A world free of malaria: It is time for Africa to actively champion and take leadership of elimination and eradication strategies

The global burden of malaria seems unabated. Africa carries the greatest burden accounting for over 95% of the annual cases of malaria. For the vision of a world free of malaria by Global Technical Strategy to be achieved, Africa must take up the stakeholder’s role. It is therefore imperative that Africa rises up to the challenge of malaria and champion the fight against it. The fight against malaria may just be a futile or mere academic venture if Africans are not directly and fully involved. This work reviews the roles playable by Africans in order to curb the malaria in Africa and the world at large

Cucumeropsis mannii seed oil ameliorates Bisphenol‐A‐induced adipokines dysfunctions and dyslipidemia

From Wiley via Jisc Publications RouterHistory: received 2022-12-25, rev-recd 2023-01-07, accepted 2023-02-06, pub-electronic 2023-02-18Article version: VoRPublication status: PublishedThis study demonstrated the therapeutic potentials of Cucumeropsis mannii seed oil (CMSO) capable of alleviating BPA‐induced dyslipidemia and adipokine dysfunction. In this study, we evaluated the effects of CMSO on adipokine dysfunctions and dyslipidemia in bisphenol‐A (BPA)‐induced male Wistar rats. Six‐week‐old 36 albino rats of 100–200 g weight were assigned randomly to six groups, which received varied doses of BPA and/or CMSO. The administration of BPA and CMSO was done at the same time for 42 days by oral intubation. The adipokine levels and lipid profile were measured in adipose tissue and plasma using standard methods. BPA induced significant (p < .05) increases in triglycerides, cholesterol, leptin, LDL‐C, and atherogenic and coronary risk indices in adipose tissue and plasma, as well as a decrease in adiponectin and HDL‐C levels in Group II animals. BPA administration significantly (p < .05) elevated Leptin levels and reduced adiponectin levels. BPA plus CMSO reduced triglycerides, cholesterol, leptin, LDL‐C, and atherogenic and coronary risk indices while increasing adiponectin levels and HDL‐C in adipose tissue and plasma (p < .05). The results showed that BPA exposure increased adipose tissue as well as serum levels of the atherogenic index, triglycerides, cholesterol, coronary risk index, LDL‐C, leptin, and body weight with decreased adiponectin levels and HDL‐C. Treatment with CMSO reduced the toxicities caused by BPA in rats by modulating the body weight, adiponectin/leptin levels, and lipid profiles in serum and adipose tissue. This study has shown that CMSO ameliorates BPA‐induced dyslipidemia and adipokine dysfunctions. We suggest for further clinical trial to establish the clinical applications

Implications of redox mechanisms in the mode of action of antimalarials and resistance to artemisinin

Le paludisme est une maladie à transmission vectorielle causée par Plasmodium transmis par les moustiques femelles du genre Anopheles. En dépit des nombreux efforts déployés, le paludisme reste un problème majeur de santé publique avec plus de 400 000 décès chaque année. Le développement des antipaludiques fait face à l’émergence quasi-systématique de parasites résistants. La résistance aux médicaments actuels de référence, l'artémisinine et ses dérivés, a été signalée pour la première fois au Cambodge en 2008 et s'est depuis étendue à toute l’Asie. Des premiers cas de résistance ont également été rapportés récemment en Amérique du Sud et en Afrique. Il est donc urgent de proposer de nouvelles stratégies thérapeutiques pertinentes. Notre travail s’est concentré sur l’étude, chez Plasmodium falciparum, de l’implications de mécanismes redox dans i) le mode d’action de différentes molécules antipaludiques et ii) dans le phénomène de résistance associé à l’artémisinine. Pour cela, nous avons tout d’abord développé une nouvelle méthode d’analyse de la quantification des espèces réactives de l’oxygène (ROS) intra-érythrocytaire par chromatographie liquide couplée à la spectrométrie de masse (LC-MS). Ce protocole a ainsi permis de mettre en évidence l'implication des radicaux superoxydes dans le mécanisme d'action de différentes classes d'antipaludiques telles que les artémisinines ou l’atovaquone. Dans un second temps, nous avons étudié chez Plasmodium falciparum, le rôle du processus redox dans la résistance aux artémisinines en comparant une souche sensible et une souche résistante à l’artémisinine, à l’état basal et après traitement. Différents marqueurs de la régulation redox ont été suivis et comparés tels que la production de ROS, le niveau d’oxydation des protéines et l'expression de molécules ou d’enzymes aux propriétés antioxydantes. Nous avons démontré, grâce à différentes techniques analytiques originales, que les parasites résistants aux artémisinines ont une capacité accrue à gérer la production de ROS induite par le traitement, comparativement aux parasites sensibles et que ce phénomène est notamment lié à une surexpression d'antioxydants. Ce travail apporte des éléments nouveaux concernant le mécanisme d'action d’antipaludiques majeurs et met en évidence le rôle essentiel des mécanismes redox dans la résistance de Plasmodium falciparum à l'artémisinine. Ces résultats seront à prendre en compte dans le développement de nouveaux antipaludiques afin de contourner la résistance aux artémisinines et vaincre le paludisme.Malaria is a vector-borne disease caused by Plasmodium and transmitted by female Anopheles mosquitoes. Despite numerous efforts, malaria remains a major public health problem with more than 400,000 deaths each year. The development of antimalarial drugs is faced with the almost systematic emergence of resistant parasites. Resistance to the current gold standard drug, artemisinin, was first reported in Cambodia in 2008 and has since spread throughout Asia. First cases of resistance have also been reported recently in South America and Africa. There is therefore an urgent need to propose new relevant therapeutic strategies. Our work focused on the study, in Plasmodium falciparum, of the implications of redox mechanisms i) in the mode of action of different antimalarials and ii) in the resistance phenomenon associated with artemisinin. For this, we first developed a new analytical method based on liquid chromatography coupled to mass spectrometry (LC-MS), adapted to the quantification of reactive oxygen species (ROS) in erythrocytes. This protocol thus made it possible to demonstrate the involvement of superoxide radical anions in the mechanism of action of different classes of antimalarial drugs such as artemisinins and atovaquone. In the second segment, we studied the role of redox processes in artemisinin resistance in Plasmodium falciparum, by comparing an artemisinin-sensitive and an artemisinin-resistant strain at the steady state and after artemisinin treatment. Different markers of redox regulation such as ROS production, protein oxidation level and expression of antioxidant molecules or enzyme were compared. We demonstrated, using different original analytical methods, that artemisinin-resistant parasites managed ROS production from artemisinin treatment better than sensitive parasites and that this phenomenon was notably linked to an overexpression of antioxidants. This work brings new perspectives concerning the mechanism of action of major antimalarial drugs and highlights the essential role of redox mechanisms in the resistance of Plasmodium falciparum to artemisinin. These results will be taken into account in the development of new antimalarial drugs in order to bypass artemisinin resistance and win the war against malaria

Reactive Oxygen Species as the Brainbox in Malaria Treatment

Several measures are in place to combat the worldwide spread of malaria, especially in regions of high endemicity. In part, most common antimalarials, such as quinolines and artemisinin and its derivatives, deploy an ROS-mediated approach to kill malaria parasites. Although some antimalarials may share similar targets and mechanisms of action, varying levels of reactive oxygen species (ROS) generation may account for their varying pharmacological activities. Regardless of the numerous approaches employed currently and in development to treat malaria, concerningly, there has been increasing development of resistance by Plasmodium falciparum, which can be connected to the ability of the parasites to manage the oxidative stress from ROS produced under steady or treatment states. ROS generation has remained the mainstay in enforcing the antiparasitic activity of most conventional antimalarials. However, a combination of conventional drugs with ROS-generating ability and newer drugs that exploit vital metabolic pathways, such antioxidant machinery, could be the way forward in effective malaria control

Reactive Oxygen Species as the Brainbox in Malaria Treatment

International audienceSeveral measures are in place to combat the worldwide spread of malaria, especially in regions of high endemicity. In part, most common antimalarials, such as quinolines and artemisinin and its derivatives, deploy an ROS-mediated approach to kill malaria parasites. Although some antimalarials may share similar targets and mechanisms of action, varying levels of reactive oxygen species (ROS) generation may account for their varying pharmacological activities. Regardless of the numerous approaches employed currently and in development to treat malaria, concerningly, there has been increasing development of resistance by Plasmodium falciparum, which can be connected to the ability of the parasites to manage the oxidative stress from ROS produced under steady or treatment states. ROS generation has remained the mainstay in enforcing the antiparasitic activity of most conventional antimalarials. However, a combination of conventional drugs with ROS-generating ability and newer drugs that exploit vital metabolic pathways, such antioxidant machinery, could be the way forward in effective malaria control

An LC–MS Assay to Measure Superoxide Radicals and Hydrogen Peroxide in the Blood System

International audienceRed blood cells are constantly exposed to reactive species under physiological or pathological conditions or during administration of xenobiotics. Regardless of the source, its accurate quantification is paramount in the area of theragnostics, which had been elusive up until now. Even if there are a lot of approaches to evaluate the oxidative stress, very sensitive methods are missing for the blood system. We therefore sought to apply a highly sensitive approach, by liquid chromatography coupled to mass spectrometry (UPLC&ndash;MS), for the quantification of reactive species such as superoxide radical and hydrogen peroxide using dihydroethidium (DHE) and coumarin boronic acid (CBA) probes respectively through the detection of 2-hydroxyethidium (2OH-E+) and 7-hydroxycoumarin (COH). The use of the high-resolution mass spectrometry associated to UPLC ensured a selective detection of superoxide and hydrogen peroxide in the blood system under diverse conditions such as oxidized red blood cells (RBCs), untreated and treated parasitized RBCs. Moreover, this technique allowed the determination of reactive species in human plasma. This protocol provides a huge opportunity for in-depth study of several pathological conditions vis-a-vis their treatment in modern medicine

Resistance to artemisinin in falciparum malaria parasites: A redox-mediated phenomenon

International audienceMalaria remains a major public health disease due to its high yearly mortality and morbidity. Resistance to the gold standard drug, artemisinin, is worrisome and needs better understanding in order to be overcome. In this work, we sought to study whether redox processes are involved in artemisinin resistance. As artemisinin is known to act among others via production of reactive species, we first compared the production of reactive oxygen species and concomitant protein oxidation in artemisinin-sensitive and artemisinin-resistant parasites when treated with artemisinin. The results undoubtedly demonstrated, using different original methods, that the level of ROS, including superoxide production, and oxidized protein were lower in the resistant strain. Interestingly, the major in-between strain difference was reported at the earlier ring stages, which are the forms able to enter in a quiescence state according to the ART resistance phenomenon. Moreover, we demonstrated a better homeostasis regulation in relation with higher expression of antioxidants in the artemisinin-resistant parasites than their sensitive counterparts after artemisinin exposure, notably, superoxide dismutase and the glutathione (GSH) system. These findings enrich the body of knowledges about the multifaceted mechanism of artemisinin resistance and will help in the design and development of newer antimalarials strategies active against resistant parasites

Superoxide: A major role in the mechanism of action of essential antimalarial drugs

International audienceUnderstanding the mode of action of antimalarials is central to optimizing their use and the discovery of new therapeutics. Currently used antimalarials belong to a limited series of chemical structures and their mechanisms of action are coutinuously debated. Whereas the involvement of reactive species that in turn kill the parasites sensitive to oxidative stress, is accepted for artemisinins, little is known about the generation of such species in the case of quinolines or hydroxynaphtoquinone. Moreover, the nature of the reactive species involved has never been characterized in Plasmodium-infected erythrocytes. The aim of this work was to determine and elucidate the production of the primary radical, superoxide in Plasmodium-infected erythrocytes treated with artemisinin, dihydroartemisinin, chloroquine and atovaquone, as representatives of three major classes of antimalarials. The intracellular generation of superoxide was quantified by liquid chromatography coupled to mass spectrometry (LC-MS). We demonstrated that artemisinins, atovaquone and to a lesser extent chloroquine, generate significant levels of superoxide radicals in Plasmodium falciparum sensitive strains. More so, the production of superoxide was lowered in chloroquine-resistant strain of Plasmodium treated with chloroquine. These results consolidate the knowledge about the mechanism of action of these different antimalarials and should be taken into consideration in the design of future drugs to fight drug-resistant parasites

Impact of Drug Pressure versus Limited Access to Drug in Malaria Control: The Dilemma

Malaria burden has severe impact on the world. Several arsenals, including the use of antimalarials, are in place to curb the malaria burden. However, the application of these antimalarials has two extremes, limited access to drug and drug pressure, which may have similar impact on malaria control, leading to treatment failure through divergent mechanisms. Limited access to drugs ensures that patients do not get the right doses of the antimalarials in order to have an effective plasma concentration to kill the malaria parasites, which leads to treatment failure and overall reduction in malaria control via increased transmission rate. On the other hand, drug pressure can lead to the selection of drug resistance phenotypes in a subpopulation of the malaria parasites as they mutate in order to adapt. This also leads to a reduction in malaria control. Addressing these extremes in antimalarial application can be essential in maintaining the relevance of the conventional antimalarials in winning the war against malaria

In Vitro and In Silico Antimalarial Evaluation of FM-AZ, a New Artemisinin Derivative

International audienceArtemisinin-based Combination Therapies (ACTs) are currently the frontline treatment against Plasmodium falciparum malaria, but parasite resistance to artemisinin (ART) and its derivatives, core components of ACTs, is spreading in the Mekong countries. In this study, we report the synthesis of several novel artemisinin derivatives and evaluate their in vitro and in silico capacity to counteract Plasmodium falciparum artemisinin resistance. Furthermore, recognizing that the malaria parasite devotes considerable resources to minimizing the oxidative stress that it creates during its rapid consumption of hemoglobin and the release of heme, we sought to explore whether further augmentation of this oxidative toxicity might constitute an important addition to artemisinins. The present report demonstrates, in vitro, that FM-AZ, a newly synthesized artemisinin derivative, has a lower IC50 than artemisinin in P. falciparum and a rapid action in killing the parasites. The docking studies for important parasite protein targets, PfATP6 and PfHDP, complemented the in vitro results, explaining the superior IC50 values of FM-AZ in comparison with ART obtained for the ART-resistant strain. However, cross-resistance between FM-AZ and artemisinins was evidenced in vitro