Haemozoin: From melatonin pigment to drug target, diagnostic tool, and immune modulator

Department of Chemistry, University of Cape Town, Kaapstad, Western Cape, South Africa
The Lancet Infectious Diseases (Impact Factor: 22.43). 11/2007; 7(10):675-85. DOI: 10.1016/S1473-3099(07)70238-4
Source: PubMed


Plasmodium spp produce a pigment (haemozoin) to detoxify the free haem that is generated by haemoglobin degradation. Haemozoin was originally thought to be an inert waste byproduct of the parasite. However, recent research has led to the recognition that haemozoin is possibly of great importance in various aspects of malaria. Haemozoin is the target of many antimalarial drugs, and the unravelling of the exact modes of action may allow the design of novel antimalarial compounds. The detection of haemozoin in erythrocytes or leucocytes facilitates the diagnosis of malaria. The number of haemozoin-containing monocytes and granulocytes has been shown to correlate well with disease severity and may hold the potential for becoming a novel, automated laboratory marker in the assessment of patients. Finally, haemozoin has a substantial effect on the immune system. Further research is needed to clarify these aspects, many of which are important in clinical practice.

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    • "While dissecting a culicine mosquito, he found the avian malaria parasite Plasmodium relictum in the stomach tissue of the mosquito . Using the microscope, Ross also identified the malaria parasite by its darkly pigmented cells (now known as hemozoin, the black malaria pigment, derived from discomposed hemoglobin) (Hänscheid et al. 2007). Using an experimental malaria model in birds, he demonstrated in 1898 that the parasite developed in mosquitoes and migrated to its salivary glands, allowing the infected mosquito to infect other birds during consecutive bites. "
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    ABSTRACT: Malaria is an ancient disease continuing to pose an enormous health, social, and economic burden. It is caused by infection with protozoan parasites belonging to the genus Plasmodium transmitted via the bite of female Anopheles species mosquitoes. Of more than 100 different species infecting a wide range of animals from rodents and birds to mammals, five species of malaria parasites are known to infect humans: Plasmodium falciparum, P. vivax, P. ovale (now being recognized as consisting of two subspecies), P. malariae and P. knowlesi. P. falciparum is most likely to cause severe disease and, if not promptly treated, may lead to death. References to the disease occur in the Chinese canon of medicine, clay tablets from Mesopotamia, Egyptian papyri and Indian medical works. Descriptions of malaria from classic Greece and the Roman Empire are abundant. It was commonly believed that malaria was caused by marsh water and foul vapors emanating from swamps, hence the word mal’aria, from the Italian for “bad air”. For thousands of years, no effective treatment was available. This changed with the discovery of Artemisia annua (sweet wormwood) in China and the use of quinine from Peruvian bark as potent and effective drugs against malaria. The current understanding of the malaria parasites and their lifecycle starts in the end of the nineteenth century with the discovery of the malaria parasites in the blood of malaria patients by Alphonse Laveran in 1880. Subsequently, Ronald Ross discovered in 1897 that a bird malaria parasite was transmitted by mosquitoes. In 1898 Giovanni Grassi, Camillo Golgi, Ettore Marchiafava, Amico Bignami, Angelo Celli and Giuseppe Bastianelli confirmed that malaria in humans was also a mosquito-borne disease, in this case Anopheles species. Grassi and Filetti introduced the names of P. vivax and P. malariae in 1890. The causative agent of what was dubbed ‘malignant malaria’ was baptized P. falciparum by William Welch in 1897 and P. ovale by John Stephens in 1922. The discovery of a liver stage before malaria enters the bloodstream was made by Henry Shortt and Cyril Garnham in 1948. The existence of dormant stages, in P. vivax and P. ovale was shown in 1982 by Wojciech Krotoski. This article describes the key discoveries and provides a short overview of the multifaceted history of malaria.
    Discoveries in Modern Science: Exploration, Invention, Technology, 1st Edition edited by James Trefil, Patricia Daniels, Donna McPhie, Craig Schiffries, 10/2014: chapter Malaria Is Transmitted by Mosquitoes: pages 640-647; Macmillan Reference USA., ISBN: 0028662482
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    • "If these lipid profile changes are characteristic for malaria, one could expect more pronounced lipid alterations in severe malaria compared to uncomplicated malaria; this is confirmed by three studies [12,30,42]. Biological mechanisms of lipid profile changes may be partly host-related, i.e., related to an acute phase reaction [18] or parasite-related [20] or a combination of these two. "
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    ABSTRACT: Serum lipid profile changes have been observed during malaria infection. The underlying biological mechanisms remain unclear. The aim of this paper is to provide an overview on those serum lipid profile changes, and to discuss possible underlying biological mechanisms and the role of lipids in malaria pathogenesis. A systematic review and meta-analysis to determine lipid profile changes during malaria was conducted, following PRISMA guidelines. Without language restrictions, Medline/PubMed, Embase, Cochrane Central Register of Controlled Trials, Web of Science, LILACS, Biosis Previews and the African Index Medicus were searched for studies published up to 11 July, 2013, that measured serum lipid parameters in malaria patients. Also, major trial registries were searched. Mean differences in lipid profile parameters were combined in fixed and random effects meta-analysis, with a separate analysis for different groups of controls (healthy, other febrile illnesses or very low parasitaemia). These parameters were also compared between severe malaria and uncomplicated malaria. Funnel plots were used to test for publication bias. Of 2,518 studies reviewed, 42 met the criteria for inclusion in the qualitative analysis, and of these, 15 reported the necessary data for inclusion in the meta-analysis for cholesterol; nine for high-density lipoprotein (HDL), eight for low-density lipoprotein (LDL), and nine for triglycerides, respectively. Total cholesterol, HDL and LDL concentrations were lower in malaria and other febrile diseases compared to healthy controls. The decline was more pronounced and statistically significant during malaria compared to other febrile diseases. These results were consistent across included studies. Triglycerides were raised compared to healthy controls, but not statistically significant when compared to symptomatic controls. This meta-analysis suggests that the observed lipid profile changes are characteristic for malaria. Although a definite link with the pathogenesis of malaria cannot yet be demonstrated, plausible hypotheses of biological mechanisms involving host lipid alterations and the pathogenesis of malaria exist. An increased research effort to elucidate the precise pathways is warranted, since this could lead to better understanding of malaria pathophysiology and consequently to novel treatment approaches.
    Malaria Journal 12/2013; 12(1):442. DOI:10.1186/1475-2875-12-442 · 3.11 Impact Factor
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    • "The action of these anti-malarial drugs on β-haematin formation takes place during the intra-erythrocytic phase of the parasite, within the food vacuole. The parasite converts haem into the malarial pigment haemozoin [15]. Derivatives 1e and 2e derivatives exhibited similar inhibition percentages (25% and 26% respectively), whereas 1f displayed less inhibitory activity (14%) than the other tested derivatives. "
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    ABSTRACT: Background The discovery and development of anti-malarial compounds of plant origin and semisynthetic derivatives thereof, such as quinine (QN) and chloroquine (CQ), has highlighted the importance of these compounds in the treatment of malaria. Ursolic acid analogues bearing an acetyl group at C-3 have demonstrated significant anti-malarial activity. With this in mind, two new series of betulinic acid (BA) and ursolic acid (UA) derivatives with ester groups at C-3 were synthesized in an attempt to improve anti-malarial activity, reduce cytotoxicity, and search for new targets. In vitro activity against CQ-sensitive Plasmodium falciparum 3D7 and an evaluation of cytotoxicity in a mammalian cell line (HEK293T) are reported. Furthermore, two possible mechanisms of action of anti-malarial compounds have been evaluated: effects on mitochondrial membrane potential (ΔΨm) and inhibition of β-haematin formation. Results Among the 18 derivatives synthesized, those having shorter side chains were most effective against CQ-sensitive P. falciparum 3D7, and were non-cytotoxic. These derivatives were three to five times more active than BA and UA. A DiOC6(3) ΔΨm assay showed that mitochondria are not involved in their mechanism of action. Inhibition of β-haematin formation by the active derivatives was weaker than with CQ. Compounds of the BA series were generally more active against P. falciparum 3D7 than those of the UA series. Conclusions Three new anti-malarial prototypes were obtained from natural sources through an easy and relatively inexpensive synthesis. They represent an alternative for new lead compounds for anti-malarial chemotherapy.
    Malaria Journal 03/2013; 12(1):89. DOI:10.1186/1475-2875-12-89 · 3.11 Impact Factor
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