- Open Access
Anti-malarial effect of gum arabic
© Ballal et al; licensee BioMed Central Ltd. 2011
- Received: 22 February 2011
- Accepted: 20 May 2011
- Published: 20 May 2011
Gum Arabic (GA), a nonabsorbable nutrient from the exudate of Acacia senegal, exerts a powerful immunomodulatory effect on dendritic cells, antigen-presenting cells involved in the initiation of both innate and adaptive immunity. On the other hand GA degradation delivers short chain fatty acids, which in turn have been shown to foster the expression of foetal haemoglobin in erythrocytes. Increased levels of erythrocyte foetal haemoglobin are known to impede the intraerythrocytic growth of Plasmodium and thus confer some protection against malaria. The present study tested whether gum arabic may influence the clinical course of malaria.
Human erythrocytes were in vitro infected with Plasmodium falciparum in the absence and presence of butyrate and mice were in vivo infected with Plasmodium berghei ANKA by injecting parasitized murine erythrocytes (1 × 106) intraperitoneally. Half of the mice received gum arabic (10% in drinking water starting 10 days before the day of infection).
According to the in vitro experiments butyrate significantly blunted parasitaemia only at concentrations much higher (3 mM) than those encountered in vivo following GA ingestion (<1 μM). According to the in vivo experiments the administration of gum arabic slightly but significantly decreased the parasitaemia and significantly extended the life span of infected mice.
GA moderately influences the parasitaemia and survival of Plasmodium- infected mice. The underlying mechanism remained, however, elusive.
Gum arabic favourably influences the course of murine malaria.
- Infected Erythrocyte
- Foetal Haemoglobin
- Plasmodium Berghei
- Haemolytic Uremic Syndrome
Gum Arabic (GA) from gummy exudates of Acacia Senegal  is a water-soluble  polysaccharide based on branched chains of (1-3) linked β-D-galactopyranosyl units containing α-L-arabinofuranosyl, α-L-rhamnopyranosyl, β-D-glucuronopyranosyl and 4-O-methyl-β-D-glucuronopyranosyl units . It is considered one of the safest dietary fibers . In Middle Eastern countries GA is employed in the treatment of patients with chronic renal disease and end stage renal failure . Gum arabic increases the faecal nitrogen excretion  and decreases the production of free oxygen radicals .
Recent in vitro experiments revealed a powerful immunomodulary effect of GA on dendritic cells  antigen-presenting cells orchestrating the initiation of both innate and adaptive immunity and thus playing a pivotal role in the regulation of the immune response [8–11].
The intestinal fermentation of gum arabic leads to the formation of several degradation products including short-chain fatty acids . Accordingly, GA treatment may enhance the serum butyrate concentrations . Butyrate compounds have been shown to up-regulate the formation of foetal haemoglobin [13–15], which may in turn confer some protection against a severe course of malaria [16–18]. Specifically, foetal haemoglobin has been shown to delay the haemoglobin degradation and thus to impede the intraerythrocyte growth of Plasmodium. Accordingly, expression of foetal haemoglobin protects against a severe course of malaria [17, 18].
Moreover, foetal haemoglobin may increase the susceptibility of foetal erythrocytes to oxidative stress . As Plasmodium falciparum imposes oxidative stress on infected cells, it may trigger eryptosis, the suicidal death of erythrocytes [20, 21]. Eryptosis is characterized by cell membrane scrambling with phosphatidylserine exposure at the cell surface [22–26]. The cell membrane scrambling is triggered by increased cytosolic Ca2+ activity [23–27] and/or ceramide . Ca2+ enters erythrocytes through Ca2+-permeable cation channels, which are activated by osmotic shock, oxidative stress or energy depletion [29–33]. In addition, Ca2+ stimulates Ca2+-sensitive K+ channels [27, 34, 35], followed by cellular loss of KCl and osmotically obliged water leading to cell shrinkage . The Ca2+-permeable cation channels are activated by oxidative stress , which thus stimulates eryptosis . Excessive cytosolic Ca2+ concentrations stimulate similarly apoptosis of nucleated cells .
Phosphatidylserine-exposing cells are recognized [39, 40] and phagocytosed [41, 42] by macrophages. Eryptotic cells are thus rapidly cleared from circulating blood . The accelerated clearance of infected erythrocytes  may counteract the development of parasitaemia . Enhanced susceptibility to eryptosis and accelerated clearance of Plasmodium-infected erythrocytes may confer relative protection against a severe course of malaria in carriers of sickle-cell trait, beta-thalassaemia-trait, homozygous Hb-C and G6PD-deficiency [46–50], in iron deficiency , as well as during treatment with lead , chlorpromazine  and cyclosporine . The erythrocyte cation channel is inhibited by erythropoietin , which may again influence the course of malaria .
The present study explored, whether gum arabic favourably influences parasitaemia and host survival during malaria.
Animal experiments were performed according to the German animal protection law and approved by the local authorities (registration number PY 2/06). Experiments were performed in healthy SV129/J wild type mice (aged 4 months, both male and female). The animals had free access to standard chow (ssniff, Soest, Germany) and drinking water. Murine erythrocytes were drawn from the animals by incision of the tail vein.
Human erythrocytes were drawn from healthy volunteers. The study was approved by the Ethical commission of the University of Tübingen.
In vitro experiments were performed at 37°C in Ringer solution containing (in mM) 125 NaCl, 5 KCl, 1 MgSO4, 32 N-2-hydroxyethylpiperazine-N-2-ethanesulfonic acid (HEPES)/NaOH (pH 7.4), 5 glucose, 1 CaCl2 . Butyrate was added to the NaCl Ringer at final concentrations varying from 0.3 to 10 mM (Sigma, Schnelldorf, Germany). For in vitro treatment, the final haematocrit was adjusted to 0.3%.
For determination of phosphatidylserine exposure, FACS analysis was performed as described . After incubation in the presence or absence of gum arabic, suspensions of P. falciparum- infected erythrocytes were stained with annexin V-APC (BD Biosciences Pharmingen, Heidelberg, Germany) and/or with the DNA/RNA specific dye Syto16 (Molecular Probes, Göttingen, Germany) to identify phosphatidylserine-exposing and infected erythrocytes, respectively. For annexin V-binding, erythrocytes were washed, resuspended in annexin V-binding buffer (Ringer solution containing 5 mM CaCl2. pH 7.4), stained with annexin V-APC (dilution 1:20), incubated for 20 min at room temperature, and diluted 1:5 with annexin V-binding buffer. Syto16 (final concentration of 20 nM) was added directly to the diluted erythrocyte suspension or co-incubated in the annexin V-binding buffer. Cells were analyzed by flow cytometry (FACS-Calibur, Becton Dickinson, Heidelberg, Germany) in fluorescence channel FL-1 for Syto16 (detected at 530 nm) and in FL-4 for annexin V-APC fluorescence intensity (detected at 660 nm).
For infection of human erythrocytes the human pathogen P. falciparum strain BinH  was grown in vitro . Parasites were cultured as described earlier [58, 59] at a haematocrit of 2% and a parasitaemia of 2-10% in RPMI 1640 medium supplemented with Albumax II (0.5%; Gibco, Karlsruhe, Germany) in an atmosphere of 90% N2, 5% CO2, 5% O2 [60, 61].
For infection of mice Plasmodium berghei ANKA-parasitized murine erythrocytes (1 × 106) were injected intraperitoneally [62, 63] into wildtype mice. Where indicated gum arabic (10% in drinking water) was administered starting 10 days before the day of infection. Blood was collected from the mice 8 days after infection by incision of the tail. Parasitaemia was determined by Syto-16 staining in FACS analysis.
To estimate the in vitro growth of P. falciparum, the BinH strain was cultured and synchronized to the ring stage by sorbitol treatment as described previously . For the in vitro growth assay, synchronized parasitized erythrocytes were aliquoted in 96-well plates (200 μl aliquots, 1% haematocrit, 0.5-2% parasitaemia) and grown for 48 h in the presence or absence of butyrate (0.3 mM - 10 mM). The parasitaemia was assessed at time 0 and after 48 h of culture by flow cytometry. Parasitaemia was defined by the percentage of erythrocytes stained with the DNA/RNA specific fluorescence dye Syto16.
To estimate DNA/RNA amplification of the intraerythrocytic parasite, the culture was ring stage-synchronized, and re-synchronized after 6 h of culture (to narrow the developmental parasite stage), aliquoted (200 μl aliquots, 2% haematocrit and 10% parasitaemia) and cultured for further 16 h in the presence or absence of butyrate (0.3 mM - 10 mM). Thereafter, the DNA/RNA amount of the parasitized erythrocytes was determined by Syto16 fluorescence as a measure of intraerythrocytic parasite copies.
Data are expressed as arithmetic means ± SEM and statistical analysis was made by t-test or ANOVA using Tukey's test as post hoc test, as appropriate. p < 0.05 was considered as statistically significant. The mouse survival was analysed utilizing the Kaplan-Meier estimator method.
Arithmetic means (± SEM, n = 7) of erythrocyte parameters of noninfected and infected mice without or with gum arabic treatment (10% in drinking water)
Erythrocyte number (106/mm3)
10.78 ± 0.19
11.03 ± 0.10
6.79 ± 1.01#, *
8.32 ± 0.95#, *
15.57 ± 0.32
16.35 ± 0.16
9.47 ± 1.38#, *
11.77 ± 1.39#, *
43.34 ± 0.32
44.5 ± 0.39
28.27 ± 4.3#, *
34.31 ± 3.72#, *
Mean erythrocyte volume (MCV) (fl)
40.2 ± 0.38
40.47 ± 0.16
41.35 ± 0.63
41.37 ± 0.39
Erythrocyte haemoglobin concentration (MCHC) (g/dl)
35.91 ± 0.20
36.75 ± 0.13
33.88 ± 0.55#
34.04 ± 0.49#
14.4 ± 0.20
14.88 ± 0.07
14.01 ± 0.13
14.07 ± 0.10
To determine the effect of infection and butyrate on suicidal erythrocyte death (eryptosis), the percentage of phosphatidylserine-exposing erythrocytes was estimated by measurement of annexin V-binding in FACS analysis. In vitro infection tended to increase the percentage of annexin V-binding erythrocytes (Figure 1C). The addition of butyrate tended to decrease the percentage of annexin V-binding cells, an effect, however, not reaching statistical significance (Figure 1C).
Infection with P. berghei significantly decreased the erythrocyte number per μl, haematocrit (packed cell volume) and blood haemoglobin concentration (Table 1), effects all significantly blunted by treatment with GA (Table 1).
The present study reveals a completely novel effect of gum arabic, i.e. an influence on the course of malaria. Treatment with GA delayed a lethal course of malaria following infection of mice with P. berghei. As shown earlier, the infection of mice with P. berghei is followed by an invariably lethal course of malaria . Treatment with GA did not prevent a lethal course of malaria but extended the survival of the infected animals. Accordingly, when all untreated animals had died, still more than half of the GA treated animals were alive.
The present observations do not allow safe conclusions as to the mechanisms underlying the moderate beneficial effect of GA treatment. Gum arabic treatment delayed the development of parasitaemia and blunted the decrease of blood erythrocyte number and haemoglobin concentration and thus significantly counteracted the development of anemia.
In theory, GA could affect parasitaemia and host survival by increasing the erythrocyte content of foetal haemoglobin, which is known to delay the intraerythrocytic growth of the parasite [17, 18]. The effect would be apparent particularly following pretreatment of the mice with GA. While butyrate requires excessive concentrations to be effective in vitro, much lower concentrations could modify the formation of foetal hamoglobin [13–15] and thus susceptibility to malaria [16–18].
Foetal hemoglobin (HbF) has a higher O2 affinity than adult haemoglobin  and influences erythrocyte K+ transport and O2 dependence of erythrocyte glycolysis . Increased HbO2 affinity may result in enhanced lactate formation with subsequent decrease of HCO3- and thus increased CO2/HCO3- ratio. CO2 fosters SOD1 peroxidation, promoting the release of pro-inflammatory cytokines from activated macrophages leading to metabolic syndrome . Those events may affect erythrocyte survival in parasitized erythrocytes.
Gum arabic, butyrate and/or foetal haemoglobin may affect parasitaemia and host survival by accelerating the suicidal death of infected erythrocytes . Phosphatidylserine-exposing erythrocytes are phagocytosed [41, 42] and thus rapidly cleared from circulating blood . Eryptosis is triggered by a wide variety of substances [68–74]. Several of those substances have been shown to decrease parasitaemia and to extend the survival of infected mice [52, 75–78]. Moreover, eryptosis is enhanced in several clinical conditions, such as iron deficiency , sickle-cell anaemia [79, 80], beta-thalassaemia , glucose-6-phosphate dehydrogenase (G6PD)-deficiency , phosphate depletion , Haemolytic uremic syndrome , sepsis , malaria  and Wilson's disease . Some of those diseases have similarly been shown to favourably influence the course of malaria, i.e. sickle-cell trait, beta-thalassaemia-trait, homozygous Hb-C and G6PD-deficiency [22, 46–50] as well as iron deficiency . However, most of those diseases and substances exert a profound effect on parasitaemia.
In conclusion, in mice, gum arabic provides extended survival following the invariably lethal infection with P. berghei. Gum arabic is particularly effective in preventing an early death from this devastating disease.
This study was supported by the Deutsche Forschungsgemeinschaft (La 315/6-1 and La 315/13-1). The authors acknowledge the meticulous preparation of the manuscript by Sari Rübe and Mara Koch.
- Younes H, Garleb K, Behr S, Remesy C, Demigne C: Fermentable fibers or oligosaccharides reduce urinary nitrogen excretion by increasing urea disposal in the rat cecum. J Nutr. 1995, 125: 1010-1016.PubMedGoogle Scholar
- Tiss A, Carriere F, Verger R: Effects of gum arabic on lipase interfacial binding and activity. Anal Biochem. 2001, 294: 36-43. 10.1006/abio.2001.5095.View ArticlePubMedGoogle Scholar
- Deckwer WD, Dill B, Eisenbrand E, Bornscheuer U, Pühler A, Heiker FR, Kirschning A, Schreier P, Fugmann B, Pohnert G: Römpp Online. 2006, Georg-Thieme-VerlagGoogle Scholar
- Anderson DM: Evidence for the safety of gum arabic (Acacia senegal (L.) Willd.) as a food additive--a brief review. Food Addit Contam. 1986, 3: 225-230.View ArticlePubMedGoogle Scholar
- Al Majed AA, Mostafa AM, Al Rikabi AC, Al Shabanah OA: Protective effects of oral arabic gum administration on gentamicin-induced nephrotoxicity in rats. Pharmacol Res. 2002, 46: 445-451. 10.1016/S1043661802001251.View ArticlePubMedGoogle Scholar
- Bliss DZ, Stein TP, Schleifer CR, Settle RG: Supplementation with gum arabic fiber increases fecal nitrogen excretion and lowers serum urea nitrogen concentration in chronic renal failure patients consuming a low-protein diet. Am J Clin Nutr. 1996, 63: 392-398.PubMedGoogle Scholar
- Xuan NT, Shumilina E, Nasir O, Bobbala D, Gotz F, Lang F: Stimulation of mouse dendritic cells by Gum Arabic. Cell Physiol Biochem. 2010, 25: 641-648. 10.1159/000315083.View ArticlePubMedGoogle Scholar
- Adler HS, Steinbrink K: Tolerogenic dendritic cells in health and disease: friend and foe!. Eur J Dermatol. 2007, 17: 476-491.PubMedGoogle Scholar
- Banchereau J, Briere F, Caux C, Davoust J, Lebecque S, Liu YJ, Pulendran B, Palucka K: Immunobiology of dendritic cells. Annu Rev Immunol. 2000, 18: 767-811. 10.1146/annurev.immunol.18.1.767.View ArticlePubMedGoogle Scholar
- Steinman RM, Nussenzweig MC: Avoiding horror autotoxicus: the importance of dendritic cells in peripheral T cell tolerance. Proc Natl Acad Sci USA. 2002, 99: 351-358. 10.1073/pnas.231606698.PubMed CentralView ArticlePubMedGoogle Scholar
- van Duivenvoorde LM, Han WG, Bakker AM, Louis-Plence P, Charbonnier LM, Apparailly F, van der Voort EI, Jorgensen C, Huizinga TW, Toes RE: Immunomodulatory dendritic cells inhibit Th1 responses and arthritis via different mechanisms. J Immunol. 2007, 179: 1506-1515.View ArticlePubMedGoogle Scholar
- Matsumoto N, Riley S, Fraser D, Al Assaf S, Ishimura E, Wolever T, Phillips GO, Phillips AO: Butyrate modulates TGF-beta1 generation and function: potential renal benefit for Acacia(sen) SUPERGUM (gum arabic)?. Kidney Int. 2006, 69: 257-265. 10.1038/sj.ki.5000028.View ArticlePubMedGoogle Scholar
- Goren A, Simchen G, Fibach E, Szabo PE, Tanimoto K, Chakalova L, Pfeifer GP, Fraser PJ, Engel JD, Cedar H: Fine tuning of globin gene expression by DNA methylation. PLoS One. 2006, 1: e46-10.1371/journal.pone.0000046.PubMed CentralView ArticlePubMedGoogle Scholar
- Mankidy R, Faller DV, Mabaera R, Lowrey CH, Boosalis MS, White GL, Castaneda SA, Perrine SP: Short-chain fatty acids induce gamma-globin gene expression by displacement of a HDAC3-NCoR repressor complex. Blood. 2006, 108: 3179-3186. 10.1182/blood-2005-12-010934.PubMed CentralView ArticlePubMedGoogle Scholar
- Perrine SP, Ginder GD, Faller DV, Dover GH, Ikuta T, Witkowska HE, Cai SP, Vichinsky EP, Olivieri NF: A short-term trial of butyrate to stimulate fetal-globin-gene expression in the beta-globin disorders. N Engl J Med. 1993, 328: 81-86. 10.1056/NEJM199301143280202.View ArticlePubMedGoogle Scholar
- Pasvol G, Weatherall DJ, Wilson RJ, Smith DH, Gilles HM: Fetal haemoglobin and malaria. Lancet. 1976, 1: 1269-1272.View ArticlePubMedGoogle Scholar
- Pasvol G, Weatherall DJ, Wilson RJ: Effects of foetal haemoglobin on susceptibility of red cells to Plasmodium falciparum. Nature. 1977, 270: 171-173. 10.1038/270171a0.View ArticlePubMedGoogle Scholar
- Shear HL, Grinberg L, Gilman J, Fabry ME, Stamatoyannopoulos G, Goldberg DE, Nagel RL: Transgenic mice expressing human fetal globin are protected from malaria by a novel mechanism. Blood. 1998, 92: 2520-2526.PubMedGoogle Scholar
- Hermle T, Shumilina E, Attanasio P, Akel A, Kempe DS, Lang PA, Podolski M, Gatz S, Bachmann R, Bachmann C, Abele H, Huber S, Wieder T, Lang F: Decreased cation channel activity and blunted channel-dependent eryptosis in neonatal erythrocytes. Am J Physiol Cell Physiol. 2006, 291: C710-C717. 10.1152/ajpcell.00631.2005.View ArticlePubMedGoogle Scholar
- Koka S, Huber SM, Boini KM, Lang C, Foller M, Lang F: Lead decreases parasitemia and enhances survival of Plasmodium berghei-infected mice. Biochem Biophys Res Commun. 2007, 363: 484-489. 10.1016/j.bbrc.2007.08.173.View ArticlePubMedGoogle Scholar
- Koka S, Foller M, Lamprecht G, Boini KM, Lang C, Huber SM, Lang F: Iron deficiency influences the course of malaria in Plasmodium berghei infected mice. Biochem Biophys Res Commun. 2007, 357: 608-614. 10.1016/j.bbrc.2007.03.175.View ArticlePubMedGoogle Scholar
- Lang KS, Roll B, Myssina S, Schittenhelm M, Scheel-Walter HG, Kanz L, Fritz J, Lang F, Huber SM, Wieder T: Enhanced erythrocyte apoptosis in sickle cell anemia, thalassemia and glucose-6-phosphate dehydrogenase deficiency. Cell Physiol Biochem. 2002, 12: 365-372. 10.1159/000067907.View ArticlePubMedGoogle Scholar
- Berg CP, Engels IH, Rothbart A, Lauber K, Renz A, Schlosser SF, Schulze-Osthoff K, Wesselborg S: Human mature red blood cells express caspase-3 and caspase-8, but are devoid of mitochondrial regulators of apoptosis. Cell Death Differ. 2001, 8: 1197-1206. 10.1038/sj.cdd.4400905.View ArticlePubMedGoogle Scholar
- Brand VB, Sandu CD, Duranton C, Tanneur V, Lang KS, Huber SM, Lang F: Dependence of Plasmodium falciparum in vitro growth on the cation permeability of the human host erythrocyte. Cell Physiol Biochem. 2003, 13: 347-356. 10.1159/000075122.View ArticlePubMedGoogle Scholar
- Bratosin D, Estaquier J, Petit F, Arnoult D, Quatannens B, Tissier JP, Slomianny C, Sartiaux C, Alonso C, Huart JJ, Montreuil J, Ameisen JC: Programmed cell death in mature erythrocytes: a model for investigating death effector pathways operating in the absence of mitochondria. Cell Death Differ. 2001, 8: 1143-1156. 10.1038/sj.cdd.4400946.View ArticlePubMedGoogle Scholar
- Daugas E, Cande C, Kroemer G: Erythrocytes: death of a mummy. Cell Death Differ. 2001, 8: 1131-1133. 10.1038/sj.cdd.4400953.View ArticlePubMedGoogle Scholar
- Lang PA, Kaiser S, Myssina S, Wieder T, Lang F, Huber SM: Role of Ca2+-activated K+ channels in human erythrocyte apoptosis. Am J Physiol Cell Physiol. 2003, 285: C1553-C1560.View ArticlePubMedGoogle Scholar
- Lang KS, Myssina S, Brand V, Sandu C, Lang PA, Berchtold S, Huber SM, Lang F, Wieder T: Involvement of ceramide in hyperosmotic shock-induced death of erythrocytes. Cell Death Differ. 2004, 11: 231-243. 10.1038/sj.cdd.4401311.View ArticlePubMedGoogle Scholar
- Lang KS, Duranton C, Poehlmann H, Myssina S, Bauer C, Lang F, Wieder T, Huber SM: Cation channels trigger apoptotic death of erythrocytes. Cell Death Differ. 2003, 10: 249-256. 10.1038/sj.cdd.4401144.View ArticlePubMedGoogle Scholar
- Bernhardt I, Weiss E, Robinson HC, Wilkins R, Bennekou P: Differential effect of HOE642 on two separate monovalent cation transporters in the human red cell membrane. Cell Physiol Biochem. 2007, 20: 601-606. 10.1159/000107543.View ArticlePubMedGoogle Scholar
- Duranton C, Huber SM, Lang F: Oxidation induces a Cl(-)-dependent cation conductance in human red blood cells. J Physiol. 2002, 539: 847-855. 10.1113/jphysiol.2001.013040.PubMed CentralView ArticlePubMedGoogle Scholar
- Foller M, Kasinathan RS, Koka S, Lang C, Shumilina E, Birnbaumer L, Lang F, Huber SM: TRPC6 contributes to the Ca(2+) leak of human erythrocytes. Cell Physiol Biochem. 2008, 21: 183-192. 10.1159/000113760.View ArticlePubMedGoogle Scholar
- Huber SM, Gamper N, Lang F: Chloride conductance and volume-regulatory nonselective cation conductance in human red blood cell ghosts. Pflugers Arch. 2001, 441: 551-558. 10.1007/s004240000456.View ArticlePubMedGoogle Scholar
- Bookchin RM, Ortiz OE, Lew VL: Activation of calcium-dependent potassium channels in deoxygenated sickled red cells. Prog Clin Biol Res. 1987, 240: 193-200.PubMedGoogle Scholar
- Brugnara C, de Franceschi L, Alper SL: Inhibition of Ca(2+)-dependent K+ transport and cell dehydration in sickle erythrocytes by clotrimazole and other imidazole derivatives. J Clin Invest. 1993, 92: 520-526. 10.1172/JCI116597.PubMed CentralView ArticlePubMedGoogle Scholar
- Duranton C, Huber S, Tanneur V, Lang K, Brand V, Sandu C, Lang F: Electrophysiological properties of the Plasmodium falciparum-induced cation conductance of human erythrocytes. Cell Physiol Biochem. 2003, 13: 189-198. 10.1159/000072421.View ArticlePubMedGoogle Scholar
- Tyurina YY, Tyurin VA, Zhao Q, Djukic M, Quinn PJ, Pitt BR, Kagan VE: Oxidation of phosphatidylserine: a mechanism for plasma membrane phospholipid scrambling during apoptosis?. Biochem Biophys Res Commun. 2004, 324: 1059-1064. 10.1016/j.bbrc.2004.09.102.View ArticlePubMedGoogle Scholar
- McConkey DJ, Orrenius S: The role of calcium in the regulation of apoptosis. Biochem Biophys Res Commun. 1997, 239: 357-366. 10.1006/bbrc.1997.7409.View ArticlePubMedGoogle Scholar
- Fadok VA, Bratton DL, Rose DM, Pearson A, Ezekewitz RA, Henson PM: A receptor for phosphatidylserine-specific clearance of apoptotic cells. Nature. 2000, 405: 85-90. 10.1038/35011084.View ArticlePubMedGoogle Scholar
- Henson PM, Bratton DL, Fadok VA: The phosphatidylserine receptor: a crucial molecular switch?. Nat Rev Mol Cell Biol. 2001, 2: 627-633. 10.1038/35085094.View ArticlePubMedGoogle Scholar
- Boas FE, Forman L, Beutler E: Phosphatidylserine exposure and red cell viability in red cell aging and in hemolytic anemia. Proc Natl Acad Sci USA. 1998, 95: 3077-3081. 10.1073/pnas.95.6.3077.PubMed CentralView ArticlePubMedGoogle Scholar
- Yamanaka M, Eda S, Beppu M: Carbohydrate chains and phosphatidylserine successively work as signals for apoptotic cell removal. Biochem Biophys Res Commun. 2005, 328: 273-280. 10.1016/j.bbrc.2004.12.171.View ArticlePubMedGoogle Scholar
- Kempe DS, Lang PA, Duranton C, Akel A, Lang KS, Huber SM, Wieder T, Lang F: Enhanced programmed cell death of iron-deficient erythrocytes. FASEB J. 2006, 20: 368-370.PubMedGoogle Scholar
- Schwarzer E, Turrini F, Ulliers D, Giribaldi G, Ginsburg H, Arese P: Impairment of macrophage functions after ingestion of Plasmodium falciparum-infected erythrocytes or isolated malarial pigment. J Exp Med. 1992, 176: 1033-1041. 10.1084/jem.176.4.1033.View ArticlePubMedGoogle Scholar
- Lang F, Lang PA, Lang KS, Brand V, Tanneur V, Duranton C, Wieder T, Huber SM: Channel-induced apoptosis of infected host cells-the case of malaria. Pflugers Arch. 2004, 448: 319-324. 10.1007/s00424-004-1254-9.View ArticlePubMedGoogle Scholar
- Ayi K, Turrini F, Piga A, Arese P: Enhanced phagocytosis of ring-parasitized mutant erythrocytes: a common mechanism that may explain protection against falciparum malaria in sickle trait and beta-thalassemia trait. Blood. 2004, 104: 3364-3371. 10.1182/blood-2003-11-3820.View ArticlePubMedGoogle Scholar
- Cappadoro M, Giribaldi G, O'Brien E, Turrini F, Mannu F, Ulliers D, Simula G, Luzzatto L, Arese P: Early phagocytosis of glucose-6-phosphate dehydrogenase (G6PD)-deficient erythrocytes parasitized by Plasmodium falciparum may explain malaria protection in G6PD deficiency. Blood. 1998, 92: 2527-2534.PubMedGoogle Scholar
- de Jong K, Emerson RK, Butler J, Bastacky J, Mohandas N, Kuypers FA: Short survival of phosphatidylserine-exposing red blood cells in murine sickle cell anemia. Blood. 2001, 98: 1577-1584. 10.1182/blood.V98.5.1577.View ArticlePubMedGoogle Scholar
- Kean LS, Brown LE, Nichols JW, Mohandas N, Archer DR, Hsu LL: Comparison of mechanisms of anemia in mice with sickle cell disease and beta-thalassemia: peripheral destruction, ineffective erythropoiesis, and phospholipid scramblase-mediated phosphatidylserine exposure. Exp Hematol. 2002, 30: 394-402. 10.1016/S0301-472X(02)00780-4.View ArticlePubMedGoogle Scholar
- Kuypers FA, Yuan J, Lewis RA, Snyder LM, Kiefer CR, Bunyaratvej A, Fucharoen S, Ma L, Styles L, de Jong K, Schrier SL: Membrane phospholipid asymmetry in human thalassemia. Blood. 1998, 91: 3044-3051.PubMedGoogle Scholar
- Koka S, Lang C, Boini KM, Bobbala D, Huber SM, Lang F: Influence of chlorpromazine on eryptosis, parasitemia and survival of Plasmodium berghei- infected mice. Cell Physiol Biochem. 2008, 22: 261-268. 10.1159/000149804.View ArticlePubMedGoogle Scholar
- Bobbala D, Alesutan I, Foller M, Huber SM, Lang F: Effect of anandamide in Plasmodium berghei-infected mice. Cell Physiol Biochem. 2010, 26: 355-362. 10.1159/000320559.View ArticlePubMedGoogle Scholar
- Myssina S, Huber SM, Birka C, Lang PA, Lang KS, Friedrich B, Risler T, Wieder T, Lang F: Inhibition of erythrocyte cation channels by erythropoietin. J Am Soc Nephrol. 2003, 14: 2750-2757. 10.1097/01.ASN.0000093253.42641.C1.View ArticlePubMedGoogle Scholar
- Wiese L, Hempel C, Penkowa M, Kirkby N, Kurtzhals JA: Recombinant human erythropoietin increases survival and reduces neuronal apoptosis in a murine model of cerebral malaria. Malar J. 2008, 7: 3-10.1186/1475-2875-7-3.PubMed CentralView ArticlePubMedGoogle Scholar
- Duranton C, Tanneur V, Lang C, Brand VB, Koka S, Kasinathan RS, Dorsch M, Hedrich HJ, Baumeister S, Lingelbach K, Lang F, Huber SM: A high specificity and affinity interaction with serum albumin stimulates an anion conductance in malaria-infected erythrocytes. Cell Physiol Biochem. 2008, 22: 395-404. 10.1159/000185483.View ArticlePubMedGoogle Scholar
- Binh VQ, Luty AJ, Kremsner PG: Differential effects of human serum and cells on the growth of Plasmodium falciparum adapted to serum-free in vitro culture conditions. Am J Trop Med Hyg. 1997, 57: 594-600.PubMedGoogle Scholar
- Huber SM, Uhlemann AC, Gamper NL, Duranton C, Kremsner PG, Lang F: Plasmodium falciparum activates endogenous Cl(-) channels of human erythrocytes by membrane oxidation. EMBO J. 2002, 21: 22-30. 10.1093/emboj/21.1.22.PubMed CentralView ArticlePubMedGoogle Scholar
- Jensen JB, Trager W: Plasmodium falciparum in culture: establishment of additional strains. Am J Trop Med Hyg. 1978, 27: 743-746.PubMedGoogle Scholar
- Trager W, Jensen JB: Human malaria parasites in continuous culture. Science. 1976, 193: 673-675. 10.1126/science.781840.View ArticlePubMedGoogle Scholar
- Brand VB, Koka S, Lang C, Jendrossek V, Huber SM, Gulbins E, Lang F: Influence of amitriptyline on eryptosis, parasitemia and survival of Plasmodium berghei- infected mice. Cell Physiol Biochem. 2008, 22: 405-412. 10.1159/000185482.View ArticlePubMedGoogle Scholar
- Koka S, Lang C, Niemoeller OM, Boini KM, Nicolay JP, Huber SM, Lang F: Influence of NO synthase inhibitor L-NAME on parasitemia and survival of Plasmodium berghei infected mice. Cell Physiol Biochem. 2008, 21: 481-488. 10.1159/000129641.View ArticlePubMedGoogle Scholar
- Huber SM, Duranton C, Henke G, Van De SC, Heussler V, Shumilina E, Sandu CD, Tanneur V, Brand V, Kasinathan RS, Lang KS, Kremsner PG, Hubner CA, Rust MB, Dedek K, Jentsch TJ, Lang F: Plasmodium induces swelling-activated ClC-2 anion channels in the host erythrocyte. J Biol Chem. 2004, 279: 41444-41452. 10.1074/jbc.M407618200.View ArticlePubMedGoogle Scholar
- Lackner P, Hametner C, Beer R, Burger C, Broessner G, Helbok R, Speth C, Schmutzhard E: Complement factors C1q, C3 and C5 in brain and serum of mice with cerebral malaria. Malar J. 2008, 7: 207-10.1186/1475-2875-7-207.PubMed CentralView ArticlePubMedGoogle Scholar
- Bursaux E, Poyart C, Guesnon P, Teisseire B: Comparative effects of CO2 on the affinity for O2 of fetal and adult erythrocytes. Pflugers Arch. 1979, 378: 197-203. 10.1007/BF00592736.View ArticlePubMedGoogle Scholar
- Weber RE: Lacking deoxygenation-linked interaction between cytoplasmic domain of band 3 and HbF from fetal red blood cells. Acta Physiol (Oxf). 2007, 191: 247-252. 10.1111/j.1748-1716.2007.01736.x.View ArticleGoogle Scholar
- Zappulla D: Environmental stress, erythrocyte dysfunctions, inflammation, and the metabolic syndrome: adaptations to CO2 increases?. J Cardiometab Syndr. 2008, 3: 30-34. 10.1111/j.1559-4572.2008.07263.x.View ArticlePubMedGoogle Scholar
- Geiger C, Foller M, Herrlinger KR, Lang F: Azathioprine-induced suicidal erythrocyte death. Inflamm Bowel Dis. 2008, 14: 1027-1032. 10.1002/ibd.20433.View ArticlePubMedGoogle Scholar
- Lang F, Gulbins E, Lerche H, Huber SM, Kempe DS, Foller M: Eryptosis, a window to systemic disease. Cell Physiol Biochem. 2008, 22: 373-380. 10.1159/000185448.View ArticlePubMedGoogle Scholar
- Bhavsar SK, Bobbala D, Xuan NT, Foller M, Lang F: Stimulation of suicidal erythrocyte death by alpha-lipoic acid. Cell Physiol Biochem. 2010, 26: 859-868. 10.1159/000323995.View ArticlePubMedGoogle Scholar
- Bhavsar SK, Eberhard M, Bobbala D, Lang F: Monensin induced suicidal erythrocyte death. Cell Physiol Biochem. 2010, 25: 745-752. 10.1159/000315094.View ArticlePubMedGoogle Scholar
- Eberhard M, Ferlinz K, Alizzi K, Cacciato PM, Faggio C, Foller M, Lang F: FTY720-induced suicidal erythrocyte death. Cell Physiol Biochem. 2010, 26: 761-766. 10.1159/000322343.View ArticlePubMedGoogle Scholar
- Lang F, Gulbins E, Lang PA, Zappulla D, Foller M: Ceramide in suicidal death of erythrocytes. Cell Physiol Biochem. 2010, 26: 21-28. 10.1159/000315102.View ArticlePubMedGoogle Scholar
- Mahmud H, Mauro D, Qadri SM, Foller M, Lang F: Triggering of suicidal erythrocyte death by amphotericin B. Cell Physiol Biochem. 2009, 24: 263-270. 10.1159/000233251.View ArticlePubMedGoogle Scholar
- Mahmud H, Dalken B, Wels WS: Induction of programmed cell death in ErbB2/HER2-expressing cancer cells by targeted delivery of apoptosis-inducing factor. Mol Cancer Ther. 2009, 8: 1526-1535. 10.1158/1535-7163.MCT-08-1149.View ArticlePubMedGoogle Scholar
- Foller M, Bobbala D, Koka S, Huber SM, Gulbins E, Lang F: Suicide for survival--death of infected erythrocytes as a host mechanism to survive malaria. Cell Physiol Biochem. 2009, 24: 133-140. 10.1159/000233238.View ArticlePubMedGoogle Scholar
- Koka S, Bobbala D, Lang C, Boini KM, Huber SM, Lang F: Influence of paclitaxel on parasitemia and survival of Plasmodium berghei infected mice. Cell Physiol Biochem. 2009, 23: 191-198. 10.1159/000204107.View ArticlePubMedGoogle Scholar
- Lang PA, Kasinathan RS, Brand VB, Duranton C, Lang C, Koka S, Shumilina E, Kempe DS, Tanneur V, Akel A, Lang KS, Foller M, Kun JF, Kremsner PG, Wesselborg S, Laufer S, Clemen CS, Herr C, Noegel AA, Wieder T, Gulbins E, Lang F, Huber SM: Accelerated clearance of Plasmodium-infected erythrocytes in sickle cell trait and annexin-A7 deficiency. Cell Physiol Biochem. 2009, 24: 415-428. 10.1159/000257529.View ArticlePubMedGoogle Scholar
- Siraskar B, Ballal A, Bobbala D, Foller M, Lang F: Effect of amphotericin B on parasitemia and survival of Plasmodium berghei-infected mice. Cell Physiol Biochem. 2010, 26: 347-354. 10.1159/000320558.View ArticlePubMedGoogle Scholar
- Hebbel RP: Beyond hemoglobin polymerization: the red blood cell membrane and sickle disease pathophysiology. Blood. 1991, 77: 214-237.PubMedGoogle Scholar
- Wood BL, Gibson DF, Tait JF: Increased erythrocyte phosphatidylserine exposure in sickle cell disease: flow-cytometric measurement and clinical associations. Blood. 1996, 88: 1873-1880.PubMedGoogle Scholar
- Birka C, Lang PA, Kempe DS, Hoefling L, Tanneur V, Duranton C, Nammi S, Henke G, Myssina S, Krikov M, Huber SM, Wieder T, Lang F: Enhanced susceptibility to erythrocyte "apoptosis" following phosphate depletion. Pflugers Arch. 2004, 448: 471-477.View ArticlePubMedGoogle Scholar
- Lang PA, Beringer O, Nicolay JP, Amon O, Kempe DS, Hermle T, Attanasio P, Akel A, Schafer R, Friedrich B, Risler T, Baur M, Olbricht CJ, Zimmerhackl LB, Zipfel PF, Wieder T, Lang F: Suicidal death of erythrocytes in recurrent hemolytic uremic syndrome. J Mol Med. 2006, 84: 378-388. 10.1007/s00109-006-0058-0.View ArticlePubMedGoogle Scholar
- Kempe DS, Akel A, Lang PA, Hermle T, Biswas R, Muresanu J, Friedrich B, Dreischer P, Wolz C, Schumacher U, Peschel A, Gotz F, Doring G, Wieder T, Gulbins E, Lang F: Suicidal erythrocyte death in sepsis. J Mol Med. 2007, 85: 269-277.View ArticleGoogle Scholar
- Lang PA, Kaiser S, Myssina S, Birka C, Weinstock C, Northoff H, Wieder T, Lang F, Huber SM: Effect of Vibrio parahaemolyticus haemolysin on human erythrocytes. Cell Microbiol. 2004, 6: 391-400. 10.1111/j.1462-5822.2004.00369.x.View ArticlePubMedGoogle Scholar
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