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BMC Microbiology Feb 2022Leishmaniasis is a vector-borne disease that is endemic in the tropical and sub-tropical areas of the world. Low efficacy and high cytotoxicity of the current treatment...
BACKGROUND
Leishmaniasis is a vector-borne disease that is endemic in the tropical and sub-tropical areas of the world. Low efficacy and high cytotoxicity of the current treatment regimens for leishmaniasis is one of the most important health problems. In this experimental study, anti-leishmanial effects of different concentrations of resveratrol and resveratrol nano-emulsion (RNE) were assessed.
METHODS
RNE was prepared using the probe ultra-sonication method. The cytotoxicity was evaluated using the MTT technique on the L929 cell line. The anti-leishmanial activities on promastigotes of leishmania were assessed using vital staining and infected BALB/c mice were used to assess the in vivo anti-leishmanial effects.
RESULTS
In vitro and in vivo assays revealed that all concentrations of resveratrol and RNE had valuable inhibitory effects against Leishmania major in comparison to the control group (P < 0.05). The half maximal inhibitory concentration (IC) values were calculated as 16.23 and 35.71 µg/mL for resveratrol and RNE, respectively. Resveratrol and RNE showed no cytotoxicity against the L929 cell line.
CONCLUSIONS
According to the potent in vitro and in vivo anti-leishmanial activity of RNE at low concentration against L. major, we suggest that it could be a promising anti-leishmanial therapeutic against L. major in the future.
Topics: Animals; Antiprotozoal Agents; Cell Line; Emulsions; Female; Leishmania major; Leishmaniasis, Cutaneous; Macrophages; Mice; Mice, Inbred BALB C; Nanoparticles; Resveratrol
PubMed: 35168553
DOI: 10.1186/s12866-022-02455-8 -
Revista Iberoamericana de Micologia 2021A review on the current evidence of the efficacy and security of liposomal amphotericinB (L-AmB) for the treatment of visceral leishmaniasis (VL) has been performed. In... (Review)
Review
A review on the current evidence of the efficacy and security of liposomal amphotericinB (L-AmB) for the treatment of visceral leishmaniasis (VL) has been performed. In the Indian subcontinent, a single dose of 10mg/kg has shown effectiveness in the treatment of VL due to Leishmania donovani. In contrast, higher doses of L-AmB (up to 30mg/kg) are required in Africa to treat a VL of the same etiology. When treating VL by Leishmania infantum acquired in the Americas and Europe the usual dose of L-AmB is 20-21mg/kg. In HIV co-infected patients the required doses are usually higher, up to 60mg/kg, and if it is administered in a prophylactic schedule after the treatment of VL relapses are reduced. L-AmB has shown synergism with other antiparasitic drugs, especially with paromomycin in the Indian subcontinent and with miltefosin in patients coinfected with HIV in East Africa. Due to its efficacy and safety profile, L-AmB is the first therapeutic option for VL.
Topics: Antiprotozoal Agents; Humans; Leishmania infantum; Leishmaniasis; Leishmaniasis, Visceral; Liposomes
PubMed: 34127386
DOI: 10.1016/j.riam.2021.04.002 -
Scientific Reports Jun 2022Natural products have been proven to be important starting points for the development of new drugs. Bacteria in the genera Photorhabdus and Xenorhabdus produce...
Natural products have been proven to be important starting points for the development of new drugs. Bacteria in the genera Photorhabdus and Xenorhabdus produce antimicrobial compounds as secondary metabolites to compete with other organisms. Our study is the first comprehensive study screening the anti-protozoal activity of supernatants containing secondary metabolites produced by 5 Photorhabdus and 22 Xenorhabdus species against human parasitic protozoa, Acanthamoeba castellanii, Entamoeba histolytica, Trichomonas vaginalis, Leishmania tropica and Trypanosoma cruzi, and the identification of novel bioactive antiprotozoal compounds using the easyPACId approach (easy Promoter Activated Compound Identification) method. Though not in all species, both bacterial genera produce antiprotozoal compounds effective on human pathogenic protozoa. The promoter exchange mutants revealed that antiprotozoal bioactive compounds produced by Xenorhabdus bacteria were fabclavines, xenocoumacins, xenorhabdins and PAX peptides. Among the bacteria assessed, only P. namnaoensis appears to have acquired amoebicidal property which is effective on E. histolytica trophozoites. These discovered antiprotozoal compounds might serve as starting points for the development of alternative and novel pharmaceutical agents against human parasitic protozoa in the future.
Topics: Antiprotozoal Agents; Entamoeba histolytica; Humans; Photorhabdus; Trypanosoma cruzi; Xenorhabdus
PubMed: 35750682
DOI: 10.1038/s41598-022-13722-z -
Frontiers in Cellular and Infection... 2023Current treatment for visceral leishmaniasis is based on drugs such as pentavalent antimony and amphotericin B. However, this treatment remains mostly ineffective and...
Current treatment for visceral leishmaniasis is based on drugs such as pentavalent antimony and amphotericin B. However, this treatment remains mostly ineffective and expensive, resulting in several side effects and generating resistance. Apigenin, a flavonoid present in fruits and vegetables, has demonstrated several biological functions. In the present study, we observed a concentration-dependent inhibition of the promastigote in the presence of apigenin, exhibiting an IC value of 29.9 µM. Its effect was also evaluated in -infected murine peritoneal macrophages, presenting an C value against intracellular amastigotes of 2.3 µM and a selectivity index of 34.3. In a murine model of visceral leishmaniasis, the effect of apigenin was measured using short-term and long-term treatment schemes. Treatment with apigenin demonstrated 99.7% and 94% reductions in the liver parasite load in the short-term and long-term treatment schemes, respectively. Furthermore, no alterations in serological and hematological parameters were observed. Taken together, these results suggest that apigenin is a potential candidate for visceral leishmaniasis chemotherapy by oral administration.
Topics: Animals; Mice; Leishmaniasis, Visceral; Apigenin; Leishmania infantum; Amphotericin B; Antiprotozoal Agents; Mice, Inbred BALB C
PubMed: 37091674
DOI: 10.3389/fcimb.2023.1066407 -
Biochimie Oct 2021Leishmaniasis is a neglected parasitic disease for which the conventional treatment can be considered inefficient and extremely aggressive, generating several and severe...
Leishmaniasis is a neglected parasitic disease for which the conventional treatment can be considered inefficient and extremely aggressive, generating several and severe side effects. Therefore, the discovery of new drug candidates is important for the improvement in the quality of life of patients. Previously, we reported the promising results of isopentyl caffeate (ICaf) against Leishmania chagasi (agent of visceral leishmaniasis) and Leishmania amazonensis (agent of cutaneous leishmaniasis) promastigotes, displaying IC of 1.56 and 1.71 μM, respectively. Herein, we aimed to decipher the mechanisms of anti-Leishmania action of ICaf. Light and scanning electron microscopy assays showed relevant morphological changes in promastigotes when treated with ICaf, including rounding of the parasite body, shortening of the flagellum, blebs on the plasma membrane and cellular aggregation. The parasite mitochondrion was targeted by ICaf, resulting in a significant reduction in its metabolic activity and electric membrane potential followed by an increase in the production of reactive oxygen species, which culminated in the loss of plasma membrane integrity and parasite death. Relevantly, ICaf also had a potent anti-amastigote action. The IC values calculated for intracellular amastigotes of L. amazonensis were 3.27, 1.60 and 1.52 μM, while for L. chagasi the values were 2.48, 1.84 and 1.60 μM, respectively, after treating the infected macrophages with ICaf for 24, 48 and 72 h. ICaf was well tolerated by THP-1 macrophages, which gave rise to excellent selectivity indexes considering both Leishmania species. The current results suggest that ICaf may emerge as a chemotherapeutic alternative for the treatment of leishmaniasis.
Topics: Antiprotozoal Agents; Caffeic Acids; Humans; Leishmania infantum; Leishmaniasis, Visceral; Macrophages; THP-1 Cells
PubMed: 34216704
DOI: 10.1016/j.biochi.2021.06.015 -
Clinical Infectious Diseases : An... May 2021Control of cutaneous leishmaniasis (CL) relies on chemotherapy, yet gaps in our understanding of the determinants of therapeutic outcome impede optimization of...
BACKGROUND
Control of cutaneous leishmaniasis (CL) relies on chemotherapy, yet gaps in our understanding of the determinants of therapeutic outcome impede optimization of antileishmanial drug regimens. Pharmacodynamic (PD) parameters of antimicrobials are based on the relationship between drug concentrations/exposure and microbial kill. However, viable Leishmania persist in a high proportion of individuals despite clinical resolution, indicating that determinants other than parasite clearance are involved in drug efficacy.
METHODS
In this study, the profiles of expression of neutrophils, monocytes, Th1 and Th17 gene signatures were characterized in peripheral blood mononuclear cells (PBMCs) during treatment with meglumine antimoniate (MA) and clinical cure of human CL caused by Leishmania (Viannia). We explored relationships of immune gene expression with plasma and intracellular antimony (Sb) concentrations.
RESULTS
Our findings show a rapid and orchestrated modulation of gene expression networks upon exposure to MA. We report nonlinear pharmacokinetic/pharmacodynamic (PK/PD) relationships of Sb and gene expression dynamics in PBMCs , concurring with a time lag in the detection of intracellular drug concentrations and with PK evidence of intracellular Sb accumulation.
CONCLUSIONS
Our results quantitatively portray the immune dynamics of therapeutic healing, and provide the knowledge base for optimization of antimonial drug treatments, guiding the selection and/or design of targeted drug delivery systems and strategies for targeted immunomodulation.
Topics: Antiprotozoal Agents; Humans; Leishmania; Leishmaniasis, Cutaneous; Leukocytes, Mononuclear; Meglumine Antimoniate
PubMed: 32818964
DOI: 10.1093/cid/ciaa1206 -
International Journal of Antimicrobial... Aug 2022A growing number of studies have demonstrated the in vitro potential of an impressive number of antileishmanial candidates in the past years. However, the lack of... (Review)
Review
A growing number of studies have demonstrated the in vitro potential of an impressive number of antileishmanial candidates in the past years. However, the lack of uniformity regarding the choice of cell types for cytotoxicity assays may lead to uncomparable and inconclusive data. In vitro assays relying solely on non-phagocytic cell models may not represent a realistic result as the effect of an antileishmanial agent should ideally be presented based on its cytotoxicity profile against reticuloendothelial system cells. In the present review, we have assembled studies published in the scientific literature from 2015 to 2021 that explored leishmanicidal candidates, emphasising the main host cell models used for cytotoxicity assays. The pros and cons of different host cell types as well as primary cells and cell lines are discussed in order to draw attention to the need to establish standardised protocols for preclinical testing when assessing new antileishmanial candidates.
Topics: Antiprotozoal Agents; Cell Line
PubMed: 35691601
DOI: 10.1016/j.ijantimicag.2022.106612 -
Journal of Enzyme Inhibition and... Dec 2020A series of new 2,4-bis[(substituted-aminomethyl)phenyl]quinoline, 1,3-bis[(substituted-aminomethyl)phenyl]isoquinoline, and...
Design, synthesis, and antiprotozoal evaluation of new 2,4-bis[(substituted-aminomethyl)phenyl]quinoline, 1,3-bis[(substituted-aminomethyl)phenyl]isoquinoline and 2,4-bis[(substituted-aminomethyl)phenyl]quinazoline derivatives.
A series of new 2,4-bis[(substituted-aminomethyl)phenyl]quinoline, 1,3-bis[(substituted-aminomethyl)phenyl]isoquinoline, and 2,4-bis[(substituted-aminomethyl)phenyl]quinazoline derivatives was designed, synthesised, and evaluated against three protozoan parasites (, , and ). Biological results showed antiprotozoal activity with IC values in the µM range. In addition, the cytotoxicity of these original molecules was assessed with human HepG2 cells. The quinoline was identified as the most potent antimalarial candidate with a ratio of cytotoxic to antiparasitic activities of 97 against the CQ-sensitive strain 3D7. The quinazoline was also identified as the most potent trypanosomal candidate with a selectivity index (SI) of 43 on strain. Moreover, as the telomeres of the parasites and are possible targets of this kind of nitrogen heterocyclic compounds, we have also investigated stabilisation of the and telomeric G-quadruplexes by our best compounds through FRET melting assays.
Topics: Antiprotozoal Agents; Drug Design; Hep G2 Cells; Humans; Leishmania donovani; Plasmodium falciparum; Quinolines; Structure-Activity Relationship; Trypanosoma brucei brucei
PubMed: 31899980
DOI: 10.1080/14756366.2019.1706502 -
Molecules (Basel, Switzerland) Jan 2022Human protozoan diseases represent a serious health problem worldwide, affecting mainly people in social and economic vulnerability. These diseases have attracted little... (Review)
Review
Human protozoan diseases represent a serious health problem worldwide, affecting mainly people in social and economic vulnerability. These diseases have attracted little investment in drug discovery, which is reflected in the limited available therapeutic arsenal. Authorized drugs present problems such as low efficacy in some stages of the disease or toxicity, which result in undesirable side effects and treatment abandonment. Moreover, the emergence of drug-resistant parasite strains makes necessary an even greater effort to develop safe and effective antiparasitic agents. Among the chemotypes investigated for parasitic diseases, the indole nucleus has emerged as a privileged molecular scaffold for the generation of new drug candidates. In this review, the authors provide an overview of the indole-based compounds developed against important parasitic diseases, namely malaria, trypanosomiasis and leishmaniasis, by focusing on the design, optimization and synthesis of the most relevant synthetic indole scaffolds recently reported.
Topics: Animals; Antiprotozoal Agents; Chemistry Techniques, Synthetic; Drug Development; Humans; Indoles; Leishmania; Leishmaniasis; Malaria; Parasitic Sensitivity Tests; Plasmodium; Structure-Activity Relationship; Trypanosoma; Trypanosomiasis
PubMed: 35011552
DOI: 10.3390/molecules27010319 -
Molecules (Basel, Switzerland) Oct 2022Quinones and quinols are secondary metabolites of higher plants that are associated with many biological activities. The oxidative dearomatization of phenols induced by...
Efficient Oxidative Dearomatisations of Substituted Phenols Using Hypervalent Iodine (III) Reagents and Antiprotozoal Evaluation of the Resulting Cyclohexadienones against and Strain NF54.
Quinones and quinols are secondary metabolites of higher plants that are associated with many biological activities. The oxidative dearomatization of phenols induced by hypervalent iodine(III) reagents has proven to be a very useful synthetic approach for the preparation of these compounds, which are also widely used in organic synthesis and medicinal chemistry. Starting from several substituted phenols and naphthols, a series of cyclohexadienone and naphthoquinone derivatives were synthesized using different hypervalent iodine(III) reagents and evaluated for their in vitro antiprotozoal activity. Antiprotozoal activity was assessed against NF54 and STIB900. Cytotoxicity of all compounds towards L6 cells was evaluated and the respective selectivity indices (SI) were calculated. We found that benzyl naphthoquinone was the most active and selective molecule against (IC = 0.08 μM, SI = 275). Furthermore, the antiprotozoal assays revealed no specific effects. In addition, some key physicochemical parameters of the synthesised compounds were calculated.
Topics: Antiprotozoal Agents; Cyclohexenes; Humans; Hydroquinones; Indicators and Reagents; Iodine; Malaria, Falciparum; Naphthols; Naphthoquinones; Oxidative Stress; Parasitic Sensitivity Tests; Phenols; Plasmodium falciparum; Trypanosoma brucei rhodesiense
PubMed: 36235096
DOI: 10.3390/molecules27196559