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Sent on Wednesday, 2011 Jun 08Search kinetoplastids OR kinetoplastid OR Kinetoplastida OR "trypanosoma brucei" OR leishmania OR brucei OR leishmaniasis OR "African trypanosomiasis"
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| PubMed Results |
| 1. | Antimicrob Agents Chemother. 2011 Jun 6. [Epub ahead of print]Sitamaquine overcomes the ABC-mediated resistance to Miltefosine and Antimony in Leishmania.Pérez-Victoria JM, Bavchvarov BI, Torrecillas IR, Martínez-García M, López-Martín C, Campillo M, Castanys S, Gamarro F.SourceInstituto de Parasitología y Biomedicina "López-Neyra", Consejo Superior de Investigaciones Científicas (IPBLN-CSIC), Parque Tecnológico de Ciencias de la Salud, Avda. del Conocimiento s/n, 18100 Armilla, Granada, Spain. AbstractAlthough oral miltefosine represented an important therapeutic advance in the treatment of leishmaniasis, the appearance of resistance remains a serious threat. LMDR1/LABCB4, a P-glycoprotein-like transporter included in the Leishmania ABC (ATP-binding cassette) family, was the first molecule shown to be involved in experimental miltefosine resistance. LMDR1 pumps drugs out of the parasite, thereby decreasing their intracellular accumulation. Sitamaquine, another promising oral drug for leishmaniasis, is currently in Phase 2b clinical trials. The physicochemical features of this drug suggested to us that it could be considered for use as an LMDR1 inhibitor. Indeed, we report herein that non-leishmanicidal concentrations of sitamaquine reverse miltefosine resistance in a multidrug-resistance Leishmania line that overexpresses LMDR1. This reversal effect is due to a modulation of the LMDR1-mediated efflux of miltefosine. In addition, sitamaquine is not a substrate of LMDR1 as this transporter does not affect sitamaquine accumulation or sensitivity in the parasite. Likewise, we show that ketoconazole, another oral leishmanicidal drug known to interact with ABC transporters, is also able to reverse LMDR1-mediated miltefosine resistance, although with a lower efficiency than sitamaquine. Molecular docking on a 3D homology model of LMDR1 showed different preferential binding sites for each substrate-inhibitor pair, thus explaining this different behaviour. Finally, we show that sitamaquine is also able to modulate the antimony resistance mediated by MRPA/LABCC3, another ABC transporter involved in experimental and clinical antimony resistance in this parasite. Taken together, these data suggest that the combination of sitamaquine with miltefosine or antimony could avoid the appearance of resistance mediated by these membrane transporters in Leishmania. |
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| 2. | Arch Biochem Biophys. 2011 May 27. [Epub ahead of print]Crystal structure of UDP-galactose 4-epimerase from the hyperthermophilic archaeon Pyrobaculum calidifontis.Sakuraba H, Kawai T, Yoneda K, Ohshima T.SourceDepartment of Applied Biological Science, Faculty of Agriculture, Kagawa University, 2393 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0795, Japan. AbstractThe crystal structure of a highly thermostable UDP-galactose 4-epimerase (GalE) from the hyperthermophilic archaeon Pyrobaculum calidifontis was determined at a resolution of 1.8Å. The asymmetric unit contained one subunit, and the functional dimer was generated by a crystallographic two-fold axis. Each monomer consisted of a Rossmann-fold domain with NAD bound and a carboxyl terminal domain. The overall structure of P. calidifontis GalE showed significant similarity to the structures of the GalEs from Escherichia coli, human and Trypanosoma brucei. However, the sizes of several surface loops were markedly smaller in P. calidifontis GalE than the corresponding loops in the other enzymes. Structural comparison revealed that the presence of an extensive hydrophobic interaction at the subunit interface is likely the main factor contributing to the hyperthermostability of the P. calidifontis enzyme. Within the NAD-binding site of P. calidifontis GalE, a loop (NAD-binding loop) tightly holds the adenine ribose moiety of NAD. Moreover, a deletion mutant lacking this loop bound NAD in a loose, reversible manner. Thus the presence of the NAD-binding loop in GalE is largely responsible for preventing the release of the cofactor from the holoenzyme. Copyright © 2011. Published by Elsevier Inc. |
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| 3. | Skinmed. 2011 Mar-Apr;9(2):129-30.Pruritus as an unusual symptom in multiple piloleiomyoma.< a href="http://www.ncbi.nlm.nih.gov/pubmed?term=%22Sadeghian%20G%22%5BAuthor%5D">Sadeghian G, Ziaei H.SourceDisease and Leishmaniasis Research Center, Isfahan University of Medical Sciences, Isfahan, Iran. sadeghian@sdlrc.mcui.a.ir AbstractA 30-year-old woman presented with multiple pruritic raised skin lesions at the proximal part of her left arm for the past 15 years. At the age of 15, the patient noticed red nodules accompanied with severe pruritus over the arm, which started to spread and involved the dorsal aspect of her scapula (Figure 1). They had been increasing in number during the past 15 years. There was no history of pain either spontaneously or in response to cold, tactile, or emotional stress, with no bleeding or oozing. There was no family history of similar skin lesions; however, she had a history of gynecologic problems for 10 years, and examination of her uterus showed uterine leiomyomas. The patient complained about severe pruritus. This symptom was exaggerated with sun exposure, cold, emotional stress, and rough cloths. It was so severe that it caused sleep disturbances. Clinical examination showed multiple pink and red nodules ranging from 5 mm to 20 mm over the above-described sites. The lesions were firm, smooth, not mobile, and nontender, with no pain on touch. Routine hematologic and biochemical investigations were normal. Kidney and pelvic ultrasonography showed myomatous uterus and normal kidneys. Microscopic examination of one of the nodules in hematoxylin and eosin-stained sections showed proliferation of smooth muscle cells with fascicular aspect in dermis. These cells had thin, elongated eel-like nuclei with blunt edges (Figure 2 and Figure 3). The diagnosis of leiomyoma was made and the patient was referred for surgical excision. Due to the extension and site of the lesions, the plastic surgeon did not recommend surgical procedure and the patient was treated with an antihistamine (loratadine 10 mg/d). |
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| 4. | Am J Trop Med Hyg. 2011 Apr;84(4):575-80.Humoral immune response against P2β from Trypanosoma cruzi in persons with chronic Chagas disease: its relationship with treatment against para sites and myocardial damage.Fabbro DL, Olivera V, Bizai ML, Denner S, Diez C, Mancipar I, Streiger M, Arias E, del Barco M, Mendicino D, Bottasso O.SourceCentro de Investigaciones Sobre Endemias Nacionales, Laboratorio de Tecnología Inmunológica, Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Santa Fe, Argentina. dfabbro@fbcb.unl.edu.ar AbstractWe investigated the relationship between potentially pathogenic antibodies against a Trypanosoma cruzi ribosomal protein (P2β) and the evolution of Chagas disease and the effect of trypanocidal treatment on these variables. Seventy-eight patients with chronic Chagas disease who were followed-up for more than 20 years were divided into three groups: 30 asymptomatic persons undergoing specific treatment (group A), 37 asymptomatic persons not undergoing specific treatment (group B), and 11 patients with chronic chagasic cardiomyopathy (CCC) who were not treated. Five patients in group B showed evolution to myocardial abnormalities. Among persons with CCC, six showed no changes; the remaining persons showed progression of cardiac involvement. Levels of antibodies to P2β in persons in group A decreased from their initial values. This finding was not observed in persons in groups B and C. Comparisons at the end of the follow-up showed lower amounts of antibodies to P2β in groups A and C. These findings support the benefits of specific treatment during chronic infection. |
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