curcumin and Leishmaniasis--Visceral

In recent years, antimonial agents and other synthetic antileishmanial drugs, such as amphotericin B, paromomycin, and many other drugs, have restrictions in use due to the toxicity risk, high cost, and emerging resistance to these drugs. The present study aimed to review the antileishmanial effects of curcumin, its derivatives, and other relevant pharmaceutical formulations on leishmaniasis.. The present study was carried out according to the 06-preferred reporting items for systematic reviews and meta-analyses (PRISMA) guideline and registered in the CAMARADES-NC3Rs Preclinical Systematic Review and Meta-Analysis Facility (SyRF) database. Some English-language databases including PubMed, Google Scholar, Web of Science, EBSCO, Science Direct, and Scopus were searched for publications worldwide related to antileishmanial effects of curcumin, its derivatives, and other relevant pharmaceutical formulations, without date limitation, to identify all the published articles (in vitro, in vivo, and clinical studies). Keywords included "curcumin", "Curcuma longa", "antileishmanial", "Leishmania", "leishmaniasis", "cutaneous leishmaniasis", "visceral leishmaniasis", "in vitro", and "in vivo".. Out of 5492 papers, 29 papers including 20 in vitro (69.0%), 1 in vivo (3.4%), and 8 in vitro/in vivo (27.6%) studies conducted up to 2020, met the inclusion criteria for discussion in this systematic review. The most common species of the Leishmania parasite used in these studies were L. donovani (n = 13, 44.8%), L. major (n = 10, 34.5%), and L. amazonensis (n = 6, 20.7%), respectively. The most used derivatives in these studies were curcumin (n = 15, 33.3%) and curcuminoids (n = 5, 16.7%), respectively.. In the present review, according to the studies in the literature, various forms of drugs based on curcumin and their derivatives exhibited significant in vitro and in vivo antileishmanial activity against different Leishmania spp. The results revealed that curcumin and its derivatives could be considered as an alternative and complementary source of valuable antileishmanial components against leishmaniasis, which had no significant toxicity. However, further studies are required to elucidate this concluding remark, especially in clinical settings.

Topics: Antiprotozoal Agents; Curcumin; Humans; Leishmania; Leishmaniasis, Cutaneous; Leishmaniasis, Visceral

Visceral leishmaniasis (VL, also known as kala-azar) is a vector borne disease caused by obligate intracellular protozoan parasite Leishmania donovani. To overcome the limitations of currently available drugs for VL, molecular target-based study is a promising tool to develop new drugs to treat this neglected tropical disease. One such target we recently identified from L. donovani (Ld) genome (WGS, clinical Indian isolate; BHU 1220, AVPQ01000001) is a small GTP-binding protein, Rab6 protein. We now report a specific inhibitor of the GTPase activity of Rab6 protein of L. donovani (LdRab6) without restricting host enzyme activity. First, to understand the nature of LdRab6 protein, we generated recombinant LdRab6 mutant proteins (rLdRab6) by systematically introducing deletion (two cysteine residues at C-terminal) and mutations [single amino acid substitutions in the conserved region of GTP (Q84L)/GDP(T38N) coding sequence]. The GTPase activity of rLdRab6:GTP and rLdRab6:GDP locked mutant proteins showed ~ 8-fold and ~ 1.5-fold decreases in enzyme activity, respectively, compared to the wild type enzyme activity. The mutant protein rLdRab6:ΔC inhibited the GTPase activity. Sequence alignment analysis of Rab6 protein of L. donovani with Homo sapiens showed identical amino acids in the G conserved region (GTP/GDP-binding sites) but it differed in the C-terminal region. We then evaluated the inhibitory activity of trans-dibenzalacetone (DBA, a synthetic analog of curcumin with strong antileishmanial activity reported earlier by us) in the GTPase activity of LdRab6 protein. Comparative molecular docking analysis of DBA and specific inhibitors of Rab proteins (Lovastatin, BFA, Zoledronate, and NE10790) indicated that DBA had optimum binding affinity with LdRab6 protein. This was further confirmed by the GTPase activity of DBA-treated LdRab6 which showed a basal GTP level significantly lower than that of the wild-type rLdRab6. The results confirm that DBA inhibits the GTPase activity of LdRab6 protein from L. donovani (LdRab6), a potential target for its antileishmanial effect.

Topics: Amino Acid Sequence; Antiprotozoal Agents; Binding Sites; Curcumin; Enzyme Inhibitors; Humans; Leishmania donovani; Leishmaniasis, Visceral; Molecular Docking Simulation; Pentanones; Protozoan Proteins; rab GTP-Binding Proteins; Sequence Alignment

Aim was to fabricate and optimize CUR-loaded mannose-functionalized chitosan nanoparticles (Cur-MCN) which overcome the limitations of drugs to reach the intracellular locations and to establish its therapeutic potential in visceral leishmaniasis by targeting of CUR to macrophages. Cur-MCN were developed by mannose-conjugated chitosan and have been tested for their efficacy and toxicit. In vivo antileishmanial activity in hamsters has shown significantly greater suppression of parasite replication in the spleen with Cur-MCN than unconjugated chitosan nanoparticles. The in vitro cytotoxicity study against the J774A.1 cell line demonstrated its comparative non-toxicity towards the macrophage cells. The potential of Cur-MCN was also confirmed by minimal observed cytotoxicity in our in vivo studies.

Topics: Cell Line; Chitosan; Curcumin; Drug Carriers; Humans; Leishmania donovani; Leishmaniasis, Visceral; Macrophages; Mannose; Nanoparticles

Curcumin is the major phenolic compound found in turmeric, a dry powder of rhizomes and roots of the plant, Curcuma longa L., which is widely used as spice and food colorant around the world, and in herbal medicinal practice in Asian countries. The present study reports the leishmanicidal activity of trans-dibenzalacetone (DBA), a synthetic monoketone analog of curcumin, against Leishmania donovani parasites. We for the first time report the antiproliferative effect of a curcumin analog (DBA) on the intracellular amastigotes of L. donovani, the clinically more relevant stage of the parasite than its promastigotes stage. The leishmanicidal effect of DBA was further confirmed by scanning and transmission electron microscopies. Cell growth was arrested in G0/G1 phase with increased concentration of cytosolic calcium and dissipation of mitochondrial membrane potential. Further, the unique trypanothione/trypanothione reductase (TR) system of Leishmania cells was significantly inhibited by DBA. This economically synthesizable simple monoketone analog of curcumin has the potential for field use against visceral leishmaniasis which is currently widespread in tropical and subtropical developing countries of the world. In conclusion, we have identified an analog of curcumin for potential applications against leishmaniasis, based on its strong antiparasitic activity and low toxicity. This curcumin analog compares favorably, at least in vitro, with the existing medication miltefosine.

Topics: Animals; Antiprotozoal Agents; Apoptosis; Calcium; Cell Proliferation; Chemoprevention; Curcumin; Cytoplasm; Leishmania donovani; Leishmaniasis, Visceral; Macrophages; Membrane Potential, Mitochondrial; Mice; Microscopy, Electron, Scanning; Mitochondria; Pentanones

Topics: Administration, Oral; Animals; Antiprotozoal Agents; Cell Proliferation; Cricetinae; Curcumin; Disease Models, Animal; Drug Carriers; Drug Combinations; Drug Resistance; Drug Synergism; Humans; Leishmania donovani; Leishmaniasis, Visceral; Lymphocytes; Male; Medicine, Ayurvedic; Nanoparticles; Phagocytosis; Phosphorylcholine; Reactive Nitrogen Species; Reactive Oxygen Species

The study aims at formulation and optimization of macrophage-targeted curcumin-loaded mannosylated chitosan nanoparticles (Cur-MCNPs) of curcumin (CUR) to improve its therapeutic potential in the treatment of visceral leishmaniasis (VL).. Response surface methodology (RSM) using central composite design was employed to study the effect of formulation factors on physicochemical-dependent characteristics. Chitosan was coupled with d-mannose, by reductive amination, to prepare a mannosylated chitosan, a conjugate polymer and a subsequent formulation of Cur-MCNPs. Optimized formulation prepared using RSM was evaluated for in vitro release kinetics at physiological pH 7.4 and endosomal macrophage pH 4.5; in vivo pharmacokinetic profile and targeting potential were evaluated by fluorescence microscopy.. Optimized Cur-MCNPs exhibited spherical and smooth surface with a mean particle size of 215 nm, polydispersity index of 0.381, zeta potential of + 24.37 mV and % entrapment efficiency of 82.12%. The pharmacokinetic study of optimized Cur-MCNPs showed significant improvement in the value of mean resident time (39.38 h) compared to free CUR solution (0.30 h) (p < 0.05). In vivo uptake study indicated that endocytosis took place effectively within the macrophages of reticuloendothelial system.. Thus, Cur-MCNPs could be considered as a promising delivery strategy towards active targeting of CUR to macrophages for the effective treatment of VL.

Topics: Animals; Biological Transport; Chemistry, Pharmaceutical; Chitosan; Curcumin; Drug Carriers; Drug Stability; Hydrogen-Ion Concentration; Leishmaniasis, Visceral; Male; Mannose; Microscopy, Atomic Force; Microscopy, Electron, Scanning; Microscopy, Fluorescence; Nanoparticles; Rats; Spectroscopy, Fourier Transform Infrared; Surface Properties

Leishmaniasis is an endemic disease having a wide spectrum ranging from visceral, cutaneous and mucocutaneous forms caused by unicellular, obligate intracellular parasites of the monocyte-macrophage system. The aim of the present study was to develop an effective, nontoxic and biodegradable polymeric drug-delivery system encapsulating curcumin in its hydrophobic core for the treatment of visceral leishmaniasis.. We have reported a co-polymeric micelle of N-isopropyl acrylamide, vinyl pyrrolidone and acrylic acid in 85:10:5 M ratios through free radical polymerization. The characterization of curcumin-loaded nanoparticles (40-50 nm) was done by transmission electron microscopy, dynamic light scattering and spectroscopic methods such as NMR which ensures polymerization and formation of nanoparticles has been achieved. Nanocurcumin was evaluated as an antileishmanial agent through spleenomegaly and delayed-type hypersensitivity experiments.. Nanocurcumin has shown significantly greater in vivo therapeutic efficacy than pentamidine and free curcumin in an animal model of visceral leishmaniasis. The use of nanocurcumin compared with conventional drugs and free curcumin may prove more feasible and provide a better approach towards treatment of leishmaniasis.

Topics: Animals; Antiprotozoal Agents; Curcumin; Drug Delivery Systems; Female; Leishmaniasis, Visceral; Mice; Mice, Inbred BALB C; Nanoparticles

Inflammation is considered the underlying cause of numerous disorders, and the practice of taking antiinflammatories as diet supplements has become increasingly prevalent. This study addresses the bioavailablity of a well-established dietary antiinflammatory, curcumin, and examines its effect on adaptive immunity. Visceral leishmaniasis is a major parasitic disease which protection relies on cell-mediated immunity and production of nitric oxide. We found that long-term, low-dose, oral consumption of curcumin activates peroxisome proliferator-activated receptor-gamma, deactivates type 1 response, inhibits inducible nitric oxide synthase, and interferes with adaptive immunity to exacerbate the pathogenesis of Leishmania donovani infection in vivo. These in vivo effects can be correlated to activities on infected residential macrophages in vitro. Therefore, when reactive radicals generated from inflammation play the dominant role in elimination of pathogens, excessive use of the antioxidative supplements may compromise microbial defense. Nonetheless, it should be noted with equal importance that our finding, conversely, also strengthens the prospect that curcumin may alleviate type 1 response disorders.

Topics: Animals; Anti-Inflammatory Agents; Curcumin; Cytokines; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Immunity, Cellular; Leishmaniasis, Visceral; Macrophages; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Nitric Oxide Synthase Type II; PPAR gamma; Reverse Transcriptase Polymerase Chain Reaction