Nasib Singh

Publications

• 1.60

  Impact points

  Leishmania donovani: oral therapy with glycosyl 1,4-dihydropyridine analogue showing apoptosis like phenotypes targeting pteridine reductase 1 in intracellular amastigotes.

  Jaspreet Kaur, Nasib Singh, Biswajit Kumar Singh, Anuradha Dube, Rama Pati Tripathi, Prashant Singh, Neeloo Singh

  Experimental parasitology. 02/2010; 125(3):310-4.

  Glycosyl 1,4-dihydropyridine analogue (2,6-dimethyl-4-(3-O-benzyl-1,2-O-isopropylidene-beta-l-threo pentofuranos-4-yl)-1-phenyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid diethyl ester) synthesized in our laboratory, inhibited Leishmania donovani infection in vitro and in hamsters (Mesocricetus aura... [more] Glycosyl 1,4-dihydropyridine analogue (2,6-dimethyl-4-(3-O-benzyl-1,2-O-isopropylidene-beta-l-threo pentofuranos-4-yl)-1-phenyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid diethyl ester) synthesized in our laboratory, inhibited Leishmania donovani infection in vitro and in hamsters (Mesocricetus auratus) when administered orally. This analogue is nontoxic, cell-permeable and orally effective. This glycosyl dihydropyridine analogue functioned through arrest of cells in sub-G0/G1-phase, triggering mitochondrial membrane depolarization-mediated programmed cell death of the intracellular amastigotes.
• 4.96

  Impact points

  Reporter genes facilitating discovery of drugs targeting protozoan parasites.

  Anuradha Dube, Reema Gupta, Nasib Singh

  Trends in parasitology. 10/2009; 25(9):432-9.

  Transfection of protozoan parasites, such as Plasmodium, Leishmania, Trypanosoma and Toxoplasma, with various reporter gene constructs, has revolutionized studies to understand the biology of the host-parasite interactions at the cellular level. It has provided impetus to the development of rapid an... [more] Transfection of protozoan parasites, such as Plasmodium, Leishmania, Trypanosoma and Toxoplasma, with various reporter gene constructs, has revolutionized studies to understand the biology of the host-parasite interactions at the cellular level. It has provided impetus to the development of rapid and reliable drug screens both for established drugs and for new molecules against different parasites and other pathogens. Furthermore, reporter genes have proved to be an excellent and promising tool for studying disease progression. Here, we review the recent advances made by using reporter genes for in vitro and in vivo drug screening, high-throughput screening, whole-animal non-invasive imaging for parasites and for the study of several aspects of host-parasite interactions.
• 1.51

  Impact points

  An orally effective dihydropyrimidone (DHPM) analogue induces apoptosis-like cell death in clinical isolates of Leishmania donovani overexpressing pteridine reductase 1.

  Neeloo Singh, Jaspreet Kaur, Pranav Kumar, Swati Gupta, Nasib Singh, Angana Ghosal, Avijit Dutta, Ashutosh Kumar, RamaPati Tripathi, Mohammad Siddiqi, Chitra Mandal, Anuradha Dube

  Parasitology research. 08/2009;

  The protozoan parasite Leishmania donovani is the causative agent of visceral leishmaniasis. The enzyme pteridine reductase 1 (PTR1) of L. donovani acts as a metabolic bypass for drugs targeting dihydrofolate reductase (DHFR); therefore, for successful antifolate chemotherapy to be developed against... [more] The protozoan parasite Leishmania donovani is the causative agent of visceral leishmaniasis. The enzyme pteridine reductase 1 (PTR1) of L. donovani acts as a metabolic bypass for drugs targeting dihydrofolate reductase (DHFR); therefore, for successful antifolate chemotherapy to be developed against Leishmania, it must target both enzyme activities. Leishmania cells overexpressing PTR1 tagged at the N-terminal with green fluorescent protein were established to screen for proprietary dihydropyrimidone (DHPM) derivatives of DHFR specificity synthesised in our laboratory. A cell-permeable molecule with impressive antileishmanial in vitro and in vivo oral activity was identified. Structure activity relationship based on homology model drawn on our recombinant enzyme established the highly selective inhibition of the enzyme by this analogue. It was seen that the leishmanicidal effect of this analogue is triggered by programmed cell death mediated by the loss of plasma membrane integrity as detected by binding of annexin V and propidium iodide (PI), loss of mitochondrial membrane potential culminating in cell cycle arrest at the sub-G0/G1 phase and oligonucleosomal DNA fragmentation. Hence, this DHPM analogue [(4-fluoro-phenyl)-6-methyl-2-thioxo-1, 2, 3, 4-tetrahydropyrimidine-5-carboxylic acid ethyl ester] is a potent antileishmanial agent that merits further pharmacological investigation.
• 4.35

  Impact points

  Transgenic Leishmania donovani clinical isolates expressing green fluorescent protein constitutively for rapid and reliable ex vivo drug screening.

  Nasib Singh, Reema Gupta, Anil K Jaiswal, Shyam Sundar, Anuradha Dube

  The Journal of antimicrobial chemotherapy. 07/2009;

  Objectives Several Leishmania strains with episomal expression of green fluorescent protein (GFP) require constant drug pressure for its continuous expression and hence limit its use in ex vivo or in vivo systems. The aim of this study was to alleviate this problem by stably integrating the GFP gene... [more] Objectives Several Leishmania strains with episomal expression of green fluorescent protein (GFP) require constant drug pressure for its continuous expression and hence limit its use in ex vivo or in vivo systems. The aim of this study was to alleviate this problem by stably integrating the GFP gene into the parasite genome, so as to use these transfectants for ex vivo and in vivo drug screening. Methods The GFP gene was integrated downstream of the 18S ribosomal promoter region of Leishmania donovani. After initial selection, GFP-expressing parasites-both sodium stibogluconate (SAG)-susceptible (2001) and -resistant (2039) isolates-were grown without adding G418. The infectivity of these transfectants to macrophages (J774.1) as well as to hamsters was checked. The ex vivo screening assay was standardized using standard antileishmanial drugs. Results A constitutive and enhanced expression of GFP in promastigote and amastigote stages was achieved for approximately 12 months without any need for drug pressure. These transfectants were highly infective to macrophage cell lines as well as to hamsters, as observed by fluorescence microscopy and flow cytometry (FACS). GFP-tagged promastigotes as well as intracellular amastigotes were found to be highly susceptible to miltefosine, amphotericin B and pentamidine, in a concentration-dependent manner. SAG was inactive against the GFP-promastigotes, as well as SAG-resistant intracellular amastigotes, correlating well with earlier reports. Conclusions The GFP-transfectants were found to be suitable for FACS-based ex vivo screening assays. They were also infective to hamsters up to day 60 post-infection.
• 0.81

  Impact points

  Constituents of Tinospora sinensis and their antileishmanial activity against Leishmania donovani.

  Rakesh Maurya, Prasoon Gupta, Kailash Chand, Manmeet Kumar, Preety Dixit, Nasib Singh, Anuradha Dube

  Natural product research. 02/2009; 23(12):1134-43.

  Two new compounds 4-methyl-heptadec-6-enoic acid ethyl ester (2) and 3-hydroxy-2,9,11-trimethoxy-5,6-dihydro isoquino[3,2-a]isoquinolinylium (7) were isolated from an ethanolic extract of the stems of Tinospora sinensis, along with six known compounds (1, 3-6 and 8). The structures of new compounds ... [more] Two new compounds 4-methyl-heptadec-6-enoic acid ethyl ester (2) and 3-hydroxy-2,9,11-trimethoxy-5,6-dihydro isoquino[3,2-a]isoquinolinylium (7) were isolated from an ethanolic extract of the stems of Tinospora sinensis, along with six known compounds (1, 3-6 and 8). The structures of new compounds were established on the basis of detailed spectroscopic studies. Compound 7 exhibited the highest in vitro antileishmanial activity against Leishmania donovani promastigotes and intracellular amastigotes, whereas compounds 2, 4, 5 and 6 demonstrated moderate activity. Other compounds were found to be inactive.
• 1.51

  Impact points

  Antileishmanial activity in vitro and in vivo of constituents of sea cucumber Actinopyga lecanora.

  Nasib Singh, Rajesh Kumar, Swati Gupta, Anuradha Dube, V Lakshmi

  Parasitology research. 08/2008; 103(2):351-4.

  In the search of new antileishmanial drugs from marine resources, we have investigated Actinopyga lecanora, a coral reef sea cucumber, for its in vitro and in vivo activities. Methanol extract and n-butanol fraction of A. lecanora exhibited excellent Leishmania donovani inhibition. Among the two gly... [more] In the search of new antileishmanial drugs from marine resources, we have investigated Actinopyga lecanora, a coral reef sea cucumber, for its in vitro and in vivo activities. Methanol extract and n-butanol fraction of A. lecanora exhibited excellent Leishmania donovani inhibition. Among the two glycosides isolated from n-butanol fraction, holothurin B (2) displayed excellent in vitro and moderate in vivo leishmanicidal activity, whereas holothurin A (1) revealed only moderate action. These findings provide an important marine lead toward the development of new antileishmanial drugs and necessitate the further exploration of rich and diverse marine resources for more potent bioactive molecules.
• 1.60

  Impact points

  Leishmania donovani pteridine reductase 1: Biochemical properties and structure-modeling studies.

  Pranav Kumar, Ashutosh Kumar, Shyam Sundar Verma, Namrata Dwivedi, Nasib Singh, Mohammad Imran Siddiqi, Rama Pati Tripathi, Anuradha Dube, Neeloo Singh

  Experimental parasitology. 07/2008;

  Pteridine reductase 1 (PTR1, EC 1.5.1.33) is a NADPH dependent short-chain reductase (SDR) responsible for the salvage of pterins in the protozoan parasite Leishmania. This enzyme acts as a metabolic bypass for drugs targeting dihydrofolate reductase, therefore, for successful antifolate chemotherap... [more] Pteridine reductase 1 (PTR1, EC 1.5.1.33) is a NADPH dependent short-chain reductase (SDR) responsible for the salvage of pterins in the protozoan parasite Leishmania. This enzyme acts as a metabolic bypass for drugs targeting dihydrofolate reductase, therefore, for successful antifolate chemotherapy to be developed against Leishmania, it must target both enzyme activities. Based on homology model drawn on recombinant pteridine reductase isolated from a clinical isolate of L. donovani, we carried out molecular modeling and docking studies with two compounds of dihydrofolate reductase specificity showing promising antileishmanial activity in vitro. Both the inhibitors appeared to fit well in the active pocket revealing the tight binding of the carboxylic acid ethyl ester group of pyridine moiety to pteridine reductase and identify the important interactions necessary to assist the structure based development of novel pteridine reductase inhibitors.
• 1.51

  Impact points

  Evaluation of antileishmanial potential of Tinospora sinensis against experimental visceral leishmaniasis.

  Nasib Singh, Awanish Kumar, Prasoon Gupta, Kailash Chand, Mukesh Samant, Rakesh Maurya, Anuradha Dube

  Parasitology research. 03/2008; 102(3):561-5.

  The chemotherapeutic interventions against visceral leishmaniasis (VL) are limited and facing serious concerns of toxicity, high cost, and emerging drug resistance. There is a greater interest in new drug developments from traditionally used medicinal plants which offers unprecedented diversity in s... [more] The chemotherapeutic interventions against visceral leishmaniasis (VL) are limited and facing serious concerns of toxicity, high cost, and emerging drug resistance. There is a greater interest in new drug developments from traditionally used medicinal plants which offers unprecedented diversity in structures and bioactivity. With this rationale, ethanolic extract of Tinospora sinensis Linn and its four fractions were tested in vitro against promastigotes and intracellular amastigotes and in vivo in Leishmania donovani infected hamsters. Ethanolic extract exhibited an appreciable activity against promastigotes (IC(50) 37.6+/-6.2 microg/ml) and intracellular amastigotes (IC(50) 29.8+/-3.4 microg/ml). In hamsters, it resulted in 76.2+/-9.2% inhibition at 500 mg/kg/day x 5 oral dose level. Among fractions, n-butanol imparted highest in vitro and in vivo activities. Ethanolic extract and butanol fraction also enhances reactive oxygen species (ROS) and nitric oxide (NO) release. The results indicate that T. sinensis may provide new lead molecules for the development of alternative drugs against VL.
• 1.51

  Impact points

  Age-influenced population kinetics and immunological responses of Leishmania donovani in hamsters.

  Nasib Singh, Mukesh Samant, Shraddha K Gupta, Awanish Kumar, Anuradha Dube

  Parasitology research. 10/2007; 101(4):919-24.

  Susceptibility of animals to infections depends upon various factors including sex and age of the host, which plays a pivotal role. In this communication, we have investigated the "intake" of Leishmania donovani infection in young (3-4 weeks old) and adult (15-16 weeks old) golden hamsters... [more] Susceptibility of animals to infections depends upon various factors including sex and age of the host, which plays a pivotal role. In this communication, we have investigated the "intake" of Leishmania donovani infection in young (3-4 weeks old) and adult (15-16 weeks old) golden hamsters. The splenic parasite load in young hamsters on day 15 post infection (p.i.) was 54 +/- 4 amastigotes/100 macrophage nuclei and increased to 106.3 +/- 3.5 on day 30 p.i. However, adult group showed 2.2-(P < 0.001) and 1.75-fold (P < 0.001) lesser parasite burden on these days, respectively. But as the disease progresses further, differences in parasite burden become less significant, as revealed by comparable levels of parasite loads at 2 months p.i. Spleen weight measurements correspond to the above observations. In the young group, the levels of antileishmanial antibody rise two and 4.5 times on days 15 and 30 p.i., respectively, as compared to only 1.3 and 2.3 times increase in their respective adult counterparts. However, after 2 months of infection both groups recorded analogous (12-fold) rise in antibody levels. Both mitogenic and antigenic responses in adult hamsters were less suppressed compared to young hamsters on days 15 and 30 p.i. However, both groups exhibited highly suppressed cell-mediated immune (CMI) responses after 2 months of infection. These findings implicate that age of the host may influence the susceptibility and resistance to Leishmania infection.
• 2.08

  Impact points

  Proteophosphoglycan is differentially expressed in sodium stibogluconate-sensitive and resistant Indian clinical isolates of Leishmania donovani.

  M Samant, A A Sahasrabuddhe, N Singh, S K Gupta, S Sundar, A Dube

  Parasitology. 09/2007; 134(Pt 9):1175-84.

  Leishmania produce several types of mucin-like glycoproteins called proteophosphoglycans (PPGs) some of which are secreted while others are found on the surface of promastigotes and amastigotes. These proteins are thought to be important in the transmission, invasion and subsequent intracellular sur... [more] Leishmania produce several types of mucin-like glycoproteins called proteophosphoglycans (PPGs) some of which are secreted while others are found on the surface of promastigotes and amastigotes. These proteins are thought to be important in the transmission, invasion and subsequent intracellular survival of parasites. The structure and function of PPGs are species and stage-specific in the case of L. major and L. mexicana, but no such information has hitherto been available for L. donovani. This study presents, for the first time, an initial characterization (localization) of PPG in sodium stibogluconate (SSG)-resistant and sensitive clinical isolates of L. donovani from Bihar (India) by confocal microscopy, flow cytometry and Western blotting using antibodies to L. major PPG. Confocal microscopy analysis revealed that both promastigotes and amastigotes possess PPG on their cell membrane and flagellar pocket membrane but its expression was variable in different isolates. The quantitative analysis by FACS and Western blotting showed that the expression and intensity of PPG bands was higher in SSG-resistant isolates. This study suggests the possibilities of involvement of PPG in drug-resistant mechanisms and of using PPG abundance as a marker for identifying drug-resistant clinical isolates in Indian kala azar.
• 1.51

  Impact points

  Antileishmanial potential of a marine sponge, Haliclona exigua (Kirkpatrick) against experimental visceral leishmaniasis.

  Anuradha Dube, Nasib Singh, A Saxena, V Lakshmi

  Parasitology research. 08/2007; 101(2):317-24.

  In this study, we are reporting antileishmanial activity of a marine sponge Haliclona exigua, belonging to phylum Porifera. The crude methanol extract and its three fractions were tested both in vitro and in vivo. The crude extract exerted almost complete inhibition of promastigotes at 50 microg/ml ... [more] In this study, we are reporting antileishmanial activity of a marine sponge Haliclona exigua, belonging to phylum Porifera. The crude methanol extract and its three fractions were tested both in vitro and in vivo. The crude extract exerted almost complete inhibition of promastigotes at 50 microg/ml and 76.4 +/- 6.5% inhibition of intracellular amastigotes at 100 microg/ml concentration with IC50 values of 18.6 microg/ml and 47.2 microg/ml, respectively. When administered to Leishmania donovani infected hamsters at a dose of 500 mg/kg x 5, p.o., it resulted in 72.2 +/- 10.4% inhibition of intracellular amastigotes. At a lower dose (250 mg/kg), it exhibited 43.9 +/- 5.1% inhibition. Among the fractions, highest antileishmanial activity both in vitro (>90%) and in vivo (60.9 +/- 18.3%) was observed in n-butanol (soluble) fraction with IC50 values of 8.2 mug/ml and 31.2 microg/ml against promastigotes and intracellular amastigotes, respectively. Hexane fraction also showed comparatively good activity against both the stages of parasites in vitro but was moderately active in leishmania-infected hamsters. Chloroform fraction resulted in 45 +/- 10.2% inhibition in vivo at a dose of 500 mg/kg x 5, p.o., whereas it was inactive in vitro. n-Butanol (insoluble) fraction was inactive both in vitro and in vivo. Araguspongin C, an alkaloid isolated from n-butanol (soluble) fraction exhibited moderate inhibition of promastigotes and intracellular amastigotes at 100 microg/ml but showed weak antileishmanial action in vivo. Our findings indicate that this marine sponge has the potential to provide new lead toward development of an effective antileishmanial agent and, hence, calls for more exhaustive studies for exploiting the vast world of marine resources to combat the scourge of several parasitic diseases.
• 2.17

  Impact points

  In vitro and in vivo leishmanicidal activity of Dysoxylum binectariferum and its fractions against Leishmania donovani.

  V Lakshmi, K Pandey, A Kapil, N Singh, M Samant, A Dube

  Phytomedicine : international journal of phytotherapy and phytopharmacology. 02/2007; 14(1):36-42.

  The leishmanicidal effect of crude ethanolic extract of stem bark of Dysoxylum binectariferum and its fractions has been investigated against Leishmania donovani, the causative agent of visceral leishmaniasis. Ethanolic extract was lethal to promastigotes as well as amastigote forms in macrophage sy... [more] The leishmanicidal effect of crude ethanolic extract of stem bark of Dysoxylum binectariferum and its fractions has been investigated against Leishmania donovani, the causative agent of visceral leishmaniasis. Ethanolic extract was lethal to promastigotes as well as amastigote forms in macrophage system at the concentration of 100 microg/ml. Chloroform fraction significantly inhibited promastigote multiplication and was also active against amastigotes in infected J774A.1 macrophages at 100 microg/ml. Hexane fraction was moderately active and the other fractions were inactive against both the forms. When tested in vivo in hamsters, ethanolic extract was toxic at 500 mg/kg whereas exhibited marginal activity (67.7+/-5.3%) at 250 mg/kg x 5, p.o. on day 7 post treatment (p.t.) which increases slightly (69+/-4.7) by day 30 p.t. Chloroform and n-hexane fractions exhibited 64.3+/-4% and 47.8+/-4.6% parasite inhibition at the dose of 100 mg/kg x 5 p.o., respectively. The pure compound, rohitukine, obtained from chloroform fraction showed weaker in vitro activity and was ineffective in infected hamsters. The lead potential of this plant need further investigations.

• Landrace/gender-based differences in phenol and thiocyanate contents and biological activity in Piper betle L

  Shweta Tripathi, Nasib Singh, Shilpi Shakya, Anil Daangi, Shailja Misra-Bhattacharya, Anuradha Dube, N. Kumar

  Current Science. 01/2006; 91:746-749.

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• 2.65

  Impact points

  Glycolipids and other constituents from Desmodium gangeticum with antileishmanial and immunomodulatory activities.

  Pushpesh Kumar Mishra, Nasib Singh, Ghufran Ahmad, Anuradha Dube, Rakesh Maurya

  Bioorganic & medicinal chemistry letters. 11/2005; 15(20):4543-6.

  Nineteen compounds of various classes, such as flavonoid glycosides, pterocarpanoids, lipids, glycolipids, and alkaloids, were isolated and identified from the Desmodium gangeticum whole plant. Aminoglucosyl glycerolipid (8) is reported here for the first time. Its structure has been elucidated by s... [more] Nineteen compounds of various classes, such as flavonoid glycosides, pterocarpanoids, lipids, glycolipids, and alkaloids, were isolated and identified from the Desmodium gangeticum whole plant. Aminoglucosyl glycerolipid (8) is reported here for the first time. Its structure has been elucidated by spectroscopic and degradation studies. This novel compound exhibited in vitro antileishmanial and immunomodulatory activities, as it enhanced nitric oxide (NO) production and provided resistance against infection established in peritoneal macrophages by the protozoan parasite Leishmania donovani. Another known compound, glycosphingolipid (cerebroside) (7) was found to possess significant in vitro antileishmanial and immunomodulatory activities against the same parasite. Other compounds were found to be inactive.
• 1.51

  Impact points

  Refractoriness to the treatment of sodium stibogluconate in Indian kala-azar field isolates persist in in vitro and in vivo experimental models.

  Anuradha Dube, Nasib Singh, Shyam Sundar, Neeloo Singh

  Parasitology research. 07/2005; 96(4):216-23.

  Ever since their discovery about 60 years ago as therapeutic agent for visceral leishmaniasis (VL) or kala-azar, pentavalent antimonials (Sb(v)) have remained the first line treatment of choice all over the world including India. But recently, the number of kala-azar patients unresponsive to sodium ... [more] Ever since their discovery about 60 years ago as therapeutic agent for visceral leishmaniasis (VL) or kala-azar, pentavalent antimonials (Sb(v)) have remained the first line treatment of choice all over the world including India. But recently, the number of kala-azar patients unresponsive to sodium stibogluconate (SSG) therapy, is steadily increasing in India. In this study, three clinical isolates, of which two were from SSG unresponsive and one from SSG responsive patients were evaluated for their infectivity and for their chemotherapeutic responses in vitro (macrophage-amastigote system) and in vivo (in hamsters). Persistence of SSG resistance was also checked by repeated passages in vitro as well as in vivo. The drug resistant strains (2039 and 2041) did not respond to SSG therapy both in vitro as well as in vivo but strains 2001 and Dd8 showed full sensitivity to SSG treatment. All the four strains responded well to amphotericin B and miltefosine treatment both in macrophages and in hamsters. The specific chemotherapeutic responses of all the strains to SSG were consistently persistent after repeated passages in cultures and in vivo, which indicates that these isolates are truly refractory to SSG treatment in field conditions. Two isolates were also transfected with green fluorescent protein (GFP) for the development of in vitro assay for studying antileishmanial activities of new and reference drugs in macrophages by flow cytometry.
• 2.32

  Impact points

  Efficacy of Desmodium gangeticum extract and its fractions against experimental visceral leishmaniasis.

  Nasib Singh, Pushpesh Kumar Mishra, Aruna Kapil, Kamal Ram Arya, Rakesh Maurya, Anuradha Dube

  Journal of ethnopharmacology. 04/2005; 98(1-2):83-8.

  Crude ethanolic extract of Indian medicinal plant, Desmodium gangeticum (A001) and its three fractions-hexane (F002), n-butanol (F003) and aqueous (F004) were evaluated chemoprophylactically and chemotherapeutically against experimental visceral leishmaniasis in hamsters. Ethanolic extract showed 41... [more] Crude ethanolic extract of Indian medicinal plant, Desmodium gangeticum (A001) and its three fractions-hexane (F002), n-butanol (F003) and aqueous (F004) were evaluated chemoprophylactically and chemotherapeutically against experimental visceral leishmaniasis in hamsters. Ethanolic extract showed 41.2+/-5.3% inhibition of parasite multiplication when administered at a dose of 250 mg/kgx2 on day -7 and +7 of Leishmania donovani challenge. Its n-butanol fraction exhibited better efficacy than the ethanolic extract to the tune of 66.7+/-6.1% inhibition when administered at similar dose schedule. But the other two fractions failed to exert any action prophylactically. F003 also imparted significant (P<0.001) non-specific resistance to peritoneal macrophages against Leishmania infection. F003 also showed moderate antileishmanial activity when tested against established infection of Leishmania donovani in hamsters but the rest three fractions failed to show any significant inhibition of parasite multiplication. These findings revealed that this plant has potential prophylactic and therapeutic efficacy against Leishmania infection and warrants detailed investigations on its possible immunopotentiatory actions.

• Experimental models for Kala azar vaccine and drug development research

  Anuradha Dube, Nasib Singh

  01/2005: pages 193-214;
• 2.71

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  Efficacy of human beta-casein fragment (54-59) and its synthetic analogue compound 89/215 against Leishmania donovani in hamsters.

  Preeti Sharma, Nasib Singh, Ravendra Garg, Wahajul Haq, Anuradha Dube

  Peptides. 12/2004; 25(11):1873-81.

  The characteristic feature of visceral leishmaniasis (VL) is the profound impairment of immune system of the infected host, which contributes significantly to the partial success of antileishmanial chemotherapy. Since in VL, cure is the combinatorial effect of drug and immune status of the host, the... [more] The characteristic feature of visceral leishmaniasis (VL) is the profound impairment of immune system of the infected host, which contributes significantly to the partial success of antileishmanial chemotherapy. Since in VL, cure is the combinatorial effect of drug and immune status of the host, the rationale approach towards antileishmanial chemotherapy would be to potentiate the immune functioning of the host to extract desired results. Towards this direction several rationally designed analogues of human beta-casein fragment (54-59) were evaluated for their ability to stimulate the non-specific resistance in hamsters against Leishmania donovani infection. By virtue of being derived from the food protein casein derivatives may be devoid of unwanted side effects associated with the substances of microbial origin, e.g. muramyl dipeptide (MDP). Out of this one peptide Val-Glu-Gly-Ile-Pro-Tyr (compound 89/215) had been reported to have such activity. In this communication, the prophylactic and therapeutic efficacy of the peptide along with its natural sequence has been evaluated in detail against experimental VL in hamsters. Their use as an adjunct to chemotherapy was also explored. Human beta-casein fragment, compound 89/215 and MDP were tested in vivo at various dose levels wherein compound 89/215 showed superiority over MDP at 3 mg/kg x 2 given intraperitoneally (i.p.). Compound 89/215 sensitized peritoneal macrophages acquired considerable resistance and only 24% of the cells were found infected in comparison to control peritoneal macrophages where 76.4% of the cells were found infected. Similarly, the efficacy of sodium antimony gluconate (SAG) in hamsters pretreated with compound 89/215 enhanced significantly (P < 0.001). This peptide also exhibited considerably good therapeutic efficacy when evaluated either alone or in combination with SAG in established infection of L. donovani.