Cholesterol, phytosterols, malaria, chlorogenic acid and virus

Cholesterol und Phytosterole

The Plasmodium parasite needs cholesterol for survival and multiplication. This fact was well documented in a WHO document in 1977 and in subsequent papers George G. Holz, Jr. Lipids and the malarial parasite. Bull World Health Organ. 1977; 55(2-3): 237–248 Krishnegowda G, Gowda DC Intraerythrocytic Plasmodium falciparum incorporates extraneous fatty acids to its lipids without any structural modification. Mol Biochem Parasitol. 2003 Nov;132(1):55-8. Moll GN, Vial HJ, Ancelin ML, Op den Kamp JA, Roelofsen B, van Deenen L. Phospholipid uptake by Plasmodium knowlesi infected erythrocytes. FEBS Lett. 1988 May 23;232(2):341-6. Mi-Ichi F, Kita K, Mitamura T. Intraerythrocytic Plasmodium falciparum utilize a broad range of serum-derived fatty acids with limited modification for their growth. Parasitology. 2006 Oct;133(Pt 4):399-410. The replicative capacity of Plasmodium liver forms is remarkable, achieving the fastest growth rates known. Plasmodium starts its lifecycle in the liver. Cholesterol either originates from the diet or is synthesized, mostly in the liver. Cholesterol and malaria sporozoites may use the same doorway into liver cells. A research group from Lisbon Rodrigues, C. D., Hannus, M., Prudencio, M., Martin, C., Goncalves, L. A., Portugal, S. Mota, M. M. (2008). Host scavenger receptor SR-BI plays a dual role in the establishment of malaria parasite liver infection. Cell Host & Microbe, 4(3), 271-282. DOI: 10.1016/j.chom.2008.07.012 Hanson KK, Ressurreição AS, Beatty WL, Wirth DF, Hänscheid T, Moreira R, Marti M, Mota MM. (2013) Torins are potent antimalarials that block replenishment of Plasmodium liver stage parasitophorous vacuole membrane proteins. Proc Natl Acad Sci USA. 110(30): E2838-47 showed that the SR-BI receptor which is the entry port for HDL cholesterol also opens the door for malaria parasites. This establishes a first clear link between malaria infection and cholesterol uptake pathways, and a new intervention strategy against malaria. This was confirmed by CORDIS project 235864: uptake of exogenous cholesterol, rather than host cell de novo biosynthesis is important for the Plasmodium falciparum liver stage. Infected erythrocytes contain twice as much cholesterol as the uninfected. Increases in the membrane surface area of the parasite, and in some cases of the erythrocyte, parallel parasite growth and segmentation. Augmentation of all the membrane systems of the infected erythrocyte causes the lipid content to rise rapidly, but the parasite lipid composition differs from that of the erythrocyte Nirianne Marie Q. Palacpac, Yasushi Hiramine, Fumika Mi-ichi, Motomi Torii, Kiyoshi Kita, Ryuji Hiramatsu, Toshihiro Horii, Toshihide Mitamura. Developmental-stage-specific triacylglycerol biosynthesis, degradation and trafficking as lipid bodies in Plasmodium falciparum-infected erythrocytes. Journal of Cell Science 2004 117: 1469-1480; doi: 10.1242/jcs.00988 In vitro human HDL cholesterol is also necessary for the culture of P falciparum. Several intraerythrocytic growth cycles of Plasmodium falciparum could be achieved in vitro using a serum free medium supplemented only with a human high density lipoprotein (HDL) fraction (d = 1.063-1.210). The parasitemia obtained was similar to that in standard culture medium containing human serum. The parasite development was incomplete with the low density lipoprotein (LDL) fraction and did not occur with the VLDL fraction. Devendra Bansal, Harinderpal Singh Bhatti and Rakesh Sehgal. Role of cholesterol in parasitic infections. Lipids in Health and Disease20054:10. DOI: 10.1186/1476-511X-4-10 Grellier P1, Rigomier D, Clavey V, Fruchart JC, Schrevel J. Lipid traffic between high density lipoproteins and Plasmodium falciparum-infected red blood cells. J Cell Biol. 1991 Jan;112(2):267-77. In vivo Plasmodium continuously diverts cholesterol from hepatocytes and erythrocytes which leads to a lower cholesterol level in malaria patients. In malaria endemic areas significantly lower levels of cholesterol and triglycerides are found in children infected with Plasmodium falciparum. Chuckwuocha, UM. and Eke, KN., Malaria parasite status and cholesterol level of malaria patients in the IMO River Basin Nigeria. Asian Pac J Trop Med., 4-12, 2011, 993-4 A recent paper from Saudi Arabia showed that Ithere is a significant inverse correlation between parasite count and cholesterol level in patients. The same effect on cholesterol depletion in murine malaria has been noticed. And more recently in malaria infected children in Cameroon, malaria patients presented significantly lower levels of total cholesterol and HDL cholesterol than control. On the other hand LDL cholesterol and triglycerides were higher. A. Al-Omar, A.M. Eligail, R.M. Al-Ashban, A.H. Shah. Effect of falciparum malaria infection on blood cholesterol and platelets Volume 14, Journal of Saudi Chemical Society. Issue 1, January 2010, Pages 83–89 doi.org/10.1016/j.jscs.2009.12.013 Tuekam Kouam Hermine, Evaluation du profil lipidique chez les enfants paludens de 0 à 5 ans de Douala, Maîtrise en Biochimie, 2005, Université de Douala. Several studies confirm the same trend. In summary, it may be said that HDL is significantly decreased, LDL moderately but VLDL and tryglycerides are increased. HDL cholesterol is essential for a good health. Too low values lead to general weakness, prostration and finally to death. The liver is also rich in glycogen, another nutrient for the parasites. Any perturbation in this power plant will put the parasite in a state of starvation and inhibit formation of merozoites. It had already been shown in 1957 that the liver glycogen of rats infected with Plasmodium berghei is depleted. Mercado TI. Paralysis associated with Plasmodium berghei malaria in the rat13982. J. Infect Dis 1965 115:465–472 Different sterols occur in different life forms: cholesterol is the predominant sterol in vertebrates, ergosterol in yeast and other fungi, and phytosterols are the major sterols in plants. Most animal and human studies show that phytosterols reduce serum /or plasma total cholesterol and low density lipoprotein (LDL) cholesterol levels. Phytosterols are structurally very similar to cholesterol except that they always contain some substitutions at the C24 position on the sterol side chain. Plasma phytosterol levels in mammalian tissue are normally very low due primarily to poor absorption from the intestine and faster excretion from liver compared to cholesterol. It is however sufficient to displace cholesterol from the micelles. Phytosterols alter whole-body cholesterol metabolism in a dose-dependent manner. They increase the fecal cholesterol excretion. Susan B Racette, Xiaobo Lin, Michael Lefevre, Catherine Anderson Spearie, Marlene M Most, Lina Ma, and Richard E Ostlund, Dose effects of dietary phytosterols on cholesterol metabolism: a controlled feeding study1 Jr Am J Clin Nutr. 2010 Jan; 91(1): 32–38. A recent study from Maastricht shows that plant sterols not only reduce the bioavailability of cholesterol in a high fat diet but they also have a strong protective role in liver inflammation. Jogchum Plat, Tim Hendrikx, Veerle Bieghs, Mike L. J. Jeurissen, Sofie M. A. Walenbergh, Patrick J. van Gorp, Ronit Shiri-Sverdlov. Protective Role of Plant Sterol and Stanol Esters in Liver Inflammation: Insights from Mice and Humans. PLOS October 30, 2014 doi.org/10.1371/journal.pone.0110758 The cholesterol lowering effect of plant sterols was discovered first in the early 1950s. Plant sterols have the same structure as cholesterol but have a higher solubility and are more easily hydrolyzed than cholesterol. Their presence in the intestine thus adversely affects the solubilization and absorption of cholesterol from food. G V Vahouny, W E Connor, S Subramaniam, D S Lin, and L L Gallo. Comparative lymphatic absorption of sitosterol, stigmasterol, and fucosterol and differential inhibition of cholesterol absorption. Am J Clin Nutr May 1983 vol. 37 no. 5 805-809 This is the main reason phytosterols are added to margarine. But they are not all taken up to the same degree: it is higher for campesterol in many animal species. In the protozoan Paramecium they even are the main nutrient and cholesterol not. The question remains and needs to be resolved: do phytosterols reduce the number of merozoites and trophozoites because of the lower availability of cholesterol or are they a more efficient replacement? They could also promote hemozoin crystallization as cholesterol does. Phytosterols are well present in many vegetal oils (on the average 600 mg/100g), in nuts and kernels like avocado (250 mg/kg) and in most vegetables (30mg/kg) and fruits (20 mg/kg). Medicinal herbs contain higher concentrations than other plants. The Artemisia genus contains around 200 mg of phytosterols per 100g of dry matter. Bianca Ivanescu, PhD Thesis IASI University Romania, 2010 All species of Artemisia contain phytosterols. Tan, RX; Lu, H; Wolfender, JL; Yu, TT; Zheng, WF; Yang, L; Gafner, S; Hostettmann, K.Mono- and sesquiterpenes and antifungal constituents from Artemisia species. Planta Med 1999, 65-1, 64-67) Tang HQ, Hu J, Yang L, Tan RX. Terpenoids and flavonoids from Artemisia species. Planta Med. 2000 May;66(4):391-3. A review of Chinese traditional herbal medicines confirms that they are rich in phytosterols. Some contain up to 280 mg/100g. Han J, He M, Zhou S, Wang G. Analysis of phytosterol contents in food plant materials and Chinese traditional medicines. Wei Sheng Yan Jiu. 2009 Mar;38(2):188-91. The fact that phytosterols have been neglected in the fingerprint analysis of A annua and other medicinal plants is because they are difficult to analyze. They lack a good chromophore and thus require derivatization for measurement by HPLC-UV. The claim that a diet rich in dietary fibres may reduce the level of cholesterol could be related to the high concentration of phytosterols in fibres and dry plant matter. Nuts are claimed to reduce cardiovascular problems. But the dietary fibres or polysaccharides like inulin decrease cholesterol by themselves. Elke A. Trautwein, Dörte Rieckhoff, and Helmut F. Erbersdobler. Dietary Inulin Lowers Plasma Cholesterol and Triacylglycerol and Alters Biliary Bile Acid Profile in Hamsters. J. Nutr. November 1, 1998 vol. 128 no. 11 1937-1943 Corn stigmasterols are also used in conditions of high uric acid such as gout and some types of arthritis. The same effect was noticed by (personal communication) for Artemisia annua stem infusions. It is also the case for the plant Costus igneus used in India as cure against urinary stones. The aqueous stem extract of this plant is very rich in stigmasterol and lupeol. All this is relevant to malaria because plasmodium generates pro-inflammatory uric acid. Many medicinal plants are known for their hypolipidemic and hypoglycemic effect, essentially by the action of phytosterols. This is the case for Hypericum perforatum (St John’s Wort), Azaradirachta indica (Neem), Moringa olifeira, Hypoxis hemerocalliedea (African potato). Artemisia plants are known for their lipid-lowering effect, an effect similar to that obtained with statins. The aqueous extracts of Artemisia sieberi significantly lower total cholesterol, HDL, LDL and triglycerides in diabetic rats. Mansi K, Lahham J. Effects of Artemisia sieberi Besser (A. herba-alba) on heart rate and some hematological values in normal and alloxan-induced diabetic rats. J Basic ApplSci. 2008; 1(4): 57-62. This is also the case for ethanolic extract of Artemisia princeps. U J Jung, N-I Baek, , J-S Yoo, T S Jeong, K-T Lee, Y J Kang, M K Lee, H J Kim, J Y Yeo, M S Choi.The anti-diabetic effects of ethanol extract from two variants of Artemisia princeps Pampanini in C57BL/KsJ-db/db mice. Food Chem Toxicol 2007 Oct 22;45(10):2022-9. A recent paper from Korea documents similar effects for Artemisia capillaris. Their results show that extracts of this plant enhance the lipid metabolism, reduce cholesterol, reduce hepatic lipid contents and the serum ALAT and ASAT levels. Dong Wook Lim, Yun Tai Kim , Yu-Jung Jang, Young-Eon Kim and Daeseok Han . Anti-Obesity Effect of Artemisia capillaris Extracts in High-Fat Diet-Induced Obese Rats Molecules 2013, 18(8), 9241-9252; doi:10.3390/molecules18089241 In the erythrocytes it is likely that the parasite converts cholesterol into fragments and lipids, which are activating the hemozoin formation. Orjih AU. On the mechanism of hemozoin production in malaria parasites: activated erythrocyte membranes promote beta-hematin synthesis. Exp Biol Med (Maywood). 2001 Sep;226(8):746-52. Phytosterols are able to replace cholesterol in cell membranes. Artemisia plants differ from other plants by a higher proportion of stigmasterol than beta-sitosterol which is the predominant sterol in all plants. Stigmasterol was found to modify the properties of cell Hac-Wydro K. The replacement of cholesterol by phytosterols and the increase of total sterol content in model erythrocyte membranes. Chem Phys Lipids. 2010 Sep;163(7):689-97. doi: 10.1016/j.chemphyslip.2010.07.001. It also inhibits the synthesis of cholesterol much more than beta-sitosterol. Phytosterols also inhibit isoprenylation of proteins in Plasmodium falciparum. Yang C, Yu L, Li W, Xu F, Cohen JC, Hobbs HH. Disruption of cholesterol homeostasis by plant sterols. J Clin Invest. 2004 Sep;114(6):813-22. To survive the parasite needs to digest the proteins present in cholesterol. The need of intracellular parasites to retrieve nutrients and fulfill their energy needs is achieved by manipulating the host metabolism. Apicomplexa parasites like Plasmodium have lost a substantial number of genes related to biosynthetic functions. Phytosterols may deactivate the parasite’s final digestive machinery, thus making it impossible to survive as it stops receiving nutrients. The cholesterol absorption from test meals is substantially lower after consumption of phytosterol rich food. Ostlund RE Jr, Racette SB, Stenson WF. Inhibition of cholesterol absorption by phytosterol-replete wheat germ compared with phytosterol-depleted wheat germ. Am J Clin Nutr. 2003 Jun;77(6):1385-9. Some polysaccharides also have a cholesterol lowering effect. Y Cheng, K Tang, S Wu, B Liu. Astragalus polysaccharides lowers plasma cholesterol through mechanisms distinct from statins. PLOS ONE 2011, 6, 11, e 27437 This leads to a depletion of erythrocyte membrane of cholesterol and inhibits the “raft” function of cholesterol for the inward transport of nutrients to the vacuole of the parasite Sarah Frankland, Timothy Schneider, Salenna R. Elliott, Ellen Knuepfer, Alan F. Cowman, Chris I. Newbold and Leann TilleyDelivery of the Malaria Virulence Protein PfEMP1 to the Erythrocyte Surface Requires Cholesterol-Rich Domains. Eukaryotic Cell, 2006, 849-860 and the penetration of parasites into cells. Steroids and sterols may influence the biological membrane function of erythrocytes by modifying permeability, metabolite transport and energy metabolism. Research work from Colombia shows that the majority of merozoites are unable to invade RBCs which have been treated with steroids of Solanum nudum. Mary Luz López, Silvia Blair, Jairo Sáez, Cesar Segura. Effect of Solanum nudum steroids on uninfected and Plasmodiumfalciparum-infected erythrocytes. Mem Inst Oswaldo Cruz, Rio de Janeiro, Vol. 104(5): 683-688, August 2009 This also is valid for viral infections. This was first described in a paper from India. M.M. Abid Ali Khan, D.C. Jain, R.S. Bhakuni, Mohd. Zaim and R.S. Thakur Occurrence of some antiviral sterols in Artemisia annua (1991)., Plant Science (Ireland) 75, 161-165. A study comparing the antiviral effect of 7 Artemisia species found that Artemisia annua was always the strongest and often stronger than acyclovir. MK Karamoddini, SA Emami, MS Ghannad, A Sahebcar. Asian Biomedicine vol 5-1, 2011, 63-68. Out of the 21 medicinal plants evaluated for their virus inhibitory activity against tobamoviruses on their test hosts reacting hypersensitively, extracts of Lawsonia alba, Artemisia annua and Cornus capitata showed high virus inhibitory activity. The virus inhibitory agent (s) occurring in A. annua plant was isolated by conventional methods and identified as sterols as sitosterol and stigmasterol. M.M. Abid Ali Khan ∗, D.C. Jain, R.S. Bhakuni, Mohd. Zaim, R.S. Thakur. Occurrence of some antiviral sterols in Artemisia annua. Plant Science. Volume 75, Issue 2, 1991, Pages 161-165 doi:10.1016/0168-9452(91)90230-6 In another study, the sterols from Artemisia annua had higher virus inhibitory properties than other molecules from this plant, like artemisinin or arteannuin-B, and Artemisia annua had higher virus inhibitory activity than 20 other medicinal plants. Many viruses build up a cholesterol envelope to enter the cells. This is for example the case for influenza virus where envelope cholesterol depletion markedly influences influenza virus aggression. Xiangjie Sun and Gary R. Whittaker. Role for Influenza Virus Envelope Cholesterol in Virus Entry and Infection. J Virol. 2003 Dec; 77(23): 12543–12551. doi: 10.1128/JVI.77.23.12543-12551.2003 Dengue virus infection increases intracellular cholesterol levels at early stages post infection by triggering the uptake of LDL particles. Rubén Soto-Acosta, Clemente Mosso, Rosa María del Angel. The increase in cholesterol levels at early stages after dengue virus infection correlates with an augment in LDL particle uptake and HMG-CoA reductase activity. Virology, Volume 442, Issue 2, Pages 132-147 We need to report here an anecdotic report from Vanuatu. A major dengue fever outbreak took place in this island in 2014, with several hundred cases. A female person living in Vanuata was infected by this virus. The infection was classified as dengue by clinical analysis in the hospital where she spent a week. She claims to have recovered after drinking Artemisia annua infusion (origin of the herb: Luxembourg). Subsequently several of her relatives suffered from the same symptoms and were all cured in a few days after tea A annua consumption. The Health Authorities confirm that these people were infected by the dengue virus. This is the first in vivo report on the efficiency of Artemisia annua against dengue. It needs of course to be confirmed by clinical trials in accordance with the WHO protocol. Saddi M, Sanna A, Cottiglia F, Chisu L, Casu L. Antiherpevirus activity of Artemisia arborescens essential oil and inhibition of lateral diffusion in Vero cells. Ann Clin Microbiol Antimicrob. 2007; 6. Calderone V, Nicoletti E, Martinotti E. In vitro antiviral effects of an aqueous extract of Artemisia verlotorum Lamotte (Asteraceae). Phytother Res. 1998; 12:595-7. Efferth T, Romero MR, Wolf DG, Stamminger T, Marin. JJG, Marschall M. The antiviral activities of artemisinin and artesunate. Clin Infect Dis. 2008; 47:804-11. Abid Ali Khan MM, Jain DC, Bhakuni RS, Zaim Mohd Thakur RS. Occurrence of some antiviral sterols in Artemisia annua. Plant Sci. 1991; 75:161-5. Several plants were studied in Colombia for their inhibitory effect against the yellow fever virus which is of the same Flavivirus genus as dengue. Essential oil from Artemisia vulgaris like several other plants seems to lead to a direct virus inactivation. Rocío Meneses, Raquel E Ocazionez, Jairo R Martínez and Elena E Stashenko. Inhibitory effect of essential oils obtained from plants grown in Colombia on yellow fever virus replication in vitro. Annals of Clinical Microbiology and Antimicrobials20098:8. DOI: 10.1186/1476-0711-8-8 Proanthocyanidins also are efficient against virus. Masahiko Takeshita, Yo-ichi Ishida, Ena Akamatsu, Yusuke Ohmori, Hiroaki Kataoka. Proanthocyanidin from Blueberry Leaves Suppresses Expression of Subgenomic Hepatitis C Virus RNA. J Biol Chem. 2009 Aug 7; 284(32): 21165–21176. doi: 10.1074/jbc.M109.004945 Beta-sitosterol and stigmasterol inhibit pro-inflammatory leukines TNF-α, IL-1β. Il-8 and are probably responsible for the anti-osteoarthritic properties of Artemisia tea. Stigmasterol is a phytosterol with potential anti-osteoarthritic properties O. Gabay, C. Sanchez, C. Salvat, F. Chevy, M. Breton, G. Nourissat, C. Wolf. Stigmasterol: a phytosterol with potential anti-osteoarthritic properties. DOI: doi.org/10.1016/j.joca.2009.08.019. Osteoarthritis and Cartilage, 2010, 18, 106-116. Stigmasterol and β-sitosterol from Artemisia ageratum are effective topic anti-inflammatory agents. M. A. G ómez, M. T. Sáenz, M. D. G arcía and M. A. Fernández. Study of the Topical Anti-Inflammatory Activity of Achillea ageratum on Chronic and Acute Inflammation Models. Z.Naturforsch, 54c, 1999, 937-941 Infection with HIV is also associated with elevated IL-6 levels and production which phytosterols are able to lower. Breen EC, Rezai AR, Nakajima K, Beall GN, Martinez-Maza O Infection with HIV is associated with elevated IL-6 levels and production. J Immunol. 1990 Jan 15;144(2):480-4. In fact, the antiviral effect of β-sitosterol and stigmasterol from Artemisia annua is well known by the Chinese, since 30 years. Tan RV, Zheng WF, Tang HQ. Biologically active substances from the genus Artemisia. Planta Med. 1998; 64:295-302. This antiviral effect however is not an inherent property of these molecules but attributable to enhanced activity of cell-mediated immune response which controls viral replication. The antiviral properties of β-sitosterol and β-sitosterol glucoside have event been patented. against HIV. They stabilize the CD4 of infected persons and reduce the IL-6. The authors of the patent describe these effects in a paper. Use of a combination of beta-sitosterol and beta-sitosterol glucoside for treating HIV infection EP 0858806 A1 Bouic PJ, Lamprecht JH. Plant sterols and sterolins: a review of their immune-modulating properties. Altern Med Rev. 1999 Jun;4(3):170-7. Artemisia plants are also rich in chlorogenic acid and other caffeoylquinic acids and are used for the treatment of hepatitis and other viral diseases. And as the Chinese claim the plant Artemisia annua contains other interesting and potent molecules. Zhan Y, Geng CA, Chen JJ, Anti-HBV active chlorogenic acid analogues from Artemisia capillaris as a tradional Chines herb for treating hepatitis. J Ethnopharmacol 2014 156 147-54 Wenwen Zhao, Weina Zhang, Kewe Dai, Identification and purification of novel chlorogenic acids in Artemisia annua. J Exp Biol and Agricult Sc. ISSN 2320-8694 Wu YH, Hao BJ, Anti-hepatitis B virus effect and possible mechanism of action of 3,4-o-dicaffeoylquinic acid in vitro and in vivo. Evid Based Complement Anternat Med, 2012:356806 Ding Y, Cao Z, Xiao W, Antiviral activity of chlorogenic acid against influenza A (H1N1/H3N2 virus. Sci Rep 2017 10:7:45723 Heyman HM, Senejoux F, Meyer JJ, Idenditication of anti-HIV active dicaffeoylquinic and tricaffeoylquinic acids. Fitoterapia. 2015 103. 155-164. MM Makola, IA Dubery, NE Madala, The effect of geometric isomerism of 3,5.dicaffeoylquinic acid on its binding affinity to the HIV-Integrase enzyme. Evid Based Compl Aölter Medicine, 2016, article 4138263. The antiviral and antimalarial properties of Inula viscosa are well known in the Middle East. The plant is rich in dicaffeoylquinic acid M. Akkawi. Abbasi, S. Jaber, Q. Aburemeleh, A. Naseredin and Pierre Lutgen. Investigation of Traditional Palestinian Medicinal Plant Inula viscosa as Potential Antimalarial Agent British Journal of Pharmacology and Toxicology 2014 Dicaffeoylquinic acid in propolis also has antiviral properties. T Takemura. K Kuwata. 3,4-dicaffeoylquinic from Brazilian propolis extends the lifetime of mice infected with the Influena A virus. Evid Based Compl Alt Med, 2012 article 946867 Breaking news on anti-HIV had already come from the University of Leiden in 2012. This was confirmed recently by a US study and they relate this anti-HIV property to dicaffeoylquinic acids. Andrea Lubbe, Isabell Seibert, Thomas Klimkait, Frank van der Kooy. Ethnopharmacology in overdrive: The remarkable anti-HIV activity of Artemisia annua. Journal of Ethnopharmacology (2012) JEP-7371; X Zheng, R Renslow, M Makola, E Baker. Structural eleucidation of cis/trans dicaffeoylquinic acid J Phys Chem Letters 2017, 8, 1381-1388. A Japanese patent describes the antiviral properties od Artemisia absinthium Nakamura T, Matsuda Kosuke. Virus diffusion preventing agent obtained from Artemisia absinthium WO/2015/155903

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