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Evaluation of the in vitro and in vivo inhibitory effect of thymoquinone on piroplasm parasites.

ABSTRACT:

Background

Developing new antibabesial drugs with a low toxic effect to the animal and with no resistance from Babesia parasites is in urgent demand. In this concern, the antimalarial, anticancer and antioxidant effect of thymoquinone (TQ), a phytochemical compound found in the plant Nigella sativa, has been reported. Therefore, in the present study, the antibabesial effect of this compound was evaluated on the growth of piroplasm parasites.

Results

Significant inhibition (P < 0.05) of the in vitro growth of piroplasm parasites were observed after treatment by TQ with IC₅₀ values of 35.41 ± 3.60, 7.35 ± 0.17, 0.28 ± 0.016, 74.05 ± 4.55 and 67.33 ± 0.94 ?M for Babesia bovis, Babesia bigemina, Babesia divergens, Theileria equi and Babesia caballi, respectively. The in vitro inhibitory effect of TQ was significantly enhanced (P < 0.05) when used in combination with either diminazene aceturate on bovine Babesia and equine Babesia and Theileria cultures. In B. microti-infected mice, oral and intraperitoneal administrations of TQ showed significant (P < 0.05) inhibition of parasite growth at a dose of 70 mg/kg and 50 mg/kg, respectively, compared to the control group.

Conclusions

The obtained results indicate that thymoquinone might be a promising medicinal compound for use in the treatment of animal piroplasmosis.

SUBMITTER: El-Sayed SAE

PROVIDER: S-EPMC6335684 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Evaluation of the in vitro and in vivo inhibitory effect of thymoquinone on piroplasm parasites.

El-Sayed Shimaa Abd El-Salam SAE Rizk Mohamed Abdo MA Yokoyama Naoaki N Igarashi Ikuo I

Parasites & vectors 20190116 1

<h4>Background</h4>Developing new antibabesial drugs with a low toxic effect to the animal and with no resistance from Babesia parasites is in urgent demand. In this concern, the antimalarial, anticancer and antioxidant effect of thymoquinone (TQ), a phytochemical compound found in the plant Nigella sativa, has been reported. Therefore, in the present study, the antibabesial effect of this compound was evaluated on the growth of piroplasm parasites.<h4>Results</h4>Significant inhibition (P < 0.0 ...[more]

PMID: 30651142

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Project description:BackgroundTreatment is the principle way to control and eliminate piroplasmosis. The search for new chemotherapy against Babesia and Theileria has become increasingly urgent due to parasite resistance to current drugs. Ivermectin (IVM) was the world's first endectocide, capable of killing a wide variety of parasites and vectors, both inside and outside the body. It is currently authorized to treat onchocerciasis, lymphatic filariasis, strongyloidiasis, and scabies. The current study documented the efficacy of IVM on the growth of Babesia and Theileria in vitro and in vivo.MethodsThe fluorescence-based assay was used for evaluating the inhibitory effect of IVM on four Babesia species, including B. bovis, B. bigemina, B. divergens, B. caballi, and Theileria equi, the combination with diminazene aceturate (DA), clofazimine (CF), and atovaquone (AQ) on in vitro cultures, and on the multiplication of a B. microti-infected mouse model. The cytotoxicity of compounds was tested on Madin-Darby bovine kidney (MDBK), mouse embryonic fibroblast (NIH/3 T3), and human foreskin fibroblast (HFF) cell lines.ResultsThe half-maximal inhibitory concentration (IC50) values determined for IVM against B. bovis, B. bigemina, B. divergens, B. caballi, and T. equi were 53.3 ± 4.8, 98.6 ± 5.7, 30.1 ± 2.2, 43.7 ± 3.7, and 90.1 ± 8.1 μM, respectively. Toxicity assays on MDBK, NIH/3 T3, and HFF cell lines showed that IVM affected the viability of cells with a half-maximal effective concentration (EC50) of 138.9 ± 4.9, 283.8 ± 3.6, and 287.5 ± 7.6 μM, respectively. In the in vivo experiment, IVM, when administered intraperitoneally at 4 mg/kg, significantly (p < 0.05) inhibited the growth of B. microti in mice by 63%. Furthermore, combination therapies of IVM-DA, IVM-AQ, and IVM-CF at a half dose reduced the peak parasitemia of B. microti by 83.7%, 76.5%, and 74.4%, respectively. Moreover, this study confirmed the absence of B. microti DNA in groups treated with combination chemotherapy of IVM + DA and IVM + AQ 49 days after infection.ConclusionsThese findings suggest that IVM has the potential to be an alternative remedy for treating piroplasmosis.

Project description:Diminazene aceturate (DA) and imidocarb dipropionate are commonly used in livestock as antipiroplasm agents. However, toxic side effects are common in animals treated with these two drugs. Therefore, evaluations of novel therapeutic agents with high efficacy against piroplasm parasites and low toxicity to host animals are of paramount importance. In this study, the 400 compounds in the Pathogen Box provided by the Medicines for Malaria Venture foundation were screened against Babesia bovis, Babesia bigemina, Babesia caballi, and Theileria equi. A fluorescence-based method using SYBR Green 1 stain was used for initial in vitro screening and determination of the half maximal inhibitory concentration (IC50). The initial in vitro screening performed using a 1 μM concentration as baseline revealed nine effective compounds against four tested parasites. Two "hit" compounds, namely MMV021057 and MMV675968, that showed IC50 < 0.3 μM and a selectivity index (SI)> 100 were selected. The IC50s of MMV021057 and MMV675968 against B. bovis, B. bigemina, T. equi and B. caballi were 23, 39, 229, and 146 nM, and 2.9, 3, 25.7, and 2.9 nM, respectively. In addition, a combination of MMV021057 and DA showed additive or synergistic effects against four tested parasites, while combinations of MMV021057 with MMV675968 and of MMV675968 with DA showed antagonistic effects. In mice, treated with 50 mg/kg MMV021057 and 25 mg/kg MMV675968 inhibited the growth of Babesia microti by 54 and 64%, respectively, as compared to the untreated group on day 8. Interestingly, a combination treatment with 6.25 mg/kg DA and 25 mg/kg MMV021057 inhibited B. microti by 91.6%, which was a stronger inhibition than that by single treatments with 50 mg/kg MMV021057 and 25 mg/kg DA, which showed 54 and 83% inhibition, respectively. Our findings indicated that MMV021057, MMV675968, and the combination treatment with MMV021057 and DA are prospects for further development of antipiroplasm drugs.

Project description:Thymoquinone is a natural bioactive with significant therapeutic activity against multiple ailments including wound healing. The poor aqueous solubility and low skin permeability limit its therapeutic efficacy. The present investigation aimed to improve the biopharmaceutical attributes of thymoquinone to enhance its topical efficacy in wound healing. A nanoemulsion-based hydrogel system was designed and characterized as a nanotechnology-mediated drug delivery approach to improve the therapeutic efficacy of thymoquinone, utilizing a high-energy emulsification technique. The black seed oil, as a natural home of thymoquinone, was utilized to improve the drug loading capacity of the developed nanoemulsion system and reduced the oil droplet size to <100 nm through ultrasonication. The influence of formulation composition, and the ultrasonication process conditions, were investigated on the mean globule size and polydispersity index of the generated nanoemulsion. Irrespective of surfactant/co-surfactant ratio and % concentration of surfactant/co-surfactant mixture, the ultrasonication time had a significant (p < 0.05) influence on the mean droplet size and polydispersity index of the generated nanoemulsion. The developed nanoemulgel system of thymoquinone demonstrated the pseudoplastic behavior with thixotropic properties, and this behavior is desirable for topical application. The nanoemulgel system of thymoquinone exhibited significant enhancement (p < 0.05) in skin penetrability and deposition characteristics after topical administration compared to the conventional hydrogel system. The developed nanoemulgel system of thymoquinone exhibited quicker and early healing in wounded Wistar rats compared to the conventional hydrogel of thymoquinone, while showing comparable healing efficacy with respect to marketed silver sulfadiazine (1%) cream. Furthermore, histopathology analysis of animals treated with a developed formulation system demonstrated the formation of the thick epidermal layer, papillary dermis along with the presence of extensive and organized collagen fibers in newly healed tissues. The outcome of this investigation signifies that topical delivery of thymoquinone through nanoemulgel system is a promising candidate which accelerates the process of wound healing in preclinical study.

Project description:BackgroundAlthough 5-HT2A serotonergic antagonists have been used to treat vascular disease in patients with diabetes mellitus or obesity, their effects on leukocyte-endothelial interactions have not been fully investigated. In this study, we assessed the effects of sarpogrelate hydrochloride (SRPO), a 5-HT2A receptor inverse agonist, on leukocyte-endothelial cell interactions in obesity both in vivo and in vitro.Methods and findingsIn the in vivo experiment, C57BL/6 mice were fed a high-fat high-fructose diet (HFFD), comprising 20% fat and 30% fructose, with or without intraperitoneal injection of 5 mg/kg/day SRPO for 4 weeks. The body weight, visceral fat weight, and serum monocyte chemoattractant protein-1 levels in the mice increased significantly with the HFFD, but these effects were prevented by chronic injections of SRPO. Intravital microscopy of the femoral artery detected significant leukocyte-endothelial interactions after treatment with HFFD, but these leukocyte-endothelial interactions were reduced in the mice injected with SRPO. In the in vitro experiment, pre-incubation of activated human umbilical vein endothelial cells (HUVECs) with platelet-rich plasma (PRP) induced THP-1 cell adhesion under physiological flow conditions, but the adhesion was reduced by pretreatment of PRP with SRPO. A fluorescent immunobinding assay showed that PRP induced significant upregulation of E-selectin in HUVECs, but this upregulation was reduced by pretreatment of PRP with SRPO. In other in vitro conditions, pre-incubation of THP-1 cells with phorbol 12-myristate 13-acetate increased the adhesion of THP-1 cells to activated HUVECs under rotational conditions, but this adhesion was reduced by pretreatment with SRPO. Western blotting analysis showed that protein kinase C ? activation in THP-1 cells was inhibited by SRPO.ConclusionOur findings indicated that SRPO inhibits vascular inflammation in obesity via inactivation of platelets and leukocytes, and improvement of obese.

Dataset Information

Evaluation of the in vitro and in vivo inhibitory effect of thymoquinone on piroplasm parasites.

Background

Results

Conclusions

Publications

Evaluation of the in vitro and in vivo inhibitory effect of thymoquinone on piroplasm parasites.

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