Download or read book Characterization of Plasmodium falciparum membrane transporters as potential antimalarial targets written by Stéphanie Bosne and published by . This book was released on 2014 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: La découverte de nouveaux agents antipaludiques est primordiale. A travers le monde, les chercheurs se sont focalisés sur plusieurs stratégies. Les plus développées sont : soit les tests de molécules issues de bibliothèques chimiques dans une recherche phénotypique (comme le test direct d'agents sur des cultures de parasites in vitro), soit la recherche de nouvelles molécules agissant sur l'activité d'une cible ou d'une voie spécifique et essentielle. Cette thèse est centrée sur le second type d'approche. Nous nous sommes intéressés aux transporteurs membranaires de P. falciparum. Pour cela, nous exprimons les protéines d'intérêt dans la levure et nous les purifions. Nous optimisons les tests fonctionnels, dans le but de : a) déterminer l'effet des molécules sur les cibles spécifiques ; b) tester leur effet sur les cultures d'érythrocytes infectés par P. falciparum in vitro ; c) vérifier leur toxicité sur des cellules de mammifères ; et d) réaliser le test des molécules les plus efficaces in vivo dans un modèle de paludisme murin. Notre travail actuel est focalisé sur l'ATPase6 de P. falciparum (PfATP6) et l'adénylate translocase (PfAdT), deux protéines membranaires essentielles localisées respectivement sur le réticulum endoplasmique et la membrane mitochondriale. Nous exprimons de manière hétérologue PfATP6 dans les membranes de levure, nous purifions la protéine et mesurons une activité ATPase spécifique. Nous avons ainsi pu tester une bibliothèque chimique importante et identifier des inhibiteurs spécifiques. Ces derniers ont ensuite été testés pour évaluer leur effet sur les stades érythrocytaires du parasite in vitro et leur cytotoxicité sur des cellules de mammifères. Pour le transporteur PfAdT, nous procédons comme pour PfATP6, mais nous avons choisi un autre type de test fonctionnel dans lequel la protéine est directement exprimée sur la membrane plasmique d'E. coli. Cela devrait permettre de mesurer le transport d'ATP radiomarqué, et l'identification d'inhibiteurs spécifiques dont les effets pourront être évalués sur des cultures de parasites in vitro et dans des essais de cytotoxicité.

Download or read book Characterization of Plasmodium Falciparum Choline Transporters written by and published by . This book was released on 2005 with total page 54 pages. Available in PDF, EPUB and Kindle. Book excerpt: Plasmodium falciparum is the causative agent of severe human malaria. The rapid multiplication of the parasite within human red blood cells requires an active synthesis of new membranes. Choline analogs are potent antimalarial drugs. Although Choline transport has been suggested to be the target of these compounds, their exact mode of action is unknown. We identified two genes PfGAT and PfCTL1 as potential targets of these compounds. Here we report evidence that PfGAT encodes a Glycerol-3-phosphate acyltransferase enzyme responsible for the initial step of synthesis of P. falciparum membranes. Genetic data suggest that this pathway is essential for parasite survival and is a good target for development of new antimalarial drugs. We have also initiated a thorough genetic and biochemical characterization of PfCTL. Our data suggest that membrane proteins of the CTL family are not choline transporters. We generated transgenic parasites lacking PfCTL1, and showed that PfCTL is not essential for parasite intraerythrocytic development and survival. Finally we provide biochemical and genetic data suggesting that choline analogs act by specifically inhibiting phospholipid me%tabolism and the ability of the parasite to generate new membranes.

Download or read book Characterization of Plasmodium Falciparum Resistance to Novel Drugs written by Sonia Edayé and published by . This book was released on 2015 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: "Plasmodium falciparum is the deadly protozoan parasite responsible for malaria. Malaria is one of the most important infectious diseases that has been raging for millennia and affecting almost half of the world's population. The treatment regimen that was based on quinoline drugs such as chloroquine (CQ), was efficient for decades. Nowadays, the use of this class of drugs is doomed to failure due to the emergence of quinoline-resistant parasites. Today, artemisinin-based combination therapies (ACTs) are the first-line drugs for uncomplicated falciparum malaria treatment. ACTs improve the cure rate of malaria and thus are seen as efficient treatment against uncomplicated forms of the disease. Despite their efficiency, these drugs are currently facing the development of resistance. PfCRT and PfMDR1, which are membrane transporters, have been shown to be involved in malaria parasites drug resistance. To tackle the inefficiency of existing drugs in regard to the development of resistance, alternative therapies must be discovered. In this thesis, antimalarial activity of novel potential drugs against P. falciparum is assessed and the interaction of these drugs with PfCRT and PfMDR1 is determined. Furthermore, because many ABC transporter genes play a key role in drug resistance, the characterization of an ABC transporter member of the ABCG family in Plasmodium is addressed and its role in drug resistance investigated.In the first part of this thesis, MK571 (a quinoline analogue) activity against P. falciparum parasites is investigated. MK571 is found to be more toxic to most of the CQ-resistant strains than to the CQ-sensitive strains. In addition, we determine that MK571 is not a substrate of PfCRT as are other quinoline drugs, but is instead a substrate of PfMDR1. Therefore, it can be a good complement to existing quinoline drugs in the treatment of uncomplicated malaria. In the second part, novel compound analogues of chloroquine are tested for their antimalarial activity against CQ-sensitive and -resistant parasites. Although chloroquine analogues tested possess the quinoline ring structure of chloroquine, they are less efficient than chloroquine and are not substrates of PfCRT. One of the analogues (3-ICQ) reverses the resistance of CQ-resistant strains to chloroquine and therefore, could be used in combination with chloroquine in cases of CQ-resistant malaria. In the third part of the thesis we conduct the characterization of PfABCG, the sole member of the P. falciparum ABCG family. The characterization study demonstrates that PfABCG is localized on the parasite plasma membrane and is expressed throughout the asexual life cycle of the parasite. In addition, PfABCG is differentially expressed in various Plasmodium strains. This expression does not correlate with the resistance to chloroquine but to the sensitivity of the parasite to an antihistaminic drug named ketotifen. Overall, this thesis sheds light on challenges and understanding of the complex resistance machinery deployed by the P. falciparum parasite from novel drug discovery to characterization of proteins. " --

Download or read book Malaria written by Institute of Medicine and published by National Academies Press. This book was released on 1991-02-01 with total page 312 pages. Available in PDF, EPUB and Kindle. Book excerpt: Malaria is making a dramatic comeback in the world. The disease is the foremost health challenge in Africa south of the Sahara, and people traveling to malarious areas are at increased risk of malaria-related sickness and death. This book examines the prospects for bringing malaria under control, with specific recommendations for U.S. policy, directions for research and program funding, and appropriate roles for federal and international agencies and the medical and public health communities. The volume reports on the current status of malaria research, prevention, and control efforts worldwide. The authors present study results and commentary on the: Nature, clinical manifestations, diagnosis, and epidemiology of malaria. Biology of the malaria parasite and its vector. Prospects for developing malaria vaccines and improved treatments. Economic, social, and behavioral factors in malaria control.

Download or read book Heterologous Expression and Functional Characterization of Plasmodium Falciparum ABCG in Mammalian Cells written by Khlood Ali AlSulami and published by . This book was released on 2017 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: "Malaria affects more than a quarter of this planet's population with 214 million infections and 438,000 deaths annually. In the absence of an effective malaria vaccine, the rise and spread of drug resistant strains coupled with the slow development of new antimalarials is a potential human tragedy. Research to date has led to the identification of several proteins that can mediate parasite resistance to most antimalarials. Two of the latter proteins (e.g., PfMDR1 and PfMRP1) are members of a large and evolutionary conserved family of ATP-dependent membrane transporters (e.g., ABC transporters). The P. falciparum genome encodes 16 different ABC transporters, including one member of the ABCG subfamily (e.g., PfABCG). By contrast, the human genome encodes 48 members of the ABC transporters, including five members of the ABCG subfamily (huABCG1, G2, G4, G5 and G8). With the exception of huABCG2, which transports many anti-cancer drugs and some normal cell metabolites, huABCG1, G4, G5 and G8 mediate the transport of cholesterol and other sterols. Earlier studies using PfABCG-knockout clones of P. falciparum have suggested that PfABCG may play a role in the parasite's sensitivity to ketotifen (an anti-histamine drug), and in the accumulation of neutral lipids in PfABCG-knockout clones. Moreover, we have shown that PfABCG shares 24.3 % and 26.5 % amino acid sequence identity with huABCG1 and huABCG2, respectively. Hence, it is presently not clear if PfABCG is functionally more like huABCG1, huABCG2, or both. In an effort to characterize the functions of PfABCG, it was of interest to compare its substrate specificity and subcellular localization to that of huABCG1 and G2 in the same expression system, using mammalian HEK-293 cells. Our results show the stable expression of PfABCG in HEK-293, as a fusion protein with GFP sequence linked to PfABCG N-terminal. In addition, relying on the fluorescence of GFP in PfABCG-HEK-293 transfectants, we have demonstrated the localization of GFP-PfABCG to the endosomal membranes, likely the endoplasmic reticulum. We also show that HEK-293 cells stably transfected with GFP-PfABCG are more sensitive to ketotifen in the presence of reseripine, a calcium channel blocker and an inhibitor of huABCB1 and huABCG2 expressed at low levels in HEK-293 cells. Efforts are on going to further characterize the functions of PfABCG and its substrate specificity and how these functions relate to those of huABCG1 and G2." --

Download or read book The Blood brain Barrier written by William M. Pardridge and published by Lippincott Williams & Wilkins. This book was released on 1993 with total page 504 pages. Available in PDF, EPUB and Kindle. Book excerpt: The characterization of the blood-brain barrier (BBB) is undergoing a paradigm shift as the century-old concept of a passive, impermeable barrier that segregates blood and brain interstitial fluid is giving way to the idea that the BBB is a dynamic conduit for the transport between blood and brain of those nutrients, peptides, proteins, or immune cells that have access to certain transport systems localized within the BBB membranes. This volume contains 20 contributed chapters organized in four parts: cell-cell interactions, subcellular organelle function, signal transduction mechanisms, and gene expression. There is also a foreword by the late W.H. Oldendorf (1925-1992) on the teleology of the blood-brain barrier and the survival advantage conferred upon the organism by its presence in the vertebrate brain. Annotation copyright by Book News, Inc., Portland, OR

Download or read book Rodent Malaria written by R. Killick-Kendrick and published by Elsevier. This book was released on 2012-12-02 with total page 435 pages. Available in PDF, EPUB and Kindle. Book excerpt: Rodent Malaria reviews significant findings concerning malaria parasites of rodents, including their taxonomy, zoogeography, and evolution, along with life cycles and morphology; genetics and biochemistry; and concomitant infections. This volume is organized into eight chapters and begins by sketching out the history of the discovery of rodent as well as aspects of parasitology, immunology, and chemotherapy. These concepts are investigated two decades following Ignace Vincke's major discovery and Meir Yoeli's successful establishment of the method of cyclical transmission of the parasite. The following chapters focus on the taxonomy and systematics of the subgenus Vinckeia, with reference to the concepts of species and subspecies of animals and the degree to which they apply to malaria parasites, in particular to those of rodents. The discussion then shifts to how the rodent malaria parasites provide a unique insight into the subcellular organization of Plasmodium species, the use of rodent malaria as an experimental model to study immunological responses, and infectious agents that interact with malaria parasites. The book concludes with a chapter on malaria chemotherapy, with emphasis on the value of rodent malaria in antimalarial drug screening and the use of antimalarial drugs as biological probes. This book will be of interest to protozoologists and physicians as well as those from other disciplines including biochemistry, immunology, pharmacology, cell biology, and genetics.

Download or read book Encyclopedia of Malaria written by and published by Springer. This book was released on 2018-07-12 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: The Encyclopedia of Malaria represents a vast databank of information about the study of malaria. It provides an overview of the historical, rapid and significant developments that have occurred in malaria research, including the 2002 genome sequencing of Plasmodium falciparum and its mosquito vector, Anopheles gambiae. This work provides a concise source of up-to-date research findings in the form of definitions and essays and present comprehensive coverage of topics from history to findings to diagnosis and treatment, written by recognized malaria researchers with practical experience. It appeals to a diverse audience, including malaria researchers, teachers, investigators and public health professionals.

Download or read book World Malaria Report 2014 written by World Health Organization and published by World Health Organization. This book was released on 2015-07-07 with total page 241 pages. Available in PDF, EPUB and Kindle. Book excerpt: The World malaria report 2014 summarizes information received from 97 malaria endemic countries and other sources and updates the analyses presented in 2013. It assesses global and regional malaria trends highlights progress made towards global targets and describes opportunities and challenges in controlling and eliminating the disease. Most of the data presented in this report are for 2013.

Download or read book Saving Lives Buying Time written by Institute of Medicine and published by National Academies Press. This book was released on 2004-09-09 with total page 384 pages. Available in PDF, EPUB and Kindle. Book excerpt: For more than 50 years, low-cost antimalarial drugs silently saved millions of lives and cured billions of debilitating infections. Today, however, these drugs no longer work against the deadliest form of malaria that exists throughout the world. Malaria deaths in sub-Saharan Africaâ€"currently just over one million per yearâ€"are rising because of increased resistance to the old, inexpensive drugs. Although effective new drugs called "artemisinins" are available, they are unaffordable for the majority of the affected population, even at a cost of one dollar per course. Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance examines the history of malaria treatments, provides an overview of the current drug crisis, and offers recommendations on maximizing access to and effectiveness of antimalarial drugs. The book finds that most people in endemic countries will not have access to currently effective combination treatments, which should include an artemisinin, without financing from the global community. Without funding for effective treatment, malaria mortality could double over the next 10 to 20 years and transmission will intensify.

Download or read book An Overview of Tropical Diseases written by Amidou Samie and published by BoD – Books on Demand. This book was released on 2015-12-02 with total page 214 pages. Available in PDF, EPUB and Kindle. Book excerpt: Tropical diseases affect millions of people throughout the world and particularly in the developing countries. The millennium development goals had specifically targeted HIV/AIDS and Malaria for substantial reduction as well as Tuberculosis while many other tropical diseases have been neglected. The new sustainable development goals have not made such distinction and have targeted all diseases for elimination for the improvement of the quality of life of human beings on earth. The present book was developed to provide an update on issues relevant to the treatment of selected tropical diseases such as tuberculosis, malaria, leishmaniasis, schistosomiasis and ectoparasites such as chiggers which are widely distributed throughout the world. The control of these infections has been hampered by the development of drug resistance and the lack of the development of new and more effective drugs. The understanding of the biochemical processes underlying drug activity is therefore essential for the potential elimination of these infections.

Download or read book World Malaria Report 2019 written by World Health Organization and published by . This book was released on 2019-08-28 with total page 224 pages. Available in PDF, EPUB and Kindle. Book excerpt: The World Malaria Report 2019 provides a comprehensive update on global and regional malaria data and trends. The report tracks investments in malaria programs and research as well as progress across all intervention areas: prevention, diagnosis, treatment, elimination, and surveillance. It also includes dedicated chapters on the consequences of malaria on maternal infant and child health the "High Burden to High Impact" approach as well as biological threats to the fight against malaria. The 2019 report is based on information received from more than 80 countries and areas with ongoing malaria transmission. This information is supplemented by data from national household surveys and databases held by other organizations.

Download or read book Assessment of Long Term Health Effects of Antimalarial Drugs When Used for Prophylaxis written by National Academies of Sciences, Engineering, and Medicine and published by National Academies Press. This book was released on 2020-04-24 with total page 427 pages. Available in PDF, EPUB and Kindle. Book excerpt: Among the many who serve in the United States Armed Forces and who are deployed to distant locations around the world, myriad health threats are encountered. In addition to those associated with the disruption of their home life and potential for combat, they may face distinctive disease threats that are specific to the locations to which they are deployed. U.S. forces have been deployed many times over the years to areas in which malaria is endemic, including in parts of Afghanistan and Iraq. Department of Defense (DoD) policy requires that antimalarial drugs be issued and regimens adhered to for deployments to malaria-endemic areas. Policies directing which should be used as first and as second-line agents have evolved over time based on new data regarding adverse events or precautions for specific underlying health conditions, areas of deployment, and other operational factors At the request of the Veterans Administration, Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis assesses the scientific evidence regarding the potential for long-term health effects resulting from the use of antimalarial drugs that were approved by FDA or used by U.S. service members for malaria prophylaxis, with a focus on mefloquine, tafenoquine, and other antimalarial drugs that have been used by DoD in the past 25 years. This report offers conclusions based on available evidence regarding associations of persistent or latent adverse events.

Download or read book Natural Remedies in the Fight Against Parasites written by Hanem Khater and published by BoD – Books on Demand. This book was released on 2017-07-12 with total page 250 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book emphasizes past and current research efforts about principles of natural control of major parasites affecting humans, animals, and crops. Each chapter is a complete and integrated subject that presents a problem and confers on the safe alternatives to chemicals. This book discusses and updates information about three major topics of natural remedies. The first topic is represented in a chapter outlining important information on biological control of parasites, the second topic is represented in three chapters dealing with botanicals as promising antiparasitic agents, and the last four chapters deal with miscellaneous control strategies against parasites. This easily readable book is designed precisely for students as well as professors linked with the field of parasitic control. We enhanced words with breathing areas in the form of graphical abstracts, figures, photographs, and tables.

Download or read book The Malaria Genome Projects written by Irwin W. Sherman and published by World Scientific. This book was released on 2012 with total page 389 pages. Available in PDF, EPUB and Kindle. Book excerpt: The year 2012 marks the tenth anniversary of the announcement of the genome sequence of the human malaria parasite Plasmodium falciparum and that of its mosquito vector Anopheles. The genome sequences were a result of the Plasmodium falciparum Genome Project. This book covers in detail the biology of malaria parasites and the mosquitoes that transmit the disease, how the Genome Project came into being, the people who created it, and the cadre of scientists who are attempting to see the promise of the Project realized. The promise was: a more complete understanding of the genes of the parasite (and its vector) would provide a rational basis for the development of antimalarial drugs and vaccines, allow a better understanding of the regulation of the complex life cycle in the red blood and liver cells of the human, identify the genes the parasite uses to thwart the host immune response and the ways in which the parasite evades cure by drug treatments, as well as leading to more effective measures of control transmission. The hope was that cracking the genetic code of Plasmodium and Anopheles would reveal the biochemical Achilles heel of the parasite and its vector, leading to the development of novel drugs and better methods of control, and by finding the targets of protective immunity could result in the manufacture of effective vaccines. Through a historic approach, this book will allow for those new to the field, or those with insufficient background in the sciences, to have an easier entry point. Even scientists already working in the field may better appreciate how discoveries made in the past can impact the direction of future research.

Download or read book Handbook of Antimicrobial Resistance written by Matthias Gotte and published by Springer. This book was released on 2018-02-12 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: While many volumes have been written about various aspects of antimicrobial resistance, this book is a comprehensive reference work. All manifestations of resistance are addressed: viral; bacterial, parasitical and fungal are given dedicated sections. The underlining molecular mechanisms, which depend not only on the microbe but on the specific drug (target), are highly diverse. This work discusses and compares the biological, biochemical and structural aspects of resistance and its evolution.

Download or read book Guidelines for the Treatment of Malaria Third Edition written by World Health Organization and published by World Health Organization. This book was released on 2015-08-13 with total page 317 pages. Available in PDF, EPUB and Kindle. Book excerpt: Malaria remains an important cause of illness and death in children and adults in countries in which it is endemic. Malaria control requires an integrated approach including prevention (primarily vector control) and prompt treatment with effective antimalarial agents. Malaria case management consisting of prompt diagnosis and effective treatment remains a vital component of malaria control and elimination strategies. Since the publication of the first edition of the Guidelines for the treatment of malaria in 2006 and the second edition in 2010 all countries in which P. falciparum malaria is endemic have progressively updated their treatment policy from use of ineffective monotherapy to the currently recommended artemisinin-based combination therapies (ACT). This has contributed substantially to current reductions in global morbidity and mortality from malaria. Unfortunately resistance to artemisinins has arisen recently in P. falciparum in South-East Asia which threatens these gains. This third edition of the WHO Guidelines for the treatment of malaria contains updated recommendations based on a firmer evidence base for most antimalarial drugs and in addition include recommendation on the use of drugs to prevent malaria in groups at high risk. The Guidelines provide a framework for designing specific detailed national treatment protocols taking into account local patterns of resistance to antimalarial drugs and health service capacity. It provides recommendations on treatment of uncomplicated and severe malaria in all age groups all endemic areas in special populations and several complex situations. In addition on the use of antimalarial drugs as preventive therapy in healthy people living in malaria-endemic areas who are high risk in order to reduce morbidity and mortality from malaria. The Guidelines are designed primarily for policy-makers in ministries of health who formulate country-specific treatment guidelines. Other groups that may find them useful include health professionals and public health and policy specialists that are partners in health or malaria control and the pharmaceutical industry. The treatment recommendations in the main document are brief; for those who wish to study the evidence base in more detail a series of annexes is provided with references to the appropriate sections of the main document.