Saponin lowers iron, glucose, uric acid, cholesterol: key factors in malaria

Saponins are a class of chemical compounds found in particular abundance in various plant species. More specifically, they are amphipathic glycosides grouped phenomenologically by the soap-like foaming they produce when shaken in aqueous solutions, and structurally by having one or more hydrophilic glycoside moieties combined with a lipophilic triterpene derivative. Most research work on Artemisia annua has ignored saponins and polysaccharides because these are only soluble in water and in the search of the golden fleece or the exceptional antimalarial molecule most extracts are obtained with organic solvents. Saponins are found in many plants, often in desert plants and are also present in some marine organisms. Most medicinal plants are rich in saponins, which to some extent are responsible for their bitterness. In fact saponins protect plants from phytopathogenic microorganisms, phytophagous mammalian and insects. The major commercial sources of saponins are yucca, soya, alfalfa, broad beans, chick-pea. Saponins are widely distributed secondary plant metabolites. They are amphiphilic like soaps combining a lipophilic chain with an hydrophilic attachment, a sugar moiety linked to a hydrophobic aglycone. The great complexity of saponin structure arises from the variability in the aglycone structure and the nature of the side chains. This renders a quantitative determination by spectroscopy very difficult and their presence or concentration is generally assessed by the froth test based on the foaming properties. Saponins are used to increase the foaming of beer ! Most saponins are highly surface-active, and many form addition-complexes with sterols, including those of fungal, plant and animal cells. This leads to membrane destabilization and cell lysis. The ability of many saponins to cause hemolysis in vitro is a property that is widely used in the design of quantitative bioassays. For the same reason saponins are used as adjuvants in vaccines. The uses of saponins as adjuvants in vaccines may also be related to the activation of lymphocytes. S R Chavali, L D Barton, and J B Campbell. Immunopotentiation by orally-administered Quillaja saponins: effects in mice vaccinated intraperitoneally against rabies. Clin Exp Immunol. 1988 Dec; 74(3): 339–343. Chavali SR, Campbell JB. Immunomodulatory effects of orally-administered saponins and nonspecific resistance against rabies infection. Int Arch Allergy Appl Immunol. 1987;84(2):129-34. Zahid Iqbal Rajput, Song-hua Hu, Chen-wen Xiao, and Abdullah G. Arijo. Adjuvant effects of saponins on animal immune responses. J Zhejiang Univ Sci B. 2007 Mar; 8(3): 153–161. doi: 10.1631/jzus.2007.B0153 In 2010 we noticed (personal communication) a much stronger activation of lymphocytes by Artemisia annua tea from Luxembourg than from Cameroon. As per the froth test the tea from Luxembourg contains much more saponins. A British study shows that the saponins from three different plants increase the permeability of the small intestinal mucosal cells, facilitating the uptake of material to which the gut would normally be impermeable. Johnson IT, Gee JM, Price K, Curl C, Fenwick GR. Influence of saponins on gut permeability and active nutrient transport in vitro. J Nutr. 1986 Nov;116(11):2270-7. A study on medicinal plants from Iran containing saponins Artemisia dracunculus, Heracleum persicum, Cuminum cynimum shows that the aqueous extract from Artemisia dracunculus has the highest hemolytic effect Gholamreza Dehghan Noudeh, Fariba Sharififar, Mehdi Khatib, Effat Behravan4 and Masoud Ahmadi Afzadi. Study of aqueous extract of three medicinal plants on cell membrane–permeabilizing and their surface properties. Afr J Biotechnol, 2010, 9, 110-116 A German research paper shows that the incubation of cells and tissues with saponin makes the lipid bilayer permeable to macromolecules, by affecting the interaction between transmembrane proteins and the cytoskeleton. This will admit the access of antibodies to the cytoplasmic surface of cells. Baumann E, Stoya G, Völkner A, Richter W, Lemke C, Linss W. Hemolysis of human erythrocytes with saponin affects the membrane structure. Acta Histochem. 2000 Feb;102(1):21-35. Saponin from medicinal herbs also activates calcium-dependent potassium channels. McManus OB, Harris GH, Giangiacomo KM, Feigenbaum P, Reuben JP, Addy ME, Burka JF, Kaczorowski GJ, Garcia ML. McManus et al., An activator of calcium-dependent potassium channels isolated from a medicinal herb. OB Biochemistry. 1993 Jun 22;32(24):6128-33 They modulate the sodium pump and ATPase. Aloa Machado de Souza, Lucienne da Silva Lara, Jose Osvaldo Previato, Anı´bal Gil Lopes, Celso Caruso-Neves, Bernadete Pereira da Silva, and Jose Paz Parente. Modulation of Sodium Pumps by Steroidal Saponins. Zeitung Naturforschung, 59c 2003 432-436 In the Chinese pharmacopeia plant mixtures rich in saponins have been used to enhance the bioavailability of artemisinin. For example, in the herbal “Wen Bing Tiao Bian” (1798), an infusion of A. annua together with Amyda sinensis, Rehmannia glutinosa, Anemarrhena asphodeloides and Paeonia suffructicosa is described. It is quite possible that saponins, or other components from the latter three herbs which are capable of acting as detergents, might be able to assist the dissolution of artemisinin in water. Because in plasmodium infected erythrocytes the permeability is 27x lower than for non-infected ones, because the parasite has translocated most of the membrane components for the formation of the parasitophorous vacuole. A U Orjih Requirements for Maximal. Enrichment of Viable Intraerythrocytic Plasmodium falciparum Rings by Saponin Hemolysis. Exp Biol and Med, 2008, 233, 1359-1367). The nutritional significance of saponins for humans stems largely from their hypocholesterolemic action, which has been extensively studied in laboratory animals. S Southon, I T Johnson, J M Gee, K R Price The effect of Gypsophila saponins in the diet on mineral status and plasma cholesterol concentration in the rat. Br J Nutr 1988 Jan;59(1):49-55 Saponins bind with cholesterol. Cholesterol is continually secreted into the intestine via the bile, with much of it subsequently reabsorbed. Saponins cause a depletion of body cholesterol by preventing its re-absorption, thus increasing its excretion in much the same way as other cholesterol-lowering drugs do. Sadia Afrose, Sharoare Hossain, Takaaki Maki Hypocholesterolemic Response to Karaya Saponin and Rhodobacter capsulatus in Broiler Chickens Asian-Aust. J. Anim. Sci. 2010 Vol. 23, No. 6 : 733 – 741 Saponins from Medicago sativa (lucerne) and Gypsophilia Southon S, Wright AJ, Price KR, Fairweather-Tait SJ, Fenwick GR. The effect of three types of saponin on iron and zinc absorption from a single meal in the rat. Br J Nutr. 1988 May;59(3):389-96. reduced Fe absorption from a single meal rich in iron by 17%. Iron forms very stable complexes with saponins and that is why iron absorption is reduced. S S Khan , S A Kazmi, H Anwer. Cyclic Voltammetric Study of Complexes of Fe (III) with Saponins Isolated from Cicer aritinum and Glycyrrhizin, J.Chem.Soc.Pak.,Vol. 35, No.2, 2013 554 Saponins have ammonia-binding activity. When ammonia is processed by the liver, uric acid is created. Saponins cause notable delays in uric acid crystallization. They accelerate the excretion of uric acid. Chen GL, Wei W, Xu SY. Effect and mechanism of total saponin of Dioscorea on animal experimental hyperuricemia. Am J Chin Med. 2006;34(1):77-85. Similar effects were observed in the presence of a surfactant, lauryl sulfate. Whitaferin, a saponin, which is called Indian ginseng, or Smilax riparia, in China also alleviates gout. Wu XH, Zhang J, Wang SQ, Yang VC, Anderson S, Zhang YW. Riparoside B and timosaponin J, two steroidal glycosides from Smilax riparia, resist to hyperuricemia based on URAT1 in hyperuricemic mice. Phytomedicine. 2014 Sep 15;21(10):1196-201. doi: 10.1016/j.phymed.2014.03.009. Saponins inhibit the intestinal permeability of glucose and may consequently inhibit the growth of Plasmodium falciparum which uses glucose as food. They facilitate however the uptake of other materials to which the gut would normally not be permeable. Johnson IT, Gee JM, Price K, Curl C, Fenwick GR. Influence of saponins on gut permeability and active nutrient transport in vitro. J Nutr. 1986 Nov;116(11):2270-7. There are many anecdotical claims that Artemisia annua stems are more efficient against several diseases than leaves. The problem is that it is very difficult, even impossible to find quantitative data on saponins in any Artemisia species The pharmacological activity of Centella asiatica is attributed mainly to saponins i.e. centellosides, mainly asiaticoside. The plant contains up to 4% of saponins on dry weight and is used in China against leprosy. Viola Müller. Relevance of mineral nutrition and light quality for theaccumulation of secondary metabolites in Centella asiatica and Hydrocotyle leucocephala.Inaugural-Dissertation zur Erlangung des Grades Doktor der Agrarwissenschaften (Dr. agr.) der Landwirtschaftlichen Fakultät der Rheinischen Friedrich-Wilhelms-Universität Bonn vorgelegt am 21.11.2013 The anti-inflammatory effect of the saponin extracts of 5 Nigerian plants rich in saponin : Schwenkia americana (2.74% saponin), Asparagus africanus (3.59%), Dichrostachys cinerea (1.62%), Ficus iteophylla (=,81%), and Indigofera pulchra (1.57%) has been described and is equivalent to Ketoprofen. H S Hassan, M I Sule, A M Musa, K Y Musa, M S Abubakar, and A S Hassan. Anti-Inflammatory Activity of Crude Saponin Extracts from Five Nigerian Medicinal. Plants Afr J Tradit Complement Altern Med. 2012; 9(2): 250–255. An extensive study has been run on the antioxidant activity of saponins isolated from Ivy Hedera helix. At the concentration of 75 mg/L they showed 85% inhibition on lipid peroxidation. Their DPPH, superoxide radical and H2O2 scavenging properties were equivalent to alpha-tocopherol and butylated hydroxytoluene D. Gülcin, R. Elias, E. Koksal, “Antioxidant Secoiridoids from Fringe Tree (Chionanthusvirginicus L.),” Wood Science and Technology, Vol. 43, No. 3-4, 2009, pp. 195-212. Ginsengoside, the saponin of ginseng, has strong wound healing properties. Young Soo Kim, Ik-Hyun Cho, Moon-Jin Jeong, Therapeutic Effect of Total Ginseng Saponin on Skin Wound Healing. J Ginseng Res. 2011 Sep; 35(3): 360–367. Similar wound healing properties are described in Uganda for the saponin rich JENAᴿ phytoproduct. Ogwang PE; Kyakulaga AH, Preclinical efficacy of herbal formulation for management of wounds. Afr Health Sci, 2011, 11-3, 524-529 through the promotion of anti-oxidant and anti-inflammatory effects, the promotion of matrix synthesis and re-epithelization. Saponin as coadjuvant was very efficient in a vaccine against hemorrhagic septicemia in mice and buffalo calves, increasing CD4 and CD8 cell populations and improving the humoral immune response. Sujeet Kumar, V K Chaturvedi, B Kumar, P Kumar, S R Somarajan, A Kumar, A S Yadav, B SharmaImproved humoral immune response of oil adjuvant vaccine by saponin coadjuvantation against haemorrhagic septicaemia in mice and buffalo calves. Indian J Animal Sc. 2012, 82, 9. M-A Lacaille-Dubois. Immunomodulatory Agents from Plants, ed Paniham, 1999 The University of Al Quds in Palestine found that saponin inhibits beta-hematin crystallization (Personal communication from Mutaz Akkawi). Saponin is anthelmintic and inhibits hepatitis C virus propagation. Lee J, Lim S, Kang S-M, Min S, Son K, et al. (2012) Saponin Inhibits Hepatitis C Virus Propagation by Up-regulating Suppressor of Cytokine Signaling. PLoS ONE 7(6): e39366. The stems of the medicinal plant Cissus populnea from Niger are rich in saponins and are used by the Fulanis to feed their cattle, ostensibly to increase milk production. Soladoye, M. O., & Chukwuma, O. (2012). Phytochemical analysis of stem and root of Cissus populnae (Vitaceae)- an important medicinal plant in Central Nigeria. Phytologia Balcanica, 18(2)., 149-153. Trifolium plants are also rich in saponins. They increase the milk production in cattle. Moorby JM, Lee MR, Davies DR, Kim EJ, Nute GR, Ellis NM, Scollan ND. Assessment of dietary ratios of red clover and grass silages on milk production and milk quality in dairy cows. J Dairy Sci. 2009 Mar;92(3):1148-60. doi: 10.3168/jds.2008-1771. The plant Achyrantus bidentata rich in saponins has strong analgesic and anti-inflammatory properties. Gao CK, Gao J, Ma RL, Xu XX, Huang P, Ni SD (2003). Research on analgesic and anti-inflammatory and invigorate circulation effects of total saponins of Achyranthes. Anhui Mel. Pharm. J. 7, 248–249. In Brazil, the Brachiara bizantha grass is used in cattle feeding. In this plant, the concentration of saponins decreases from 3 % in spring to 0.6% in autum. Flavia Gontijo de Lima, Stephen Thomas LeeII, James Alan Pfister, Eliane Sayuri MiyagiI,. O efeito da ensilagem e fenação sobre as concentrações de saponina esteroide em duas espécies degramínea Brachiaria. Ciência Rural, Santa Maria, v.45, n.5, p.858-863, mai, 2015 The most complete study for the plant Achyrantus bidentata on accumulation and dynamics of saponins in vegetative organs has been run in China. J Li Z Hu. Accumulation and Dynamic Trends of Triterpenoid Saponin in Vegetative Organs of Achyranthus bidentat. J Integrative Plant Biology 2009, 51-2, 122-129DOI: 10.1111/j.1744-7909.2008.00764 From August to November, in the leaves the saponin decreases from 4.09% in August to 0.06% in November, but in the stems it only decreases from 4.13 to 1.47. This may explain to some extent why leaves of Artemisia annua harvested in October have lost a lot of their efficiency, for example in the beta-hematin inhibition test. In alfa alfa grass saponins the decrease of saponins in senescence is also remarkable. Pecett L, Biazzi, Tava A. Variation in saponin content during the growing season of Medicago. J.Sci. Food Agric 2010. Nov 90 2405-10 The average saponin content in vegetables is 0.4%, except for asparagus and beans where it is higher. In mate tea in Argentina it is 1%. Based on all these data on vegetables and medicinal plants our best estimate for saponins in Artemisia plants is around 1%. Which is a lot compared to other constituents like individual terpenes or coumarins. The molecule definitely deserves more research: hidden treasures in the jungle?