scholarly journals Evaluating the Potential of Ursolic Acid as Bioproduct for Cutaneous and Visceral Leishmaniasis

Molecules ◽  
2020 ◽  
Vol 25 (6) ◽  
pp. 1394 ◽  
Author(s):  
Pablo Bilbao-Ramos ◽  
Dolores R. Serrano ◽  
Helga Karina Ruiz Saldaña ◽  
Juan J. Torrado ◽  
Francisco Bolás-Fernández ◽  
...  
Keyword(s):  
Ursolic Acid ◽  
Chronic Infection ◽  
Acute Infection ◽  
Parasite Burden ◽  
Immunological Response ◽  
Lesion Size ◽  
Experimental Models ◽  
Infection Model

Leishmaniasis affects around 12 million people worldwide and is estimated to cause the ninth-largest disease burden. There are three main forms of the disease, visceral (VL), cutaneous (CL), and mucocutaneous (MCL), leading to more than one million new cases every year and several thousand deaths. Current treatments based on chemically synthesized molecules are far from ideal. In this study, we have tested the in vitro and in vivo efficacy of ursolic acid (UA), a multifunctional triterpenoid with well-known antitumoral, antioxidant, and antimicrobial effects on different Leishmania strains. The in vitro antileishmanial activity against the intracellular forms was six and three-fold higher compared to extracellular forms of L. amazonensis and L. infantum, respectively. UA also showed to be a potent antileishmanial drug against both VL and CL manifestations of the disease in experimental models. UA parenterally administered at 5 mg/kg for seven days significantly reduced the parasite burden in liver and spleen not only in murine acute infection but also in a chronic-infection model against L. infantum. In addition, UA ointment (0.2%) topically administered for four weeks diminished (50%) lesion size progression in a chronic infection model of CL caused by L. amazonensis, which was much greater than the effect of UA formulated as an O/W emulsion. UA played a key role in the immunological response modulating the Th1 response. The exposure of Leishmania-infected macrophages to UA led to a significant different production in the cytokine levels depending on the Leishmania strain causing the infection. In conclusion, UA can be a promising therapy against both CL and VL.

scholarly journals Targeted Disruption of the GRA2 Locus inToxoplasma gondii Decreases Acute Virulence in Mice

1998 ◽  
Vol 66 (9) ◽  
pp. 4176-4182 ◽  
Author(s):  
Corinne Mercier ◽  
Daniel K. Howe ◽  
Dana Mordue ◽  
Maren Lingnau ◽  
L. David Sibley
Keyword(s):  
Chronic Infection ◽  
Parasitophorous Vacuole ◽  
Acute Infection ◽  
Early Death ◽  
Dense Granule ◽  
Positive Serology ◽  
Targeted Disruption ◽  
The Brain

ABSTRACT Following invasion into the host cell, the protozoanToxoplasma gondii secretes a variety of proteins that modify the parasitophorous vacuole. Within the vacuole, the 28-kDa dense granule protein known as GRA2 is specifically targeted to the tubulovesicular network which forms connections with the vacuolar membrane. To investigate the importance of GRA2, we derived from strain RH a mutant T. gondii line in which GRA2 was disrupted by replacement with the marker Ble (selecting for phleomycin resistance). The Δgra2 mutant invaded and grew normally in both fibroblasts and macrophages in vitro; however, it was less virulent during acute infection in mice. The survival rate of mice inoculated with Δgra2 was significantly higher; some infected mice survived the acute infection, whereas all mice infected with the wild-type strain RH succumbed to early death. Chronic infection by Δgra2 was detected by positive serology, immunohistochemical detection of parasites and cysts in the brain, and reisolation of parasites by bioassay at 6 weeks postinfection. Thus, absence of GRA2 partially attenuates the virulence of T. gondii during the acute phase of infection and allows for establishment of chronic infection by the otherwise highly virulent RH strain. These results establish that GRA2 plays an important role during in vivo infection and provide a potential model for examining acute pathogenesis by T. gondii.

scholarly journals PREPARATION AND CHARACTERIZATION OF ANDROGRAPHOLIDE NANOPARTICLES FOR VISCERAL LEISHMANIASIS CHEMOTHERAPY: IN VITRO AND IN VIVO EVALUATIONS

2016 ◽  
Vol 8 (12) ◽  
pp. 102
Author(s):  
Pallab Ghosh ◽  
Subhasish Mondal ◽  
Tanmoy Bera
Keyword(s):  
Visceral Leishmaniasis ◽  
Leishmania Donovani ◽  
Parasite Burden ◽  
Plga Nanoparticles ◽  
Antileishmanial Activity ◽  
Infection Model ◽  
Vitamin E Tpgs ◽  
Polyethylene Glycol 1000

<p><strong>Objective: </strong>To overcome low physiological solubility, poor bioavailability, the short plasma half-life of andrographolide (AG), a delivery system based on poly (D, L-lactide-co-glycolide) (PLGA) nanoparticles (NPs) were developed to increase the efficiency of AG against visceral leishmaniasis (VL).<strong> </strong></p><p><strong>Methods: </strong>Andrographolide-PLGA nanoparticles (AGnp) were prepared with Pgp efflux inhibitor vitamin E TPGS (D-α-tocopheryl polyethylene glycol 1000 succinate) by emulsion solvent evaporation method and characterized. Antileishmanial activity was evaluated using<em> in vitro</em> and<em> in vivo</em> VL infection model. <strong></strong></p><p><strong>Results: </strong>The particle size of AGnp was found to be171.4±11.5 nm with an encapsulation efficiency of 81%. The AGnp reduced AG cellular toxicity, retained it's<em> in vitro</em> antileishmanial activity and lead to a reduction (99.9%) of parasite burden in the <em>Leishmania donovani</em> infected spleen and liver. AGnp was more active in infected mice liver at low dose than in spleen. Therapeutic indexes (TI) were 6.9-fold greater in AG and 68-fold in AGnp compared to amphotericin B (AmB) when evaluated in <em>L. donovani</em> infected spleen.<strong> </strong></p><p><strong>Conclusion: </strong>Incorporation of AG in PLGA nanoparticles, provided controlled and improved <em>in vivo</em> performance against VL</p>

Activity of antimalarial drugs in vitro and in a murine model of cutaneous leishmaniasis

2013 ◽  
Vol 62 (7) ◽  
pp. 1001-1010 ◽  
Author(s):  
Vinícius Pinto Costa Rocha ◽  
Fabiana Regina Nonato ◽  
Elisalva Teixeira Guimarães ◽  
Luiz Antônio Rodrigues de Freitas ◽  
Milena Botelho Pereira Soares
Keyword(s):  
Cutaneous Leishmaniasis ◽  
Parasite Burden ◽  
Lesion Size ◽  
Oral Route ◽  
Antimalarial Drugs ◽  
Endocytic Pathway ◽  
Multivesicular Bodies ◽  
Draining Lymph Nodes

The currently used treatments for leishmaniasis, a neglected parasitic disease, are associated with several side effects, high cost and resistance of the Leishmania parasites. Here we evaluated in vitro and in vivo the antileishmanial activity of five antimalarial drugs against Leishmania amazonensis. Mefloquine was effective against promastigotes in axenic cultures and showed an IC50 (concentration giving half-maximal inhibition) value of 8.4±0.7 µM. In addition, mefloquine, chloroquine and hydroxychloroquine were active against intracellular amastigotes in macrophage-infected cultures, presenting IC50 values of 1.56±0.19 µM, 0.78±0.08 µM and 0.67±0.12 µM, respectively. The ultrastructural analysis of chloroquine- or mefloquine-treated amastigotes showed an accumulation of multivesicular bodies in the cytoplasm of the parasite, suggesting endocytic pathway impairment, in addition to the formation of myelin-like figures and enlargement of the Golgi cisternae. CBA mice were infected with L. amazonensis in the ear dermis, and treated by oral and/or topical routes with chloroquine and mefloquine. Treatment of L. amazonensis-infected mice with chloroquine by the oral route reduced lesion size, which was associated with a decrease in the number of parasites in the ear, as well as the parasite burden in the draining lymph nodes. In contrast, mefloquine administration by both routes decreased the lesion size in infected mice without causing a reduction in parasite burden. Our results revealed a promising antileishmanial effect of chloroquine and suggest its use in cutaneous leishmaniasis treatment.

scholarly journals Effect of Foeniculum Vulgare Aqueous and Alcoholic Seed Extract against Zoonotic Cutaneous Leishmaniasis

2021 ◽  
Vol 31 (2) ◽  
Author(s):  
Gholamrezaei Mostafa ◽  
Jalallou Nahid ◽  
Seyyedtabaei Seyyed javad ◽  
Dadashi Alireza ◽  
Salimi Sabour Ebrahim
Keyword(s):  
Body Weight ◽  
Side Effects ◽  
Cutaneous Leishmaniasis ◽  
Parasite Burden ◽  
Lesion Size ◽  
Cytotoxicity Assay ◽  
Alcoholic Extract ◽  
Foeniculum Vulgare

BACKGROUND፡ Cutaneous leishmaniasis is considered one of the major neglected tropical diseases. Drug resistance, limitary efficacy, and severe side effects remain a challenge for treatment. Foeniculum vulgare is known as a medicinal plant belonging to the Apiaceae, and anti-microbial properties of this plant have already been confirmed.METHOD: The F.vulgare sterile aqueous and alcoholic extracts were prepared. In vitro has used RAW 264.7 cell line and L. major parasite (MRHO/IR/75/ER). Cytotoxicity assay on macrophages (CC50), cytotoxicity assay on promastigotes (IC50), and cytotoxicity assay on infected macrophages (EC50) were accomplished with both extracts by MTT and light microscopy methods. Four in vivo were allocated in four groups and five BALB/c mice each group. Stationary phase promastigotes were inoculated into the base of mice tails subcutaneously (SC).Measurement of the body weight, lesion size, parasite burden of the lesion, and spleen after 4 weeks for evaluation effects of the alcoholic extract on CL was done.RESULTS: The results of in vitro revealed that the optimal concentrations of both extracts reducing the promastigotes and amastigotes growth. Alcoholic extract no harmful side effects for the host macrophages, while were indicated has a potent action against L. major. In vivo results after 4 weeks did not show any variation in lesion size and body weight. Also, lesion size and spleen parasite burden decreased in comparison to no treatment group.CONCLUSION: The alcoholic extract could be a new alternative treatment for cutaneous leishmaniasis. However this extract needs more investigation for novel herbal drugs against CL. 

scholarly journals In Vitro and In Vivo Anti-Parasitic Activity of Artemisinin Combined With Glucantime and Shark Cartilage Extract on Iranian Strain of Leishmania major (MRHO/IR/75/ER)

2021 ◽  
Vol 14 (3) ◽  
Author(s):  
Fatemeh Ghaffarifar ◽  
Soheila Molaei ◽  
Zuhair Mohammad Hassan ◽  
Mohammad Saaid Dayer ◽  
Abdolhossein Dalimi ◽  
...  
Keyword(s):  
Leishmania Major ◽  
Human Subjects ◽  
Parasite Burden ◽  
Lesion Size ◽  
In Vivo Experiments ◽  
Parasitic Activity ◽  
Shark Cartilage ◽  
Immune System Modulation

Background: The adverse effects and increased resistance of drugs necessities the discovery of novel combination therapy. Objectives: This study aimed to examine the effects of Artemisinin plus glucantime or shark cartilage extract on the Iranian strain of Leishmania major (MRHO/IR/75/ER) in vitro and in vivo. Methods: In in vitro experiments, the effects of drugs and their combination in different concentrations (3.12 - 400 µg/mL) on the promastigotes, amastigotes, and un-infected macrophage cells were evaluated. In in vivo experiments, infected BALB/c mice were used as a cutaneous leishmaniasis model to evaluate the effects of the drugs and their combinations with different routes of administrations (namely Artemisinin: oral, ointment, and intraperitoneal; glucantime: intraperitoneal, intramuscular, intralesional, and subcutaneous; shark cartilage extract: oral) on parasite burden, lesion size, and immune system modulation. Results: The results revealed that Artemisinin and glucantime in combination with shark cartilage extract had greater effects on promastigotes than either Artemisinin or glucantime (P < 0.05), and that the combinations also had high cytotoxic effects on promastigotes and uninfected macrophages (P = 0.001). These combinations had more inhibitory effects on amastigotes and infected macrophages than promastigotes. The lesion sizes and parasite burden in the spleen decreased against the combinations of the drugs in different administrations. It was also noticed that the best combination administration route of Artemisinin and glucantime, as strong inducers of INF-γ and Th1 immune response, were ointment and IM, respectively (P < 0.05). Conclusions: The findings indicate that Artemisinin- glucantime or Artemisinin- Shark cartilage combinations are effective inhibitors of L. major. However, further clinical trials are recommended to evaluate the effects of these combinations in human subjects.

scholarly journals Chemistry and Leishmanicidal Activity of the Essential Oil from Artemisia absinthium from Cuba

2014 ◽  
Vol 9 (12) ◽  
pp. 1934578X1400901 ◽  
Author(s):  
Lianet Monzote ◽  
Abel Piñón ◽  
Ramón Scull ◽  
William N. Setzer
Keyword(s):  
Chemical Analysis ◽  
Essential Oil ◽  
Parasite Burden ◽  
Chemical Characterization ◽  
Lesion Size ◽  
Artemisia Absinthium ◽  
Main Component ◽  
Promising Source

Historically, natural products have been a rich source of lead molecules in drug discovery. In particular, products to treat infectious diseases have been developed and several reports about potentialities of essential oils (EO) against Leishmania could be found. In this study, we report the chemical characterization, anti-leishmanial effects and cytotoxicity of the EO from Artemisia absinthium L. Chemical analysis revealed the EO to be composed of 18 compounds, 11 of which were identified, accounting for 64.1% of the composition. The main component of the EO was trans-sabinyl acetate, which made up 36.7%. In vitro anti-leishmanial screening showed that the A. absinthium EO inhibited the growth of promastigotes (14.4 ± 3.6 μg/mL) and amastigotes (13.4 ± 2.4 μg/mL) of L. amazonensis; while cytotoxicity evaluation caused 6 fold higher values than those for the parasites. In a model of experimental cutaneous leishmaniasis in BALB/c mice, five doses of EO at 30 mg/kg by intralesional route demonstrated control of lesion size and parasite burden ( p< 0.05) compared with animals treated with glucantime and untreated mice. In conclusion, in vitro and in vivo results showed the potential of EO from A. absinthium as a promising source for lead or active compounds against Leishmania, which could be explored.

Analogs of marinopyrrole A show enhancement to observed in vitro potency against acute Toxoplasma gondii infection

2021 ◽  
Author(s):  
Matthew C. Martens ◽  
Yan Liu ◽  
Austin G. Sanford ◽  
Alexander I. Wallick ◽  
Rosalie C. Warner ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Acute Infection ◽  
Standard Of Care ◽  
Host Cells ◽  
Infection Model ◽  
Current Standard ◽  
Clinical Consequences ◽  
Toxoplasma Gondii Infection

The apicomplexan parasite Toxoplasma gondii is the causative agent of toxoplasmosis, a globally distributed infection with severe clinical consequences for immunocompromised individuals and developing fetuses. There are few available treatments, and these are associated with potentially severe adverse effects. Marinopyrrole A, a compound discovered in a marine Streptomyces species, has previously been found to exhibit potent antimicrobial activity, prompting our interest in exploring efficacy against Toxoplasma gondii . We found that marinopyrrole A was a highly potent anti- Toxoplasma molecule, with an in vitro 50% maximal inhibitory concentration (IC 50 ) of 0.31 μM corresponding to a higher potency than that of the current standard of care (pyrimethamine); however, addition of 20% serum led to abrogation of potency, and toxicity to human cell lines was observed. Yet, application of marinopyrrole A to an in vivo lethal acute infection model facilitated significantly enhanced survival at doses of 5, 10, and 20 mg/kg. We then tested a series of marinopyrrole A analogs—RL002, RL003, and RL125—demonstrating significantly increased potency in vitro , with IC 50 values ranging from 0.09-0.17 μM (3.6-6.8X increase relative to pyrimethamine). No detectable cytotoxicity was observed up to 50 μM in human foreskin fibroblasts, with cytotoxicity in HepG2 cells ranging from ∼28-50 μM, corresponding to >200X selectivity for parasites over host cells. All analogs additionally showed reduced sensitivity to serum. Further, RL003 potently inhibited in vitro -generated bradyzoites at 0.245 μM. Taken together, these data support further development of marinopyrrole A analogs as promising anti- Toxoplasma molecules to further combat this prevalent infection.

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 Establishment of a Chronic Trypanosoma Equiperdum Infection Model in Mice

2020 ◽  
Author(s):  
Yusuke Tanaka ◽  
Keisuke Suganuma ◽  
Kenichi Watanabe ◽  
Yoshiyasu Kobayashi
Keyword(s):  
Chronic Infection ◽  
Histopathological Examination ◽  
Experimental Studies ◽  
Clinical Signs ◽  
Disease Process ◽  
Infection Model ◽  
Sequential Method ◽  
Trypanosoma Equiperdum

Abstract Dourine, caused by chronic infection with Trypanosoma equiperdum, is one of the African trypanosomiasis in equids. Since the pathogenesis of dourine has not yet been elucidated, experimental studies using mouse infection models are needed. However, mice cannot be infected with most T. equiperdum strains or rapidly develop parasitemia if infection is established and die within a few days. A sequential method of isolating parasites from dourine-affected horses and adapting them to in vitro cultures using soft agarose media was recently developed. Various T. equiperdum strains adapted to in vitro conditions have since been established using this technique. We used one of these strains, the T. equiperdum IVM-t2 strain. In the present study, we inoculated mice with the IVM-t2 strain and successfully produced a chronic infection model in mice. In the clinical examination, periodic parasitemia and skin plaques, which are characteristic clinical signs of dourine-affected horses, were observed. A histopathological examination revealed that some of the lesions observed in infected horses, such as vaginitis, trypanosomal sand, and peripheral neuritis, were reproduced in mice. This mouse model will be a valuable tool for pathological, immunological, and parasitological in vivo research, and will contribute to investigations on the mechanisms underlying the disease process and the host-protozoa relationship.

scholarly journals Broad-Spectrum In Vitro Activity and In Vivo Efficacy of the Antiviral Protein Griffithsin against Emerging Viruses of the Family Coronaviridae

2009 ◽  
Vol 84 (5) ◽  
pp. 2511-2521 ◽  
Author(s):  
Barry R. O'Keefe ◽  
Barbara Giomarelli ◽  
Dale L. Barnard ◽  
Shilpa R. Shenoy ◽  
Paul K. S. Chan ◽  
...  
Keyword(s):  
Immunological Response ◽  
Large Family ◽  
Infection Model ◽  
Human Pathogens ◽  
Emerging Viruses ◽  
Antiviral Protein ◽  
The Family ◽  
Positive Strand Rna

ABSTRACT Viruses of the family Coronaviridae have recently emerged through zoonotic transmission to become serious human pathogens. The pathogenic agent responsible for severe acute respiratory syndrome (SARS), the SARS coronavirus (SARS-CoV), is a member of this large family of positive-strand RNA viruses that cause a spectrum of disease in humans, other mammals, and birds. Since the publicized outbreaks of SARS in China and Canada in 2002-2003, significant efforts successfully identified the causative agent, host cell receptor(s), and many of the pathogenic mechanisms underlying SARS. With this greater understanding of SARS-CoV biology, many researchers have sought to identify agents for the treatment of SARS. Here we report the utility of the potent antiviral protein griffithsin (GRFT) in the prevention of SARS-CoV infection both in vitro and in vivo. We also show that GRFT specifically binds to the SARS-CoV spike glycoprotein and inhibits viral entry. In addition, we report the activity of GRFT against a variety of additional coronaviruses that infect humans, other mammals, and birds. Finally, we show that GRFT treatment has a positive effect on morbidity and mortality in a lethal infection model using a mouse-adapted SARS-CoV and also specifically inhibits deleterious aspects of the host immunological response to SARS infection in mammals.

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