N-Chlorotaurine shows high in vitro activity against promastigotes and amastigotes of Leishmania species

2009 ◽  
Vol 58 (10) ◽  
pp. 1298-1302 ◽  
Author(s):  
Ursula Fürnkranz ◽  
Markus Nagl ◽  
Waldemar Gottardi ◽  
Ulrich Matt ◽  
Horst Aspöck ◽  
...  
Keyword(s):  
Leishmania Donovani ◽  
Leishmania Species ◽  
Protozoan Parasites ◽  
First Line ◽  
Mucocutaneous Leishmaniasis ◽  
Causative Agents ◽  
Life Threatening ◽  
Susceptibility Tests

Protozoan parasites of the genus Leishmania are the causative agents of life-threatening visceral as well as cutaneous and mucocutaneous leishmaniasis. First-line drugs are antimonials, but toxicity and resistance in some endemic areas cause serious problems. In the current study, the antileishmanial activity of the weak oxidant N-chlorotaurine (NCT) was investigated. NCT is a derivative of the amino acid taurine produced by granulocytes and monocytes during oxidative burst, but can also be synthesized chemically and used topically as an antiseptic at a concentration of 1 % (55 mM) in vivo. NCT susceptibility tests were performed in vitro with promastigotes and amastigotes of Leishmania infantum and Leishmania donovani. As NH4Cl is known to increase the activity of NCT by the formation of monochloramine (NH2Cl), co-treatment assays were included in the study. Mean EC50 values after 1 h of treatment were 5.94 mM for L. infantum and 9.8 mM for L. donovani promastigotes. Co-treatment with 5.5 mM NCT plus 19 mM NH4Cl led to complete killing of promastigotes of both strains within 15 min. Amastigotes were inactivated by treatment with 2 mM NCT alone. The results of this study indicate a high potential of NCT against Leishmania species.

scholarly journals In Vitro and In Vivo Activities of a Triterpenoid Saponin Extract (PX-6518) from the Plant Maesa balansae against Visceral Leishmania Species

2004 ◽  
Vol 48 (1) ◽  
pp. 130-136 ◽  
Author(s):  
Louis Maes ◽  
Dirk Vanden Berghe ◽  
Nils Germonprez ◽  
Ludo Quirijnen ◽  
Paul Cos ◽  
...  
Keyword(s):  
Leishmania Donovani ◽  
Human Fibroblasts ◽  
Subcutaneous Administration ◽  
Leishmania Species ◽  
Host Cells ◽  
Triterpenoid Saponin ◽  
Sodium Stibogluconate ◽  
Triterpenoid Saponins

ABSTRACT The in vitro and in vivo activities of a mixture of six oleane triterpene saponins, recovered from the methanolic extract of the leaves of the Vietnamese plant Maesa balansae (PX-6518), were evaluated against drug-sensitive visceral Leishmania strains. The in vitro 50% inhibitory concentration (IC50) against intracellular Leishmania infantum amastigotes was 0.04 μg/ml. The cytotoxic concentrations causing 50% cell death (CC50s) were about 1 μg/ml in murine macrophage host cells and >32 μg/ml in human fibroblasts (MRC-5 cell line). Evaluation in the Leishmania donovani BALB/c mouse model indicated that a single subcutaneous administration of 0.4 mg/kg at 1 day after infection reduced liver amastigote burdens by about 95% in all treated animals. If treatment was delayed until 14 days after infection, a dose of 1.6 mg/kg of body weight was required to maintain the same level of activity. Single 250-mg/kg doses of sodium stibogluconate (Pentostam) 1 and 14 days after infection produced comparable efficacies. A single dose of PX-6518 at 2.5 mg/kg administered 5 days before infection was still 100% effective in preventing liver infection, suggesting a particularly long residual action. Spleen and bone marrow could not be cleared by PX-6518 nor sodium stibogluconate. PX-6518 did not show activity after oral dosing at up to 200 mg/kg for 5 days. This study concludes that triterpenoid saponins from M. balansae show promising in vitro and in vivo antileishmanial potential and can be considered as new lead structures in the search for novel antileishmanial drugs.

scholarly journals Preformed Membrane-Associated Stores of Interleukin (Il)-12 Are a Previously Unrecognized Source of Bioactive IL-12 That Is Mobilized within Minutes of Contact with an Intracellular Parasite

2000 ◽  
Vol 192 (4) ◽  
pp. 507-516 ◽  
Author(s):  
Marlon Quinones ◽  
Sunil K. Ahuja ◽  
Peter C. Melby ◽  
Lyle Pate ◽  
Robert L. Reddick ◽  
...  
Keyword(s):  
Leishmania Donovani ◽  
Leishmania Species ◽  
Interferon Γ ◽  
Host Responses ◽  
Prevailing Paradigm ◽  
Helper Cell Type ◽  
Experimental Approaches

The prevailing paradigm is that production of the interleukin (IL)-12 p70 heterodimer, a critical T helper cell type 1 (Th1)–inducing cytokine, depends on the induced transcription of the p40 subunit. Concordant with this paradigm, we found that dendritic cells (DCs) produced IL-12 p70 only after at least 2–4 h of stimulation with lipopolysaccharide plus interferon γ. However, using several complementary experimental approaches, including electron and confocal microscopy, we now show that resting murine and human myeloid cells, including macrophages/DCs and DC-rich tissues, contain a novel source of bioactive IL-12 that is preformed and membrane associated. These preformed, membrane-associated IL-12 p70 stores are released within minutes after in vitro or in vivo contact with Leishmania donovani, an intracellular pathogen. Our findings highlight a novel source of bioactive IL-12 that is readily available for the rapid initiation of Th1 host responses to pathogens such as Leishmania species.

scholarly journals Peroxisome Proliferator-Activated Receptor-γ-Mediated Polarization of Macrophages inLeishmaniaInfection

PPAR Research ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Marion M. Chan ◽  
Nagasuresh Adapala ◽  
Cui Chen
Keyword(s):  
Visceral Leishmaniasis ◽  
Leishmania Donovani ◽  
Parasitic Infection ◽  
Peroxisome Proliferator ◽  
Nuclear Factor ◽  
Protozoan Parasites ◽  
Peroxisome Proliferator Activated Receptor

Infection is the outcome of a contest between a pathogen and its host. In the disease leishmaniasis, the causative protozoan parasites are harbored inside the macrophages.Leishmaniaspecies adapt strategies to make the infection chronic, keeping a balance between their own and the host's defense so as to establish an environment that is favorable for survival and propagation. Activation of peroxisome proliferator-activated receptor (PPAR) is one of the tactics used. This ligand-activated nuclear factor curbs inflammation to protect the host from excessive injuries by setting a limit to its destructive force. In this paper, we report the interaction of host PPARs and the pathogen for visceral leishmaniasis,Leishmania donovani,in vivoandin vitro. PPAR expression is induced by parasitic infection. Leishmanial activation of PPARγpromotes survival, whereas blockade of PPARγfacilitates removal of the parasite. Thus,Leishmaniaparasites harness PPARγto increase infectivity.

scholarly journals SARS-CoV-2: An Update on Potential Antivirals in Light of SARS-CoV Antiviral Drug Discoveries

Vaccines ◽  
2020 ◽  
Vol 8 (2) ◽  
pp. 335 ◽  
Author(s):  
Hatem A. Elshabrawy
Keyword(s):  
Antiviral Drug ◽  
Severe Respiratory Distress ◽  
Respiratory Illnesses ◽  
High Fatality Rate ◽  
Causative Agents ◽  
Life Threatening ◽  
Current Outbreak ◽  
Severe Respiratory Distress Syndrome

Coronaviruses (CoVs) are a group of RNA viruses that are associated with different diseases in animals, birds, and humans. Human CoVs (HCoVs) have long been known to be the causative agents of mild respiratory illnesses. However, two HCoVs associated with severe respiratory diseases are Severe Acute Respiratory Syndrome-CoV (SARS-CoV) and Middle East Respiratory Syndrome-CoV (MERS-CoV). Both viruses resulted in hundreds of deaths after spreading to several countries. Most recently, SARS-CoV-2 has emerged as the third HCoV causing severe respiratory distress syndrome and viral pneumonia (known as COVID-19) in patients from Wuhan, China, in December 2019. Soon after its discovery, SARS-CoV-2 spread to all countries, resulting in millions of cases and thousands of deaths. Since the emergence of SARS-CoV, many research groups have dedicated their resources to discovering effective antivirals that can treat such life-threatening infections. The rapid spread and high fatality rate of SARS-CoV-2 necessitate the quick discovery of effective antivirals to control this outbreak. Since SARS-CoV-2 shares 79% sequence identity with SARS-CoV, several anti-SARS-CoV drugs have shown promise in limiting SARS-CoV-2 replication in vitro and in vivo. In this review, we discuss antivirals described for SARS-CoV and provide an update on therapeutic strategies and antivirals against SARS-CoV-2. The control of the current outbreak will strongly depend on the discovery of effective and safe anti-SARS-CoV-2 drugs.

Naphthoquinones and derivatives for chemotherapy: perspectives and limitations of their anti-trypanosomatids activities

2020 ◽  
Vol 26 ◽  
Author(s):  
Luíza Dantas-Pereira ◽  
Edézio F. Cunha-Junior ◽  
Valter V. Andrade-Neto ◽  
John F. Bower ◽  
Guilherme A. M. Jardim ◽  
...  
Keyword(s):  
Large Scale ◽  
Neglected Tropical Diseases ◽  
Folk Medicine ◽  
Leishmania Species ◽  
Parasitic Infections ◽  
Mechanistic Analysis ◽  
Leishmania Spp ◽  
Nanomolar Range

: Chagas disease, Sleeping sickness and Leishmaniasis, caused by trypanosomatids Trypanosoma cruzi, Trypanosoma brucei and Leishmania spp., respectively, are considered neglected tropical diseases, and they especially affect impoverished populations in the developing world. The available chemotherapies are very limited and a search for alternatives is still necessary. In folk medicine, natural naphthoquinones have been employed for the treatment of a great variety of illnesses, including parasitic infections. This review is focused on the anti-trypanosomatid activity and mechanistic analysis of naphthoquinones and derivatives. Among all the series of derivatives tested in vitro, naphthoquinone-derived 1,2,3-triazoles were very active on T. cruzi infective forms in blood bank conditions, as well as in amastigotes of Leishmania spp. naphthoquinones containing a CF3 on a phenyl amine ring inhibited T. brucei proliferation in the nanomolar range, and naphthopterocarpanquinones stood out for their activity on a range of Leishmania species. Some of these compounds showed a promising selectivity index (SI) (30 to 1900), supporting further analysis in animal models. Indeed, high toxicity to the host and inactivation by blood components are crucial obstacles to be overcome to use naphthoquinones and/or their derivatives for chemotherapy. Multidisciplinary initiatives embracing medicinal chemistry, bioinformatics, biochemistry, and molecular and cellular biology need to be encouraged to allow the optimization of these compounds. Large scale automated tests are pivotal for the efficiency of the screening step, and subsequent evaluation of both the mechanism of action in vitro and pharmacokinetics in vivo are essential for the development of a novel, specific and safe derivative, minimizing adverse effects.

scholarly journals Preclinical Studies in Anti-Trypanosomatidae Drug Development

2021 ◽  
Vol 14 (7) ◽  
pp. 644
Author(s):  
Cintya Perdomo ◽  
Elena Aguilera ◽  
Ileana Corvo ◽  
Paula Faral-Tello ◽  
Elva Serna ◽  
...  
Keyword(s):  
Rural Communities ◽  
Chagas Disease ◽  
Murine Model ◽  
Mammalian Cells ◽  
Drug Candidate ◽  
Murine Macrophages ◽  
Causative Agents ◽  
Trypanosomatid Parasites

The trypanosomatid parasites Trypanosoma brucei, Trypanosoma cruzi and Leishmania are the causative agents of human African trypanosomiasis, Chagas Disease and Leishmaniasis, respectively. These infections primarily affect poor, rural communities in the developing world, and are responsible for trapping sufferers and their families in a disease/poverty cycle. The development of new chemotherapies is a priority given that existing drug treatments are problematic. In our search for novel anti-trypanosomatid agents, we assess the growth-inhibitory properties of >450 compounds from in-house and/or “Pathogen Box” (PBox) libraries against L. infantum, L. amazonensis, L.braziliensis, T. cruzi and T. brucei and evaluate the toxicities of the most promising agents towards murine macrophages. Screens using the in-house series identified 17 structures with activity against and selective toward Leishmania: Compounds displayed 50% inhibitory concentrations between 0.09 and 25 μM and had selectivity index values >10. For the PBox library, ~20% of chemicals exhibited anti-parasitic properties including five structures whose activity against L. infantum had not been reported before. These five compounds displayed no toxicity towards murine macrophages over the range tested with three being active in an in vivo murine model of the cutaneous disease, with 100% survival of infected animals. Additionally, the oral combination of three of them in the in vivo Chagas disease murine model demonstrated full control of the parasitemia. Interestingly, phenotyping revealed that the reference strain responds differently to the five PBox-derived chemicals relative to parasites isolated from a dog. Together, our data identified one drug candidate that displays activity against Leishmania and other Trypanosomatidae in vitro and in vivo, while exhibiting low toxicity to cultured mammalian cells and low in vivo acute toxicity.

scholarly journals The loss of SHMT2 mediates 5-fluorouracil chemoresistance in colorectal cancer by upregulating autophagy

Oncogene ◽  
2021 ◽  
Author(s):  
Jian Chen ◽  
Risi Na ◽  
Chao Xiao ◽  
Xiao Wang ◽  
Yupeng Wang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Patient Survival ◽  
Serine Hydroxymethyltransferase ◽  
First Line ◽  
Xenograft Models ◽  
Potential Opportunity ◽  
First Line Treatment ◽  
Novel Therapeutic

Abstract5-Fluorouracil (5-FU)-based chemotherapy is the first-line treatment for colorectal cancer (CRC) but is hampered by chemoresistance. Despite its impact on patient survival, the mechanism underlying chemoresistance against 5-FU remains poorly understood. Here, we identified serine hydroxymethyltransferase-2 (SHMT2) as a critical regulator of 5-FU chemoresistance in CRC. SHMT2 inhibits autophagy by binding cytosolic p53 instead of metabolism. SHMT2 prevents cytosolic p53 degradation by inhibiting the binding of p53 and HDM2. Under 5-FU treatment, SHMT2 depletion promotes autophagy and inhibits apoptosis. Autophagy inhibitors decrease low SHMT2-induced 5-FU resistance in vitro and in vivo. Finally, the lethality of 5-FU treatment to CRC cells was enhanced by treatment with the autophagy inhibitor chloroquine in patient-derived and CRC cell xenograft models. Taken together, our findings indicate that autophagy induced by low SHMT2 levels mediates 5-FU resistance in CRC. These results reveal the SHMT2–p53 interaction as a novel therapeutic target and provide a potential opportunity to reduce chemoresistance.

scholarly journals Inhibition of platelet phagocytosis as an in vitro predictor for therapeutic potential of RBC antibodies in murine ITP

Blood ◽  
2020 ◽  
Vol 135 (26) ◽  
pp. 2420-2424 ◽  
Author(s):  
Ramsha Khan ◽  
Melissa Menard ◽  
Chao-Ching Jen ◽  
Xi Chen ◽  
Peter A. A. Norris ◽  
...  
Keyword(s):  
Blood Cells ◽  
Immune Thrombocytopenia ◽  
Therapeutic Potential ◽  
Sufficient Condition ◽  
First Line ◽  
Phagocytosis Assay ◽  
First Line Therapy ◽  
Line Therapy

Abstract Polyclonal anti-D is a first-line therapy for immune thrombocytopenia (ITP). Monoclonal antibodies are desirable alternatives, but none have yet proven successful despite their ability to opsonize erythrocytes (or red blood cells, RBCs) and cause anemia. Here, we examined 12 murine erythrocyte–specific antibodies of different specificity and subtypes and found that 8 of these antibodies could induce anemia in antigen-positive mice. Of these 8 antibodies, only 5 ameliorated ITP. All antibodies were examined for their in vitro ability to support macrophage-mediated phagocytosis of erythrocytes. Antibodies which supported erythrocyte phagocytosis in vitro successfully ameliorated ITP in vivo. To examine the ability of each antibody to inhibit phagocytosis of platelets, the antibodies were used to sensitize erythrocytes in vitro and these were added to a platelet phagocytosis assay. Antibodies that inhibited platelet phagocytosis in vitro also all ameliorated ITP in vivo. We conclude that inducing anemia is not a sufficient condition for amelioration of ITP but that the antibody’s ability to prevent platelet phagocytosis in vitro predicted its ability to ameliorate ITP. We suggest that inhibition of in vitro platelet phagocytosis may prove to be a valuable tool for determining which erythrocyte antibodies would likely be candidates for clinical use in ITP.

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

Phytomedicine ◽  
2007 ◽  
Vol 14 (1) ◽  
pp. 36-42 ◽  
Author(s):  
V. Lakshmi ◽  
K. Pandey ◽  
A. Kapil ◽  
N. Singh ◽  
M. Samant ◽  
...  
Keyword(s):  
Leishmania Donovani ◽  
Leishmanicidal Activity ◽  
Dysoxylum Binectariferum

scholarly journals Antiparasitary Activity Of The Juglone Compound: A Narrative Review

2021 ◽  
pp. 13
Author(s):  
◽  
Keyword(s):  
Mortality Rate ◽  
Leishmania Donovani ◽  
Inhibitory Concentration ◽  
Narrative Review ◽  
Hymenolepis Nana ◽  
Compound A ◽  
Living Organisms ◽  
Nanomolar Range

Objective: To report, based on the literature, the action of the compound 5-hydroxy-1,4-naphthoquinone against parasites (protozoa and helminths) that affect humans. Methods: This is a narrative review that used Pubmed and Google Scholar as a data tool. This work included articles published until September 2020 that were directly related to the use of the compound juglone in antiparasitic trials. Results: The compound juglone demonstrated promising effects as a human and animal antiparasitic substance. In protozoa, the Apicomplexo Toxoplasma gondii parasite showed a high mortality rate in concentrations of juglone in the nanomolar range. The juglone showed an average inhibitory concentration (IC50) of 1.62 µM, >100 µM, and 2.02 µM µM for Trypanosoma cruzi, T. brucei rhodesiense, and Leishmania donovani, respectively. Also, the juglone showed antihelmintic activity on Hymenolepis nana in mice, and on adult worms of Schistosoma mansoni (LE strain) with IC50 34.16 µM, 32.14 µM, and 25 µM in the 24h, 48h, and 72 h, respectively. Conclusion: The results published so far show the in vitro antiparasitic potential of juglone, and the need for further studies on the specific mode of action that interacts with parasites. Besides, the literature is still limited to studies that evaluate in vivo the compound juglone, requiring better information on its interaction with living organisms.

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