Monidipa Ghosh

Synthesis of a novel quinoline derivative, 2-(2-methylquinolin-4-ylamino)-N-phenylacetamide—a potential antileishmanial agent

Some novel quinoline derivatives were prepared and tested for antileishmanial activity. 2-(2-Methylquinolin-4-ylamino)-N-phenylacetamide (2) was found to be significantly more active than the standard antileishmanial drug sodium antimony gluconate (SAG) in reducing the parasite load both in the spleen and liver at a much lower concentration in hamster models. The results suggest that the compound could be exploited as an antileishmanial drug.

Dendritic Cell-Based Immunotherapy Combined with Antimony-Based Chemotherapy Cures Established Murine Visceral Leishmaniasis

Dendritic cells (DCs) have been proposed to play a critical role as adjuvants in vaccination and immunotherapy. In this study we evaluated the combined effect of soluble Leishmania donovani Ag (SLDA)-pulsed syngeneic bone marrow-derived DC-based immunotherapy and antimony-based chemotherapy for the treatment of established murine visceral leishmaniasis. Three weekly injections of SLDA-pulsed DCs into L. donovani-infected mice reduced liver and splenic parasite burden significantly, but could not clear parasite load from these organs completely. Strikingly, the conventional antileishmanial chemotherapy (sodium antimony gluconate) along with injections of SLDA-pulsed DCs resulted in complete clearance of parasites from both these organs. Repetitive in vitro stimulation of splenocytes from uninfected or L. donovani-infected mice with SLDA-pulsed DCs led to the emergence of CD4+ T cells with characteristics of Th1 cells. Our data indicate that DC-based immunotherapy enhances the in vivo antileishmanial potential of antimony or vice versa.

N-acetyl cysteine enhances imatinib-induced apoptosis of Bcr-Abl+ cells by endothelial nitric oxide synthase-mediated production of nitric oxide

IntroductionImatinib, a small-molecule inhibitor of the Bcr-Abl kinase, is a successful drug for treating chronic myeloid leukemia (CML). Bcr-Abl kinase stimulates the production of H2O2, which in turn activates Abl kinase. We therefore evaluated whether N-acetyl cysteine (NAC), a ROS scavenger improves imatinib efficacy.Materials and methodsEffects of imatinib and NAC either alone or in combination were assessed on Bcr-Abl+ cells to measure apoptosis. Role of nitric oxide (NO) in NAC-induced enhanced cytotoxicity was assessed using pharmacological inhibitors and siRNAs of nitric oxide synthase isoforms. We report that imatinib-induced apoptosis of imatinib-resistant and imatinib-sensitive Bcr-Abl+ CML cell lines and primary cells from CML patients is significantly enhanced by co-treatment with NAC compared to imatinib treatment alone. In contrast, another ROS scavenger glutathione reversed imatinib-mediated killing. NAC-mediated enhanced killing correlated with cleavage of caspases, PARP and up-regulation and down regulation of pro- and anti-apoptotic family of proteins, respectively. Co-treatment with NAC leads to enhanced production of nitric oxide (NO) by endothelial nitric oxide synthase (eNOS). Involvement of eNOS dependent NO in NAC-mediated enhancement of imatinib-induced cell death was confirmed by nitric oxide synthase (NOS) specific pharmacological inhibitors and siRNAs. Indeed, NO donor sodium nitroprusside (SNP) also enhanced imatinib-mediated apoptosis of Bcr-Abl+ cells.ConclusionNAC enhances imatinib-induced apoptosis of Bcr-Abl+ cells by endothelial nitric oxide synthase-mediated production of nitric oxide.

Leishmania donovani Infection of Human Myeloid Dendritic Cells Leads to a Th1 Response in CD4+ T Cells from Healthy Donors and Patients with Kala-Azar

The role played by dendritic cells (DCs) in Leishmania donovani infection is poorly understood. Here, we report that L. donovani amastigotes efficiently infect human peripheral-blood monocyte-derived DCs. Opsonization with normal human serum enhanced the infectivity of amastigotes and promastigotes only marginally. Surface attachment versus internalization was distinguished by incubation of DCs with live, fluorescein isothiocyanate-labeled parasites, followed by quenching with crystal violet. Infection with amastigotes was accompanied by DC maturation, as was evident from the up-regulation of maturation-associated cell-surface markers, the nuclear translocation of RelB, and the release of cytokines. Amastigote-primed DCs produced inflammatory cytokines in response to subsequent treatment with interferon- gamma or anti-CD40 monoclonal antibody. When cocultured, amastigote-infected DCs induced T helper cell type 1 (Th1) responses both in naive allogeneic CD4(+) T cells and in autologous CD4(+) T cells from patients with kala-azar and up-regulated the expression of T-bet. Our data reveal that infection with L. donovani amastigotes induces a Th1 cytokine milieu in both DCs and T cells.

Present status of antileishmanial vaccines

The term leishmaniasis refers collectively to various clinical syndromes that are caused by obligate intracellular protozoa of the genus Leishmania. Approximately 350 million people in 8 countries are estimated to be threatened by the disease [1]. The World Health Organization estimated that there are 12 million cases of all forms of leishmaniasis worldwide, with over 500,000 new cases of visceral disease occurring each year [1]. Most of the drugs commonly used to treat different forms of leishmaniasis are toxic and have unacceptable side effects. Moreover, cases of drug resistant leishmaniasis are on the rise. Due to non-existence of effective vaccine to date, improved immunoprophylactic approaches still remain desirable to combat leishmaniasis. Antileishmanial vaccines developed around the globe are discussed.

Combination Therapy with Indolylquinoline Derivative and Sodium Antimony Gluconate Cures Established Visceral Leishmaniasis in Hamsters

ABSTRACT 2-(2″-Dichloroacetamidobenzyl)-3-(3′-indolylquinoline), designated indolylquinoline derivative A, reduced the splenic and the liver parasite burdens by >93.0% in Leishmania donovani-infected hamsters, whereas sodium antimony gluconate (SAG) reduced the burdens approximately 80.0%. Complete clearance of parasitemia from the livers and spleens was noticed when infected animals received indolylquinoline derivative A plus SAG, suggesting that indolylquinoline derivative A has potential as a new agent for sole or conjunctive therapy for leishmaniasis.

Reactive Oxygen Species (ROS): A Way to Stress Survival in Plants

Aerobic organisms which derive their energy from the reduction of oxygen are susceptible to the damaging actions of the small amounts of O2−, OH, and H2O2 that inevitably form during the metabolism of oxygen, especially in the reduction of oxygen by the electron transfer system of mitochondria. These three species together with unstable intermediates in the peroxidation of lipids are referred to as reactive oxygen species (ROS). They are formed as a natural by-product of the normal metabolism of oxygen and have important roles in cell signaling and homeostasis. ROS are thought to play a dual role in plant biology and are accumulated by many types of stresses. Some are highly toxic and rapidly detoxified by various cellular enzymatic and nonenzymatic mechanisms, whereas many are involved in various metabolic as well as physiological processes necessary for growth and development of plants. During environmental stress of plants (e.g., UV or heat exposure), ROS levels can increase dramatically. The ROS levels that are too low or too high impair plant growth and development, whereas maintaining ROS levels within the right range promotes plant health. Alterations in ROS levels that are part of the normal function of the plant should not exceed the threshold boundary between redox potentials and cytotoxic or cytostatic levels. Although recent studies have unraveled some of the key issues related to ROS like programmed cell death and cross talk with phytohormones during stress conditions, yet there are some unprecedented mechanisms which need to be expolred.

Competitive ability of intercrops and herbicides for controlling weeds in maize (Zea mays L.)

ABSTRACT :A field experiment was conducted in the sandy loam soil of Kanke, Ranchi during Kharif seasons of 2004 and 2005, to find out most effective combinations of intercrops and herbicides for controlling weeds in Kharif maize. The experiment was laid out in Split Plot Design comprising five cropping systems, i.e., sole maize, sole soybean, sole groundnut, intercropping of maize+soybean (1:2) and intercropping of maize+groundnut (1:2) as main plots and five weed management practices, i.e., weedy check, weeding thrice at 15, 30 and 45 days after sowing, oxyfluorfen @ 0.2 kg a.i. ha-1 as pre-emergence, alachlor @ 2.0 kg a.i. ha-1 as preemergence and butachlor @ 1.5 kg a.i. ha-1 as pre-emergence + quizalofop-ethyl @ 100 ml ha-1 as post emergence, as sub plot treatments, replicated thrice. The result showed that maize intercropped with soybean and hand weeded thrice has lowest weed density and weed dry weight, which were statistically at par with that of maize intercropped with soybean and sprayed with oxyfluorfen @ 0.2 kg a.i. ha-1 as pre-emergence. The highest maize equivalent yield of 8039 kg ha-1 was recorded with maize+groundnut and hand weeded thrice, which was found to be statistically at par with maize+groundnut, treated with oxyfluorfen @ 0.2 kg a.i. ha-1 as preemergence and maize+soybean, treated with oxyfluorfen @ 0.2 kg a.i. ha-1 as pre-emergence, having maize equivalent yields of 7595 kg ha-1 and 7189 kg ha-1, respectively. The highest net return was recorded from the intercropping of maize+groundnut, treated with oxyfluorfen @ 0.2 kg a.i. ha-1 as pre-emergence, which can be used as the most effective and profitable combination in controlling weeds in Kharif maize.