scholarly journals Antileishmanial Activity of Ziziphus spina-christi Leaves Extract and Its Possible Cellular Mechanisms

2021 ◽  
Vol 9 (10) ◽  
pp. 2113
Author(s):  
Aishah Albalawi
Keyword(s):  
Plasma Membrane ◽  
Membrane Permeability ◽  
Leishmania Major ◽  
Parasite Load ◽  
Phytochemical Analysis ◽  
No Production ◽  
Cellular Mechanisms ◽  
Plasma Membrane Permeability

This experimental investigation was designed to assess the in vitro and in vivo antileishmanial effects of Z. spina-christi methanolic extract (ZSCME) and also aims to assess some of the antileishmanial mechanisms such as the NO production, apoptosis, and plasma membrane permeability. We assessed the in vitro leishmanicidal effects of ZSCME (10–200 µg/mL) against intracellular amastigote stage of the Leishmania major (MRHO/IR/75/ER) and, then, in vivo examined male BALB/c mice infected by L. major. In addition, the rate of infectivity, Caspase 3 activity, nitric oxide (NO) production, the plasma membrane permeability, and the cytotoxic effects of ZSCME were studied. The primary phytochemical analysis of ZSCME revealed the existence of high amounts of flavonoids, tannins, glycosides, alkaloids, and saponin in this plant. The findings exhibited that ZSCME meaningfully (p < 0.001) reduced the viability of amastigotes of L. major, whereas it prompted the creation and release of NO, apoptosis, and the plasma membrane permeability (p < 0.05) and indicated no cytotoxicity in macrophage cells. The in vivo results also demonstrated that ZSCME significantly decreased the parasite load and the diameter of the lesions in the infected mice. Our results demonstrate the promising in vitro and in vivo antileishmanial effects of ZSCME against of L. major. Although the findings of the present study showed some possible antileishmanial mechanisms of ZSCME, such as stimulating NO production, apoptosis, and increasing plasma membrane permeability, additional investigations are required to confirm these results.

scholarly journals In Vitro and In Vivo Antitrypanosomal Activities of Methanol Extract of Echinops kebericho Roots

2020 ◽  
Vol 2020 ◽  
pp. 1-6
Author(s):  
Debela Abdeta ◽  
Nigatu Kebede ◽  
Mirutse Giday ◽  
Getachew Terefe ◽  
Solomon Mequanente Abay
Keyword(s):  
Body Weight ◽  
Neglected Tropical Diseases ◽  
Field Isolate ◽  
Parasite Load ◽  
Phytochemical Analysis ◽  
Isolation And Purification ◽  
Discovery Research ◽  
Drug Discovery Research

Microbial resistance to the few conventional antitrypanosomal drugs, increasing resistance of vectors to insecticides, lack of effective vaccines, and adverse effects of the existing antitrypanosomal drugs justify the urgent need for effective, tolerable, and affordable drugs. We assessed antitrypanosomal effects of the hydromethanolic extract of Echinops kebericho Mesfin roots against Trypanosoma congolense field isolate using in vitro and in vivo techniques. Parasite load, packed cell volume (PCV), body weight, and rectal temperature in Swiss albino mice were assessed. This finding is part of the outcomes of drug discovery research for neglected tropical diseases. The extract arrested the motility of trypanosomes within 40 min at 4 and 2 mg/mL concentration, whereas in the untreated control, motility continued for more than 160 min. The extract also reduced parasitemia and prevented drop in PCV and body weight significantly (p<0.05), as compared to control. Phytochemical analysis showed the presence of flavonoids, triterpenes, steroids, saponins, glycosides, tannins, and alkaloids. It is observed that this extract has activity against the parasite. Isolation and purification of specific compounds are required to identify hit compounds responsible for the antitrypanosomal activity of the studied medicinal plant.

Treatment with synthetic lipophilic tyrosyl ester controls Leishmania major infection by reducing parasite load in BALB/c mice

Parasitology ◽  
2016 ◽  
Vol 143 (12) ◽  
pp. 1615-1621 ◽  
Author(s):  
RABIAA M. SGHAIER ◽  
IMEN AISSA ◽  
HANÈNE ATTIA ◽  
AYMEN BALI ◽  
PABLO A. LEON MARTINEZ ◽  
...  
Keyword(s):  
Immune Responses ◽  
Leishmania Major ◽  
Parasite Load ◽  
Parasite Clearance ◽  
Potential Effect ◽  
Interleukin 4 ◽  
Drug Candidate ◽  
Cytokine Balance

SUMMARYSynthesized lipophilic tyrosyl ester derivatives with increasing lipophilicity were effective against Leishmania (L.) major and Leishmania infantum species in vitro. These findings prompted us to test in vivo leishmanicidal properties of these molecules and their potential effect on the modulation of immune responses. The experimental BALB/c model of cutaneous leishmaniasis was used in this study. Mice were infected with L. major parasites and treated with three in vitro active tyrosyl esters derivatives.Among these tested tyrosylcaprate (TyC) compounds, only TyC10 exhibited an in vivo anti-leishmanial activity, when injected sub-cutaneously (s.c.). TyC10 treatment of L. major-infected BALB/c mice resulted in a decrease of lesion development and parasite load. TyC10 s.c. treatment of non-infected mice induced an imbalance in interferon γ/interleukin 4 (IFN-γ/IL-4) ratio cytokines towards a Th1 response. Our results indicate that TyC10 s.c. treatment improves lesions’ healing and parasite clearance and may act on the cytokine balance towards a Th1 protective response by decreasing IL-4 and increasing IFN-γ transcripts. TyC10 is worthy of further investigation to uncover its mechanism of action that could lead to consider this molecule as a potential drug candidate.

scholarly journals Activated T Cells Induce Macrophages To Produce NO and Control Leishmania major in the Absence of Tumor Necrosis Factor Receptor p55

2000 ◽  
Vol 68 (3) ◽  
pp. 1428-1434 ◽  
Author(s):  
Michelle Nashleanas ◽  
Phillip Scott
Keyword(s):  
T Cells ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Leishmania Major ◽  
Tumor Necrosis Factor Receptor ◽  
No Production ◽  
Activated T Cells ◽  
Necrosis Factor

ABSTRACT The ability to activate macrophages in vitro for nitric oxide production and killing of Leishmania major parasites is dependent on tumor necrosis factor, although L. major-infected mice lacking the TNF receptor p55 (TNFRp55−/− mice) or both the TNFRp55 and TNFRp75 (TNFRp55p75−/− mice) are able to produce NO in vivo and eliminate the parasites. Here we report that activated T cells cocultured with macrophages results in TNFR-independent activation sufficient to control parasites and that both CD40/CD40L and LFA-1 contribute to T-cell-mediated macrophage activation. Thus, anti-CD3-stimulated T cells activated TNFR-deficient macrophages, while T cells from CD40L−/− mice were partially defective in triggering NO production by TNFRp55p75−/− macrophages. Moreover, in the presence of gamma interferon, anti-CD40 monoclonal antibody (MAb) activated TNFR-deficient macrophages. Finally, MAb blockade of LFA-1 completely inhibited macrophage NO production. Our data indicate that T cells can activate macrophages in the absence of TNF, thus providing a mechanism for how TNFR-deficient mice can control intracellular pathogens.

scholarly journals Computationally designed synthetic peptides for transporter proteins imparts allostericity in Miltefosine resistant L. major

2020 ◽  
Vol 477 (10) ◽  
pp. 2007-2026
Author(s):  
Ritika Kabra ◽  
Prajakta Ingale ◽  
Shailza Singh
Keyword(s):  
Drug Resistance ◽  
Structure Prediction ◽  
Leishmania Major ◽  
Specific Binding ◽  
Parasite Load ◽  
Dimensional Structure ◽  
Oral Drug ◽  
Transporter Proteins

The emergence of drug resistance is a major concern for combating against Cutaneous Leishmaniasis, a neglected tropical disease affecting 98 countries including India. Miltefosine is the only oral drug available for the disease and Miltefosine transporter proteins play a pivotal role in the emergence of drug-resistant Leishmania major. The cause of resistance is less accumulation of drug inside the parasite either by less uptake of the drug due to a decrease in the activity of P4ATPase–CDC50 complex or by increased efflux of the drug by P-glycoprotein (P-gp, an ABC transporter). In this paper, we are trying to allosterically modulate the behavior of resistant parasite (L. major) towards its sensitivity for the existing drug (Miltefosine, a phosphatidylcholine analog). We have used computational approaches to deal with the conservedness of the proteins and apparently its three-dimensional structure prediction through ab initio modeling. Long scale membrane-embedded molecular dynamics simulations were carried out to study the structural interaction and stability. Parasite-specific motifs of these proteins were identified based on the machine learning technique, against which a peptide library was designed. The protein–peptide docking shows good binding energy of peptides Pg5F, Pg8F and PC2 with specific binding to the motifs. These peptides were tested both in vitro and in vivo, where Pg5F in combination with PC2 showed 50–60% inhibition in resistant L. major's promastigote and amastigote forms and 80–90% decrease in parasite load in mice. We posit a model system wherein the data provide sufficient impetus for being novel therapeutics in order to counteract the drug resistance phenotype in Leishmania parasites.

scholarly journals Biodistribution and In Vivo Antileishmanial Activity of 1,2-Distigmasterylhemisuccinoyl-sn-Glycero-3-Phosphocholine Liposome-Intercalated Amphotericin B

2017 ◽  
Vol 61 (9) ◽  
Author(s):  
Maryam Iman ◽  
Zhaohua Huang ◽  
Seyedeh Hoda Alavizadeh ◽  
Francis C. Szoka ◽  
Mahmoud R. Jaafari
Keyword(s):  
Amphotericin B ◽  
Leishmania Major ◽  
Parasite Load ◽  
Tissue Concentrations ◽  
Content Type ◽  
Colloidal Properties ◽  
Covalently Linked ◽  
Antileishmanial Activities

ABSTRACT 1,2-Distigmasterylhemisuccinoyl-sn-glycero-3-phosphocholine (DSHemsPC) is a new lipid in which two molecules of stigmasterol (an inexpensive plant sterol) are covalently linked via a succinic acid to glycerophosphocholine. Our previous study revealed that liposome (Lip)-intercalated amphotericin B (AMB) prepared from DSHemsPC (DSHemsPC-AMB-Lip) possesses excellent colloidal properties and in vitro antifungal and antileishmanial activities similar to those of the liposomal AMB preparation AmBisome. The aim of this study was to determine the biodistribution and evaluate the antileishmanial effects of DSHemsPC-AMB-Lip in Leishmania major-infected BALB/c mice. The serum profile and tissue concentrations of AMB were similar in DSHemsPC-AMB-Lip- and AmBisome-treated mice after intravenous (i.v.) injection. Multiple i.v. doses of the micellar formulation of AMB (Fungizone; 1 mg/kg of body weight), DSHemsPC-AMB-Lip (5 mg/kg), and AmBisome (5 mg/kg) were used in L. major-infected BALB/c mouse models of early and established lesions. In a model of the early lesions of cutaneous leishmaniasis (CL), the results indicated that the level of footpad inflammation was significantly (P < 0.001) lower in mice treated with DSHemsPC-AMB-Lip and AmBisome than mice treated with empty liposomes or 5% dextrose. The splenic and footpad parasite load was also significantly (P < 0.001) lower in these groups of mice than in control mice that received 5% DW or free liposome. The in vivo activity of DSHemsPC-AMB-Lip was comparable to that of AmBisome, and both provided improved results compared to those achieved with Fungizone at the designated doses. The results suggest that systemic DSHemsPC-AMB-Lip administration may be useful for the treatment of leishmaniasis, and because it costs less to produce DSHemsPC-AMB-Lip than AmBisome, DSHemsPC-AMB-Lip merits further investigation.

scholarly journals Dyslipidemia inhibits Toll-like receptor–induced activation of CD8α-negative dendritic cells and protective Th1 type immunity

2007 ◽  
Vol 204 (2) ◽  
pp. 441-452 ◽  
Author(s):  
Abdijapar T. Shamshiev ◽  
Franziska Ampenberger ◽  
Bettina Ernst ◽  
Lucia Rohrer ◽  
Benjamin J. Marsland ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Modulation ◽  
Leishmania Major ◽  
Nuclear Translocation ◽  
Density Lipoprotein ◽  
Cell Mediated Immunity ◽  
Toll Like Receptor ◽  
Cellular Mechanisms

Environmental factors, including diet, play a central role in influencing the balance of normal immune homeostasis; however, many of the cellular mechanisms maintaining this balance remain to be elucidated. Using mouse models of genetic and high-fat/cholesterol diet–induced dyslipidemia, we examined the influence of dyslipidemia on T cell and dendritic cell (DC) responses in vivo and in vitro. We show that dyslipidemia inhibited Toll-like receptor (TLR)–induced production of proinflammatory cytokines, including interleukin (IL)-12, IL-6, and tumor necrosis factor-α, as well as up-regulation of costimulatory molecules by CD8α− DCs, but not by CD8α+ DCs, in vivo. Decreased DC activation profoundly influenced T helper (Th) cell responses, leading to impaired Th1 and enhanced Th2 responses. As a consequence of this immune modulation, host resistance to Leishmania major was compromised. We found that oxidized low-density lipoprotein (oxLDL) was the key active component responsible for this effect, as it could directly uncouple TLR-mediated signaling on CD8α− myeloid DCs and inhibit NF-κB nuclear translocation. These results show that a dyslipidemic microenvironment can directly interfere with DC responses to pathogen-derived signals and skew the development of T cell–mediated immunity.

scholarly journals Efficacy of Paromomycin-Chloroquine Combination Therapy in Experimental Cutaneous Leishmaniasis

2017 ◽  
Vol 61 (8) ◽  
Author(s):  
Gert-Jan Wijnant ◽  
Katrien Van Bocxlaer ◽  
Vanessa Yardley ◽  
Sudaxshina Murdan ◽  
Simon L. Croft
Keyword(s):  
Combination Therapy ◽  
Cutaneous Leishmaniasis ◽  
Leishmania Major ◽  
Q Fever ◽  
Parasite Load ◽  
Potential Candidate ◽  
Preclinical Development ◽  
Content Type

ABSTRACT The 4-aminoquinoline chloroquine (CQ) is clinically used in combination with doxycycline to cure chronic Q fever, as it enhances the activity of the antibiotic against the causative bacterium Coxiella burnetii residing within macrophage phagolysosomes. As there is a similar cellular host-pathogen biology for Leishmania parasites, this study aimed to determine whether such an approach could also be the basis for a new, improved treatment for cutaneous leishmaniasis (CL). We have evaluated the in vitro and in vivo activities of combinations of CQ with the standard drugs paromomycin (PM), miltefosine, and amphotericin B against Leishmania major and Leishmania mexicana. In 72-h intracellular antileishmanial assays, outcomes were variable for different drugs. Significantly, the addition of 10 μM CQ to PM reduced 50% effective concentrations (EC50s) by over 5-fold against L. major and against normally insensitive L. mexicana parasites. In murine models of L. major and L. mexicana CL, daily coadministration of 50 mg/kg of body weight PM and 25 mg/kg CQ for 10 days resulted in a significant reduction in lesion size but not in parasite load compared to those for mice given the same doses of PM alone. Overall, our data indicate that PM-CQ combination therapy is unlikely to be a potential candidate for further preclinical development.

scholarly journals MicroRNAs Expression Induces Apoptosis of Macrophages in Response to Leishmania major (MRHO/IR/75/ER): An In-Vitro and In-Vivo Study

2020 ◽  
Author(s):  
Mostafa GHOLAMREZAEI ◽  
Soheila ROUHANI ◽  
Mehdi MOHEBALI ◽  
Samira MOHAMMADI-YEGANEH ◽  
Mostafa HAJI MOLLA HOSEINI ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Leishmania Major ◽  
Parasite Burden ◽  
Parasite Load ◽  
Lesion Size ◽  
In Vivo Studies ◽  
Raw 264.7 Cells ◽  
Control Group

Background: We aimed to investigate the effect of miR-15a mimic and inhibitor of miR-155 expression on apoptosis induction in macrophages infected with Iranian strain of Leishmania major in-vitro and in-vivo. Methods: RAW 264.7 cells were infected with L. major promastigotes (MRHO/IR/75/ER), and then were treated with miRNAs. For in-vivo experiment, BALB/c mice were inoculated with L. major promastigotes, and then they were treated with miRNAs. For evaluation of miRNA therapeutic effect, in-vitro and in-vivo studies were performed using quantitative Real-time PCR, Flow cytometry, lesion size measurement, and Limiting Dilution Assay (LDA). This study was performed in Shahid Beheshti University of Medical Sciences in 2019. Results: In-vitro results of flow cytometry showed that using miR-15a mimic, miR-155 inhibitor or both of them increased apoptosis of macrophages. In in-vivo, size of lesion increased during experiment in control groups (P<0.05) while application of both miR-155 inhibitor and miR-15a mimic inhibited the increase in the size of lesions within 6 wk of experiment (P=0.85). LDA results showed that microRNA therapy could significantly decrease parasite load in mimic or inhibitor receiving groups compared to the control group (P<0.05). Conclusion: miR-155 inhibitor and miR-15a mimic in L. major infected macrophages can induce apoptosis and reduce parasite burden. Therefore, miRNA-based therapy can be proposed as new treatment for cutaneous leishmaniasis.

scholarly journals In Vitro and In Vivo Characterization of Potent Antileishmanial Methionine Aminopeptidase 1 Inhibitors

2020 ◽  
Vol 64 (6) ◽  
Author(s):  
Felipe Rodriguez ◽  
Sarah F. John ◽  
Eva Iniguez ◽  
Sebastian Montalvo ◽  
Karina Michael ◽  
...  
Keyword(s):  
Leishmania Major ◽  
Treatment Options ◽  
Parasite Load ◽  
Host Cells ◽  
Control Group ◽  
Severe Toxicity ◽  
Methionine Aminopeptidase ◽  
Content Type

ABSTRACT Leishmania major is the causative agent of cutaneous leishmaniasis (CL). No human vaccine is available for CL, and current drug regimens present several drawbacks, such as emerging resistance, severe toxicity, medium effectiveness, and/or high cost. Thus, the need for better treatment options against CL is a priority. In the present study, we validate the enzyme methionine aminopeptidase 1 of L. major (MetAP1Lm), a metalloprotease that catalyzes the removal of N-terminal methionine from peptides and proteins, as a chemotherapeutic target against CL infection. The in vitro antileishmanial activities of eight novel MetAP1 inhibitors (OJT001 to OJT008) were investigated. Three compounds, OJT006, OJT007, and OJT008, demonstrated potent antiproliferative effects in macrophages infected with L. major amastigotes and promastigotes at submicromolar concentrations, with no cytotoxicity against host cells. Importantly, the leishmanicidal effect in transgenic L. major promastigotes overexpressing MetAP1Lm was diminished by almost 10-fold in comparison to the effect in wild-type promastigotes. Furthermore, the in vivo activities of OJT006, OJT007, and OJT008 were investigated in L. major-infected BALB/c mice. In comparison to the footpad parasite load in the control group, OJT008 decreased the footpad parasite load significantly, by 86%, and exhibited no toxicity in treated mice. We propose MetAP1 inhibitor OJT008 as a potential chemotherapeutic candidate against CL infection caused by L. major infection.

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