Generic placeholder image

Current Bioactive Compounds

Author(s): Sunil C. Gurumallu and Rajesha Javaraiah*

DOI: 10.2174/1573407216999200612103526

DownloadDownload PDF Flyer Cite As
Bioactives in Disease Prevention and Health Promotion: Exploiting Combinatorial Effects

Page: [299 - 317] Pages: 19

  • * (Excluding Mailing and Handling)

Explore Articles
About Journal
For Authors
For Editors
For Reviewers

Abstract

Background: Many bioactive molecules, such as lycopene, resveratrol, lignan, tannins, indoles, fatty acids, etc., found in small amounts in plants, animals, and micro-organisms have been extensively investigated for their diverse preventive, therapeutic, immune-modulating and toxicological effects. Currently, the growing interest of the consumers is shifted towards a novel bioinspired strategy of cocktailing two or more bioactives at a lower concentration to reduce both side and cost effects, and to enhance positive effects for the development of novel compounds by the food, pharmaceutical, and chemical industries.

Methods: Even though there are several regularly updated and published reports showing the importance of beneficial effects of bioactives individually, no systematic reviews are outlining how the bioactives have combinatorially acted together to provide such health benefits and disease preventive effects. Hence, various electronic scientific databases, such as Pub Med, Science Direct, Google scholar, Sci-Finder were searched to collect the data of the present review.

Results: One hundred and sixty-two research and review papers collected from peer-reviewed journals are cited in the present review covering the broad spectrum of many bioactives and their importance in the field of food, feed, and drug industries.

Conclusion: The present systematic review discusses and highlights the current knowledge on the concept of synergistic and combinatorial effects of various bioactives from the plant, animal, micro- organism sources, and synthetic drugs in disease prevention and health promotion. These findings may pave a way for the discovery of new bioactive products and process development, which could add to economic importance.

Keywords: Bioactives, synergism, combinatorial potency, bioavailability, synthetic drugs, chronic diseases.

Graphical Abstract

Functional food Bad Neuenahr-Ahrweiler Wutscher F Ed Springer Germany Chadwick R. 1 2003 Chadwick R.; Functional food Bad Neuenahr-Ahrweiler Wutscher F Ed Springer Germany 2003,1-39 Chemistry and Biology Trenerry V.C. 9 595 2010 10.1016/B978-008045382-8.00211-2 Trenerry V.C.; Rochfort S.J.; Natural products research and metabolomics. Comprehensive natural products II: Chemistry and Biology 2010,9,595-628 Ultrason Sonochem Vinatoru M. 8 303 2001 10.1016/S1350-4177(01)00071-2 Vinatoru M.; An overview of the ultrasonically assisted extraction of bioactive principles from herbs. Ultrason Sonochem 2001,8(3),303-313 J Food Eng Azmir J. 117 426 2013 10.1016/j.jfoodeng.2013.01.014 Azmir J.; Zaidul I.S.M.; Rahman M.M.; Sharif K.M.; Mohamed A.; Sahena F.; Omar A.K.M.; Techniques for extraction of bioactive compounds from plant materials: A review. J Food Eng 2013,117(4),426-436 Evid Based Complement Alternat Med Pandey M.M. 2013 376327 2013 10.1155/2013/376327 Pandey M.M.; Rastogi S.; Rawat A.K.S.; Indian traditional ayurvedic system of medicine and nutritional supplementation. Evid Based Complement Alternat Med 2013,2013,376327 Food Sci Technol Int Correia R.T. 18 539 2012 10.1177/1082013211433077 Correia R.T.; Borges K.C.; Medeiros M.F.; Genovese M.I.; Bioactive compounds and phenolic-linked functionality of powdered tropical fruit residues. Food Sci Technol Int 2012,18(6),539-547 John Wiley Goldberg G. 1 2008 Goldberg G.; John Wiley 2008,1-372 Drug Discov Today Bulusu K.C. 21 225 2016 10.1016/j.drudis.2015.09.003 Bulusu K.C.; Guha R.; Mason D.J.; Lewis R.P.; Muratov E.; Kalantar Motamedi Y.; Cokol M.; Bender A.; Modelling of compound combination effects and applications to efficacy and toxicity: State-of-the-art, challenges and perspectives. Drug Discov Today 2016,21(2),225-238 J Chem Inf Model Yilancioglu K. 54 2286 2014 10.1021/ci500276x Yilancioglu K.; Weinstein Z.B.; Meydan C.; Akhmetov A.; Toprak I.; Durmaz A.; Iossifov I.; Kazan H.; Roth F.P.; Cokol M.; Target-independent prediction of drug synergies using only drug lipophilicity. J Chem Inf Model 2014,54(8),2286-2293 J Am Dent Assoc Bender I.B. 40 169 1950 10.14219/jada.archive.1950.0034 Bender I.B.; Seltzer S.; The synergistic effect of penicillin-streptomycin and its application in the treatment of infected pulpless teeth. J Am Dent Assoc 1950,40(2),169-174 Topics in Medicinal Chemistry: Antibacterials Fisher JF Mobashery S Miller MJ Eds Springer Bush K. Vol. 1 69 2017 Bush K.; Topics in Medicinal Chemistry: Antibacterials Fisher JF Mobashery S Miller MJ Eds Springer 2017,Vol. 1,69-88 Nat Rev Drug Discov Jia J. 8 111 2009 10.1038/nrd2683 Jia J.; Zhu F.; Ma X.; Cao Z.; Cao Z.W.; Li Y.; Li Y.X.; Chen Y.Z.; Mechanisms of drug combinations: Interaction and network perspectives. Nat Rev Drug Discov 2009,8(2),111-128 Molecules Poofery J. 25 231 2020 10.3390/molecules25010231 Poofery J.; Khaw-On P.; Subhawa S.; Sripanidkulchai B.; Tantraworasin A.; Saeteng S.; Siwachat S.; Lertprasertsuke N.; Banjerdpongchai R.; Potential of thai herbal extracts on lung cancer treatment by inducing apoptosis and synergizing chemotherapy. Molecules 2020,25(1),231 Curr Pharm Des Johnson G. 12 217 2006 10.2174/138161206775193127 Johnson G.; Moore S.W.; The peripheral anionic site of acetylcholinesterase: Structure, functions and potential role in rational drug design. Curr Pharm Des 2006,12(2),217-225 J Comput Chem Trott O. 31 455 2010 Trott O.; Olson A.J.; AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 2010,31(2),455-461 Molecules Balkrishna A. 24 4175 2019 10.3390/molecules24224175 Balkrishna A.; Pokhrel S.; Tomer M.; Verma S.; Kumar A.; Nain P.; Gupta A.; Varshney A.; Anti-acetylcholinesterase activities of mono-herbal extracts and exhibited synergistic effects of the phytoconstituents: a biochemical and computational study. Molecules 2019,24(22),4175 Molecules Kong X.P. 24 4567 2019 10.3390/molecules24244567 Kong X.P.; Liu E.Y.L.; Chen Z.C.; Xu M.L.; Yu A.X.D.; Wu Q.Y.; Xia Y.J.; Duan R.; Dong T.T.X.; Tsim K.W.K.; Synergistic inhibition of acetylcholinesterase by alkaloids derived from stephaniae tetrandrae radix, coptidis rhizoma and phellodendri chinensis cortex. Molecules 2019,24(24),4567 Molecules Pardo-Muras M. 24 4539 2019 10.3390/molecules24244539 Pardo-Muras M.; G Puig C.; Pedrol N.; Cytisus scoparius and Ulex europaeus produce volatile organic compounds with powerful synergistic herbicidal effects. Molecules 2019,24(24),4539 Biotechnol Adv Rao S.R. 20 101 2002 10.1016/S0734-9750(02)00007-1 Rao S.R.; Ravishankar G.A.; Plant cell cultures: Chemical factories of secondary metabolites. Biotechnol Adv 2002,20(2),101-153 Bot Bull Acad Sin Vanisree M. 45 1 2004 Vanisree M.; Lee C-Y.; Lo S-F.; Nalawade S.M.; Lin C.Y.; Tsay H-S.; Studies on the production of some important secondary metabolites from medicinal plants by plant tissue cultures. Bot Bull Acad Sin 2004,45,1-22 Int J Mol Sci Cappellari L.D.R. 21 50 2019 10.3390/ijms21010050 Cappellari L.D.R.; Santoro M.V.; Schmidt A.; Gershenzon J.; Banchio E.; Improving phenolic total content and monoterpene in mentha x piperita by using salicylic acid or methyl jasmonate combined with rhizobacteria inoculation. Int J Mol Sci 2019,21(1),50 Int J Mol Sci Swanepoel B. 20 5559 2019 10.3390/ijms20225559 Swanepoel B.; Nitulescu G.M.; Olaru O.T.; Venables L.; van de Venter M.; Anti-Cancer activity of a 5-Aminopyrazole derivative lead compound (BC-7) and potential synergistic cytotoxicity with cisplatin against human cervical cancer cells. Int J Mol Sci 2019,20(22),5559 J Cancer Schwartzberg L.S. 8 1872 2017 10.7150/jca.15407 Schwartzberg L.S.; Arena F.P.; Bienvenu B.J.; Kaplan E.H.; Camacho L.H.; Campos L.T.; Waymack J.P.; Tagliaferri M.A.; Chen M.M.; Li D.; A randomized, open-label, safety and exploratory efficacy study of Kanglaite Injection (KLTI) plus gemcitabine versus gemcitabine in patients with advanced pancreatic cancer. J Cancer 2017,8(10),1872-1883 Int J Mol Sci Qian Y. 20 5250 2019 10.3390/ijms20215250 Qian Y.; Xiong Y.; Feng D.; Wu Y.; Zhang X.; Chen L.; Gu M.; Coix seed extract enhances the anti-pancreatic cancer efficacy of gemcitabine through regulating ABCB1- and ABCG2-Mediated drug efflux: A bioluminescent pharmacokinetic and pharmacodynamic study. Int J Mol Sci 2019,20(21),5250 Oxidative medicine and cellular longevity Wagner A.E. 2013 2013 10.1155/2013/964539 Wagner A.E.; Terschluesen A.M.; Rimbach G.; Health promoting effects of brassica-derived phytochemicals: From chemopreventive and anti-inflammatory activities to epigenetic regulation. Oxidative medicine and cellular longevity 2013,2013 Int J Mol Sci Núñez-Iglesias M.J. 20 4977 2019 10.3390/ijms20204977 Núñez-Iglesias M.J.; Novío S.; García C.; Pérez-Muñuzuri E.; Soengas P.; Cartea E.; Velasco P.; Freire-Garabal M.; Glucosinolate-degradation products as co-adjuvant therapy on prostate cancer in vitro. Int J Mol Sci 2019,20(20),4977 Int J Mol Sci Ryu H. 20 4728 2019 10.3390/ijms20194728 Ryu H.; Choi H.K.; Kim H.J.; Kim A.Y.; Song J.Y.; Hwang S.G.; Kim J.S.; Kim D.U.; Kim E.H.; Kim J.; Ahn J.; Antitumor activity of a novel tyrosine kinase inhibitor aiu2001 due to abrogation of the dna damage repair in non-small cell lung cancer cells. Int J Mol Sci 2019,20(19),4728 Int J Mol Sci Park E. 20 4517 2019 10.3390/ijms20184517 Park E.; Ryu M.J.; Kim N.K.; Bae M.H.; Seo Y.; Kim J.; Yeo S.; Kanwal M.; Choi C.W.; Heo J.Y.; Jeong S.Y.; Synergistic neuroprotective effect of Schisandra chinensis and Ribes fasciculatum on neuronal cell death and scopolamine-induced cognitive impairment in rats. Int J Mol Sci 2019,20(18),4517 Biomolecules Gouveia M.J. 9 54 2019 10.3390/biom9020054 Gouveia M.J.; Brindley P.J.; Rinaldi G.; Gärtner F.; Correia da Costa J.M.; Vale N.; Combination anthelmintic/antioxidant activity against Schistosoma m. Biomolecules 2019,9(2),54 Biomolecules Solovieva M. 10 69 2020 10.3390/biom10010069 Solovieva M.; Shatalin Y.; Fadeev R.; Krestinina O.; Baburina Y.; Kruglov A.; Kharechkina E.; Kobyakova M.; Rogachevsky V.; Shishkova E.; Akatov A.V.; Vitamin B enhances the cytotoxicity of diethyldithiocarbamate in a synergistic manner, inducing the paraptosis-like death of human larynx carcinoma Cells. Biomolecules 2020,10(1),69 Phytother Res Liao X.Z. 33 2298 2019 10.1002/ptr.6392 Liao X.Z.; Gao Y.; Huang S.; Chen Z.Z.; Sun L.L.; Liu J.H.; Chen H.R.; Yu L.; Zhang J.X.; Lin L.Z.; Tanshinone IIA combined with cisplatin synergistically inhibits non-small-cell lung cancer in vitro and in vivo via down-regulating the phosphatidylinositol 3-kinase/Akt signalling pathway. Phytother Res 2019,33(9),2298-2309 Phytother Res Li K. 33 1658 2019 10.1002/ptr.6353 Li K.; Liu W.; Zhao Q.; Wu C.; Fan C.; Lai H.; Li S.; Combination of tanshinone IIA and doxorubicin possesses synergism and attenuation effects on doxorubicin in the treatment of breast cancer. Phytother Res 2019,33(6),1658-1669 J Anal Toxicol Reilly C.A. 26 313 2002 10.1093/jat/26.6.313 Reilly C.A.; Crouch D.J.; Yost G.S.; Fatah A.A.; Determination of capsaicin, nonivamide, and dihydrocapsaicin in blood and tissue by liquid chromatography-tandem mass spectrometry. J Anal Toxicol 2002,26(6),313-319 Eur J Pharm Sci Fang J.Y. 15 417 2002 10.1016/S0928-0987(02)00027-1 Fang J.Y.; Leu Y.L.; Wang Y.Y.; Tsai Y.H.; In vitro topical application and in vivo pharmacodynamic evaluation of nonivamide hydrogels using Wistar rat as an animal model. Eur J Pharm Sci 2002,15(5),417-423 Int J Obes Medina-Contreras J.M.L. 41 750 2017 10.1038/ijo.2017.33 Medina-Contreras J.M.L.; Colado-Velázquez J.; Gómez-Viquez N.L.; Mailloux-Salinas P.; Pérez-Torres I.; Aranda-Fraustro A.; Carvajal K.; Bravo G.; Effects of topical capsaicin combined with moderate exercise on insulin resistance, body weight and oxidative stress in hypoestrogenic obese rats. Int J Obes 2017,41(5),750-758 Atherosclerosis Wang Y. 260 13 2017 10.1016/j.atherosclerosis.2017.03.016 Wang Y.; Cui L.; Xu H.; Liu S.; Zhu F.; Yan F.; Shen S.; Zhu M.; TRPV1 agonism inhibits endothelial cell inflammation via activation of eNOS/NO pathway. Atherosclerosis 2017,260,13-19 Phytother Res Sivasinprasasn S. 33 1815 2019 10.1002/ptr.6369 Sivasinprasasn S.; Wikan N.; Tocharus J.; Pantan R.; Chaichompoo W.; Suksamrarn A.; Tocharus C.; Synergistic effects of the capsaicinoid nonivamide and rosuvastatin on obesity-related endothelial dysfunction in rat fed a high-fat diet. Phytother Res 2019,33(7),1815-1826 Food Chem Toxicol Formica J.V. 33 1061 1995 10.1016/0278-6915(95)00077-1 Formica J.V.; Regelson W.; Review of the biology of Quercetin and related bioflavonoids. Food Chem Toxicol 1995,33(12),1061-1080 Crit Rev Food Sci Nutr Wang D. 1 2018 Wang D.; Sun-Waterhouse D.; Li F.; Xin L.; Li D.; MicroRNAs as molecular targets of quercetin and its derivatives underlying their biological effects: A preclinical strategy. Crit Rev Food Sci Nutr 2018,1-13 Phytother Res Li T. 33 756 2019 10.1002/ptr.6268 Li T.; Li F.; Liu X.; Liu J.; Li D.; Synergistic anti-inflammatory effects of quercetin and catechin via inhibiting activation of TLR4-MyD88-mediated NF-κB and MAPK signaling pathways. Phytother Res 2019,33(3),756-767 Int J Mol Sci Bandolik J.J. 20 3052 2019 10.3390/ijms20123052 Bandolik J.J.; Hamacher A.; Schrenk C.; Weishaupt R.; Kassack M.U.; Class I-Histone Deacetylase (HDAC) inhibition is superior to pan-HDAC inhibition in modulating cisplatin potency in high grade serous ovarian cancer cell lines. Int J Mol Sci 2019,20(12),3052 Int J Mol Sci Liu J.J. 20 3383 2019 10.3390/ijms20143383 Liu J.J.; Ho J.Y.; Lee H.W.; Baik M.W.; Kim O.; Choi Y.J.; Hur S.Y.; Inhibition of Phosphatidylinositol 3-Kinase (PI3K) signaling synergistically potentiates antitumor efficacy of paclitaxel and overcomes paclitaxel-mediated resistance in cervical cancer. Int J Mol Sci 2019,20(14),3383 BioMed Res Int Morán-Santibañez K. 2016 8502123 2016 10.1155/2016/8502123 Morán-Santibañez K.; Cruz-Suárez L.E.; Ricque-Marie D.; Robledo D.; Freile-Pelegrín Y.; Peña-Hernández M.A.; Rodríguez-Padilla C.; Trejo-Avila L.M.; Synergistic effects of sulfated polysaccharides from Mexican seaweeds against measles virus. BioMed Res Int 2016,2016,8502123 Front Pharmacol Zhou X. 7 201 2016 10.3389/fphar.2016.00201 Zhou X.; Seto S.W.; Chang D.; Kiat H.; Razmovski-Naumovski V.; Chan K.; Bensoussan A.; Synergistic effects of Chinese herbal medicine: A comprehensive review of methodology and current research. Front Pharmacol 2016,7,201 Sci Rep Long F. 5 12361 2015 10.1038/srep12361 Long F.; Yang H.; Xu Y.; Hao H.; Li P.; A strategy for the identification of combinatorial bioactive compounds contributing to the holistic effect of herbal medicines. Sci Rep 2015,5,12361 J Biomol Screen Zhao W. 19 817 2014 10.1177/1087057114521867 Zhao W.; Sachsenmeier K.; Zhang L.; Sult E.; Hollingsworth R.E.; Yang H.; A new bliss independence model to analyze drug combination data. J Biomol Screen 2014,19(5),817-821 Nat Rev Microbiol Tyers M. 17 141 2019 10.1038/s41579-018-0141-x Tyers M.; Wright G.D.; Drug combinations: A strategy to extend the life of antibiotics in the 21st century. Nat Rev Microbiol 2019,17(3),141-155 Drug Discov Today Zimmermann G.R. 12 34 2007 10.1016/j.drudis.2006.11.008 Zimmermann G.R.; Lehár J.; Keith C.T.; Multi-target therapeutics: When the whole is greater than the sum of the parts. Drug Discov Today 2007,12(1-2),34-42 J Antibiot (Tokyo) Bérdy J. 58 1 2005 10.1038/ja.2005.1 Bérdy J.; Bioactive microbial metabolites. J Antibiot (Tokyo) 2005,58(1),1-26 J Antibiot (Tokyo) Bérdy J. 65 385 2012 10.1038/ja.2012.27 Bérdy J.; Thoughts and facts about antibiotics: Where we are now and where we are heading. J Antibiot (Tokyo) 2012,65(8),385-395 Molecules Yusof K.M. 20 10280 2015 10.3390/molecules200610280 Yusof K.M.; Makpol S.; Jamal R.; Harun R.; Mokhtar N.; Ngah W.Z.; γ-Tocotrienol and 6-Gingerol in combination synergistically induce cytotoxicity and apoptosis in HT-29 and SW837 human colorectal cancer cells. Molecules 2015,20(6),10280-10297 Phytomedicine Hemaiswarya S. 15 639 2008 10.1016/j.phymed.2008.06.008 Hemaiswarya S.; Kruthiventi A.K.; Doble M.; Synergism between natural products and antibiotics against infectious diseases. Phytomedicine 2008,15(8),639-652 Nat Prod Res Liu Z.H. 32 1287 2018 10.1080/14786419.2017.1333989 Liu Z.H.; Luo Z.W.; Li D.W.; Wang D.M.; Ji X.; Synergistic effects and related bioactive mechanisms of Potentilla fruticosa Linn. leaves combined with green tea polyphenols studied with Microbial Test System (MTS). Nat Prod Res 2018,32(11),1287-1290 Bacterial Pathogenesis and Antibacterial Control Sahra Ed London Intech Open Stefanović O.D. 2017 Stefanović O.D.; Synergistic Activity of Antibiotics and Bioactive Plant Extracts: A Study against Gram-Positive and Gram-Negative Bacteria. Bacterial Pathogenesis and Antibacterial Control Sahra Ed London Intech Open 2017 Carcinogenesis Komaki C. 17 1897 1996 10.1093/carcin/17.9.1897 Komaki C.; Okuno M.; Onogi N.; Moriwaki H.; Kawamori T.; Tanaka T.; Mori H.; Muto Y.; Synergistic suppression of azoxymethane-induced foci of colonic aberrant crypts by the combination of β-carotene and perilla oil in rats. Carcinogenesis 1996,17(9),1897-1901 J Dairy Res Caroprese M. 83 289 2016 10.1017/S0022029916000431 Caroprese M.; Ciliberti M.G.; Marino R.; Santillo A.; Sevi A.; Albenzio M.; Polyunsaturated fatty acid supplementation: effects of seaweed Ascophyllum nodosum and flaxseed on milk production and fatty acid profile of lactating ewes during summer. J Dairy Res 2016,83(3),289-297 Small Rumin Res Caroprese M. 102 177 2012 10.1016/j.smallrumres.2011.07.010 Caroprese M.; Albenzio M.; Bruno A.; Annichiarico G.; Marino R.; Sevi A.; Effects of shade and flaxseed supplementation on welfare of lactating ewes under high ambient temperatures. Small Rumin Res 2012,102,177-185 J Dairy Sci Toral P.G. 93 1655 2010 10.3168/jds.2009-2769 Toral P.G.; Hervás G.; Gómez-Cortés P.; Frutos P.; Juárez M.; de la Fuente M.A.; Milk fatty acid profile and dairy sheep performance in response to diet supplementation with sunflower oil plus incremental levels of marine algae. J Dairy Sci 2010,93(4),1655-1667 Curr Bioact Compd Bata M. 13 157 2017 10.2174/1573407213666170109151904 Bata M.; Rahayua S.; Evaluation of bioactive substances in Hibiscus tiliaceus and its potential as a ruminant feed additive. Curr Bioact Compd 2017,13(2),157-164 Prostaglandins Leukot Essent Fatty Acids Joshi K. 74 17 2006 10.1016/j.plefa.2005.10.001 Joshi K.; Lad S.; Kale M.; Patwardhan B.; Mahadik S.P.; Patni B.; Chaudhary A.; Bhave S.; Pandit A.; Supplementation with flax oil and vitamin C improves the outcome of Attention Deficit Hyperactivity Disorder (ADHD). Prostaglandins Leukot Essent Fatty Acids 2006,74(1),17-21 Food Chem Toxicol Makni M. 48 2239 2010 10.1016/j.fct.2010.05.055 Makni M.; Fetoui H.; Garoui M.; Gargouri N.K.; Jaber H.; Makni J.; Boudawara T.; Zeghal N.; Hypolipidemic and hepatoprotective seeds mixture diet rich in ω-3 and ω-6 fatty acids. Food Chem Toxicol 2010,48(8-9),2239-2246 Res Vet Sci Martínez-Pérez J.M. 97 71 2014 10.1016/j.rvsc.2014.05.009 Martínez-Pérez J.M.; Robles-Pérez D.; Benavides J.; Morán L.; Andrés S.; Giráldez F.J.; Rojo-Vázquez F.A.; Martínez-Valladares M.; Effect of dietary supplementation with flaxseed oil or vitamin E on sheep experimentally infected with Fasciola hepatica. Res Vet Sci 2014,97(1),71-79 J Dairy Sci da Silva D.C. 90 2928 2007 10.3168/jds.2006-573 da Silva D.C.; Santos G.T.; Branco A.F.; Damasceno J.C.; Kazama R.; Matsushita M.; Horst J.A.; dos Santos W.B.; Petit H.V.; Production performance and milk composition of dairy cows fed whole or ground flaxseed with or without monensin. J Dairy Sci 2007,90(6),2928-2936 Food Chem Rubió L. 149 277 2014a 10.1016/j.foodchem.2013.10.075 Rubió L.; Macià A.; Castell-Auví A.; Pinent M.; Blay M.T.; Ardévol A.; Romero M.P.; Motilva M.J.; Effect of the co-occurring olive oil and thyme extracts on the phenolic bioaccessibility and bioavailability assessed by in vitro digestion and cell models. Food Chem 2014a,149,277-284 Food Funct Rubió L. 5 740 2014b 10.1039/c3fo60446b Rubió L.; Serra A.; Chen C.Y.O.; Macià A.; Romero M.P.; Covas M.I.; Solà R.; Motilva M.J.; Effect of the co-occurring components from olive oil and thyme extracts on the antioxidant status and its bioavailability in an acute ingestion in rats. Food Funct 2014b,5(4),740-747 Current bioactive compounds Oyama M. 13 170 2017 Oyama M.; Tokiwano T.; Kawaii S.; Yoshida Y.; Mizuno K.; Oh K.; Yoshizawa Y.; Protodioscin, isolated from the rhizome of Dioscorea tokoro collected in northern Japan is the major antiproliferative compound to HL-60 leukemic cells. Current bioactive compounds 2017,13(2),170-174 Food Chem Dong X. 141 1923 2013 10.1016/j.foodchem.2013.04.109 Dong X.; Xu W.; Sikes R.A.; Wu C.; Combination of low dose of genistein and daidzein has synergistic preventive effects on isogenic human prostate cancer cells when compared with individual soy isoflavone. Food Chem 2013,141(3),1923-1933 Molecules Rahman A.A. 19 14528 2014a 10.3390/molecules190914528 Rahman A.A.; Makpol S.; Jamal R.; Harun R.; Mokhtar N.; Ngah W.Z.; Tocotrienol-rich fraction, [6]-gingerol and epigallocatechin gallate inhibit proliferation and induce apoptosis of glioma cancer cells. Molecules 2014a,19(9),14528-14541 BMC Complement Altern Med Abdul Rahman A. 14 213 2014b 10.1186/1472-6882-14-213 Abdul Rahman A.; Jamal A.R.A.; Harun R.; Mohd Mokhtar N.; Wan Ngah W.Z.; Gamma-tocotrienol and hydroxy-chavicol synergistically inhibits growth and induces apoptosis of human glioma cells. BMC Complement Altern Med 2014b,14(1),213 J Food Sci Liu Z. 81 C1091 2016 10.1111/1750-3841.13292 Liu Z.; Luo Z.; Jia C.; Wang D.; Li D.; Synergistic effects of Potentilla fruticosa L. Leaves combined with green tea polyphenols in a variety of oxidation systems. J Food Sci 2016,81(5),C1091-C1101 Int J Biol Macromol Vimalraj S. 93 1457 2016 10.1016/j.ijbiomac.2015.12.083 Vimalraj S.; Saravanan S.; Vairamani M.; Gopalakrishnan C.; Sastry T.P.; Selvamurugan N.; A Combinatorial effect of carboxymethyl cellulose based scaffold and microRNA-15b on osteoblast differentiation. Int J Biol Macromol 2016,93(Pt B),1457-1464 Nutrients Xu J. 9 271 2017 10.3390/nu9030271 Xu J.; Rong S.; Gao H.; Chen C.; Yang W.; Deng Q.; Huang Q.; Xiao L.; Huang F.; A combination of flaxseed oil and astaxanthin improves hepatic lipid accumulation and reduces oxidative stress in high fat-diet fed rats. Nutrients 2017,9(3),271 J Nat Prod Hussein G. 69 443 2006 10.1021/np050354+ Hussein G.; Sankawa U.; Goto H.; Matsumoto K.; Watanabe H.; Astaxanthin, a carotenoid with potential in human health and nutrition. J Nat Prod 2006,69(3),443-449 J Child Adolesc Psychopharmacol Vesco A.T. 25 526 2015 10.1089/cap.2013.0141 Vesco A.T.; Lehmann J.; Gracious B.L.; Arnold L.E.; Young A.S.; Fristad M.A.; Omega-3 supplementation for psychotic mania and comorbid anxiety in children. J Child Adolesc Psychopharmacol 2015,25(7),526-534 Metab Brain Dis Gomes L.M. 32 519 2017 10.1007/s11011-016-9942-7 Gomes L.M.; Carvalho-Silva M.; Teixeira L.J.; Rebelo J.; Mota I.T.; Bilesimo R.; Michels M.; Arent C.O.; Mariot E.; Dal-Pizzol F.; Scaini G.; Quevedo J.; Streck E.L.; Omega-3 fatty acids and mood stabilizers alter behavioral and oxidative stress parameters in animals subjected to fenproporex administration. Metab Brain Dis 2017,32(2),519-528 Mol Psychiatry Seung Kim H.F. 6 246 2001 10.1038/sj.mp.4000837 Seung Kim H.F.; Weeber E.J.; Sweatt J.D.; Stoll A.L.; Marangell L.B.; Inhibitory effects of omega-3 fatty acids on protein kinase C activity in vitro. Mol Psychiatry 2001,6(2),246-248 Mol Psychiatry Rao J.S. 13 585 2008 10.1038/mp.2008.31 Rao J.S.; Lee H.J.; Rapoport S.I.; Bazinet R.P.; Mode of action of mood stabilizers: Is the arachidonic acid cascade a common target? Mol Psychiatry 2008,13(6),585-596 Arch Gen Psychiatry Stoll A.L. 56 407 1999 10.1001/archpsyc.56.5.407 Stoll A.L.; Severus W.E.; Freeman M.P.; Rueter S.; Zboyan H.A.; Diamond E.; Cress K.K.; Marangell L.B.; Omega 3 fatty acids in bipolar disorder: A preliminary double-blind, placebo-controlled trial. Arch Gen Psychiatry 1999,56(5),407-412 J Integr Med Chakraborty S. 16 350 2018 10.1016/j.joim.2018.07.005 Chakraborty S.; Afaq N.; Singh N.; Majumdar S.; Antimicrobial activity of Cannabis sativa, Thuja orientalis and Psidium guajava leaf extracts against methicillin-resistant Staphylococcus aureus. J Integr Med 2018,16(5),350-357 Clin Microbiol Infect Deurenberg R.H. 13 222 2007 10.1111/j.1469-0691.2006.01573.x Deurenberg R.H.; Vink C.; Kalenic S.; Friedrich A.W.; Bruggeman C.A.; Stobberingh E.E.; The molecular evolution of methicillin-resistant Staphylococcus aureus. Clin Microbiol Infect 2007,13(3),222-235 Nutrients Lim Y. 11 108 2019 10.3390/nu11010108 Lim Y.; Song T.J.; Hwang W.; Kim J.Y.; Lee D.; Kim Y.J.; Kwon O.; Synergistic effects of sanghuang-danshen bioactives on arterial stiffness in a randomized clinical trial of healthy smokers: An integrative approach to in silico network analysis. Nutrients 2019,11(1),108 Science Funk C.D. 294 1871 2001 10.1126/science.294.5548.1871 Funk C.D.; Prostaglandins and leukotrienes: advances in eicosanoid biology. Science 2001,294(5548),1871-1875 Oncol Lett Li Z. 8 1603 2014 10.3892/ol.2014.2368 Li Z.; Wu C.; Wu J.; Ji M.; Shi L.; Jiang J.; Xu B.; Yuan J.; Synergistic antitumor effects of combined deguelin and cisplatin treatment in gastric cancer cells. Oncol Lett 2014,8(4),1603-1607 Int J Adv Res (Indore) Twinkle G. 5 995 2017 10.21474/IJAR01/5616 Twinkle G.; Aarti A.; Nilanjan D.; Sabiha I.; Synergistic activity of plant based bioactives in combating cancer: An overview. Int J Adv Res (Indore) 2017,5(10),995-1002 J Chem Pharm Res Suman K. 9 253 2017 Suman K.; Hitesh K.; Preeti J.; Synergistic interactions of chloroform extract of medicinal plants with antibiotics against bacteria of clinical relevance. J Chem Pharm Res 2017,9(5),253-256 Proc Natl Acad Sci, India, Sect B Biol Sci Venkatesan R. 89 173 2019 10.1007/s40011-017-0930-4 Venkatesan R.; Karuppiah P.S.; Arumugam G.; Balamuthu K.; β-asarone exhibits antifungal activity by inhibiting ergosterol biosynthesis in Aspergillus niger ATCC 16888. Proc Natl Acad Sci, India, Sect B Biol Sci 2019,89(1),173-184 Nature Amin A.H. 184 1317 1959 10.1038/1841317a0 Amin A.H.; Mehta D.R.; A bronchodilator alkaloid (vasicinone) from Adhatoda vasica Nees. Nature 1959,184(4695)(Suppl. 17),1317-1317 Med Chem Res Li R. 19 1092 2010 10.1007/s00044-009-9255-z Li R.; Chen W.C.; Wang W.P.; Tian W.Y.; Zhang X.G.; Extraction of essential oils from garlic (Allium sativum) using ligarine as solvent and its immunity activity in gastric cancer rat. Med Chem Res 2010,19(9),1092-1105 Med Aromat Plant Sci Biotechnol Datta A.K. 6 1 2012 Datta A.K.; Mandal A.; Teixeira da Silva J.; Saha A.; Paul R.; Sengupta S.; Halder S.; An updated overview on Aloe vera (L.) Burm. F. Med Aromat Plant Sci Biotechnol 2012,6(1),1-11 Front Plant Sci Czechowski T. 10 984 2019 10.3389/fpls.2019.00984 Czechowski T.; Rinaldi M.A.; Famodimu M.T.; Van Veelen M.; Larson T.R.; Winzer T.; Rathbone D.A.; Harvey D.; Horrocks P.; Graham I.A.; Flavonoid versus artemisinin anti-malarial activity in Artemisia annua whole-leaf extracts. Front Plant Sci 2019,10,984 Food Funct Williams R. 5 517 2014 10.1039/C3FO60467E Williams R.; Münch G.; Gyengesi E.; Bennett L.; Bacopa monnieri (L.) exerts anti-inflammatory effects on cells of the innate immune system in vitro. Food Funct 2014,5(3),517-520 Pharmacogn Commun Winnett V. 4 42 2014 10.5530/pc.2014.1.7 Winnett V.; Boyer H.; Sirdaarta J.; Cock I.E.; The potential of Tasmannia lanceolata as a natural preservative and medicinal agent: Antimicrobial activity and toxicity. Pharmacogn Commun 2014,4(1),42-52 Maced J Med Sci Abo-Salem O.M. 7 424 2014 10.3889/oamjms.2014.073 Abo-Salem O.M.; Kaempferol attenuates the development of diabetic neuropathic pain in mice: Possible anti-inflammatory and anti-oxidant mechanisms. Maced J Med Sci 2014,7(3),424-430 Hand book of Food chemistry Zhang X. 1009 2015 10.1007/978-3-642-36605-5_14 Zhang X.; Chen F.; Wang M.; Bioactive substance of Animal origin. Hand book of Food chemistry 2015,1009-1033 Pharmacol Res Variya B.C. 111 180 2016 10.1016/j.phrs.2016.06.013 Variya B.C.; Bakrania A.K.; Patel S.S.; Emblica officinalis (Amla): A review for its phytochemistry, ethnomedicinal uses and medicinal potentials with respect to molecular mechanisms. Pharmacol Res 2016,111,180-200 Pharmacogn Rev Jamadagni P.S. 11 141 2017 10.4103/phrev.phrev_31_16 Jamadagni P.S.; Pawar S.D.; Jamadagni S.B.; Chougule S.; Gaidhani S.N.; Murthy S.N.; Review of Holarrhena antidysenterica (L.) Wall. ex A. DC.: Pharmacognostic, pharmacological, and toxicological perspective. Pharmacogn Rev 2017,11(22),141-144 J Ethnopharmacol Huang L. 120 123 2008 10.1016/j.jep.2008.07.045 Huang L.; Yagura T.; Chen S.; Sedative activity of hexane extract of Keampferia galanga L. and its active compounds. J Ethnopharmacol 2008,120(1),123-125 Microvasc Res Kumar B. 87 65 2013 10.1016/j.mvr.2013.01.002 Kumar B.; Gupta S.K.; Srinivasan B.P.; Nag T.C.; Srivastava S.; Saxena R.; Jha K.A.; Hesperetin rescues retinal oxidative stress, neuroinflammation and apoptosis in diabetic rats. Microvasc Res 2013,87,65-74 PLoS One Zhang X. 9 e107072 2014 10.1371/journal.pone.0107072 Zhang X.; Wang G.; Gurley E.C.; Zhou H.; Flavonoid apigenin inhibits lipopolysaccharide-induced inflammatory response through multiple mechanisms in macrophages. PLoS One 2014,9(9),e107072 Ann Intern Med Micozzi M.S. 133 487 2000 10.7326/0003-4819-133-6-200009190-00032 Micozzi M.S.; American pharmaceutical association practical guide to natural medicines. Ann Intern Med 2000,133(6),487-487 Anc Sci Life Saha S. 31 151 2012 10.4103/0257-7941.107344 Saha S.; Ghosh S.; Tinospora cordifolia: One plant, many roles. Anc Sci Life 2012,31(4),151-159 J Altern Complement Med Gauthaman K. 9 257 2003 10.1089/10755530360623374 Gauthaman K.; Ganesan A.P.; Prasad R.N.V.; Sexual effects of puncturevine (Tribulus terrestris) extract (protodioscin): An evaluation using a rat model. J Altern Complement Med 2003,9(2),257-265 Biotechnological strategies for the conservation of medicinal and ornamental climbers, Berlin, Heidelberg Springer Shahzad A. 239 2016 Shahzad A.; Upadhyay A.; Sharma S.; Saeed T.; Tylophora indica (Burm. f.) Merrill: medicinal uses, propagation, and replenishment. Biotechnological strategies for the conservation of medicinal and ornamental climbers, Berlin, Heidelberg Springer 2016,239-258 Bangladesh J Pharmacol Bhuiyan M.N.I. 3 69 2008 10.3329/bjp.v3i2.844 Bhuiyan M.N.I.; Chowdhury J.U.; Begum J.; Volatile constituents of essential oils isolated from leaf and rhizome of Zingiber cassumunar Roxb. Bangladesh J Pharmacol 2008,3(2),69-73 Biol Trace Elem Res Rajan I. 155 455 2013 10.1007/s12011-013-9801-x Rajan I.; Narayanan N.; Rabindran R.; Jayasree P.R.; Manish Kumar P.R.; Zingerone protects against stannous chloride-induced and hydrogen peroxide-induced oxidative DNA damage in vitro. Biol Trace Elem Res 2013,155(3),455-459 Food Funct Zang Y. 6 834 2015 10.1039/C4FO00844H Zang Y.; Zhang L.; Igarashi K.; Yu C.; The anti-obesity and anti-diabetic effects of kaempferol glycosides from unripe soybean leaves in high-fat-diet mice. Food Funct 2015,6(3),834-841 Br J Pharmacol Gong Y. 172 5647 2015 10.1111/bph.12986 Gong Y.; Lin M.; Piao L.; Li X.; Yang F.; Zhang J.; Xiao B.; Zhang Q.; Song W.L.; Yin H.; Zhu L.; Funk C.D.; Yu Y.; Aspirin enhances protective effect of fish oil against thrombosis and injury-induced vascular remodelling. Br J Pharmacol 2015,172(23),5647-5660 Nutr Res Mokkala K. 36 246 2016 10.1016/j.nutres.2015.11.014 Mokkala K.; Laitinen K.; Röytiö H.; Bifidobacterium lactis 420 and fish oil enhance intestinal epithelial integrity in Caco-2 cells. Nutr Res 2016,36(3),246-252 Nutr Res Lawler J.M. 65 17 2019 10.1016/j.nutres.2018.12.013 Lawler J.M.; Garcia-Villatoro E.L.; Guzzoni V.; Hord J.M.; Botchlett R.; Holly D.; Lawler M.S.; Janini Gomes M.; Ryan P.; Rodriguez D.; Kuczmarski J.M.; Fluckey J.D.; Talcott S.; Effect of combined fish oil Adv Pharmacol Sci Shiassi Arani F. 2019 7581318 2019 10.1155/2019/7581318 Shiassi Arani F.; Karimzadeh L.; Ghafoori S.M.; Nabiuni M.; Antimutagenic and synergistic cytotoxic effect of cisplatin and honey bee venom on 4T1 invasive mammary carcinoma cell line. Adv Pharmacol Sci 2019,2019,7581318 Cancer Lett Rady I. 402 16 2017 10.1016/j.canlet.2017.05.010 Rady I.; Siddiqui I.A.; Rady M.; Mukhtar H.; Melittin, a major peptide component of bee venom, and its conjugates in cancer therapy. Cancer Lett 2017,402,16-31 J Neurosci Res Radermacher S.W. 36 657 1993 10.1002/jnr.490360606 Radermacher S.W.; Schoop V.M.; Schluesener H.J.; Bactenecin, a leukocytic antimicrobial peptide, is cytotoxic to neuronal and glial cells. J Neurosci Res 1993,36(6),657-662 Antiviral Res Shestakov A. 100 455 2013 10.1016/j.antiviral.2013.08.019 Shestakov A.; Jenssen H.; Hancock R.E.; Nordström I.; Eriksson K.; Synthetic analogues of bovine bactenecin dodecapeptide reduce herpes simplex virus type 2 infectivity in mice. Antiviral Res 2013,100(2),455-459 J Dairy Sci Rizzello C.G. 88 2348 2005 10.3168/jds.S0022-0302(05)72913-1 Rizzello C.G.; Losito I.; Gobbetti M.; Carbonara T.; De Bari M.D.; Zambonin P.G.; Antibacterial activities of peptides from the water-soluble extracts of Italian cheese varieties. J Dairy Sci 2005,88(7),2348-2360 Drugs Today (Barc) Prommer E. 42 369 2006 10.1358/dot.2006.42.6.973534 Prommer E.; Ziconotide: A new option for refractory pain. Drugs Today (Barc) 2006,42(6),369-378 Mar Drugs Esmaeelian B. 11 3802 2013 10.3390/md11103802 Esmaeelian B.; Benkendorff K.; Johnston M.R.; Abbott C.A.; Purified brominated indole derivatives from Dicathais orbita induce apoptosis and cell cycle arrest in colorectal cancer cell lines. Mar Drugs 2013,11(10),3802-3822 Biochem Biophys Res Commun Morikawa N. 189 184 1992 10.1016/0006-291X(92)91542-X Morikawa N.; Hagiwara K.; Nakajima T.; Brevinin-1 and -2, unique antimicrobial peptides from the skin of the frog, Rana brevipoda porsa. Biochem Biophys Res Commun 1992,189(1),184-190 Haematologica Pigneux A. 92 1327 2007 10.3324/haematol.11068 Pigneux A.; Perreau V.; Jourdan E.; Vey N.; Dastugue N.; Huguet F.; Sotto J.J.; Salmi L.R.; Ifrah N.; Reiffers J.; Adding lomustine to idarubicin and cytarabine for induction chemotherapy in older patients with acute myeloid leukemia: The BGMT 95 trial results. Haematologica 2007,92(10),1327-1334 Boll Mus Ist Biol Univ Genova Cerrano C. 68 239 2004 Cerrano C.; Lagoon sponges from Carrie Bow Cay (Belize): Ecological benefits of selective sediment incorporation. Boll Mus Ist Biol Univ Genova 2004,68,239-252 Antimicrob Agents Chemother Ramón-García S. 55 3861 2011 10.1128/AAC.00474-11 Ramón-García S.; Ng C.; Anderson H.; Chao J.D.; Zheng X.; Pfeifer T.; Av-Gay Y.; Roberge M.; Thompson C.J.; Synergistic drug combinations for tuberculosis therapy identified by a novel high-throughput screen. Antimicrob Agents Chemother 2011,55(8),3861-3869 J Food Sci Technol VidyaLaxme B. 51 3072 2014 10.1007/s13197-012-0834-5 VidyaLaxme B.; Rovetto A.; Grau R.; Agrawal R.; Synergistic effects of probiotic Leuconostoc mesenteroides and Bacillus subtilis in malted ragi (Eleucine corocana) food for antagonistic activity against V. cholerae and other beneficial properties. J Food Sci Technol 2014,51(11),3072-3082 Asian J Pharm Clin Res Rafiq Z. 10 1 2017 Rafiq Z.; Narasimhan S.; Haridoss M.; Vennila R.; Vaidyanathan R.; Punica granatum rind extract: Antibiotic potentiator and efflux pump inhibitor of multidrug resistant Klebsiella pneumoniae clinical isolates. Asian J Pharm Clin Res 2017,10,1-5 Sci Hortic (Amsterdam) da Silva J.A. 160 85 2013 10.1016/j.scienta.2013.05.017 da Silva J.A.; Rana T.S.; Narzary D.; Verma N.; Meshram D.T.; Ranade S.; Pomegranate biology and biotechnology: A review. Sci Hortic (Amsterdam) 2013,160(8),85-107 Sci Rep Di Lodovico S. 9 4646 2019 10.1038/s41598-019-40991-y Di Lodovico S.; Napoli E.; Di Campli E.; Di Fermo P.; Gentile D.; Ruberto G.; Nostro A.; Marini E.; Cellini L.; Di Giulio M.; Pistacia vera L. oleoresin and levofloxacin is a synergistic combination against resistant Helicobacter pylori strains. Sci Rep 2019,9(1),4646-4646 J Plant Dis Prot Krebs B. 105 181 1998 Krebs B.; Höding B.; Kübart S.; Workie M.A.; Junge H.; Schmiedeknecht G.; Hevesi M.; Use of Bacillus subtilis as biocontrol agent. I. Activities and characterization of Bacillus subtilis strains. J Plant Dis Prot 1998,105(2),181-197 Tetrahedron Lett Trischman J.A. 35 5571 1994 10.1016/S0040-4039(00)77249-2 Trischman J.A.; Jensenm P.R.; Fenical W.; Halobacillin: A cytotoxic cyclic acylpeptide of the iturin class produced by a marine Bacillus. Tetrahedron Lett 1994,35(31),5571-5574 Nature Nathan C. 431 899 2004 10.1038/431899a Nathan C.; Antibiotics at the crossroads. Nature 2004,431(7011),899-902 J Bacteriol Fan L. 193 1276 2011 10.1128/JB.01351-10 Fan L.; Bo S.; Chen H.; Ye W.; Kleinschmidt K.; Baumann H.I.; Imhoff J.F.; Kleine M.; Cai D.; Genome sequence of Bacillus subtilis subsp. spizizenii gtP20b, isolated from the Indian ocean. J Bacteriol 2011,193(5),1276-1277 IJSN Karunai Selvi B. 5 147 2014 Karunai Selvi B.; Balagengatharathilagam P.; Isolation and screening of endophytic fungi from medicinal plants of Virudhunagar district for antimicrobial activity. IJSN 2014,5(1),147-155 J Nat Prod Guo B. 63 602 2000 10.1021/np990467r Guo B.; Dai J.R.; Ng S.; Huang Y.; Leong C.; Ong W.; Carté B.K.; Cytonic acids A and B: Novel tridepside inhibitors of hCMV protease from the endophytic fungus Cytonaema species. J Nat Prod 2000,63(5),602-604 J Am Acad Dermatol García-Montero P. 80 508 2019 10.1016/j.jaad.2018.09.050 García-Montero P.; Del Boz J.; Baselga-Torres E.; Azaña-Defez J.M.; Alcaraz-Vera M.; Tercedor-Sánchez J.; Noguera-Morel L.; Vera-Casaño Á.; Use of topical rapamycin in the treatment of superficial lymphatic malformations. J Am Acad Dermatol 2019,80(2),508-515 FEMS Microbiol Lett Castillo U.F. 255 296 2006 10.1111/j.1574-6968.2005.00080.x Castillo U.F.; Strobel G.A.; Mullenberg K.; Condron M.M.; Teplow D.B.; Folgiano V.; Gallo M.; Ferracane R.; Mannina L.; Viel S.; Codde M.; Robison R.; Porter H.; Jensen J.; Munumbicins E-4 and E-5: Novel broad-spectrum antibiotics from Streptomyces NRRL 3052. FEMS Microbiol Lett 2006,255(2),296-300 Curr Opin Chem Biol Liu R. 38 117 2017 10.1016/j.cbpa.2017.03.017 Liu R.; Li X.; Lam K.S.; Combinatorial chemistry in drug discovery. Curr Opin Chem Biol 2017,38,117-126 PharmaTutor Narang H. 5 37 2017 Narang H.; Shastri S.; Combinatorial chemistry-modern synthesis approach. PharmaTutor 2017,5(5),37-63 Cancer Res DeWys W.D. 40 2202 1980 DeWys W.D.; Bathina S.H.; Synergistic antileukemic effect of theophylline and 1,3-bis(2-chloroethyl)-1-nitrosourea. Cancer Res 1980,40(7),2202-2208 Mol Cell Biochem Yamaguchi M. 178 377 1998 10.1023/A:1006809031836 Yamaguchi M.; Gao Y.H.; Anabolic effect of genistein and genistin on bone metabolism in the femoral-metaphyseal tissues of elderly rats: The genistein effect is enhanced by zinc. Mol Cell Biochem 1998,178(1-2),377-382 J Bone Miner Metab Yamaguchi M. 18 77 2000 10.1007/s007740050015 Yamaguchi M.; Gao Y.H.; Ma Z.J.; Synergistic effect of genistein and zinc on bone components in the femoral-metaphyseal tissues of female rats. J Bone Miner Metab 2000,18(2),77-83 Cancer Biol Ther Jiang Y. 12 574 2011 10.4161/cbt.12.7.15971 Jiang Y.; DiVittore N.A.; Kaiser J.M.; Shanmugavelandy S.S.; Fritz J.L.; Heakal Y.; Tagaram H.R.; Cheng H.; Cabot M.C.; Staveley-O’Carroll K.F.; Tran M.A.; Fox T.E.; Barth B.M.; Kester M.; Combinatorial therapies improve the therapeutic efficacy of nanoliposomal ceramide for pancreatic cancer. Cancer Biol Ther 2011,12(7),574-585 J Med Microbiol Hwang I.S. 61 1719 2012 10.1099/jmm.0.047100-0 Hwang I.S.; Hwang J.H.; Choi H.; Kim K.J.; Lee D.G.; Synergistic effects between silver nanoparticles and antibiotics and the mechanisms involved. J Med Microbiol 2012,61(Pt 12),1719-1726 S Afr J Bot Taukoorah U. 105 133 2016 10.1016/j.sajb.2016.01.006 Taukoorah U.; Lall N.; Mahomoodally F.; Piper betle L. (betel quid) shows bacteriostatic, additive, and synergistic antimicrobial action when combined with conventional antibiotics. S Afr J Bot 2016,105,133-140 Biochem Biophys Res Commun Lu J.W. 491 595 2017 10.1016/j.bbrc.2017.07.157 Lu J.W.; Hsieh P.S.; Lin C.C.; Hu M.K.; Huang S.M.; Wang Y.M.; Liang C.Y.; Gong Z.; Ho Y.J.; Synergistic effects of combination treatment using EGCG and suramin against the Chikungunya virus. Biochem Biophys Res Commun 2017,491(3),595-602 Microb Pathog Sivasankar C. 110 66 2017 10.1016/j.micpath.2017.06.026 Sivasankar C.; Gayathri S.; Bhaskar J.P.; Krishnan V.; Pandian S.K.; Evaluation of selected Indian medicinal plants for antagonistic potential against Malassezia spp. and the synergistic effect of embelin in combination with ketoconazole. Microb Pathog 2017,110,66-72 J Ethnopharmacol Kumara Swamy H.M. 109 529 2007 10.1016/j.jep.2006.09.003 Kumara Swamy H.M.; Krishna V.; Shankarmurthy K.; Abdul Rahiman B.; Mankani K.L.; Mahadevan K.M.; Harish B.G.; Raja Naika H.; Wound healing activity of embelin isolated from the ethanol extract of leaves of Embelia ribes Burm. J Ethnopharmacol 2007,109(3),529-534 Chem Biol Interact Joshi R. 167 125 2007 10.1016/j.cbi.2007.02.004 Joshi R.; Kamat J.P.; Mukherjee T.; Free radical scavenging reactions and antioxidant activity of embelin: Biochemical and pulse radiolytic studies. Chem Biol Interact 2007,167(2),125-134 Eur J Pharmacol Kalyan Kumar G. 662 63 2011 10.1016/j.ejphar.2011.04.037 Kalyan Kumar G.; Dhamotharan R.; Kulkarni N.M.; Mahat M.Y.; Gunasekaran J.; Ashfaque M.; Embelin reduces cutaneous TNF-α level and ameliorates skin edema in acute and chronic model of skin inflammation in mice. Eur J Pharmacol 2011,662(1-3),63-69 BMC Complement Altern Med Debebe Y. 15 187 2015 10.1186/s12906-015-0711-7 Debebe Y.; Tefera M.; Mekonnen W.; Abebe D.; Woldekidan S.; Abebe A.; Belete Y.; Menberu T.; Belayneh B.; Tesfaye B.; Nasir I.; Yirsaw K.; Basha H.; Dawit A.; Debella A.; Evaluation of anthelmintic potential of the Ethiopian medicinal plant Embelia schimperi Vatke in vivo and in vitro against some intestinal parasites. BMC Complement Altern Med 2015,15,187 Planta Med Tullio V. 78 1633 2012 10.1055/s-0032-1315153 Tullio V.; Mandras N.; Allizond V.; Nostro A.; Roana J.; Merlino C.; Banche G.; Scalas D.; Cuffini A.M.; Positive interaction of thyme (red) essential oil with human polymorphonuclear granulocytes in eradicating intracellular Candida albicans. Planta Med 2012,78(15),1633-1635 Food Chem Nabavi S.M. 173 339 2015 10.1016/j.foodchem.2014.10.042 Nabavi S.M.; Marchese A.; Izadi M.; Curti V.; Daglia M.; Nabavi S.F.; Plants belonging to the genus Thymus as antibacterial agents: From farm to pharmacy. Food Chem 2015,173,339-347 Nat Prod Res Scazzocchio F. 23 1 2015 Scazzocchio F.; Garzoli S.; Conti C.; Leone C.; Renaioli C.; Pepi F.; Angiolella, L. Properties and limits of some essential oils: Chemical characterisation, antimicrobial activity, interaction with antibiotics and cytotoxicity. Nat Prod Res 2015,23,1-10 Nat Prod Res Cannas S. 30 332 2016 10.1080/14786419.2015.1060592 Cannas S.; Usai D.; Tardugno R.; Benvenuti S.; Pellati F.; Zanetti S.; Molicotti P.; Chemical composition, cytotoxicity, antimicrobial and antifungal activity of several essential oils. Nat Prod Res 2016,30(3),332-339 BMC Complement Altern Med Scalas D. 18 143 2018 10.1186/s12906-018-2219-4 Scalas D.; Mandras N.; Roana J.; Tardugno R.; Cuffini A.M.; Ghisetti V.; Benvenuti S.; Tullio V.; Use of Pinus sylvestris L. (Pinaceae), Origanum vulgare L. (Lamiaceae), and Thymus vulgaris L. (Lamiaceae) essential oils and their main components to enhance itraconazole activity against azole susceptible/not-susceptible Cryptococcus neoformans strains. BMC Complement Altern Med 2018,18(1),143 J Infect Dis Dobard C.W. 212 1988 2015 10.1093/infdis/jiv334 Dobard C.W.; Taylor A.; Sharma S.; Anderson P.L.; Bushman L.R.; Chuong D.; Pau C.P.; Hanson D.; Wang L.; Garcia-Lerma J.G.; McGowan I.; Rohan L.; Heneine W.; Protection against rectal chimeric simian/human immunodeficiency virus transmission in macaques by rectal-specific gel formulations of maraviroc and tenofovir. J Infect Dis 2015,212(12),1988-1995 AIDS Herrera C. 30 1015 2016 10.1097/QAD.0000000000001043 Herrera C.; Armanasco N.; García-Pérez J.; Ziprin P.; Olejniczak N.; Alcamí J.; Nuttall J.; Shattock R.J.; Maraviroc and reverse transcriptase inhibitors combinations as potential preexposure prophylaxis candidates. AIDS 2016,30(7),1015-1025 Emerg Microbes Infect Yang Y. 6 1 2017 10.1038/emi.2017.26 Yang Y.; Zhu J.; Hassink M.; Jenkins L.M.M.; Wan Y.; Appella D.H.; Zhang X.; A novel preventive strategy against HIV-1 infection: Combinatorial use of inhibitors targeting the nucleocapsid and fusion proteins: Combination of SAMT10 and SFT against HIV-1. Emerg Microbes Infect 2017,6(1),1-8 AMB Express Hu F. 9 37 2019 10.1186/s13568-019-0760-2 Hu F.; Hu Y.; Peng F.; Synergistic and protective effect of atorvastatin and amygdalin against histopathological and biochemical alterations in Sprague-Dawley rats with experimental endometriosis. AMB Express 2019,9(1),37 Biochem Biophys Res Commun Jiagang D. 411 523 2011 10.1016/j.bbrc.2011.06.162 Jiagang D.; Li C.; Wang H.; Hao E.; Du Z.; Bao C.; Lv J.; Wang Y.; Amygdalin mediates relieved atherosclerosis in apolipoprotein E deficient mice through the induction of regulatory T cells. Biochem Biophys Res Commun 2011,411(3),523-529 Drug Store News for the Pharmacist Anonymous. 5 41 1995 Anonymous. ; Shark cartilage. Drug Store News for the Pharmacist 1995,5,41 Iran J Basic Med Sci Molaie S. 22 146 2019 Molaie S.; Ghaffarifar F.; Dalimi A.; Zuhair M.H.; Sharifi Z.; Evaluation of synergistic therapeutic effect of shark cartilage extract with artemisinin and glucantime on visceral leishmaniasis in BALB/c mice. Iran J Basic Med Sci 2019,22(2),146-153 Int J Antimicrob Agents Thomas V.M. 53 663 2019 10.1016/j.ijantimicag.2019.03.009 Thomas V.M.; Brown R.M.; Ashcraft D.S.; Pankey G.A.; Synergistic effect between nisin and polymyxin B against pandrug-resistant and extensively drug-resistant Acinetobacter baumannii. Int J Antimicrob Agents 2019,53(5),663-668 Lancet Respir Med Yang X. S2213-2600(20)30079-5 2020 10.1016/S2213-2600(20)30079-5 Yang X.; Yu Y.; Xu J.; Shu H.; Xia J.; Liu H.; Wu Y.; Zhang L.; Yu Z.; Fang M.; Yu T.; Wang Y.; Pan S.; Zou X.; Yuan S.; Shang Y.; Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med 2020,S2213-2600(20)30079-5 Coronavirus. xmlns:xlink="http://www.w3.org/1999/xlink" https://www.worldometers.info [Accessed on April 15, 2020]. The Economic Times. Tradition comes to rescue: China administers 3,000-year-old medicine on patients affected by Coronavirus. xmlns:xlink="http://www.w3.org/1999/xlink" https://economictimes.indiatimes.com/magazines/panache/tradition-comes-to-rescue-china-administers-3000-year-old-medicine-on-patients-affected-by-coronavirus/articleshow/74149838.cms [Accessed on February 15, 2020].