Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CD36 is a multiligand receptor associated with a broad array of physiological processes and involved in markedly diverse disorders, including atherosclerosis, insulin resistance and diabetes, dyslipidemia, tumor angiogenesis, and host defense against Plasmodium falciparum. CD36 deficiency has proved to be common, particularly in ethnic groups such as African Americans and Asians. CD36 is commonly expressed on blasts in acute monocytic leukemia, megakaryoblastic leukemia, and erythroleukemia. The role of CD36 in sickle cell crises and cerebral malaria is debatable. As a receptor for thrombospondin 1, CD36 plays a role in the regulation of angiogenesis, which may be a therapeutic strategy for controlling the dissemination of malignant neoplasms. The future challenge will be to further understand the mechanisms by which CD36 affects these diverse functions and to design therapeutic strategies that can alter the course of the diseases.
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PMID:CD36: a multiligand molecule. 1579 May 50

Our current studies focus on the molecular changes induced by aging. During aging, changes in proteins occur that alter their function and render them immunogenic. These "neoantigens" are recognized by physiologic autoantibodies. Physiologic autoantibodies and their corresponding antigens offer therapeutic strategies for disease intervention through the innate immune response. Early studies done in the 1970s showed humans and animals to have physiologic antibodies that bind to a neoantigen called senescent cell antigen (SCA), which appears on senescent and damaged cells and initiates their removal by macrophages. These studies led to the discovery that oxidation can generate a new antigen in situ. Oxidation accelerated aging of red cells, generated SCA and IgG binding, and triggered removal of red cells by macrophages. Since then, a number of laboratories have found that oxidation can generate other neoantigens. For example, oxidized LDL (OxLDL) induces antibodies that can modify the natural progression of atherosclerosis. Apoptotic cells express oxidatively modified moieties on their surfaces that are involved in macrophage recognition and phagocytosis. Physiologic autoantibodies were used to isolate SCA from brain tissue. HPLC and fast atom bombardment ionization mass spectrometry (FAB-MS) of the isolated antigen suggested that the aging antigen is a subset of band 3, a family of proteins also called anion exchange proteins (AE1-3). FAB-MS results indicate that residues matching all three band 3 isoforms (AE1, AE2, and AE3) are detected in aging antigen fractions. Among the fragments identified with FAB-MS was a sequence corresponding to an aging epitope, human band 3 sequence LFKPPKYHPDVPYVKR, residue 812-830 in AE1; HHPDVTYVK, residue 1144-1152 in AE2; or HHPEQPYVTK, residue 1135-1144 in AE3. A residue that is close to that region was identified in mouse AE1 ASGPGAAAQIQEVK, residue 762-775. The potential for altering the natural progression of diseases using select peptide-defined epitopes within or overlapping the aging antigenic site (547-553 and 824-829) is discussed using the innate immune response to band 3 in malaria as an example.
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PMID:Immunoregulation of cellular life span. 1639 89

Cholesterol is important for cell membrane structure and functions as well as for production of steroid hormones and bile acids. It is transported through the body as lipoprotein particles of varying density and composition. Cholesterol homeostasis is maintained through finely tuned mechanisms regulating dietary uptake, hepatic biosynthesis and secretion as well as plasma clearance. Proprotein convertase subtilisin/kexin type 9 (PCSK9) reduces cellular uptake of plasma low-density lipoprotein-cholesterol (LDL-C) by promoting LDL receptor (LDLR) degradation. Two nonsense single-nucleotide polymorphisms (SNPs) at the PCSK9 locus have been associated with life-long hypocholesterolemia and a remarkable reduction of the risk for coronary heart disease (CHD) in African-Americans. These loss-of-function SNPs presumably render PCSK9 less capable of inducing LDLR catabolism, effectively increasing LDLR availability and allowing efficient removal of plasma LDL-C. The combined frequency of heterozygosity for these nonsense SNPs is approximately 3-4% in populations of African descent. Homozygosity for either SNP, which would aggravate hypocholesterolemia, is reportedly rare. Whether such an aggravation would represent a health risk is still a matter of debate. From an evolutionary point of view, the cardioprotective effect of these nonsense SNPs may be a secondary phenotype made evident by the dyslipidemia-inducing lifestyle of today's North America. Their relatively high frequency in African-Americans must be interpreted in the context of the ancestral environment of these subjects in Africa, where diet and lifestyle were presumably less predisposing to atherosclerosis and where parasitic infections were major causes of morbidity and mortality before reproductive age. Parasites feed on host cholesterol for successful infection. The nonsense PCSK9 SNPs may have been positively selected because they reduced susceptibility to severe parasitic infections through cholesterol restriction. If so, these SNPs should be significantly more frequent in Sub-Saharan Africa where parasitic diseases, malaria in particular, have been and still are major selective forces.
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PMID:Of PCSK9, cholesterol homeostasis and parasitic infections: possible survival benefits of loss-of-function PCSK9 genetic polymorphisms. 1750 26

CD36 is a transmembrane glycoprotein of the class B scavenger receptor family. The CD36 gene is located on chromosome 7 q11.2 and is encoded by 15 exons. Defective CD36 is a likely candidate gene for impaired fatty acid metabolism, glucose intolerance, atherosclerosis, arterial hypertension, diabetes, cardiomyopathy, Alzheimer disease, and modification of the clinical course of malaria. Contradictory data concerning the effects of antiatherosclerotic drugs on CD36 expression indicate that further investigation of the role of CD36 in the development of atherosclerosis may be important for the prevention and treatment of this disease. This review summarizes current knowledge of CD36 gene structure, splicing, and mutations and the molecular, metabolic, and clinical consequences of these phenomena.
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PMID:Molecular basis of human CD36 gene mutations. 1767 38

The field of vaccines and vaccinology has seen remarkable progress during the past 20 years. Many vaccines, however, still need to be improved, either because the protection they provide is relatively short-lived and would greatly benefit from the development of booster formulations (as is the case for tuberculosis), or because they only cover part of the many serotypes of the pathogen that causes the disease (rotaviruses, papillomaviruses, or Streptococcus pneumoniae). In addition, still many diseases lack a proper preventive vaccine, such as AIDS, hepatitis C, malaria, viral pneumonias, croup and bronchiolitis, dengue fever, leishmaniasis, Staphylococcus aureus, groups A and B Streptococcus, Shigellas and enterotoxigenic Escherichia coli, to only name a few. These are the current targets of vaccines under development, a great many of which will hopefully reach the market within the coming 10 years. The development of preventive vaccines against chronic diseases such as AIDS and hepatitis C will probably require more time, due to basic science complexities to be overcome first. It is likely that the future will also see an emphasis on therapeutic vaccines targeted against noninfectious diseases such as cancers (lung, skin, prostate, etc) and metabolic or neurologic diseases (atherosclerosis, Alzheimer's disease). This review will focus on examples of preventive vaccines under development that target infectious diseases with a heavy global burden on public health.
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PMID:[Vaccines for the future]. 1944 71

The class B scavenger receptor CD36 has numerous ligands that include modified forms of low density lipoprotein, fibrillar amyloid, apoptotic cells, and Plasmodium falciparum-infected red blood cells, linking this molecule to atherosclerosis, Alzheimer disease, malaria, and other diseases. We studied the signaling events that follow receptor engagement and lead to CD36 and ligand internalization. We show that oxidized low density lipoprotein or antibody-induced clustering of CD36 triggers macropinocytosis and internalization of the receptor-ligand complex. Remarkably, however, CD36 internalization is independent of macropinocytosis and occurs by a novel endocytic mechanism that depends on actin, but not dynamin. This actin-driven endocytosis requires the activation Src family kinases, JNK, and Rho family GTPases, but, unlike macropinocytosis, it is not affected by inhibitors of phosphatidylinositol 3-kinase or Na/H exchange. Manipulation of this unique mode of internalization may prove helpful in the prevention and management of the wide range of diseases in which CD36 is implicated.
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PMID:Uptake of oxidized low density lipoprotein by CD36 occurs by an actin-dependent pathway distinct from macropinocytosis. 1974 Jul 37

Hemoglobin is a highly reactive molecule, and besides its oxygen-carrying capacity, it has multiple enzymatic and ligand-binding activities that have only recently been explored as fundamental pathophysiologic mechanisms. Nitric oxide neutralization, generation of potentially toxic radical species, and heme-mediated inflammation are among the most extensively studied mechanisms of Hb-mediated pathology. Extracellular Hb has an established role in sickle cell disease and other hemolytic disorders. However, extracellular Hb seems also to have relevant disease-modifying activities in many other important pathologic conditions, such as malaria and atherosclerosis. In this Forum, we summarize the current knowledge of mechanisms of Hb toxicity. Special emphasis is given to the highly efficient endogenous scavenger and detoxification pathways, such as alpha-hemoglobin stabilizing protein (AHSP), haptoglobin, hemopexin, CD163, and heme oxygenase. Systemic and local activity of these pathways finally determines the impact of extracellular Hb on physiology and tissue homeostasis.
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PMID:Clearance and control mechanisms of hemoglobin from cradle to grave. 1978 93

There has been growing interest in the role of host genetic factors in humans and susceptibility to infectious and inflammatory diseases. Genetic variation in Toll-like receptors (TLRs), key innate immune receptors or their signalling molecules, have been described. Variation in certain TLRs has been linked to disease susceptibility. This genetic variation can result in an altered immune response to pathogenic challenge as well as exorbitant immune activation and inflammation, and thus may influence the pathogenesis or outcome of disease. Examples include variants of TLR4 in sepsis, malaria, inflammatory bowel disease and atherosclerosis; variants in TLR2 in tuberculosis and asthma; a variant in Mal (a key signal for TLR2 and TLR4) in malaria, tuberculosis and systemic lupus erythematosus; and variants in the kinase IRAK4 in pyogenic infections. These associations provide us with a validation for the role of TLRs in human disease, and also suggest possible strategies to limit or boost TLR function in the effort to develop new therapies.
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PMID:Genetic variation in Toll-like receptor signalling and the risk of inflammatory and immune diseases. 2037 92

Platelets are the primary cell mediator of thrombosis. A deficiency of platelets can result in severe bleeding defects. "Overactive" platelets contribute to life-threatening outcomes in diseases such as heart attack, stroke, and cancer. The use of platelet inhibitors for thrombosis prevention must therefore seek a delicate balance between inhibiting platelet activation and an associated increased bleeding risk. There are currently few platelet inhibitors clinically available, making the search for novel anti-platelet drug targets a major research priority. Several newly identified pathways of platelet activation may hold hope in this area. In addition, important roles for platelets beyond hemostasis have been discovered. Platelets have recently been described as mediators of diverse inflammatory diseases such as arthritis, hepatitis, malaria, and atherosclerosis. This has heightened the need to broaden our understanding of platelet functions and platelet-derived inflammatory mediators. It has also heightened interest in a continued search for new platelet inhibitors and presents new opportunities for platelet inhibitors to be used in a wide array of disease treatment strategies.
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PMID:Our expanding view of platelet functions and its clinical implications. 2066 87

Global health continues to face increasing challenges owing to a variety of reasons that include the almost constant changes in disease appearance and evolution. Most, but not all, of these changes affect low-income countries and are influenced by climate change. Tracking the recent and anticipated changes in the demographics and global distribution of these changes is essential for evolving effective new methods for dealing with the problems. The recent recognition by the United Nations of the importance of non-communicable diseases is a major positive step. For the sake of this paper, the following diseases were chosen: dengue and malaria, to highlight the role of climate change on vector-borne diseases. Drug-resistant tuberculosis illustrates the role of globalization and reduced resources on disease evolution. The continuing rise in cardiovascular mortality and morbidity, particularly in resource-poor countries is largely attributed to lack of preventive and therapeutic measures against such conditions as hypertension, diabetes, atherosclerosis and congenital heart disease as well as neglected diseases, of which Chagas and rheumatic heart disease will be discussed further.
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PMID:Disease appearance and evolution against a background of climate change and reduced resources. 2146 67


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