Calcium-Transporting ATPases

Publication Title: 
Archives of Toxicology

This study is aimed at exploring the possible mechanism of hypnosis-enhancing effect of HgS or cinnabar (a traditional Chinese medicine containing more than 95% HgS) in mice treated with pentobarbital. We also examined whether the effect of HgS is different from that of the well-known methyl mercury (MeHg).

Author(s): 
Chuu, Jiunn-Jye
Huang, Zih-Ning
Yu, Hsun-Hsin
Chang, Liang-Hao
Lin-Shiau, Shoei-Yn
Publication Title: 
Lancet (London, England)

BACKGROUND: The borders of Thailand harbour the world's most multidrug resistant Plasmodium falciparum parasites. In 1984 mefloquine was introduced as treatment for uncomplicated falciparum malaria, but substantial resistance developed within 6 years. A combination of artesunate with mefloquine now cures more than 95% of acute infections. For both treatment regimens, the underlying mechanisms of resistance are not known.

Author(s): 
Price, Ric N.
Uhlemann, Anne-Catrin
Brockman, Alan
McGready, Rose
Ashley, Elizabeth
Phaipun, Lucy
Patel, Rina
Laing, Kenneth
Looareesuwan, Sornchai
White, Nicholas J.
Nosten, François
Krishna, Sanjeev
Publication Title: 
Antimicrobial Agents and Chemotherapy

Resistance of Plasmodium falciparum to drugs such as chloroquine and sulfadoxine-pyrimethamine is a major problem in malaria control. Artemisinin (ART) derivatives, particularly in combination with other drugs, are thus increasingly used to treat malaria, reducing the probability that parasites resistant to the components will emerge. Although stable resistance to artemisinin has yet to be reported from laboratory or field studies, its emergence would be disastrous because of the lack of alternative treatments.

Author(s): 
Afonso, A.
Hunt, P.
Cheesman, S.
Alves, A. C.
Cunha, C. V.
do Rosário, V.
Cravo, P.
Publication Title: 
Trends in Pharmacological Sciences

The ability to treat and control Plasmodium falciparum infection through chemotherapy has been compromised by the advent and spread of resistance to antimalarial drugs. Research in this area has identified the P. falciparum chloroquine resistance transporter (PfCRT) and the multidrug resistance-1 (PfMDR1) transporter as key determinants of decreased in vitro susceptibility to several principal antimalarial drugs.

Author(s): 
Valderramos, Stephanie G.
Fidock, David A.
Publication Title: 
Antimicrobial Agents and Chemotherapy

RBX11160 (OZ277) is a fully synthetic peroxidic antimalarial in clinical development. To study the possible mechanisms of action of RBX11160, we have examined its ability to inhibit PfATP6, a sarcoplasmic reticulum calcium ATPase and proposed target for semisynthetic peroxidic artemisinin derivatives. RBX11160 inhibits PfATP6 (apparent half-maximal inhibitory constant=7,700 nM) less potently than artemisinin (79 nM). Inhibition of PfATP6 is abrogated by desferrioxamine, an iron-chelating agent.

Author(s): 
Uhlemann, Anne-Catrin
Wittlin, Sergio
Matile, Hugues
Bustamante, Leyla Y.
Krishna, Sanjeev
Publication Title: 
Antimicrobial Agents and Chemotherapy

Artemisinin compounds inhibit in vitro growth of cultured Trypanosoma cruzi and Trypanosoma brucei rhodesiense at concentrations in the low micromolar range. Artemisinin also inhibits calcium-dependent ATPase activity in T. cruzi membranes, suggesting a mode of action via membrane pumps. Artemisinins merit further investigation as chemotherapeutic options for these pathogens.

Author(s): 
Mishina, Yuliya V.
Krishna, Sanjeev
Haynes, Richard K.
Meade, John C.
Publication Title: 
Antimicrobial Agents and Chemotherapy

Artemisinin is a plant sesquiterpene lactone that has become an important drug for combating malaria, especially in regions where resistance to other drugs is widespread. While the mechanism of action is debated, artemisinin has been reported to inhibit the sarcoplasmic endoplasmic reticulum Ca(2+) ATPase (SERCA) in the malaria parasite. Artemisinin is also effective against Toxoplasma in vitro and in vivo, although it is less potent and, hence, is generally not used therapeutically to treat toxoplasmosis.

Author(s): 
Nagamune, Kisaburo
Moreno, Silvia N. J.
Sibley, L. David
Publication Title: 
Malaria Journal

BACKGROUND: Artemisinin and its derivatives have been used for falciparum malaria treatment in China since late 1970s. Monotherapy and uncontrolled use of artemisinin drugs were common practices for a long period of time. In vitro tests showed that the susceptibility of Plasmodium falciparum to artemisinins was declining in China. A concern was raised about the resistance to artemisinins of falciparum malaria in the country. It has been reported that in vitro artemisinin resistance was associated with the S769N mutation in the PfATPase6 gene.

Author(s): 
Zhang, Guoqing
Guan, Yayi
Zheng, Bin
Wu, Song
Tang, Linhua
Publication Title: 
Malaria Journal

BACKGROUND: Plasmodium falciparum resistance to drugs remains a major public health issue in Niger. The therapeutic failure index for chloroquine and sulphadoxine-pyrimethamine are, respectively 20% and 21.9%. In December 2005, the National Malaria Control Programme promoted the use of artemisinin combination therapy (ACT) as first-line treatment of the uncomplicated malaria cases. Recently, studies have shown a relationship between the SERCA PfATPase6 gene and artemisinin efficacy, and pointed it out as a potential molecular marker for resistance.

Author(s): 
Ibrahim, Maman Laminou
Khim, Nimol
Adam, Hassane Hadiza
Ariey, Frédéric
Duchemin, Jean-Bernard
Publication Title: 
The American Journal of Tropical Medicine and Hygiene

The Plasmodium falciparum ATPase 6 (Pfatp6), homolog of sarco-endoplasmic reticulum, calcium-dependent ATPase in malaria parasites, has been proposed to be the main target of artemisinins. Four distinct point mutations (L263E, E431K, A623E, and S769N) have been reported to be associated with artemisinin resistance. The Pfatp6 sequence polymorphism was determined to evaluate the prevalence of these mutations in fresh clinical isolates in Yaounde, Cameroon, and compare sequence data with in vitro response to dihydroartemisinin.

Author(s): 
Tahar, Rachida
Ringwald, Pascal
Basco, Leonardo K.

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