Vijay Kumar Prajapati | Central University Of Rajasthan (original) (raw)

Papers by Vijay Kumar Prajapati

Current drug targets, 2013

Failure of conventional as well as target-based therapy against the advanced metastatic cancers i... more Failure of conventional as well as target-based therapy against the advanced metastatic cancers is a significant clinical problem. While some cancers, such as pancreatic cancer, respond poorly to any kind of therapies, tumor relapse is often observed in many other cancer types after initial therapeutic response. Hence, significant research is being conducted to understand the mechanisms underlying therapeutic refractoriness of cancer. During the past decade, cancer stem cell (CSC) hypothesis has gained significant experimental and clinical support, and CSCs have emerged as potentially useful pharmacologic targets. MicroRNAs (miRNAs) are a group of small (~18-25 nucleotides) non-protein encoding RNAs that are now established as important regulators of gene expression. They can function as tumor promoters (oncomirs) or suppressors (anti-oncomirs) and thus hold profound implications for cancer therapy. Recent studies have identified several miRNAs to be differentially expressed in CSCs and established their role in targeting genes and pathways supporting cancer stemness properties. Here, we discuss these findings and review recent advances in miRNA-based strategies to exploit therapeutic potential of miRNAs in cancer treatment.

The American journal of tropical medicine and hygiene, 2012

Regional variations in susceptibility of Leishmania donovani clinical isolates have been reported... more Regional variations in susceptibility of Leishmania donovani clinical isolates have been reported to antimonials but not other antileishmanial drugs. Therefore, we evaluated the susceptibility of four antileishmanial drugs in clinical use in 28 clinical isolates from endemic and non-endemic regions in the J774A.1 macrophage cell line, and we found increased tolerance of miltefosine and paromomycin in isolates from a patient from a high endemic region. Effective dose for 90% killing (ED 90 ) values were significantly higher for miltefosine (P = 0.005) and paromomycin (P = 0.02) in isolates from the high endemic region, although there were no significant differences between ED 50 values for paromomycin, miltefosine, and amphotericin B in the non-versus endemic region isolates. This report is the first of higher ED 90 values for miltefosine and paromomycin indicating susceptibility difference between regions for these newly introduced drugs by the parasite, and their use should be carefully monitored through directly observed therapy or multidrug treatment to preserve their efficacy for longer periods.

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2012

Background. Miltefosine is the only oral drug available for treatment of Indian visceral leishman... more Background. Miltefosine is the only oral drug available for treatment of Indian visceral leishmaniasis (VL), which was shown to have an efficacy of 94% in a phase III trial in the Indian subcontinent. Its unrestricted use has raised concern about its continued effectiveness. This study evaluates the efficacy and safety of miltefosine for the treatment of VL after a decade of use in India.

Parasitology research, 2012

Cryptolepine (5-methyl-10H-indolo [3, 2-b] quinoline), an indoloquinoline alkaloid (1) isolated f... more Cryptolepine (5-methyl-10H-indolo [3, 2-b] quinoline), an indoloquinoline alkaloid (1) isolated from a medicinal plant traditionally used in Western Africa for treatment of malaria, has been shown to possess broad spectrum biological activity in addition to its antiplasmodial effect. Here, the antileishmanial properties of 11 synthetic derivatives of cryptolepine against Leishmania donovani parasites have been evaluated for the first time. 2,7-Dibromocryptolepine (8; IC50 0.5 ± 0.1 μM) was found to be the most active analogue against the promastigote form of a classical L. donovani strain (AG83) in comparison to the natural alkaloid, cryptolepine (1; IC50 1.6 ± 0.1 μM). Further, 8 was found to substantially inhibit the intracellular amastigote forms of two clinical isolates, one of them being an SbV-resistant strain of L. donovani. Moreover, the toxicity of 8 against normal mouse peritoneal macrophage cells was markedly lower than that of 1 (IC50 values: 9.0 ± 1.2 and 1.1 ± 0.3 μM, respectively), indicating 8 to be a prospective “lead” towards novel antileishmanial therapy. This was supported by studies on the mechanism of cytotoxicity induced by 8 in L. donovani promastigotes (AG83), which revealed the cytoplasmic and nuclear features of metazoan apoptosis. Light microscopic observation demonstrated a gradual decline in the motility, cell volume, and survival of the treated parasites with increasing incubation time. Flow cytometric analysis of phosphatidylserine externalization and distribution of cells in different phases of cell cycle confirmed the presence of a substantial percentage of cells in early apoptotic stage. Disruption of mitochondrial membrane integrity in terms of depolarization of membrane potential, and finally degradation of chromosomal DNA into oligonucleosomal fragments—the hallmark event of apoptosis—characterized the mode of cell death in L. donovani promastigotes.

The American journal of tropical medicine and hygiene, 2013

Promastigote miltefosine (MIL) susceptibility was performed on Leishmania donovani isolates from ... more Promastigote miltefosine (MIL) susceptibility was performed on Leishmania donovani isolates from Indian patients with visceral leishmaniasis treated with MIL. Isolates that were obtained before the onset of MIL treatment, after completion of treatment (29th day), or at the time of treatment failure, were screened using in vitro promastigote assay. The MIL susceptibility of the pre-treatment isolates (N = 24, mean IC 50 ± SEM = 3.74 ± 0.38 μM) was significantly higher than that of the post-treatment group (N = 26, mean IC 50 ± SEM = 6.15 ± 0.52 μM; P = 0.0006) but was similar in the cured patients (N = 22, mean IC 50 ± SEM = 5.58 ± 0.56 μM) and those who failed treatment (N = 28, mean IC 50 ± SEM = 4.53 ± 0.47 μM). The pre/post-treatment results thus showed a 2-fold difference, whereas isolated from cured versus failed patients showed a similar susceptibility, suggesting that this higher tolerance is not responsible for MIL-treatment failure. Our work highlights the need for careful monitoring of MIL susceptibility for implementation in national VL elimination programs.

Current medicinal chemistry, 2012

The potential to deliver nanoparticles directly into the targeted cells is important in the thera... more The potential to deliver nanoparticles directly into the targeted cells is important in the therapeutic applications for infectious diseases. The possibility of therapeutic agent being attached to the nanoparticles by chemical modification has provided a novel drug delivery option. Interestingly, the discovery of carbon nanotubes and graphene has given an excellent imaging and therapeutic agent for the biomedical applications. In spite of continuous advancement in pharmaceutical drug delivery viz. micelles, vesicles, liquid crystals, etc., during the past decades, their prohibitive production has limited their use. Nanomaterials with their properties of biodegradation, equal biodistribution, mass production, and long time storage make them attractive alternatives for future biomedical applications. Nanoparticles surface functionalized with specific biomolecules based drug delivery has driven new direction for modulating the pharmacokinetics, pharmacodynamics, biorecognition, and increasing the efficacy of targeted drugs. These new strategies are likely to minimize drug degradation and loss, increase drug availability, and opens up new vistas for drug delivery.

Journal of clinical microbiology, 2011

Experimental parasitology, 2012

The Journal of infectious diseases, 2012

Amphotericin B (AmB), is a highly effective antileishmanial agent used as first-line treatment in... more Amphotericin B (AmB), is a highly effective antileishmanial agent used as first-line treatment in different formulations in visceral leishmaniasis endemic areas of Bihar, India. However, parenteral infusion, prolonged hospitalization, and toxicity are major hurdles. Our previous work demonstrated the efficacy and stability of functionalized carbon nanotubes as a delivery mechanism for AmB. In this study, using the hamster model, we have shown that this novel formulation of AmB can be administered orally, resulting in 99% inhibition of parasite growth following a 5-day course at 15 mg/kg body weight.

Experimental parasitology, 2013

World health organization has called for academic research and development of new chemotherapeuti... more World health organization has called for academic research and development of new chemotherapeutic strategies to overcome the emerging resistance and side effects exhibited by the drugs currently used against leishmaniasis. Diospyrin, a bis-naphthoquinone isolated from Diospyros montana Roxb., and its semi-synthetic derivatives, were reported for inhibitory activity against protozoan parasites including Leishmania. Presently, we have investigated the antileishmanial effect of a di-epoxide derivative of diospyrin (D17), both in vitro and in vivo. Further, the safety profile of D17 was established by testing its toxicity against normal macrophage cells (IC₅₀∼20.7 μM), and also against normal BALB/c mice in vivo. The compound showed enhanced activity (IC₅₀∼7.2 μM) as compared to diospyrin (IC₅₀∼12.6 μM) against Leishmania donovani promastigotes. Again, D17 was tested on L. donovani BHU1216 isolated from a sodium stibogluconate-unresponsive patient, and exhibited selective inhibition of the intracellular amastigotes (IC₅₀∼0.18 μM). Also, treatment of infected BALB/c mice with D17 at 2mg/kg/day reduced the hepatic parasite load by about 38%. Subsequently, computational docking studies were undertaken on selected enzymes of trypanothione metabolism, viz. trypanothione reductase (TryR) and ornithine decarboxylase (ODC), followed by the enzyme kinetics, where D17 demonstrated non-competitive inhibition of the L. donovani ODC, but could not inhibit TryR.

The Journal of antimicrobial chemotherapy, 2011

Objectives: This study describes the antileishmanial efficacy of the novel drug formulation of am... more Objectives: This study describes the antileishmanial efficacy of the novel drug formulation of amphotericin B (AmB) attached to functionalized carbon nanotubes (f-CNTs) and compares it with AmB.

International Journal for Parasitology

Recent clinical isolates of Leishmania donovani from the hyperendemic zone of Bihar were characte... more Recent clinical isolates of Leishmania donovani from the hyperendemic zone of Bihar were characterised in vitro in terms of their sensitivity towards sodium stibogluconate in a macrophage culture system. The resulting half maximal effective concentration (EC 50 ) values were compared with those of known sensitive isolates. Fifteen of the isolates showed decreased sensitivity towards SSG with an average EC 50 of 25.7 ± 4.5 lg/ml pentavalent antimony (defined as antimony resistant), whereas nine showed considerable sensitivity with an average EC 50 of 4.6 ± 1.7 lg/ml (defined as antimony sensitive). Out of those nine, seven were recent clinical isolates and the remaining two were known sensitive isolates. Compared with the antimony sensitive, resistant isolates showed enhanced expression of thiol metabolising enzymes in varying degrees coupled with increased intracellular non-protein thiol content, decreased fluorescence anisotropy (inversely proportional with membrane fluidity) and over-expression of the terminal glycoconjugates (N-acetyl-D-galactosaminyl residue). Macrophages infected with resistant but not with sensitive showed up-regulation of the ATP Binding Cassette transporter multidrug resistance protein 1 and permeability glycoprotein, while the supernatant contained abundant IL-10. The above results reinforce the notion that antimony resistant parasites have undergone a number of biochemical and biophysical changes as part of their adaptation to ensure their survival in the host.

The aim of the present study was to compare the efficacy of a nano form of amphotericin B deoxych... more The aim of the present study was to compare the efficacy of a nano form of amphotericin B deoxycholate with that of conventional amphotericin B deoxycholate for the treatment of visceral leishmaniasis.

Parasite Immunology, 2010

Natural regulatory T cells (CD4+ CD25+ Foxp3+), natural regulatory T cells (nTreg), play an impor... more Natural regulatory T cells (CD4+ CD25+ Foxp3+), natural regulatory T cells (nTreg), play an important role in the regulation of inflammatory immune responses. However, the immunosuppressive properties of nTreg may unfavourably affect the host’s ability to clear certain infections. In human visceral leishmaniasis (VL), reports on the frequency and function of nTreg are not conclusive. A limitation of our own previous studies that did not indicate a major role for Foxp3+ nTreg in VL pathogenesis was that Foxp3 was measured by mRNA expression alone, as other tools were not available at the time. We have in this study assessed CD4+CD25+Foxp3+ cells in splenic aspirates and peripheral blood mononuclear cells (PBMC) from an extensive series of patients with VL and endemic controls (EC) by flow cytometry (FACS). The results do not show increased frequencies of Foxp3+ cells in patient with VL pre- and post-treatment, neither were they elevated when compared to PBMC of EC. We conclude that active VL is not associated with increased frequencies of peripheral Foxp3 Treg or accumulation at the site of infection.

Journal of Clinical Microbiology, 2010

Serial dilution of blood and spleen biopsy specimens, plated on Novy-MacNeal-Nicolle (NNN) blood ... more Serial dilution of blood and spleen biopsy specimens, plated on Novy-MacNeal-Nicolle (NNN) blood agar using microtiter culture plates, is a sensitive and reproducible method for detection and growth of Leishmania parasites. Plates could be easily monitored, and growth could be rapidly detected. Moreover, parasite number may be estimated using this technique.

Infection Genetics and Evolution, 2010

PLOS Neglected Tropical Diseases, 2012

Background: With widespread resistance to antimonials in Visceral Leishmaniasis (VL) in the India... more Background: With widespread resistance to antimonials in Visceral Leishmaniasis (VL) in the Indian subcontinent, Miltefosine (MIL) has been introduced as the first line therapy. Surveillance of MIL susceptibility in natural populations of Leishmania donovani is vital to preserve it and support the VL elimination program.

PLOS Neglected Tropical Diseases, 2011