pentamethoxylated flavone from Glycosmis ovoidea promotes apoptosis through the intrinsic pathway and inhibits migration of MCF-7 breast cancer cells.

Phytother Res 2021 Mar 30;35(3):1634-1645. Epub 2020 Oct 30.

Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA.

The rare flavone 5,3'-dihydroxy-3,6,7,8,4'-pentamethoxyflavone (PMF) has been isolated from several plant species, and its cytotoxic activity has been reported against many types of cancer cells. In this study, PMF was purified from Glycomis ovoidea collected in Vietnam, and its antiproliferative effects and underlying mechanism of action were investigated against MCF-7 cells. PMF inhibited growth in MCF-7 > MCF-10A > MDA-MB-231 cells after 72 hr treatment, with IC values of 1.5, 1.9, and 8.6 μg/ml, respectively. Further experiments conducted with this compound in MCF-7 cells, showed the loss of mitochondrial membrane potential, reactive oxygen species overproduction, upregulation of BAX, cytochrome c, caspase-3 and PARP-1 and down-regulation of BCL-2 proteins as well as an increase in caspase-3/-7 activity, suggesting induction of the apoptotic intrinsic pathway. Furthermore, PMF increased cell cycle arrest in the G phase, which correlated with increments in the p53 and p21 levels. Additionally, MCF-7 cell migration was inhibited, which could be related to NF-κB p65 downregulation. Finally, PMF did not show toxicity in vivo in a zebrafish (Danio rerio) model. In conclusion, PMF induces cell death in MCF-7 cells through regulation of the BCL-2 protein family and may be proposed as a lead as a potential alternative for breast cancer therapy.
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http://dx.doi.org/10.1002/ptr.6930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005457PMC
March 2021

Secondary metabolites from Pierre leaves (Clusiaceae).

Nat Prod Res 2020 Jun 12:1-7. Epub 2020 Jun 12.

Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH, USA.

Two new glycerol esters, ()-2-hydroxy-3-(octanoyloxy)propyl tetracosanoate () and ()-3-((()-11-acetoxy octadecanoyl)oxy)propane-1,2-diyl diacetate (), and eight known compounds, docosanedioic acid (), 2,5-dimethylnonadecane (), lupeol (), stigmasterol (), β-sitosterol (), heptadecanoic acid (), hexanedioic acid, 1,6-bis[(2)-ethylhexyl] ester (), and 1,3-di--[2',2'-di-(-phenylene)] () were isolated from the leaves of Pierre, collected from Indonesia. Structural analysis of the isolates was performed using 1D- and 2D-NMR, LC- and GC-MS, IR, polarimetry, and UV-visible spectroscopic methods. Cytotoxicity assessments, as well as reactive oxygen species (ROS) analysis of the isolates, were also completed. Lupeol was the only compound found active with an IC value of 19.2µM against HT-29 colon cancer cells. Significant ROS inhibition and induction activity was observed for compounds and , respectively.
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http://dx.doi.org/10.1080/14786419.2020.1777117DOI Listing
June 2020

Na/K-ATPase-Targeted Cytotoxicity of (+)-Digoxin and Several Semisynthetic Derivatives.

J Nat Prod 2020 03 25;83(3):638-648. Epub 2020 Feb 25.

Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, United States.

(+)-Digoxin () is a well-known cardiac glycoside long used to treat congestive heart failure and found more recently to show anticancer activity. Several known cardenolides (-) and two new analogues, (+)-8(9)-β-anhydrodigoxigenin () and (+)-17--20,22-dihydro-21α-hydroxydigoxin (), were synthesized from and evaluated for their cytotoxicity toward a small panel of human cancer cell lines. A preliminary structure-activity relationship investigation conducted indicated that the C-12 and C-14 hydroxy groups and the C-17 unsaturated lactone unit are important for to mediate its cytotoxicity toward human cancer cells, but the C-3 glycosyl residue seems to be less critical for such an effect. Molecular docking profiles showed that the cytotoxic and the noncytotoxic derivative bind differentially to Na/K-ATPase. The HO-12β, HO-14β, and HO-3'aα hydroxy groups of (+)-digoxin () may form hydrogen bonds with the side-chains of Asp121 and Asn122, Thr797, and Arg880 of Na/K-ATPase, respectively, but the altered lactone unit of results in a rotation of its steroid core, which depotentiates the binding between this compound and Na/K-ATPase. Thus, was found to inhibit Na/K-ATPase, but did not. In addition, the cytotoxic did not affect glucose uptake in human cancer cells, indicating that this cardiac glycoside mediates its cytotoxicity by targeting Na/K-ATPase but not by interacting with glucose transporters.
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http://dx.doi.org/10.1021/acs.jnatprod.9b01060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7243443PMC
March 2020

Cytotoxic and non-cytotoxic cardiac glycosides isolated from the combined flowers, leaves, and twigs of Streblus asper.

Bioorg Med Chem 2020 02 7;28(4):115301. Epub 2020 Jan 7.

Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, United States. Electronic address:

A new non-cytotoxic [(+)-17β-hydroxystrebloside (1)] and two known cytotoxic [(+)-3'-de-O-methylkamaloside (2) and (+)-strebloside (3)] cardiac glycosides were isolated and identified from the combined flowers, leaves, and twigs of Streblus asper collected in Vietnam, with the absolute configuration of 1 established from analysis of its ECD and NMR spectroscopic data and confirmed by computational ECD calculations. A new 14,21-epoxycardanolide (3a) was synthesized from 3 that was treated with base. A preliminary structure-activity relationship study indicated that the C-14 hydroxy group and the C-17 lactone unit and the established conformation are important for the mediation of the cytotoxicity of 3. Molecular docking profiles showed that the cytotoxic 3 and its non-cytotoxic analogue 1 bind differentially to Na/K-ATPase. Compound 3 docks deeply in the Na/K-ATPase pocket with a sole pose, and its C-10 formyl and C-5, C-14, and C-4' hydroxy groups may form hydrogen bonds with the side-chains of Glu111, Glu117, Thr797, and Arg880 of Na/K-ATPase, respectively. However, 1 fits the cation binding sites with at least three different poses, which all depotentiate the binding between 1 and Na/K-ATPase. Thus, 3 was found to inhibit Na/K-ATPase, but 1 did not. In addition, the cytotoxic and Na/K-ATPase inhibitory 3 did not affect glucose uptake in human lung cancer cells, against which it showed potent activity, indicating that this cardiac glycoside mediates its cytotoxicity by targeting Na/K-ATPase but not by interacting with glucose transporters.
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http://dx.doi.org/10.1016/j.bmc.2019.115301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029422PMC
February 2020

Targeting Protein Translation by Rocaglamide and Didesmethylrocaglamide to Treat MPNST and Other Sarcomas.

Mol Cancer Ther 2020 03 17;19(3):731-741. Epub 2019 Dec 17.

Division of Cancer Treatment and Diagnosis, Center for Cancer Research, National Cancer Institute, NIH, Frederick, Maryland.

Malignant peripheral nerve sheath tumors (MPNST) frequently overexpress eukaryotic initiation factor 4F components, and the eIF4A inhibitor silvestrol potently suppresses MPNST growth. However, silvestrol has suboptimal drug-like properties, including a bulky structure, poor oral bioavailability (<2%), sensitivity to MDR1 efflux, and pulmonary toxicity in dogs. We compared ten silvestrol-related rocaglates lacking the dioxanyl ring and found that didesmethylrocaglamide (DDR) and rocaglamide (Roc) had growth-inhibitory activity comparable with silvestrol. Structure-activity relationship analysis revealed that the dioxanyl ring present in silvestrol was dispensable for, but may enhance, cytotoxicity. Both DDR and Roc arrested MPNST cells at G-M, increased the sub-G population, induced cleavage of caspases and PARP, and elevated the levels of the DNA-damage response marker γH2A.X, while decreasing the expression of AKT and ERK1/2, consistent with translation inhibition. Unlike silvestrol, DDR and Roc were not sensitive to MDR1 inhibition. Pharmacokinetic analysis confirmed that Roc had 50% oral bioavailability. Importantly, Roc, when administered intraperitoneally or orally, showed potent antitumor effects in an orthotopic MPNST mouse model and did not induce pulmonary toxicity in dogs as found with silvestrol. Treated tumors displayed degenerative changes and had more cleaved caspase-3-positive cells, indicative of increased apoptosis. Furthermore, Roc effectively suppressed the growth of osteosarcoma, Ewing sarcoma, and rhabdomyosarcoma cells and patient-derived xenografts. Both Roc- and DDR-treated sarcoma cells showed decreased levels of multiple oncogenic kinases, including insulin-like growth factor-1 receptor. The more favorable drug-like properties of DDR and Roc and the potent antitumor activity of Roc suggest that these rocaglamides could become viable treatments for MPNST and other sarcomas.
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http://dx.doi.org/10.1158/1535-7163.MCT-19-0809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7056570PMC
March 2020

Plant-derived glucose transport inhibitors with potential antitumor activity.

Phytother Res 2020 May 10;34(5):1027-1040. Epub 2019 Dec 10.

Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio.

Glucose, a key nutrient utilized by human cells to provide cellular energy and a carbon source for biomass synthesis, is internalized in cells via glucose transporters that regulate glucose homeostasis throughout the human body. Glucose transporters have been used as important targets for the discovery of new drugs to treat cancer, diabetes, and heart disease, owing to their abnormal expression during these disease conditions. Thus far, several glucose transport inhibitors have been used in clinical trials, and increasing numbers of natural products have been characterized as potential anticancer agents targeting glucose transport. The present review focuses on natural product glucose transport inhibitors of plant origin, including alkaloids, flavonoids and other phenolic compounds, and isoprenoids, with their potential antitumor properties also discussed.
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http://dx.doi.org/10.1002/ptr.6587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7263379PMC
May 2020

Caspase-Dependent Apoptosis in Prostate Cancer Cells and Zebrafish by Corchorusoside C from Streptocaulon juventas.

J Nat Prod 2019 06 23;82(6):1645-1655. Epub 2019 May 23.

Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy , University of Illinois at Chicago , Chicago , Illinois 60612 , United States.

Corchorusoside C (1), isolated from Streptocaulon juventas collected in Vietnam, was found to be nontoxic in a zebrafish ( Danio rerio) model and to induce cytotoxicity in several cancer cell lines with notable selective activity against prostate DU-145 cancer cells (IC 0.08 μM). Moreover, corchorusoside C induced DU-145 cell shrinkage and cell detachment. In CCD-112CoN colon normal cells, 1 showed significantly reduced cytotoxic activity (IC 2.3 μM). A preliminary mechanistic study indicated that 1 inhibits activity and protein expression of NF-κB (p50 and p65), IKK (α and β), and ICAM-1 in DU-145 cells. ROS concentrations increased at 5 h post-treatment, and MTP decreased in a dose-dependent manner. Moreover, decreased protein expression of Bcl-2 and increased expression of PARP-1 was observed. Furthermore, corchorusoside C increased both the activity and protein levels of caspases 3 and 7. Additionally, 1 induced sub-G1 population increase of DU-145 cells and modulated caspases in zebrafish with nondifferential morphological effects. Therefore, corchorusoside C (1) induces apoptosis in DU-145 cells and targets the same pathways both in vitro and in vivo in zebrafish. Thus, the use of zebrafish assays seems worthy of wider application than is currently employed for the evaluation of potential anticancer agents of natural origin.
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http://dx.doi.org/10.1021/acs.jnatprod.9b00140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6615048PMC
June 2019

Microcalcification and BMP-2 in breast cancer: correlation with clinicopathological features and outcomes.

Onco Targets Ther 2019 15;12:2023-2033. Epub 2019 Mar 15.

Department of Breast Oncology, Key Laboratory of Breast Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, People's Republic of China,

Background: Microcalcification is a very important diagnostic information in breast cancer. The purpose of this study was to determine the relationship of clinicopathological features and prognosis of breast cancer with microcalcification and to detect biomarkers related to the possible mechanisms of microcalcifications.

Patients And Methods: All 529 subjects with microcalcifications were selected from patients who had been examined using breast mammography. The control group did not have detectable microcalcifications, and was matched in a ratio of 1:3. The clinicopathological factors, progression-free survival (PFS), and overall survival were evaluated by SPSS.

Results: There was a significant difference in tumor size between the two groups, with larger tumors in the calcification group than the control group, and the proportion of patients in the calcification group with tumors of >5 cm was 20.4% vs 17.2% in the control group (=0.041). The proportion of patients with lymph node metastasis in the calcification group was higher than that of the control group (35% vs 27.9%, =0.027). The recurrence rate in ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC) patients with microcalcification was higher than that in the control group (=0.035 and 0.044). BMP-2 expression was higher in breast cancer tissues, especially in breast cancer tissues with microcalcifications. The recurrence rate in the BMP-2(+) group was higher than that in the BMP-2(-) group both in DCIS and IDC (=0.044 and 0.049). Microcalcifications and the positive expression of BMP-2 were independent factors affecting the PFS of the breast cancer patients.

Conclusion: Through the analysis of this study, it was found that the prognosis of the patients with microcalcification was relatively poor. BMP-2 was highly expressed in the breast cancer with microcalcification and was associated with poor prognosis.
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http://dx.doi.org/10.2147/OTT.S187835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6421899PMC
March 2019

Potential Anticancer Agents Characterized from Selected Tropical Plants.

J Nat Prod 2019 03 4;82(3):657-679. Epub 2019 Mar 4.

Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy , The Ohio State University , Columbus , Ohio 43210 , United States.

Higher plants are well known for their value in affording clinically useful anticancer agents, with such compounds acting against cancer cells by a range of mechanisms of action. There remains a strong interest in the discovery and development of plant secondary metabolites as additional cancer chemotherapeutic lead compounds. In the present review, progress on the discovery of plant-derived compounds of the biflavonoid, lignan, sesquiterpene, steroid, and xanthone structural types is presented. Several potential anticancer leads of these types have been characterized from tropical plants collected in three countries as part of our ongoing collaborative multi-institutional project. Preliminary structure-activity relationships and work on in vivo testing and cellular mechanisms of action are also discussed. In addition, the relevant work reported by other groups on the same compound classes is included herein.
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http://dx.doi.org/10.1021/acs.jnatprod.9b00018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6441492PMC
March 2019

Natural Product Triterpenoids and Their Semi-Synthetic Derivatives with Potential Anticancer Activity.

Planta Med 2019 Aug 18;85(11-12):802-814. Epub 2019 Jan 18.

Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio, United States.

Triterpenoids are distributed widely in higher plants and are of interest because of their structural diversity and broad range of bioactivities. In particular, there is a very large literature on the propensity of a variety of triterpenoids to act as potential anticancer agents. In the present review, the anticancer potential is summarized for naturally occurring triterpenoids and their semi-synthetic derivatives, including examples of lupane-, oleanane-, ursane-, and cucurbitane-type pentacyclic triterpenoids, along with dammarane-type tetracyclic triterpenes including ginsenosides and their sapogenins and dichapetalins, which have been characterized as antitumor leads from higher plants. Preliminary structure-activity relationships and reported mechanisms of the antineoplastic-related activity are included. Prior studies for triterpenoids of plant origin are supportive of additional work being conducted on the more detailed biological and mechanistic evaluation for the progression of this type of natural products as possible cancer chemotherapeutic agents.
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http://dx.doi.org/10.1055/a-0832-2383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6639164PMC
August 2019

The Search for Anticancer Agents from Tropical Plants.

Prog Chem Org Nat Prod 2018;107:1-94

Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH, USA.

Many of the clinically used anticancer agents in Western medicine are derived from secondary metabolites found in terrestrial microbes, marine organisms, and higher plants, with additional compounds of this type being currently in clinical trials. If plants are taken specifically, it is generally agreed that the prospects of encountering enhanced small organic-molecule chemical diversity are better if tropical rather than temperate species are investigated in drug discovery efforts. Plant collection in tropical source countries requires considerable preparation and organization to conduct in a responsible manner that abides by the provisions of the 1992 Rio Convention of Biological Diversity and the 2010 Nagoya Protocol on Access to Genetic Resources. Correct taxonomic identifications and enhanced procedures for processing and documenting plant samples when collected in often difficult terrain are required. Phytochemical aspects of the work involve solvent fractionation, known compound dereplication, preliminary in vitro testing, and prioritization, leading to "activity-guided fractionation", compound structure determination, and analog development. Further evaluation of lead compounds requires solubility, formulation, preliminary pharmacokinetics, and in vivo testing in suitable models. Covering the work of the authors carried out in two sequential multidisciplinary, multi-institutional research projects, examples of very promising compounds discovered from plants acquired from Africa, Southeast Asia, the Americas, and the Caribbean region, and with potential anticancer activity will be mentioned. These include plant secondary metabolites of the diphyllin lignan, cyclopenta[b]benzofuran, triterpenoid, and tropane alkaloid types.
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http://dx.doi.org/10.1007/978-3-319-93506-5_1DOI Listing
December 2018

A Synthetic Disaccharide Derivative of Diphyllin, TAARD, Activates Human Natural Killer Cells to Secrete Interferon-Gamma Toll-Like Receptor-Mediated NF-κB and STAT3 Signaling Pathways.

Front Immunol 2018 18;9:1509. Epub 2018 Jul 18.

The Ohio State University Comprehensive Cancer Center, Columbus, OH, United States.

Natural products and their derivatives have long been used as pharmacological agents in the fight against cancer. Human natural killer (NK) cells are critical in our immune system in that they are capable of destroying tumor cells directly. However, there are few reports that elucidate the role of natural products in activating NK cells. In this study, we discovered that a synthetic disaccharide derivative of diphyllin, 4--{[2'',3'',4''-tri--acetyl-α-D-arabinopyranosyl-(1''→4')]-2',3'-di--acetyl-α-L-rhamnopyranosyl}diphyllin (TAARD), can alone stimulate interferon (IFN)-γ secretion in primary human NK cells and the NKL cell line. Additionally, it had an additive effect with IL-12 or IL-15 on IFN-γ production, but little adverse effects on NK cells. Mechanistically, TAARD induced the phosphorylation of NF-κB and STAT3, resulting in their binding on the promoter, which was dependent on TLR1 and TLR3 signaling, respectively. STAT3 and NF-κB knockdown with lentivirus shRNA as well as the NF-κB-specific inhibitor, -tosyl-l-phenylalaninechloromethyl ketone, significantly suppressed TAARD-induced IFN-γ generation in primary NK cells. Blockade of TLR1 and TLR3 with neutralizing antibodies considerably decreased TAARD-induced activation of NF-κB and STAT3, respectively, as well as IFN-γ generation in NK cells. Collectively, our data suggest that TAARD can induce NK cell IFN-γ production through TLR1-NF-κB and TLR3-STAT3 signaling pathways, rendering its potential use as an agent for cancer prevention or treatment.
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http://dx.doi.org/10.3389/fimmu.2018.01509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6058043PMC
July 2018

Cytotoxic and NF-κB and mitochondrial transmembrane potential inhibitory pentacyclic triterpenoids from Syzygium corticosum and their semi-synthetic derivatives.

Bioorg Med Chem 2018 08 17;26(15):4452-4460. Epub 2018 Jul 17.

Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, United States. Electronic address:

Syzygium is a large genus of flowering plants, with several species, including the clove tree, used as important resources in the food and pharmaceutical industries. In our continuing search for anticancer agents from higher plants, a chloroform extract of the leaves and twigs of Syzygium corticosum collected in Vietnam was found to be active toward the HT-29 human colon cancer cell line. Separation of this extract guided by HT-29 cells and nuclear factor-kappa B (NF-κB) inhibition yielded 19 known natural products, including seven triterpenoids, three ellagic acid derivatives, two methylated flavonoids, a cyclohexanone, four megastigmanes, a small lactone, and an aromatic aldehyde. The full stereochemistry of (+)-fouquierol (2) was defined for the first time. Biological investigations showed that (+)-ursolic acid (1) is the major cytotoxic component of S. corticosum, which exhibited also potent activities in the NF-κB and mitochondrial transmembrane potential (MTP) inhibition assays conducted, with IC values of 31 nM and 3.5 µM, respectively. Several analogues of (+)-ursolic acid (1) were synthesized, and a preliminary structure-activity relationship (SAR) study indicated that the C-3 hydroxy and C-28 carboxylic acid groups and 19,20-dimethyl substitution are all essential in the mediation of the bioactivities observed for this triterpenoid.
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http://dx.doi.org/10.1016/j.bmc.2018.07.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6177235PMC
August 2018

Synthesis and antiproliferative activity of derivatives of the phyllanthusmin class of arylnaphthalene lignan lactones.

Bioorg Med Chem 2018 05 23;26(9):2354-2364. Epub 2018 Mar 23.

Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, United States. Electronic address:

A series of arylnaphthalene lignan lactones based on the structure of the phyllanthusmins, a class of potent natural products possessing diphyllin as the aglycone, has been synthesized and screened for activity against multiple cancer cell lines. SAR exploration was performed on both the carbohydrate and lactone moieties of this structural class. These studies have revealed the importance of functionalization of the carbohydrate hydroxy groups with both acetylated and methylated analogues showing increased potency relative to those with unsubstituted sugar moieties. In addition, the requirement for the presence and position of the C-ring lactone has been demonstrated through reduction and selective re-oxidation of the lactone ring. The most potent compound in this study displayed an IC value of 18 nM in an HT-29 assay with several others ranging from 50 to 200 nM. In an effort to elucidate their potential mechanism(s) of action, the DNA topoisomerase IIa inhibitory activity of the most potent compounds was examined based on previous reports of structurally similar compounds, but does not appear to contribute significantly to their antiproliferative effects.
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http://dx.doi.org/10.1016/j.bmc.2018.03.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5962029PMC
May 2018

Evaluating a framework for tuberculosis screening among healthcare workers in clinical settings, Inner Mongolia, China.

J Occup Med Toxicol 2018 20;13:11. Epub 2018 Mar 20.

2U.S. Centers for Disease Control and Prevention (CDC), 1600 Clifton Road NE, MS-93, Atlanta, GA 30329 USA.

Background: Health care workers are at high risk for tuberculosis (TB). China, a high burden TB country, has no policy on medical surveillance for TB among healthcare workers. In this paper, we evaluate whether China's national TB diagnostic guidelines could be used as a framework to screen healthcare workers for pulmonary TB disease in a clinical setting in China.

Methods: Between April-August 2010, healthcare workers from 28 facilities in Inner Mongolia Autonomous Region, China were eligible for TB screening, comprised of symptom check, chest X-ray and tuberculin skin testing. Healthcare workers were categorized as having presumptive, confirmed, or clinically-diagnosed pulmonary TB, using Chinese national guidelines.

Results: All healthcare workers (N=4347) were eligible for TB screening, of which 4285 (99%) participated in at least one TB screening test. Of the healthcare workers screened, 2% had cough for ≥ 14 days, 3% had a chest X-ray consistent with TB, and 10% had a tuberculin skin test induration ≥ 20 mm. Of these, 124 healthcare workers were identified with presumptive TB (i.e., cough for ≥ 14 days in the past 4 weeks or x-ray consistent with TB). Twelve healthcare workers met the case definition for clinically-diagnosed pulmonary TB, but none were diagnosed with TB during the study period.

Conclusion: A substantial proportion of healthcare workers in Inner Mongolia had signs, symptoms, or test results suggestive of TB disease that could have been identified using national TB diagnostic guidelines as a screening framework. However, achieving medical surveillance in China will require a framework that increases the ease, accuracy, and acceptance of TB screening in the medical community. Routine screening with improved diagnostics should be considered to detect tuberculosis disease among healthcare workers and reduce transmission in health care settings in China.
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http://dx.doi.org/10.1186/s12995-018-0192-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5859509PMC
March 2018

Parametric Study on Electric Field-Induced Micro-/Nanopatterns in Thin Polymer Films.

Langmuir 2018 04 26;34(14):4188-4198. Epub 2018 Mar 26.

Department of Mechanical Engineering , University of Michigan-Dearborn , Dearborn , Michigan 48128 , United States.

Electric field-induced micro-/nanopatterns in thin polymer films, sometimes referred as electrohydrodynamic patterning, is a promising technique to fabricate micro-/nanostructures. Extensive attention has been attracted because of its advantages in microcontact (easy demolding) and low cost. Although considerable work has been done on this technique, including both experimental and theoretical ones, there still appears a requirement for understanding the mechanism of electrohydrodynamic patterning. Thus, we systematically studied the effect of different parameters on electrohydrodynamic patterning with a numerical phase field model. Previous researchers usually employed lubrication approximation (i.e., long-wave approximation) to simplify the numerical model. However, this approximation would lose its validity if the structure height is on the same scale or larger than the wavelength, which occurs in most cases. Thus, we abandoned the lubrication approximation and solved the full governing equations for fluid flow and electric field. In this model, the deformation of polymer film is described by the phase field model. As to the electric field, the leaky dielectric model is adopted in which both electrical permittivity and conductivity are considered. The fluid flow together with electric field is coupled together in the framework of phase field. By this model, the effect of physical parameters, such as external voltage, template structure height, and polymer conductivity, is studied in detail. After that, the governing equations are nondimesionalized to analyze the relationship between different parameters. A dimensionless parameter, electrical Reynolds number E, is defined, for which, a large value would simplify the electric field to perfect dielectric model and a small value leads it to steady leaky model. These findings and results may enhance our understanding of electrohydrodynamic patterning and may be a meaningful guide for experiments.
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http://dx.doi.org/10.1021/acs.langmuir.8b00007DOI Listing
April 2018

Crystal Structures and Human Leukemia Cell Apoptosis Inducible Activities of Parthenolide Analogues Isolated from Piptocoma rufescens.

J Nat Prod 2018 03 19;81(3):554-561. Epub 2018 Jan 19.

The molecular structures of three parthenolide analogues, (-)-goyazensolide (1), (-)-15-deoxygoyazensolide (2), and (-)-ereglomerulide (3), isolated from the leaves of Piptocoma rufescens in a previous study were determined by X-ray analysis, and the absolute configuration of (-)-goyazensolide (1) was confirmed crystallographically using Cu Kα radiation at low temperature. Compounds 1-3, (+)-rufesolide A (4), and commercial parthenolide were found to be growth inhibitory toward MOLM-13 and EOL-1 human acute myeloid leukemia cells using PKC412 (midostaurin) as the positive control, with 1-3 being more active than parthenolide. Also, compounds 1-4 exhibited synergistic effects when tested with PKC412, but parthenolide did not show this type of activity. At a concentration lower than 2.0 μM, both 1 and 2 induced approximately 50% of the cells to become apoptotic at a late stage of the cell cycle, but no similar apoptotic effects were observed for 3, 4, or parthenolide. Leukemia cell apoptosis was induced by these compounds through the activation of caspase-3 and the inhibition of NF-κB, as indicated by immunoblotting analysis, and compounds 1 and 2 seem to be promising leads for development as potential antileukemic agents.
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http://dx.doi.org/10.1021/acs.jnatprod.7b01079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5866214PMC
March 2018

Genetic polymorphisms in the gene and the risk of ischemic stroke in a Chinese han population.

Oncotarget 2017 Nov 10;8(60):101936-101943. Epub 2017 Oct 10.

Department of Neurosurgery, Haikou People's Hospital, Xiangya Medical College Affiliated Haikou Hospital, Central South University, Haikou 570311, Hainan, China.

Background: Previous studies have shown that aldehyde dehydrogenase 2 () plays a role in ischemic stroke progression. In recent years, the activation of the pathway have been reported serving as a useful index in the identification of stroke-prone participants, and the pathway may be a potential target for the therapeutic intervention in ischemic stroke.

Materials And Methods: We evaluated six tagging single-nucleotide polymorphisms (SNPs) of the gene in a case-control study from Hainan of China (488 cases, 503 controls). We used SPSS version 17.0 statistical software, Excel software and other analysis software to explore associations between SNPs and the risk of ischemic stroke various genetic models (additive, dominant, and recessive).

Results: Through statistical analysis, we found that rs886205 [odds ratio (OR) = 6.39; 95% confidence interval (CI) = 1.19-34.38; = 0.03] and rs7296651 (OR = 9.29; 95% CI = 1.37-63.21; = 0.02) were associated with increased risk of ischemic stroke in recessive model analysis. In addition, we established that the "AA" genotype (OR = 5.99; 95% CI = 1.11-32.23; = 0.037) for rs886205 and the "AA" genotype (OR = 8.93; 95% CI = 1.31-60.78; = 0.025) for rs7296651 were associated with increased ischemic stroke risk.

Conclusions: Our results provide evidence that variants of gene polymorphisms influence the risk of developing ischemic stroke in Han Chinese population.
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http://dx.doi.org/10.18632/oncotarget.21803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731925PMC
November 2017

Shape-Controllable and Fluorescent Supramolecular Organic Frameworks Through Aqueous Host-Guest Complexation.

Angew Chem Int Ed Engl 2018 01 14;57(3):729-733. Epub 2017 Dec 14.

Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of the Ministry of Education, College of Chemistry and Materials Science, Northwest University, Xi'an, 710069, P. R. China.

Two kinds of shape-controllable and fluorescent supramolecular organic frameworks (cuboid or spheroid) are constructed hierarchically from CB[8] and tetraphenylethylene derivatives through host-guest interaction in water. These two fluorescent SOFs exhibit intriguing and varied photophysical properties, including large red-shifts (up to 82 nm) and stimuli-responsive behavior to competitive guest by binding with CB[8], the turn-on fluorescence of which is applied in cellular imaging.
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http://dx.doi.org/10.1002/anie.201710553DOI Listing
January 2018

Overexpression of eIF4F components in meningiomas and suppression of meningioma cell growth by inhibiting translation initiation.

Exp Neurol 2018 01 10;299(Pt B):299-307. Epub 2017 Jun 10.

Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA; Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA; Department of Otolaryngology-Head and Neck Surgery, The Ohio State University College of Medicine, Columbus, OH, USA; Department of Pathology, The Ohio State University College of Medicine, Columbus, OH, USA. Electronic address:

Meningiomas frequently display activation of the PI3K/AKT/mTOR pathway, leading to elevated levels of phospho-eukaryotic translation initiation factor 4E binding proteins, which enhances protein synthesis; however, it is not known whether inhibition of protein translation is an effective treatment option for meningiomas. We found that human meningiomas expressed high levels of the three components of the eukaryotic initiation factor 4F (eIF4F) translation initiation complex, eIF4A, eIF4E, and eIF4G. The expression of eIF4A and eIF4E was important in sustaining the growth of NF2-deficient benign meningioma Ben-Men-1 cells, as shRNA-mediated knockdown of these proteins strongly reduced cell proliferation. Among a series of 23 natural compounds evaluated, silvestrol, which inhibits eIF4A, was identified as being the most growth inhibitory in both primary meningioma and Ben-Men-1 cells. Silvestrol treatment of meningioma cells prominently induced G/M arrest. Consistently, silvestrol significantly decreased the amounts of cyclins D1, E1, A, and B, PCNA, and Aurora A. In addition, total and phosphorylated AKT, ERK, and FAK, which have been shown to be important drivers for meningioma cell proliferation, were markedly lower in silvestrol-treated Ben-Men-1 cells. Our findings suggest that inhibiting protein translation could be a potential treatment for meningiomas.
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http://dx.doi.org/10.1016/j.expneurol.2017.06.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5723558PMC
January 2018

An Intramolecular CAr-H•••O=C Hydrogen Bond and the Configuration of Rotenoids.

Planta Med 2017 Oct 20;83(14-15):1194-1199. Epub 2017 Apr 20.

Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH, United States.

Over the past half a century, the structure and configuration of the rotenoids, a group of natural products showing multiple promising bioactivities, have been established by interpretation of their NMR and electronic circular dichroism spectra and confirmed by analysis of single-crystal X-ray diffraction data. The chemical shift of the H-6' H NMR resonance has been found to be an indicator of either a or C/D ring system. In the present study, four structures representing the central rings of a -, a -, a dehydro-, and an oxadehydro-rotenoid have been plotted using the program based on X-ray crystal structures reported previously, with the conformations of the C/D ring system, the local bond lengths or interatomic distances, hydrogen bond angles, and the H-6' chemical shift of these compounds presented. It is shown for the first time that a -fused C/D ring system of rotenoids is preferred for the formation of a potential intramolecular C-H•••O=C H-bond, and that such H-bonding results in the H NMR resonance for H-6' being shifted downfield.
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http://dx.doi.org/10.1055/s-0043-108910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5617795PMC
October 2017

(+)-Strebloside-Induced Cytotoxicity in Ovarian Cancer Cells Is Mediated through Cardiac Glycoside Signaling Networks.

J Nat Prod 2017 03 24;80(3):659-669. Epub 2017 Feb 24.

Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago , Chicago, Illinois 60612, United States.

(+)-Strebloside, a cardiac glycoside isolated from the stem bark of Streblus asper collected in Vietnam, has shown some potential for further investigation as an antineoplastic agent. A mechanistic study using an in vitro assay and molecular docking analysis indicated that (+)-strebloside binds and inhibits Na/K-ATPase in a similar manner to digitoxin. Inhibition of growth of different high-grade serous ovarian cancer cells including OVCAR3, OVSAHO, Kuramochi, OVCAR4, OVCAR5, and OVCAR8 resulted from treatment with (+)-strebloside. Furthermore, this compound blocked cell cycle progression at the G2 phase and induced PARP cleavage, indicating apoptosis activation in OVCAR3 cells. (+)-Strebloside potently inhibited mutant p53 expression through the induction of ERK pathways and inhibited NF-κB activity in human ovarian cancer cells. However, in spite of its antitumor potential, the overall biological activity of (+)-strebloside must be regarded as being typical of better-known cardiac glycosides such as digoxin and ouabain. Further chemical alteration of cardiac glycosides might help to reduce negative side effects while increasing cancer cell cytotoxicity.
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http://dx.doi.org/10.1021/acs.jnatprod.6b01150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768141PMC
March 2017

Cardiac Glycoside Constituents of Streblus asper with Potential Antineoplastic Activity.

J Nat Prod 2017 03 16;80(3):648-658. Epub 2016 Dec 16.

Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago , Chicago, Illinois 60612, United States.

Three new (1-3) and two known (4 and 5) cytotoxic cardiac glycosides were isolated and characterized from a medicinal plant, Streblus asper Lour. (Moraceae), collected in Vietnam, with six new analogues and one known derivative (5a-g) synthesized from (+)-strebloside (5). A preliminary structure-activity relationship study indicated that the C-10 formyl and C-5 and C-14 hydroxy groups and C-3 sugar unit play important roles in the mediation of the cytotoxicity of (+)-strebloside (5) against HT-29 human colon cancer cells. When evaluated in NCr nu/nu mice implanted intraperitoneally with hollow fibers facilitated with either MDA-MB-231 human breast or OVCAR3 human ovarian cancer cells, (+)-strebloside (5) showed significant cell growth inhibitory activity in both cases, in the dose range 5-30 mg/kg.
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http://dx.doi.org/10.1021/acs.jnatprod.6b00924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5365359PMC
March 2017

Isolation of Bioactive Rotenoids and Isoflavonoids from the Fruits of Millettia caerulea.

Planta Med 2016 Jul 9;82(11-12):1096-104. Epub 2016 Jun 9.

Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio, United States.

Three new rotenoids (1-3), two new isoflavonoids (4 and 5), and six known analogues (6-11) were isolated from an n-hexane partition of a methanol extract of the fruits of Millettia caerulea, with the structures of the new compounds elucidated by analysis of their spectroscopic data. The relative configurations of the rotenoids were determined by interpretation of their NMR spectroscopic data, and their absolute configurations were established using electronic circular dichroism spectra and specific rotation values. All compounds isolated were evaluated for their cell growth inhibitory activity against the HT-29 human colon cancer cell line, and the known compounds, (-)-3-hydroxyrotenone (6) and (-)-rotenone (7), were found to be potently active. When tested in an NF-κB inhibition assay, compound 6 showed activity. This compound, along with the new compound, (-)-caeruleanone D (1), and the known compound, ichthynone (8), exhibited K-Ras inhibitory potency. Further bioactivity studies showed that the new compounds, (-)-3-deoxycaeruleanone D (2) and (-)-3-hydroxycaeruleanone A (3), and the known compounds 8 and 11 induced quinone reductase in murine Hepa 1c1c7 cells.
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http://dx.doi.org/10.1055/s-0042-108059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4956498PMC
July 2016

Development of Anticancer Agents from Plant-Derived Sesquiterpene Lactones.

Curr Med Chem 2016 ;23(23):2397-420

Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, United States.

Sesquiterpene lactones are of considerable interest due to their potent bioactivities, including cancer cell cytotoxicity and antineoplastic efficacy in in vivo studies. Among these compounds, artesunate, dimethylaminoparthenolide, and L12ADT peptide prodrug, a derivative of thapsigargin, are being evaluated in the current cancer clinical or preclinical trials. Based on the structures of several antitumor sesquiterpene lactones, a number of analogues showing greater potency have been either isolated as natural products or partially synthesized, and some potential anticancer agents that have emerged from this group of lead compounds have been investigated extensively. The present review focuses on artemisinin, parthenolide, thapsigargin, and their naturally occurring or synthetic analogues showing potential anticancer activity. This provides an overview of the advances in the development of these types of sesquiterpene lactones as potential anticancer agents, including their structural characterization, synthesis and synthetic modification, and antitumor potential, with the mechanism of action and structure-activity relationships also discussed. It is hoped that this will be helpful in stimulating the further interest in developing sesquiterpene lactones and their derivatives as new anticancer agents.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5012922PMC
http://dx.doi.org/10.2174/0929867323666160510123255DOI Listing
February 2017