Parasites/parasitism mammalian

The modes of action for niclosamide are interference with respiration and blockade of glucose uptake. It uncouples oxidative phosphorylation in both mammalian and taenioid mitochondria (22,23), inhibiting the anaerobic incorporation of inorganic phosphate into adenosine triphosphate (ATP). Tapeworms are very sensitive to niclosamide because they depend on the anaerobic metaboHsm of carbohydrates as their major source of energy. Niclosamide has selective toxicity for the parasites as compared with the host because Httle niclosamide is absorbed from the gastrointestinal tract. Adverse effects are uncommon, except for occasional gastrointestinal upset. 

Eflornithine (difluoromethylornithine, DFMO) inhibits the ornithine decarboxylase of the polyamine pathway, in both the trypanosome and the mammalian cell, by acting as an irreversible competitor of the natural substrate ornithine. Inhibition of ornithine decarboxylase results in depletion of the polyamines, putrescine, spermidine and spermine, which are essential for cell proliferation. Eflornithine selectively harms the parasite and not the mammalian cells, despite acting as an ornithine decarboxylase inhibitor in both cell types. This selectivity is explained by the lower rate of ornithine decarboxylase production in the parasite, as compared to mammalian cells. Due to the high turnover rate, mammalian cells are capable of quickly replenishing inhibited ornithine decarboxylase by newly... 

Denitrification involves the sequential formation of nitrite, nitric oxide, and nitrous oxide. Two aspects of nitric oxide have attracted attention (a) chemical oxidation of biogenic nitric oxide to Nq, in the context of increased ozone formation (Stohl et al. 1996) and (b) the physiological role in mammalian systems (Feldman et al. 1993 Stuehr et al. 2004), in parasitic infections (James 1995), and in the inhibition of bacterial respiration (Nagata et al. 1998). Nitric oxide may be produced microbiologically in widely different reactions such as... 

The identification of bacteria has traditionally required the establishment of a pure culture before any other steps are taken. Pure cultures of bacteria may sometimes be obtained from blood and spinal fluid, which are normally sterile, or from extreme environments like hot springs. However, because there are few such situations in nature, individual bacteria must generally be isolated from other cells and grown for one to five days to obtain pure cultures before identification. Some pathogenic bacteria are obligate intracellular parasites that are difficult or impossible to grow outside their mammalian host cells 37 for these, pure cultures are not feasible. 

Trichinellosis is caused by the parasitic nematode Trichinella spiralis. This parasite has a complex life cycle that alternates between intestinal and muscle cell compartments of the host. This nematode infection is unusual because 7. spiralis is an intracellular parasite of mammalian cells. In addition, the broad host range of this parasite includes most mammals. The disease in humans has intrigued parasitologists, other biologists and public health workers for over a century (Cambell, 1983). The attraction to trichinellosis pardy stems from the debilitating and sometimes fatal effects that characterize this disease. 

This was the original hypothesis put forward by Lee (1970) and expanded by Ogilvie et al. (1973). Secretory products of N. brasiliensis do indeed decrease the amplitude of contractions of segments of uninfected rat intestine maintained in an organ bath, but a role for AChE in this phenomenon was discounted due to the heat stability of the parasite factor, and the inability to duplicate the effect with AChE from the electric eel (Foster et al., 1994). Subsequent investigations demonstrated that the suppression of contraction could be duplicated by a 30-50 kDa fraction of secreted products, which contained a protein of 30 kDa that was immunologically cross-reactive with mammalian vasoactive intestinal peptide (VIP). Moreover, an antibody to porcine VIP significantly reduced the inhibitory effect of parasite-secreted products on contraction in vitro (Foster and Lee, 1996). 

TES-32 is the most abundant single protein product secreted by the parasite. It is also heavily labelled by surface iodination of live larvae (Maizels et al., 1984, 1987), and is known by monoclonal antibody reactivity to be expressed in the cuticular matrix of the larval parasite (Page et al, 1992a). TES-32 was cloned by matching peptide sequence derived from gel-purified protein to an expressed sequence tag (EST) dataset of randomly selected clones from a larval cDNA library (Loukas et al., 1999). Because of the high level of expression of TES-32 mRNA, clones encoding this protein were repeatedly sequenced and deposited in the dataset (Tetteh et al., 1999). Full sequence determination showed a major domain with similarity to mammalian C-type (calcium-dependent) lectins (C-TLs), together with shorter N-terminal tracts rich in cysteine and threonine residues. Native TES-32 was then shown to bind to immobilized monosaccharides in a calcium-dependent manner (Loukas et al., 1999). 

Fig. 15.5. Structures of A/-linked glycans from several different species of parasitic nematodes, illustrating both similarities with mammalian glycans (compare with Figs 15.1 and 15.2) and features unique to nematodes (e.g. tyvelose and PC capping and novel core fucosylation). The filarial nematode glycans are believed to be substituted with charged residues, which are not yet characterized.

Apicomplexan parasites cause life threatening diseases like malaria, cryptosporid-iosis, toxoplasmosis, coccidiosis. Suberic acid bisdimethylamide which also inhibits HDA selechvely arrests tumor cells as opposed to normal mammalian cells, has an in vivo cytostatic effect against the acute murine malaria Plasmodium berghei (Andrews et al, 2000). 

Trypanasoma brucei causes sleeping sickness in humans. These flagellated parasites are directly exposed to immune defences as they circulate in the mammalian host bloodstream but maintain persistent infections by undergoing antigenic variation. These parasites have been reported to have certain unusual histone modifications where the N-terminal alanine of H2A, H2B, H4 get... 

Turning to a mammalian parasite, the vampire bat, Desmodus rotundus, is very sensitive to butyric acid, a common compound given ofFby mammals. It detects 0.0039-0.00784 % (vol.) butyric acid. This is lower than the hmnan threshold (Schmidt and Greenhall, 1971). 

This drug has a direct amebicidal effect against trophozoites E. histolytica in tissues, and it is not active against cysts in either the lumen or intestinal walls, or in other organs. The mechanism of action of emetine consists of the blockage of protein synthesis in eukaryotic (but not in prokaryotic) cells. It inhibits the process of polypeptide chain formation. Protein synthesis is inhibited in parasite and mammalian cells, but not in bacteria. 

They concluded that the parasiticidal action of trioxanes involved reductive cleavage of the peroxide bond by intracellular iron-sulphur redox centres (rather than heme) and subsequent alkylation of the redox centre. This type of redox centre is known to exist in many enzymes and Wu and coworkers proposed that structural differences between those in the parasite and those in mammalian systems could account for the high selective cytotoxicity of artemisinin. 

Atovaquone is a naphthoquinone whose mechanism of action involves inhibition of the mitochondrial electron transport system in the protozoa. Malaria parasites depend on de novo pyrimidine biosynthesis through dihy-droorotate dehydrogenase coupled to electron transport. Plasmodia are unable to salvage and recycle pyrimidines as do mammalian cells. 

For many years, niclosamide (Niclocide) was widely used to treat infestations of cestodes. Niclosamide is a chlorinated salicylamide that inhibits the production of energy derived from anaerobic metabolism. It may also have adenosine triphosphatase (ATPase) stimulating properties. Inhibition of anaerobic incorporation of inorganic phosphate into ATP is detrimental to the parasite. Niclosamide can uncouple oxidative phosphorylation in mammalian mitochondria, but this action requires dosages that are higher than those commonly used in treating worm infections. 

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