Simvastatin exerts antifibrotic effect and potentiates the antischistosomal effects of praziquantel in a murine model: Role of IL10

Elmasry, Ahlam; Aladeeb, Nabil; El-Karef, Amro; Aboulfotouh, Nora

doi:10.1016/j.biopha.2017.09.136

Cited by 6 publications

(4 citation statements)

References 22 publications

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“…Our present study now reconcile such observations, demonstrating that PZQ has potential preventive antifibrotic effects while it has no efficacy in therapeutically reversing established fibrosis. This conclusion reliably recapitulates the established view of most authors on the subject 9,11,21,[53][54][55][56][57][58][59][60][61][62][63] where PZQ antifibrotic / anti-pathological potential in clinically fibrotic schistosomiasis-diseased patients might not be direct and/or effective on established fibrosis but entirely consequent to its anti-parasitic effect when administered after fibrosis development.…”

Section: Discussionsupporting

confidence: 85%

“…The extensive usage of PZQ during mass drug administration campaigns in flatworm-endemic areas has considerable health benefits for the target populations over time such as improved fitness, improved cognitive functions and reduced tissue fibrosis 13,[15][16][17][18][19][20]34,[40][41][42][43][44][45][46][47][48][49][50][51][52] . Whereas most authors associated such health benefits and particularly the improvement of tissue fibrosis in helminth-infested individuals to the sole antiparasitic potential of PZQ 9,11,21,[53][54][55][56][57][58][59][60][61][62][63] , recent reports on the drug ability to also directly mitigate tissue fibrosis have also emerged 13,[15][16][17][18][19][20]34,[40][41][42][43]…”

Section: Discussionmentioning

confidence: 99%

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Investigating the antifibrotic effect of the antiparasitic drug Praziquantel in in vitro and in vivo preclinical models

Nono

Mpotje

et al. 2020

Sci Rep

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Tissue fibrosis underlies the majority of human mortality to date with close to half of all reported deaths having a fibrotic etiology. The progression of fibrosis is very complex and reputed irreversible once established. Although some preventive options are being reported, therapeutic options are still scarce and in very high demand, given the rise of diseases linked to fibroproliferative disorders. Our work explored four platforms, complementarily, in order to screen preventive and therapeutic potentials of the antiparasitic drug Praziquantel as a possible antifibrotic. We applied the mouse CCl 4driven liver fibrosis model, the mouse chronic schistosomiasis liver fibrosis model, as well as novel 2D and 3D human cell-based co-culture of human hepatocytes, KCs (Kupffer cells), LECs (Liver Endothelial Cells), HSCs (Hepatic Stellate Cells) and/or myofibroblasts to mimic in vivo fibrotic responses and dynamics. Praziquantel showed some effect on fibrosis marker when preventively administered before severe establishment of fibrosis. However, it failed to potently reverse already established fibrosis. Together, we provided a novel sophisticated multi-assay screening platform to test preventive and therapeutic antifibrotic candidates. We further demonstrated a direct preventive potential of Praziquantel against the onset of fibrosis and the confirmation of its lack of therapeutic potential in reversing already established fibrosis. Discovered close to 50 years ago, Praziquantel (PZQ), a tetracyclic tetrahydroisoquinoline derivative administered as a racemate is the main drug therapy for combating flatworm parasites including tapeworms and schistosomes 1,2. In vitro and in vivo, the antischistosomal activity of PZQ enantiomers resides primarily in the (R)-enantiomer 3,4. The drug induces rapid paralysis of adult flatworm musculature and tegumental damage that facilitate the immunological removal of the worm from the host 5,6. As a result, the morbid manifestations of tissue-dwelling flatworm larvae were reported to be considerably, and even at times fully, controlled by PZQ treatment 7-25. One crippling and life-threatening sequelae resulting from Schistosoma eggs trapped in tissue is fibrosis 26,27. Fibrosis manifests as the uncontrolled formation of extracellular matrix in injured organ that progressively replaces the tissue parenchyma and drives pathology. Reduction of tissue fibrosis following PZQ treatment of flatworm-driven infections and injuries has been reported to be a direct consequence of the antiparasitic effect of the drug 28. The still poorly defined mode of action of the drug 5,6,29-32 has made definitive claims on its scope of action difficult. In fact, a recent report claiming PZQ-associated reduction of pathological

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Investigating the antifibrotic effect of the antiparasitic drug Praziquantel in in vitro and in vivo preclinical models

Nono

Mpotje

et al. 2020

Sci Rep

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“…Simvastatin treatment has been found to be able to reduce the expression of miR-34a, and we found that IL-10 is a potential target gene of miR-34a by searching the online miRNA database. Furthermore, it has been shown that IL-10 up-regulation could halt the progression of cirrhosis in mouse model [22]. Based on the evidence listed above, we tested the regulatory relationship between simvastatin, miR-34a and IL-10, and also investigated the anti-fibrotic effect of simvastatin in rats as well as its potential signaling pathway.…”

Section: P R E P R I N Tmentioning

confidence: 99%

Administration of simvastatin halts progression of cirrhosis via up-regulating expression of miR-34a and interleukin-10 in rats

et al. 2021

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IntroductionSimvastatin (SIM) treatment has been found to be able to reduce the expression of miR-34a, and we found that interleukin-10 (IL-10) is a potential target gene of miR-34a by searching the online microRNA (miRNA) database. Furthermore, it has been shown that IL10 up-regulation could halt the progression of cirrhosis. The objective of this study was to explore the underlying mechanism of Simvastatin/miR-34a/IL-10 involved in HBV associated cirrhosis.Material and methodsReal-time PCR, western-blot analysis, immunohistochemistry, computational analysis, luciferase assay was carried out to explore the underlying mechanism of miR-34a involved in HBV associated cirrhosis.ResultsSIM treatment dose-dependently decreased the levels of miR-34a while increasing the levels of IL-10 mRNA and protein. Levels of IL-10 mRNA and protein were remarkably decreased, while miR-34a mRNA level and active caspase-3 protein level was apparently increased in Cirrhosis group compared with sham group. Accordingly, SIM treatment obstructed the dysregulated miR-34a expression and IL-10 expression in cirrhosis animals. By performing computational analysis, we identified that a complementary binding site of miR-34a was located in IL-10 3’ untranslated region (3’UTR), and miR-34a reduced luciferase activity of wild-type IL-10 3’UTR.ConclusionsOur data also suggested that SIM may become a new therapeutic strategy for HBV-associated cirrhosis via targeting the miR-34a/IL-10 axis.

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“…Besides, although this drug appears safe and effective against all adult Schistosoma sp in general [ 23 ], an in-depth understanding of the efficacy and safety of various doses for different Schistosoma sp is necessary to extensively use PZQ. Some studies reported PZQ therapeutic failure [ 24 ], some up to 40% [ 25 ]. Above all, heavy dependence on the single available drug, which has been in use for over 40 years, is a source of serious concern.…”

Section: Introductionmentioning

confidence: 99%

The Activity of Plant Crude Extracts against Schistosoma mansoni

Basha

Mamo

2021

Journal of Parasitology Research

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Background. Schistosoma mansoni remains a significant health problem in low-income countries. Praziquantel (PZQ) is the only drug available to treat schistosomiasis, and PZQ resistance is a potential threat towards control of the disease although PZQ is currently effective against all species of schistosomes. Moreover, PZQ is less efficacious against larval stages. In response to these challenges, multiple in vivo/in vitro studies evaluated the anti-S. mansoni activity of crude plant extracts in a bid for novel drug(s). However, these studies appear fragmented and patchy. This systematic review explored the extent of such studies in the past 11 years (2010-2020). Methods. A systematic web search analysis and review of the literature on crude plant extracts tested against S. mansoni was done. Data from 17 articles meeting eligibility criteria were extracted and analyzed. Forty-three plant species have been tested by the 17 studies. The leaves, barks, stems, flowers, rhizomes, and roots of the plants as well as the whole plant part were used for the experiments. Conclusion. Nearly all of the plants significantly reduced schistosome egg output, killed adult worms, and improved liver histology and function. Further studies are required to assess the therapeutic potential of more promising plant species.

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Simvastatin exerts antifibrotic effect and potentiates the antischistosomal effects of praziquantel in a murine model: Role of IL10

Cited by 6 publications

References 22 publications

Investigating the antifibrotic effect of the antiparasitic drug Praziquantel in in vitro and in vivo preclinical models

Investigating the antifibrotic effect of the antiparasitic drug Praziquantel in in vitro and in vivo preclinical models

Administration of simvastatin halts progression of cirrhosis via up-regulating expression of miR-34a and interleukin-10 in rats

The Activity of Plant Crude Extracts against Schistosoma mansoni

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