Desert Chemotypes": the Potential of Desert Plants-Derived Metabolome to Become a Sustainable Resource for Drug Leads

Rivka Ofir. Medical Research Archives vol 8 issue 7. Medical Research Archives

RESEARCH ARTICLE

"Desert Chemotypes": The Potential of Desert Plants-Derived Metabolome to Become a Sustainable Resource for Drug Leads

Author Rivka Ofir PhD; BGU-iPSC Core Facility Regenerative Medicine & Stem Cell (RMSC) Research Center, Ben Gurion University of the Negev and Dead Sea&Arava Science Center, Israel Email: [email protected]

Abstract Plants secondary metabolites that are essential for plant survival in its environment are a useful resource for drug discovery in the area of combination therapy. Desert plants, in particular, have a lot to offer; they experience stress conditions and activation/repression of pathways that lead to biosynthesis of unique compounds. The current knowledge on the effectiveness of combination therapy as compared to single treatment support the use of active plant-derived extracts or fractions composed of several metabolites. A set of metabolites, termed "metabolite signature", within an active fraction, will serve as a guide in the process of desert plants domestication. The combination of modern methods of transcriptome, proteome and metabolome analyses with precision agriculture, will pave the way to produce sustainable plant biomass for pharmaceutical industries.

Key words: plant metabolite, combined therapy, Terpenes, Flavonoids,

Rivka Ofir. Medical Research Archives vol 8 issue 7. July 2020 Page 2 of 15

1. Many Drugs are Based on Plant– discover new agents that will act instead of, Derived Compounds or in synergy with, accepted chemotherapy Plant metabolites contribute to the chemical treatments 11. Models of neurodegenerative diversity of bioactive compounds and can brain diseases involve screening plant- serve as additional source of leads apart from derived compounds which inhibit man-made compounds. inflammation; these models are based on the Most of the existing or new drugs discovered recent documentation of neurodegeneration- so far are secondary metabolites of plant inflammation relationship in various brain origin which are used as a whole, modified, diseases 12, 13. Active plant compounds may or modeled in resemblance of phytoleads 1. slow the deterioration from Plant-derived natural products serve as a neurodegenerative brain diseases; challenging resource for novel drug leads; the pharmaceutic interventions for treating process involves screening natural chronic neurodegenerative diseases will be compounds and identifying "screening hits" focused on reducing/terminating the followed by preclinical studies in animal inflammatory state 14. models in order for the compound to be considered a "drug lead" 2. The current drug 3. Plant Metabolites as Leads- discovery process using plant extracts relies Phytochemicals (Terpenes, Flavonoids, on bioactivity-guided fractionation, which Saponins, Tannins) has led to the isolation of many important 3.1. Terpene, the largest group of natural drugs like paclitaxel, camptothecin, salicin, compounds; terpenoids, also referred to as quinine, artemisinin, forskolin, galantamine, terpenes, are classified as monoterpenes apomorphine, cannabidiol, capsaicin, (C10), sesquiterpenes (C15), diterpenes (C20), 3-9 noncatecholamine, chloroquine and more . and sesterterpenes (C25). Among the most Although the bioprospecting process in the important terpene-based pharmaceuticals are last few years has led to identifying many the anticancer drug taxol® , the antimalarial plant-derived compounds with drug artimesinin; and more terpenoid-based pharmaceutical value, it is possible that leads for drugs were documented 15. Certain advanced methods and equipment for terpenes like curcumin that showed anti- metabolites analysis will improve and hasten inflammatory, antioxidant, anticancer the discovery of more high-value plant- activities in in vitro models, are considered as derived compounds with pharmacological alternative medicine 16. Interestingly, the activity 10. content of desert plants-derived monoterpenes, oxygenated terpenes and 2. Human Diseases Models Used for sesquiterpenes is dependent on annual Screening Plant-Derived Drugs precipitation 17, 18. Many models of cancer diseases serve as targets for screening plant attributes; tumor 3.2. Flavonoids, belong to the family of cells develop resistance to chemotherapy polyphenolic secondary metabolites; plant quite rapidly, and it is an urgent need to derived flavonoids were investigated mainly

Copyright 2020 KEI Journals. All Rights Reserved http://journals.ke-i.org/index.php/mra Rivka Ofir. Medical Research Archives vol 8 issue 7. July 2020 Page 3 of 15 against cancer 19-21 and diabetes 22. The around the globe, with emphasis in more flavone skeletal structure and the phenolic detail on research of several plants from the composition have an impact on the Arava and Negev deserts of Israel. antioxidant activity of flavonoids 23-25 and on their anti-cancer activity and anti-diabetic 4.1. Global Arid Zones and Medicinal activity 26, 27. Currently, plant flavonoids are Plants routinely used as additional products by the Studies of desert plants from Mexico pharmaceutics and nutraceutics industries 28. (Jatropha dioica, Flourensia cernua, Turnera diffusa and Eucalyptus camaldulens 3.3. Saponins, are secondary metabolites of is) showed that these plants are rich in glycosidic nature consisting of a triterpene or polyphenolic compounds exhibiting steroid aglycone; they have pharmacological antioxidant activity 36. Plants from the properties related to cancer inhibition and Tunisian desert (Marribium deserti, Rhus hormones stimulation 25, 29, 30. tripartita (Rh. tripartitum),Artemisia herba- alba Asso,Colocynthis vulgaris (L.) Schard. 3.4.Tannins, are a class of complex Ephedra alata Decaisne, Astragalus biomolecules of a polyphenolic nature gombiformis Pomel Calligonum synthesized by a large variety of plants, in comsum Hérit, Nitraria retusa (Forsk) which they are used as antipredator or Asch), are used in traditional medicine; pesticide agents 31. Tannins extracted from extracts of these plants are being used for many vegetables and desert plants like drug discovery 37. Acacia mearnsii, Yellow Dock and other plants, show antioxidant activity, leading to 4.2. Middle Eastern Desert Plant Derived- the development of tannin-based dietary Metabolites supplements 32-35. 4.2.1. Achillea fragrantissima (Forssk) Sch. Bip. (Af). Extract of Af, a desert plant used 4. Desert Plants and Leads for Drugs for many years in traditional medicine in the Screening desert plant-derived Arabia region (Figure 1A), showed anti- extracts/metabolites results in the neuroinflammatory effects in vitro 38. identification of active extracts or pure Achillolide A, a sesquiterpene lactone and metabolites; these may be considered as drug Flavonoid 3,5,4′-trihydroxy-6,7,3′- leads. Extracts contain several compounds trimethoxyflavone (TTF) that were isolated and have the advantage of potential from Af, downregulated microglial activation 39 combined treatment and synergism between , prevented hydrogen peroxide (H2O2)- the activities of the compounds. When an induced astrocytes death 40, protected active pure metabolite is identified, its neuroblastoma cells from glutamate toxicity mechanism of action can be studied more 41 and interfered with Aβ-induced processes precisely. in Neuro2a (N2a) cells and protected them This review covers research on plant-derived from its toxicity 42. compounds from various desert/arid areas

4.2.2. Asteriscus graveolens (A. graveolens). type 2 (HSV-2) and respiratory syncytial Extract of A. graveolens, an endemic Middle virus type B (RSV-B) 50; the active Eastern medicinal plant, located in extreme compound, isolated using bio-guided assays, desert environments (Figure 1B), is cytotoxic was identified as guggulsterone 51. A broad- to cancer cells but not to non-cancerous cells; spectrum of activity against both Gram- its activity was accompanied by a positive and Gram-negative bacteria, in concentration- and time-dependent addition to fungi, was identified in C. appearance of apoptosis, and high levels of gileadensis 52, 53. Reactive Oxygen Species (ROS) 43. Combining a plant fraction rich in 4.2.5. Artemisia judaica L.( A. sesquiterpene lactone asteriscunolide Judaica). The essential oil of A. judaica , a isomers with several toxic chemotherapeutic medicinal plant growing in the desert areas of drugs, enabled to reduce the concentration of Jordan (Figure 1E), has therapeutic potential these toxic drugs and still achieve effective for the treatment of disseminated candidiasis, treatment in vitro 44. A. graveolens in vitro, it inhibits Nitric Oxide (NO) metabolites: cis ‐chrysanthenyl acetate, production elicited by LPS in macrophages, myrtenyl acetate, and kessane, showed highlighting its potential anti-inflammatory antimicrobial activities 45. activity 50. The main metabolic content of A. judaica from the desert of Israel and from the 4.2.3. Pulicaria incisa (Lam.) DC (Pi). desert of Sinai are artemisyl-oil type Infusion prepared from Pi, a desert plant (characterized by the existence of artemisyl- containing high amounts of unsaturated fatty skeleton-type compounds in the essential oil) acids and has been used for many years in and piperitone-oil type (characterized by the traditional medicine (Figure 1C), showed absence of artemisyl-skeleton-type antioxidant and astroprotective effects in compounds and the presence of a relatively vitro 46. Chalconoid from Pi has protective high percentage of piperitone and camphor), and antioxidant effects on brain astrocytes 47. respectively, suggesting that they represent The metabolites chrysanthenone and 2,6‐ two different plant chemotypes 54. dimethylphenol showed antimicrobial activities 45. 4.2.6. Origanum dayi (O. dayi). Extracts of O. dayi, an endemic desert plant (Figure 1F), 4.2.4. Commiphora gileadensis (C. inhibit pancreatic lipase and are suggested as gileadensis ). C. gileadensis, native to a treatment for obesity 55. They also have the southwest Arabia and Somaliland (Figure capability to kill cancer cells lines and 1D), contain β-Caryophyllene (trans- primary cultures established from patients' (1R,9S)-8-methylene-4,11,11- biopsies, in vitro 56, 57. trimethylbicyclo[7.2.0]undec-4-ene), a selective inducer of apoptosis in cancer cells 4.2.7.Rumex cyprius. The extracts of the in vitro 48, 49. A methanol extract of C. fruit of Rumex cyprius, an edible desert plant gileadensis acts against herpes simplex virus (Figure 1G), show antioxidant activity 58;

Copyright 2020 KEI Journals. All Rights Reserved http://journals.ke-i.org/index.php/mra Rivka Ofir. Medical Research Archives vol 8 issue 7. July 2020 Page 5 of 15 they also inhibit the human transcriptase 59. Interestingly, Rumex cyprius immunodeficiency virus-1 by interfering belongs to a family of plants rich in with the activity of the enzyme reverse phenylpropanoids and anthraquinones 60.

Figure 1. Plant from the Negev and Arava desert of Israel. A. Achillea fragrantissima (Forssk) Sch. Bip. (Af), B. Asteriscus graveolens (A. graveolens), C. Pulicaria incisa (Lam.) DC (Pi), D. Commiphora gileadensis (C. gileadensis ), E. Artemisia judaica L. ( A. Judaica), F. Origanum dayi (O. dayi), G. Rumex cyprius

5. Desert Chemotypes/ Chemovariations pathways are activated or suppressed 62-66. as a Rich Resource for Leads for Drugs Environmental stress affects biosynthesis of Plant locations and growth conditions plant secondary metabolites that are contribute to their metabolites content, produced from primary metabolites such as namely to their chemotypes or chemovariants amino acids, lipids, and carbohydrates 67-69. 61. Most secondary metabolites are derivatives from the following building blocks: the 5.1. Desert Stress Conditions-Derived acetate C2-unit (polyketides), the Secondary Metabolites phenylalanine/tyrosine-derived C9-unit Drought, salinity, high temperatures and (phenylpropanoids), the isopentenyl radiation are characteristics of desert diphosphate C5-unit and some amino acids environment. These stresses act as plants 70. Secondary metabolites serve the plants as triggers to express unique transcriptomes, weapons against pests and diseases; proteomes and metabolomes; various apparently, exploitation of these bioactive regulatory pathways and biosynthesis compounds is helpful in the phytoleads discovery process 1, 71, 72. When active plant

Copyright 2020 KEI Journals. All Rights Reserved http://journals.ke-i.org/index.php/mra Rivka Ofir. Medical Research Archives vol 8 issue 7. July 2020 Page 6 of 15 extracts are identified in the process of candidates for cancer combination therapies screening against disease model, a schematic 81. process of fractionation leads to an active 5.3. Mechanism of Action of Plant-Derived fraction which is composed of several Active Compounds compounds. 5.3.1.FDA Approved Drugs. Among the In most cases, plant fractions are not examples of drugs developed from plant favorable products for pharmaceutical origins based on their mode of action are: companies; their aim is to develop patentable galegine from Galega officinalis L. that drugs based on pure compounds. But, serves as a model for the synthesis of sometimes, a fraction containing several metformin and other biguanides-type compounds, each acting on different target, antidiabetic drugs and paclitaxel, that acts by can prove to be a better treatment for complex stabilizing the microtubule polymer diseases like cancer, neurodegenerative and protects it from disassembly. The latter diseases, and more. was approved by the FDA for the treatment

of ovarian cancer, and led to the development 5.2. Combined Therapy May Have a of several taxol derivatives 1. Better Outcome Than Single Treatment In combined therapy, treatment with two or 5.3.2. Desert Plant–Derived Active more drugs will achieve efficacy with lower Compounds. Selected desert plants like doses of toxic drugs, gain additive or Fagonia indica Burm. f., Calotropis synergistic effects, and may minimize procera R.Br., Zygophylum development of drug resistance 73. Some hamiense Schweinf. and Salsola combinational antibiotic therapies are imbricata Forssk., showed correlation already clinically available 74-77. As different between their biological activities mechanisms of action can be assigned to (antioxidant and hepatotoprotective) and 82 different compounds of plant-derived their phenolic composition . Phytolead extracts, multi-treatment strategies against Boswellic acid, a component in frankincense cancer can be developed 78. For example, the resin, exerts its anti-inflammatory activity combined treatment of A. graveolens through binding to the enzyme 5- fraction, sensitized cancer cells in vitro and lipoxygenase that promotes the formation of 83, cisplatin/etoposide/doxorubicin through the leukotrienes, a mediator of inflammation 84 induction of ROS and caspase-3-dependent . apoptosis 44 . The mode of action of a 6. Domestication of Desert Plants as combination of drugs is different than that of Sustainable Resource of Pharmaceuticals the same drugs acting individually; hence Based on Stress Related Metabolites isolating a single component may lose its A sustainable resource of desert plant- effectiveness 79, 80.The versatility of a natural derived biomass is the basis for developing product target network, for example, suggests pharmaceuticals based on stress related that plant extracts can serve as good metabolites. This process involves generating

Copyright 2020 KEI Journals. All Rights Reserved http://journals.ke-i.org/index.php/mra Rivka Ofir. Medical Research Archives vol 8 issue 7. July 2020 Page 7 of 15 protocols for the domestication and of flavonoids, known to be important in cultivation of the plants. Such protocols are enabling tolerance to both abiotic and biotic composed of irrigation regime, salinity level, stresses, can be induced by desert parameters fertilization etc. and are depended on basic such as UV-B light (UVB), nutrient knowledge on factors that contribute to the deprivation, salinity, water availability, and richness of desert metabolites. The aim is to more 90. In practical terms, the list of use precision agriculture in order to be able metabolites ("metabolite signature") of active to mimic desert conditions in order maintain plant extract will be the pointer for the and enrich the active compounds. To date, development of the right protocol in order to methods of transcriptome, proteome and produce enough biomass without metabolome analyses are employed also for compromising the molecular treasures found desert plants, and have become very helpful in desert conditions. for that purpose. The chemical compositions (phenolic profile, total polyphenols, 7. Conclusions flavonoids and condensed tannins) in desert Desert plants contain unique metabolites with plants are significantly dependent on plant the potential to become drug leads in the area material source; namely, there are different of combination therapy. An active fraction chemotypes/chemovariants according to can be described by its "metabolite location and growth conditions 85-87. signature". This "metabolite signature" will Functional genomic information contributes be a guide for the design of protocols for the to the current understanding of molecular domestication of desert plants in order to adaptive mechanisms to desert environment, generate a sustainable biomass for and also will be helpful in designing pharmaceutical production. protocols for the domestication of desert plants 88. Chloroplast genomics of myrrh Acknowledgement: The writing of this producing trees is an example of a basic publication was supported by the Israeli method to support the development of a Ministry of Science, Technology and Space. protocol to cultivate myrrh producing species Legend of Figures 89. It is already established that the production

8. References 1. Srivastav VK, Egbuna C, Tiwari M. Bioanalytical Chemistry: Elsevier; Chapter 1 - Plant secondary 2016. p. 83-96. metabolites as lead compounds for 7. Devaux CA, Rolain J-M, Colson P, the production of potent drugs. In: Raoult D. New insights on the Egbuna C, Kumar S, Ifemeje JC, antiviral effects of chloroquine Ezzat SM, Kaliyaperumal S, editors. against coronavirus: what to expect Phytochemicals as Lead Compounds for COVID-19? International journal for New Drug Discovery: Elsevier; of antimicrobial agents 2020:105938- 2020. p. 3-14. 38. 2. Atanasov AG, Waltenberger B, 8. Thirumaran R, Prendergast GC, Pferschy-Wenzig E-M, et al. Gilman PB. Chapter 7 - Cytotoxic Discovery and resupply of Chemotherapy in Clinical Treatment pharmacologically active plant- of Cancer. In: Prendergast GC, Jaffee derived natural products: A review. EM, editors. Cancer Immunotherapy. Biotechnology advances Burlington: Academic Press; 2007. p. 2015;33(8):1582-614. 101-16. 3. Veeresham C. Natural products 9. Coyle J, Kershaw P. Galantamine, a derived from plants as a source of cholinesterase inhibitor that drugs. Journal of Advanced allosterically modulates nicotinic Pharmaceutical Technology & receptors: effects on the course of Research 2012;3(4):200-01. Alzheimer’s disease. 4. Lampariello LR, Cortelazzo A, Biological Psychiatry Guerranti R, Sticozzi C, Valacchi G. 2001;49(3):289-99. The Magic Velvet Bean of Mucuna 10. Moses T, Goossens A. Plants for pruriens. Journal of traditional and human health: greening complementary medicine biotechnology and synthetic biology. 2012;2(4):331-39. Journal of Experimental Botany 5. Ebert TJ. 14 - Autonomic Nervous 2017;68(15):4009-11. System Pharmacology. In: 11. Harlev E, Nevo E, Lansky EP, Hemmings HC, Egan TD, editors. Lansky S, Bishayee A. Anticancer Pharmacology and Physiology for attributes of desert plants: a review. Anesthesia (Second Edition). Anticancer Drugs 2012;23(3):255- Philadelphia: Elsevier; 2019. p. 282- 71. 99. 12. Walker KA. Inflammation and 6. Hackney AC. Chapter 8 - neurodegeneration: chronicity Pharmacologic and Nutritional matters. Aging 2018;11(1):3-4. Substances to Enhance Performance 13. Chitnis T, Weiner HL. CNS or Produce Weight Loss. In: Hackney inflammation and neurodegeneration. AC, editor. Exercise, Sport, and

The Journal of clinical investigation Taverniera aegyptiaca. Nat Prod Res 2017;127(10):3577-87. 2019;33(8):1135-39. 14. DeLegge MH, Smoke A. 21. Rauf A, Imran M, Khan IA, et al. Neurodegeneration and Anticancer potential of quercetin: A Inflammation. Nutrition in Clinical comprehensive review. Phytotherapy Practice 2008;23(1):35-41. Research 2018;32(11):2109-30. 15. Wang G, Tang W, Bidigare RR. 22. Ajebli M, Eddouks M. Flavonoid- Terpenoids As Therapeutic Drugs Enriched Extract from Desert Plant and Pharmaceutical Agents. In: Warionia saharae Improves Glucose Zhang L, Demain AL, editors. and Cholesterol Levels in Diabetic Natural Products: Drug Discovery Rats. Cardiovascular & and Therapeutic Medicine. Totowa, hematological agents in medicinal NJ: Humana Press; 2005. p. 197-227. chemistry 2019;17(1):28-39. 16. Cox-Georgian D, Ramadoss N, Dona 23. Yoshikawa M, Xu F, Morikawa T, C, Basu C. Therapeutic and Ninomiya K, Matsuda H. Anastatins Medicinal Uses of Terpenes. A and B, new skeletal flavonoids with Medicinal Plants: From Farm to hepatoprotective activities from the Pharmacy 2019:333-59. desert plant Anastatica hierochuntica. 17. Geron C, Guenther A, Greenberg J, Bioorg Med Chem Lett Karl T, Rasmussen R. Biogenic 2003;13(6):1045-9. volatile organic compound emissions 24. Sak K. Anticancer effects of from desert vegetation of the flavonoids on melanoma cells: are southwestern US. Atmospheric murine cells more sensitive compared Environment 2006;40(9):1645-60. to humans? 2014 2014;5(4):5. 18. Ibrahim MA, Mäenpää M, Hassinen 25. Wishart DS FY, Guo AC, Lo EJ, V, et al. Elevation of night-time Marcu A, Grant JR, Sajed T, Johnson temperature increases terpenoid D, Li C, Sayeeda Z, Assempour N, emissions from Betula pendula and Iynkkaran I, Liu Y, Maciejewski A, Populus tremula. Journal of Gale N, Wilson A, Chin L, Experimental Botany Cummings R, Le D, Pon A, Knox C, 2010;61(6):1583-95. Wilson M. . DrugBank 5.0: a major 19. Hai LL, Wen BJ, Meng XX. update to the DrugBank database for Flavonoids: Recent Advances as 2018. . Nucleic Acids Res. 2017 Nov Anticancer Drugs. Recent Patents on 8. doi: 10.1093/nar/gkx1037 2018. Anti-Cancer Drug Discovery 26. Chahar MK, Sharma N, Dobhal MP, 2010;5(2):152-64. Joshi YC. Flavonoids: A versatile 20. Hassan AR, Amer KF, El-Toumy SA, source of anticancer drugs. Nielsen J, Christensen SB. A new Pharmacognosy reviews 2011;5(9):1- flavonol glycoside and other 12. flavonoids from the aerial parts of

27. Wenzel U. Flavonoids as drugs at the editor. Quality Control and small intestinal level. Current Evaluation of Herbal Drugs: Elsevier; Opinion in Pharmacology 2019. p. 79-149. 2013;13(6):864-68. 36. Wong Paz JE, Muñiz Márquez DB, 28. Hayat M AM, Munir F, et al. . Martínez Ávila GCG, Belmares Potential of plant flavonoids in Cerda RE, Aguilar CN. Ultrasound- pharmaceutics and nutraceutics. . J assisted extraction of polyphenols Biomol Biochem November-2017; from native plants in the Mexican 1(1): 12-17. 2017. desert. Ultrasonics Sonochemistry 29. Podolak I, Galanty A, Sobolewska D. 2015;22:474-81. Saponins as cytotoxic agents: a 37. Najjaa H, Arfa AB, Máthé Á, Neffati review. Phytochemistry reviews : M. Aromatic and Medicinal Plants of proceedings of the Phytochemical Tunisian Arid and Desert Zone Used Society of Europe 2010;9(3):425-74. in Traditional Medicine, for Drug 30. Tian X, Tang H, Lin H, et al. Discovery and Biotechnological Saponins: the potential Applications. In: Neffati M, Najjaa H, chemotherapeutic agents in pursuing Máthé Á, editors. Medicinal and new anti-glioblastoma drugs. Mini Aromatic Plants of the World - Africa Rev Med Chem 2013;13(12):1709- Volume 3. Dordrecht: Springer 24. Netherlands; 2017. p. 157-230. 31. Ferreira D, Gross GG, Hagerman AE, 38. Elmann A, Mordechay S, Erlank H, et Kolodziej H, Yoshida T. Tannins and al. Anti-neuroinflammatory effects of related polyphenols: perspectives on the extract of Achillea fragrantissima. their chemistry, biology, ecological BMC complementary and alternative effects, and human health protection. medicine 2011;11:98-98. Phytochemistry 2008;69(18):3006-8. 39. Elmann A, Telerman A, Mordechay 32. Krochmal A, Sherman P. Canaigre: A S, et al. Downregulation of microglial Desert Source of Tannin. Economic activation by achillolide A. Planta Botany 1951;5(4):367-77. Med 2015;81(3):215-21. 33. Ogawa S, Yazaki Y. Tannins from 40. Elmann A, Telerman A, Mordechay Acacia mearnsii De Wild. Bark: S, et al. 3,5,4'-Trihydroxy-6,7,3'- Tannin Determination and Biological trimethoxyflavone protects astrocytes Activities. Molecules 2018;23(4). against oxidative stress via 34. Haslam E. Natural Polyphenols interference with cell signaling and (Vegetable Tannins) as Drugs: by reducing the levels of intracellular Possible Modes of Action. Journal of reactive oxygen species. Neurochem Natural Products 1996;59(2):205-15. Int 2014;78:67-75. 35. Mukherjee PK. Chapter 4 - 41. Elmann A, Telerman A, Ofir R, Qualitative Analysis for Evaluation Kashman Y. Glutamate Toxicity to of Herbal Drugs. In: Mukherjee PK, Differentiated Neuroblastoma N2a

Cells Is Prevented by the and cellular longevity Sesquiterpene Lactone Achillolide A 2012;2012:157598-98. and the Flavonoid 3,5,4'-Trihydroxy- 47. Elmann A, Telerman A, Erlank H, et 6,7,3'-Trimethoxyflavone from al. Protective and antioxidant effects Achillea fragrantissima. J Mol of a chalconoid from Pulicaria incisa Neurosci 2017;62(1):99-105. on brain astrocytes. Oxidative 42. Elmann A, Telerman A, Ofir R, medicine and cellular longevity Kashman Y, Lazarov O. β-amyloid 2013;2013:694398-98. cytotoxicity is prevented by natural 48. Amiel E, Ofir R, Dudai N, et al. β- achillolide A. Journal of natural Caryophyllene, a Compound Isolated medicines 2018;72(3):626-31. from the Biblical Balm of Gilead 43. Tayeh Z, Dudai N, Schechter A, et al. (Commiphora gileadensis), Is a Molecular Mode of Action of Selective Apoptosis Inducer for Asteriscus graveolens as an Tumor Cell Lines. Evidence-based Anticancer Agent. International complementary and alternative journal of molecular sciences medicine : eCAM 2018;19(8):2162. 2012;2012:872394-94. 44. Tayeh Z, Ofir R. Asteriscus 49. Dudai N, Shachter A, Satyal P, Setzer graveolens Extract in Combination WN. Chemical Composition and with Monoterpenoid Enantiomeric Cisplatin/Etoposide/Doxorubicin Distribution of the Essential Oils Suppresses Lymphoma Cell Growth from Apharsemon (Commiphora through Induction of Caspase-3 gileadensis). Medicines (Basel, Dependent Apoptosis. International Switzerland) 2017;4(3):66. journal of molecular sciences 50. Abu-Darwish MS, Cabral C, 2018;19(8):2219. Gonçalves MJ, et al. Chemical 45. Chaib F, Allali H, Bennaceur M, composition and biological activities Flamini G. Chemical Composition of Artemisia judaica essential oil and Antimicrobial Activity of from southern desert of Jordan. J Essential Oils from the Aerial Parts of Ethnopharmacol 2016;191:161-68. Asteriscus graveolens (Forssk.) Less. 51. Bouslama L, Kouidhi B, Alqurashi and Pulicaria incisa (Lam.) DC.: Two YM, Chaieb K, Papetti A. Virucidal Asteraceae Herbs Growing Wild in Effect of Guggulsterone Isolated the Hoggar. Chemistry & from Commiphora gileadensis. Planta Biodiversity 2017;14(8):e1700092. Med 2019;85(16):1225-32. 46. Elmann A, Telerman A, Mordechay 52. Mahmoud Al Zoubi O. Evaluation of S, Erlank H, Ofir R. Antioxidant and Anti-microbial Activity of Ex astroprotective effects of a Pulicaria vitro and Callus Extracts from incisa infusion. Oxidative medicine Commiphora gileadensis. Pak J Biol Sci 2019;22(2):73-82.

53. Al-sieni AI. The antibacterial activity 60. Prakash Mishra A, Sharifi-Rad M, of traditionally used Salvadora Shariati MA, et al. Bioactive persica L. (miswak) and Commiphora compounds and health benefits of gileadensis (palsam) in Saudi Arabia. edible Rumex species-A review. Cell Afr J Tradit Complement Altern Med Mol Biol (Noisy-le-grand) 2014;11(1):23-7. 2018;64(8):27-34. 54. Yosef Friedjung A, Choudhary SP, 61. Fleisher Z, Fleisher A, Nachbar RB. Dudai N, Rachmilevitch S. Chemovariation of Artemisia herba Physiological conjunction of alba Asso. Aromatic Plants of the allelochemicals and desert plants. Holy Land and the Sinai. Part XVI. PloS one 2013;8(12):e81580-e80. Journal of Essential Oil Research 55. Jaradat N, Zaid AN, Hussein F, et al. 2002;14(3):156-60. Anti-Lipase Potential of the Organic 62. Reddy AR, Chaitanya KV, and Aqueous Extracts of Ten Vivekanandan M. Drought-induced Traditional Edible and Medicinal responses of photosynthesis and Plants in Palestine; a Comparison antioxidant metabolism in higher Study with Orlistat. Medicines plants. Journal of Plant Physiology (Basel, Switzerland) 2017;4(4):89. 2004;161(11):1189-202. 56. Solowey E, Lichtenstein M, Sallon S, 63. Ahanger MA, Gul F, Ahmad P, et al. Evaluating medicinal plants for Akram NA. Chapter 3 - anticancer activity. Environmental Stresses and TheScientificWorldJournal Metabolomics—Deciphering the 2014;2014:721402-02. Role of Stress Responsive 57. Abu-Darwish MS, Efferth T. Metabolites. In: Ahmad P, Ahanger Medicinal Plants from Near East for MA, Singh VP, Tripathi DK, Alam P, Cancer Therapy. Frontiers in Alyemeni MN, editors. Plant pharmacology 2018;9:56-56. Metabolites and Regulation Under 58. Jaradat NA, Damiri B, Abualhasan Environmental Stress: Academic MN. Antioxidant evaluation for Press; 2018. p. 53-67. Urtica urens, Rumex cyprius and 64. Zhang J, Feng J, Lu J, et al. Borago officinalis edible wild plants Transcriptome differences between in Palestine. Pak J Pharm Sci two sister desert poplar species under 2016;29(1 Suppl):325-30. salt stress. BMC genomics 59. el-Mekkawy S, Meselhy MR, 2014;15(1):337-37. Kusumoto IT, et al. Inhibitory effects 65. Catola S, Marino G, Emiliani G, et al. of Egyptian folk medicines on human Physiological and metabolomic immunodeficiency virus (HIV) analysis of Punica granatum (L.) reverse transcriptase. Chem Pharm under drought stress. Planta Bull (Tokyo) 1995;43(4):641-8. 2016;243(2):441-49.

66. Hasanuzzaman M, Nahar K, Fujita 72. Srivastav V, Tiwari M, Egbuna C. M, et al. Enhancing Plant Plant Secondary Metabolites as Lead Productivity Under Salt Stress: Compounds for the Production of Relevance of Poly-omics. In: Ahmad Potent Drugs; 2019. P, Azooz MM, Prasad MNV, editors. 73. Fitzgerald JB, Schoeberl B, Nielsen Salt Stress in Plants: Signalling, UB, Sorger PK. Systems biology and Omics and Adaptations. New York, combination therapy in the quest for NY: Springer New York; 2013. p. clinical efficacy. Nat Chem Biol 113-56. 2006;2(9):458-66. 67. Ashraf MA, Iqbal M, Rasheed R, et 74. Musumeci R, Speciale A, Costanzo al. Chapter 8 - Environmental Stress R, et al. Berberis aetnensis C. Presl. and Secondary Metabolites in Plants: extracts: antimicrobial properties and An Overview. In: Ahmad P, Ahanger interaction with ciprofloxacin. Int J MA, Singh VP, Tripathi DK, Alam P, Antimicrob Agents 2003;22(1):48- Alyemeni MN, editors. Plant 53. Metabolites and Regulation Under 75. Mikulášová M, Chovanová R, Environmental Stress: Academic Vaverková Š. Synergism between Press; 2018. p. 153-67. antibiotics and plant extracts or 68. Sun C, Gao X, Chen X, Fu J, Zhang essential oils with efflux pump Y. Metabolic and growth responses of inhibitory activity in coping with maize to successive drought and re- multidrug-resistant staphylococci. watering cycles. Agricultural Water Phytochemistry Reviews Management 2016;172:62-73. 2016;15(4):651-62. 69. Semel Y, Schauer N, Roessner U, 76. Santiago C, Pang EL, Lim K-H, Loh Zamir D, Fernie AR. Metabolite H-S, Ting KN. Inhibition of analysis for the comparison of penicillin-binding protein 2a (PBP2a) irrigated and non-irrigated field in methicillin resistant grown tomato of varying genotype. Staphylococcus aureus (MRSA) by Metabolomics 2007;3(3):289-95. combination of ampicillin and a 70. Verpoorte R. Exploration of nature's bioactive fraction from Duabanga chemodiversity: the role of secondary grandiflora. BMC complementary metabolites as leads in drug and alternative medicine development. Drug Discovery Today 2015;15:178-78. 1998;3(5):232-38. 77. Cheesman MJ, Ilanko A, Blonk B, 71. Arbona V, Manzi M, de Ollas Cock IE. Developing New Valverde C, Gómez-Cadenas A. Antimicrobial Therapies: Are Metabolomics as a Tool to Investigate Synergistic Combinations of Plant Abiotic Stress Tolerance in Plants. Extracts/Compounds with International journal of molecular Conventional Antibiotics the sciences 2013;14:4885-911.

Solution? Pharmacognosy reviews 84. Moussaieff A, Rimmerman N, 2017;11(22):57-72. Bregman T, et al. Incensole acetate, 78. Goyal S, Gupta N, Chatterjee S, an incense component, elicits Nimesh S. Natural Plant Extracts as psychoactivity by activating TRPV3 Potential Therapeutic Agents for the channels in the brain. FASEB journal Treatment of Cancer. Curr Top Med : official publication of the Federation Chem 2017;17(2):96-106. of American Societies for 79. Hemaiswarya S, Kruthiventi A, Experimental Biology Doble M. Synergism between natural 2008;22(8):3024-34. products and antibiotics against 85. Benabderrahim MA, Yahia Y, Infectious diseases. Phytomedicine : Bettaieb I, Elfalleh W, Nagaz K. international journal of phytotherapy Antioxidant activity and phenolic and phytopharmacology profile of a collection of medicinal 2008;15:639-52. plants from Tunisian arid and Saharan 80. Attar R, Tabassum S, Fayyaz S, et al. regions. Industrial Crops and Natural products are the future of Products 2019;138:111427. anticancer therapy: Preclinical and 86. Warren CR, Aranda I, Cano FJ. clinical advancements of Viscum Metabolomics demonstrates album phytometabolites. Cell Mol divergent responses of two Biol (Noisy-le-grand) 2015;61(6):62- Eucalyptus species to water stress. 8. Metabolomics 2012;8(2):186-200. 81. Chamberlin SR, Blucher A, Wu G, et 87. Michaletti A, Naghavi MR, Toorchi al. Natural Product Target Network M, Zolla L, Rinalducci S. Reveals Potential for Cancer Metabolomics and proteomics reveal Combination Therapies. Frontiers in drought-stress responses of leaf pharmacology 2019;10:557-57. tissues from spring-wheat. Scientific 82. Shehab NG, Abu-Gharbieh E, reports 2018;8(1):5710-10. Bayoumi FA. Impact of phenolic 88. Zhang L, Hu X, Miao X, et al. composition on hepatoprotective and Genome-Scale Transcriptome antioxidant effects of four desert Analysis of the Desert Shrub medicinal plants. BMC Artemisia sphaerocephala. PloS one Complementary and Alternative 2016;11(4):e0154300-e00. Medicine 2015;15(1):401. 89. Khan A, Asaf S, Khan AL, et al. First 83. Gilbert NC, Gerstmeier J, complete chloroplast genomics and Schexnaydre EE, et al. Structural and comparative phylogenetic analysis of mechanistic insights into 5- Commiphora gileadensis and C. lipoxygenase inhibition by natural foliacea: Myrrh producing trees. PloS products. Nature Chemical Biology one 2019;14(1):e0208511-e11. 2020. 90. Davies KM, Jibran R, Zhou Y, et al. The Evolution of Flavonoid

Biosynthesis: A Bryophyte Perspective. Frontiers in plant science 2020;11:7-7.