| According to WHO 2017 World Malaria Report,it showed that the global malaria cases have reached 216 million,445,000 deaths from the diease.In recent years,malaria parasites became more and more resistant to antimalarial drugs.Moreover the surface antigen polymorphism and antigen variation in malaria parasite caused a slow progress on malaria vaccine research.Therefore,the novel strategies to reduce the malaria mortality,alleviate the serious complications,especially inhibite the occurrence of cerebral malaria are particularly important.Due to a lack of critical vitamin C transport proteins on the surface of mature red blood cells,it lead to an indirect uptake of vitamin C which is also known as ascorbic acid(AA).Erythrocytes absorb vitamin C through the glucose transporter(GLUT),dehydroascorbate(DHA)which was then reduced to vitamin C by NADPH in the cytoplasm.Recent studies demostrated that high-dose vitamin C could selectively kill the KRAS and BRAF mutated colorectal cancer cells.The glycolysis process of tumor cells is obviously enhanced which requires a large amount of glucose,theraby leads to high expression of GLUT1.In the presence of a large quantity of vitamin C,the cells ingested the DHA through GLUT1,and then consumed the intracellular reducing substances thereby activated the oxidative stress and induced the apoptosis.Similar to tumor cells,i RBCs relied completely on the absorption of glucose in the blood circulation for energy metabolism.At first glucose enters the erythrocyte cytoplasm through the GLUTs on the erythrocytic membrane,and then through the hexose transporter.Therefore,we speculated that high doses of vitamin C could enter the i RBC and cytoplasm through the GLUTs on erythrocyte surface and HT on plasmodium plasma membrane(PPM).By disturbing the homeostasis of intracellular redox environment,the oxidative stress pathway was activated to kill the parasites.We found that the mice infected with parasites intraperitoneal injected with vitamin C(4g/kg)showed a significant inhibition of Plasmodium growth.30 m M vitamin C for 3 hours could also effectively inhibit the growth of Plasmodium falciparum in vitro culture.We used carbon-14 labeled vitamin C to explore the pathway of vitamin C into the infected red blood cells(i RBCs)and parasites,comparing the uptake of vitamin C by i RBCs and normal red blood cells.We found that the ability of vitamin C uptake by i RBCs was significantly increased,and they were more prone to absorb the oxidized form,DHA.We further explored the pathway of vitamin C entry into the red blood cells,and found that the GLUTs inhibitor WZB117 could significantly reduce the uptake of vitamin C by the i RBCs.It proved that the oxidized form of vitamin C was uptaked by RBCs through the GLUTs family;Second,Compound 3361,a specific inhibitor of HT could effectively reduce the uptake of vitamin C which proved that vitamin C entered the cytoplasm through HT.We also found that when cells absorbed oxidized vitamin C,there would be a great deal of production of ROS which could lead to a decrease production in the GSH/GSSG ratio in cells.We also found that high doses of vitamin C could induce apoptosis in the erythrocytes but had little affection on normal RBCs.High doses of vitamin C could effectively alleviate enlargement of liver and spleen,and reduce the damage of liver and spleen.Intraperitoneal injection of high-dose vitamin C also significantly reduced the blood-brain barrier damage and the incidence of experimental cerebral malaria.This study illustrated that high-dose vitamin C could enter the i RBCs through the GLUTs and HT in the form of oxidative form,then activate oxidative stress reaction,consume GSH,block the production of ATP in glycolytic pathway,and at last induce apoptosis of Plasmodium.This study provided valuable understanding and therapy strategies for exploring glucose transport pathway,oxidative stress and apoptosis pathway in malaria parasites,and also for the treatment of malaria and the reduction of incidence of cerebral malaria. |
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