Wednesday, June 24, 2009

What's new for 'Trypanosomatids' in PubMed

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Search kinetoplastids OR kinetoplastid OR Kinetoplastida OR "trypanosoma brucei" OR leishmania OR brucei OR leishmaniasis OR "African trypanosomiasis"
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PubMed Results
Items 1 -10 of 13

1: Mem Inst Oswaldo Cruz. 2009 May;104(3):473-80.

Cl gene cluster encoding several small nucleolar RNAs: a comparison amongst trypanosomatids.

Nocua P, Gómez C, Cuervo C, Puerta C.

Laboratorio de Parasitología Molecular, Departamento de Microbiología, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá, Colombia.

Small nucleolar RNAs (snoRNAs) are small non-coding RNAs that modify RNA molecules such as rRNA and snRNA by guiding 2'-O-ribose methylation (C/D box snoRNA family) and pseudouridylation reactions (H/ACA snoRNA family). H/ACA snoRNAs are also involved in trans-splicing in trypanosomatids. The aims of this work were to characterise the Cl gene cluster that encodes several snoRNAs in Trypanosoma rangeli and compare it with clusters from Trypanosoma cruzi, Trypanosoma brucei, Leishmania major, Leishmania infantum, Leishmania braziliensis and Leptomonas collosoma. The T. rangeli Cl gene cluster is an 801 base pair (bp) repeat sequence that encodes three C/D (Cl1, Cl2 and Cl4) and three H/ACA (Cl3, Cl5 and Cl6) snoRNAs. In contrast to T. brucei, the Cl3 and Cl5 homologues have not been annotated in the Leishmania or T. cruzi genome projects (http//:www.genedb.org). Of note, snoRNA transcribed regions have a high degree of sequence identity among all species and share gene synteny. Collectively, these findings suggest that the Cl cluster could constitute an interesting target for therapeutic (gene silencing) or diagnostic intervention strategies (PCR-derived tools).

PMID: 19547875 [PubMed - in process]

2: Antimicrob Agents Chemother. 2009 Jun 22. [Epub ahead of print]

In vitro susceptibility of Leishmania donovani promastigote and amastigote stages to antileishmania reference drugs: practical relevance of stage-specific differences.

Vermeersch M, Inocêncio da Luz R, Toté K, Timmermans JP, Cos P, Maes L.

Laboratory of Microbiology, Parasitology and Hygiene (LMPH), Laboratory of Cell Biology and Histology, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Groenenborgerlaan 171, 2020 Antwerp, Belgium.

The in vitro susceptibility of the reference strain Leishmania donovani MHOM/ET/67/L82 to sodium stibogluconate, amphotericin B, miltefosine and the experimental compound PX-6518, was determined for the extracellular log-phase promastigotes, established axenic amastigotes and fresh spleen-derived amastigotes, and intracellular amastigotes in primary mouse peritoneal macrophages. Amphotericin B susceptibility did not differ across the various axenic models (IC50 0.6 - 0.7 microM) and showed slightly higher potency against intracellular amastigotes (IC50 0.1 - 0.4 microM). A similar trend was observed for miltefosine with comparable efficacy against the extracellular (IC50 0.4 - 3.8 microM) and intracellular (IC50 0.9 - 4.3 microM) stages. Sodium stibogluconate, either used as Pentostam(R) or as crystalline substance was inactive against all axenic stages (IC50 >64 microg Sb(V)/ml) but showed good efficacy against intracellular amastigotes (IC50 22-28 microg Sb(V)/ml), with the crystalline substance being about 2 to 3 times more potent (IC50 9-11 microg Sb(V)/ml). The activity profile of PX-6518 was comparable to sodium stibogluconate, be it at much higher potency (IC50 0.1 microg/ml). In conclusion, the differential susceptibility determines which in vitro models are appropriate for either drug screening or resistance monitoring in clinical field isolates. Despite the more complex and labour-intensive protocol, current results support the intracellular amastigote model as the golden standard for in vitro Leishmania drug discovery research and evaluation of resistance in field strains since it also includes host cell-mediated effects. Axenic systems can only be recommended for compounds for which no cellular mechanisms are involved, for example, amphotericin B and miltefosine.

PMID: 19546361 [PubMed - as supplied by publisher]

3: Mol Biochem Parasitol. 2009 Jun 19. [Epub ahead of print]

The Trypanosoma brucei sphingolipid synthase, an essential enzyme and drug target.

Mina JG, Pan SY, Wansadhipathi NK, Bruce CR, Shams-Eldin H, Schwarz RT, Steel PG, Denny PW.

Centre for Bioactive Chemistry, Department of Chemistry and School of Biological and Biomedical Sciences, Durham University, Durham, DH1 3LE, UK; School of Medicine and Health, Durham University, Queen's Campus, Stockton-on-Tees, TS17 6BH, UK.

Sphingolipids are important components of eukaryotic membranes, particularly the plasma membrane, and are involved in a diverse array of signal transduction processes. In the Eukaryota the biosynthetic pathway for the formation of these lipid species is largely conserved. However, in contrast to mammals which produce sphingomyelin (SM), several pathogenic fungi and protozoa synthesize inositol phosphorylceramide (IPC) as the primary phosphosphingolipid. This process is catalyzed by the enzyme IPC synthase, a recognized target for anti-fungals encoded by the AUR1 gene in yeast. Recently, functional orthologues of the AUR1p have been identified in a group of insect vector-borne pathogenic protozoa, the Kinetoplastida, which are responsible for a range of so-called neglected diseases. Of these the Trypanosoma brucei species are the causative agents of human African trypanosomiasis in many of the most under-developed regions of Africa. The available treatments for these diseases are limited, of decreasing efficacy, and often demonstrate severe side-effects. Against this background the T. brucei sphingolipid synthase, an orthologue of the yeast AUR1p, may represent a promising target for novel anti-protozoals. Our studies identify an isoform of this protein as a novel bi-functional enzyme capable of catalyzing the synthesis of both IPC and SM, both known to be present in the parasite. Furthermore, the synthase is essential for parasite growth and can be inhibited by a known anti-fungal at low nanomolar levels in vitro. Most notably this drug demonstrates trypanocidal activity against cultured bloodstream form parasites. Thus, the T. brucei sphingolipid synthase represents a valid and promising drug target.

PMID: 19545591 [PubMed - as supplied by publisher]

4: Exp Parasitol. 2009 Jun 19. [Epub ahead of print]

Host peroxisomal properties are not restored to normal after treatment with sodium antimony gluconate.

Gupta S, Raychaudhury B, Datta SC.

Department of Biological Chemistry, Infectious Diseases Group Indian Institute of Chemical Biology, Kolkata 700032, India.

Reason for Post Kala-azar Dermal Leishmaniasis (PKDL) is yet to be established. Earlier it was observed that morphology and biochemical properties of host peroxisomes were impaired during Leishmania infection. As peroxisome is known to be involved in various metabolic pathways to monitor normal function of the host cells, it is essential that Leishmania-induced dysfunction of this organelle should totally be repaired during treatment of visceral leishmaniasis (VL). In this paper it has been shown that resumption of normal peroxisomal function could not be attained when one of the existing drugs sodium antimony gluconate (SAG) was used for chemotherapy against VL. Although Leishmania parasite was found to be completely eliminated from host liver and spleen after SAG treatment, normal activities of peroxisomal catalase and superoxide dismutase could not be restored. Also unusual peptides were found to be present due to abnormal proteolytic cleavage of proteins. It is proposed that peroxisomal disorder which exists even after successful chemotherapy of VL may be figured out as one of the possible reasons to develop PKDL. It may also be pointed out that continued effect of peroxisomal disorder even after complete treatment of this parasitic disease may also lead to genetic disorders not yet been explored in post-kala-azar patients.

PMID: 19545565 [PubMed - as supplied by publisher]

5: Exp Parasitol. 2009 Feb 5. [Epub ahead of print]

Development of species-specific PCR and PCR-Restriction Fragment Length Polymorphism assays for L.infantum /L.donovani discrimination.

Oshaghi MA, Ravasan NM, Javadian EA, Rassi Y, Sedaghat MM, Mohebali M, Hajjaran H.

Department of Medical Entomology and Vector Control, School of Public Health and Institute of Health Research, Tehran University of Medical Sciences, Tehran, P.O.Box: 14155 -- 6446, Iran.

Discrimination ofLeishmania infantum and L.donovani, the members of the L. (L.) donovani complex, is important for diagnosis and epidemiological studies of visceral leishmaniasis (VL). We have developed two molecular tools including a restriction fragment length polymorphisms of amplified DNA (PCR-RFLP) and a PCR that are capable to discriminate L.donovani fromL.infantum. Typing of the complex was performed by a simple PCR of cysteine protease B (cpb) gene followed by digestion with DraIII. The enzyme cuts the 741-bp amplicon of L.donovani into 400 and 341 bp fragments whereas the 702 bp ofL.infantum remains intact. The designed PCR species-specific primer pair is specific for L.donovani and is capable of amplifying a 317 bp of 3' end of cpb gene of L.donovani whereas it does not generate an amplicon for L.infantum. The species-specific primers and the restriction enzyme were designed based on a 39 bp insertion/deletion (indel) in the middle of the cysteine protease B (cpb) gene. Both assays could differentiate correctly the two species and are reliable and high-throughput alternatives for molecular diagnosis and epidemiological studies of VL in various foci.

PMID: 19545519 [PubMed - as supplied by publisher]

6: Exp Parasitol. 2009 Feb 10. [Epub ahead of print]

Sub-optimal Dose of Sodium Antimony Gluconate (SAG)-Diperoxovanadate Combination Clears Organ Parasites from BALB/c Mice Infected with Antimony Resistant Leishmania donovani by Expanding Antileishmanial T-cell Repertoire and Increasing IFN-gamma to IL-10 Ratio.

Haldar AK, Banerjee S, Naskar K, Kalita D, Islam NS, Roy S.

Department of Infectious Diseases and Immunology, Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata, 700032, India.

We demonstrate that the combination of sub-optimal doses of Sodium Antimony Gluconate (SAG) and the diperoxovanadate compound K[VO(O(2))(2)(H(2)O)], also designated as PV6, is highly effective in combating experimental infection of BALB/c mice with antimony resistant (Sb(R)) Leishmania donovani (LD) as evident from the significant reduction in organ parasite burden where SAG is essentially ineffective. Interestingly, such treatment also allowed clonal expansion of antileishmanial T-cells coupled with robust surge of IFN-gamma and concomitant decrease in IL-10 production. The splenocytes from the treated animals generated significantly higher amounts of IFN-gamma inducible parasiticidal effector molecules like superoxide and nitric oxide as compared to the infected group. Our study indicates that the combination of sub-optimal doses of SAG and PV6 may be beneficial for the treatment of SAG resistant visceral leishmaniasis patients.

PMID: 19545517 [PubMed - as supplied by publisher]

7: Cell Microbiol. 2009 Jun 22. [Epub ahead of print]

The impact of vector mediated neutrophil recruitment on cutaneous leishmaniasis.

Peters NC, Sacks DL.

Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA.

The dynamic process of pathogen transmission by the bite of an insect vector combines several biological processes that have undergone extensive co-evolution. Whereas the host response to an insect bite is only occasionally confronted with the parasitic pathogens that competent vectors might transmit, the transmitted parasites will always be confronted with the acute, wound healing response that is initiated by the bite itself. Invariably, this response involves neutrophils. In the case of Leishmania, infection is initiated in the skin following the bite of an infected sand fly, suggesting that Leishmania must possess some means to survive their early encounter with recruited neutrophils at the bite site. Here, we review the literature regarding the impact of neutrophils on the outcome of infection with Leishmania, with special attention to the role of the sand fly bite.

PMID: 19545276 [PubMed - as supplied by publisher]

8: J Infect Dis. 2009 Jun 22. [Epub ahead of print]

Highly Effective Oral Amphotericin B Formulation against Murine Visceral Leishmaniasis.

Wasan KM, Wasan EK, Gershkovich P, Zhu X, Tidwell RR, Werbovetz KA, Clement JG, Thornton SJ.

Faculty of Pharmaceutical Sciences, University of British Columbia, and 2iCo Therapeutics, Vancouver, and 3School of Health Sciences, British Columbia Institute of Technology, Burnaby, British Columbia, Canada; 4Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus; and 5Department of Pathology and Lab Medicine, Consortium for Parasitic Drug Development, University of North Carolina at Chapel Hill, Chapel Hill.

Visceral leishmaniasis is a deadly parasitic disease caused by obligate intramacrophage protozoans of the Leishmania genus. The World Health Organization estimates the annual death toll to be 50,000, with 500,000 new cases each year. Without treatment, visceral leishmaniasis is inevitably fatal. For the last 70 years, the first line of defense has been pentavalent antimonials; however, increased resistance has brought amphotericin B to the forefront of treatment options. Unfortunately, the difficult route of drug administration, toxicity issues, and cost prevent amphotericin B from reaching the infected population, and mortality continues to rise. Our reformulation of amphotericin B for oral administration has resulted in a highly efficacious antileishmanial treatment that significantly reduces or eradicates liver parasitemia in a murine model of visceral leishmaniasis. This formulation has overcome amphotericin B's significant physicochemical barriers to absorption and holds promise for the development of a self-administered oral therapy for the treatment of visceral leishmaniasis.

PMID: 19545212 [PubMed - as supplied by publisher]

9: Clin Infect Dis. 2009 Jun 15;48(12):1736-40.Click here to read LinkOut

Prevalence and vertical transmission of Trypanosoma cruzi infection among pregnant Latin American women attending 2 maternity clinics in Barcelona, Spain.

Muñoz J, Coll O, Juncosa T, Vergés M, del Pino M, Fumado V, Bosch J, Posada EJ, Hernandez S, Fisa R, Boguña JM, Gállego M, Sanz S, Portús M, Gascón J.

Barcelona Centre for International Health Research, Hospital Clinic Barcelona, IDIBAPS, c/ Villarroel, 170, Barcelona 08036, Spain. jose.munoz@manhica.net

We performed a prospective screening for Trypanosoma cruzi infection in 1350 Latin American pregnant women and their offspring in Barcelona, Spain. The rate of seroprevalence was 3.4%, and 7.3% of the newborns were infected. Routine screening and management programs in maternity wards may be warranted.

PMID: 19438393 [PubMed - indexed for MEDLINE]

10: Vet Rec. 2009 Apr 18;164(16):487-90.Click here to read LinkOut

Serum phosphorus concentrations in dogs with leishmaniosis at different stages of chronic kidney disease.

Cortadellas O, Fernández-del Palacio MJ, Talavera J, Bayón A.

Clínica Veterinaria Germanías, Avinguda de la Republica Argentina, Valencia, Spain. germanias@telefonica.net

Serum phosphorus concentrations were measured in 155 dogs with leishmaniosis at different stages of chronic kidney disease (CKD), and in 54 healthy dogs. CKD was classified into six stages, as follows: stage 0 (dogs with no evidence of CKD), serum creatinine (SCr) less than 125 micromol/l and urine protein:creatinine ratio (UPC) less than 0.2; stage 1A, SCr less than 125 micromol/l and UPC 0.2 to 0.5; stage 1B, SCr less than 125 micromol/l and UPC over 0.5; stage 2, SCr 125 micromol/l to 180 micromol/l; stage 3, SCr 181 micromol/l to 440 micromol/l; stage 4, SCr over 440 micromol/l. The dogs' serum phosphorus concentrations correlated significantly with the severity of CKD (P<0.001), and hyperphosphataemia (>1.8 mmol/l) affected 12 per cent, 11.8 per cent, 50 per cent, 76.9 per cent and 100 per cent of the dogs at stages 1A, 1B, 2, 3 and 4, respectively.

PMID: 19377087 [PubMed - indexed for MEDLINE]

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1 comment:

  1. shashankMarch 6, 2010 at 11:55 PM

    Here is a link to more information about the genetics of Peroxisomal Biosynthesis Disorders that was prepared by our genetic counselor and which has links to some useful resources for those dealing with this condition: http://www.accessdna.com/condition/Peroxisomal_Biosynthesis_Disorders/406. There is also a phone number listed if you need to speak to a genetic counselor by phone. I hope it helps. Thanks, AccessDNA

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