Prevention and treatment of Schistosoma mansoni-induced liver fibrosis in mice

El‐Agamy, Dina S.; Shebl, Abdelhadi M.; Said, Sameh M.

doi:10.1007/s10787-011-0092-6

Cited by 31 publications

(27 citation statements)

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“…We have previously demonstrated that silymarin reduces granuloma area and collagen deposition during acute S. mansoni infection (8). It has been previously demonstrated that other antioxidants also have the ability to prevent schistosomiasis-induced fibrosis when adminis- tered in the acute phase (4,5). El-Lakkany and coworkers (2012), treating infected mice with silymarin from 84 to 126 dpi, observed a slight decrease in the parasite burden and then in fibrosis, but the effect was smaller than that of praziquantel alone and possibly secondary to the decrease in burden (42).…”

Section: Discussionmentioning

confidence: 99%

Silymarin Reduces Profibrogenic Cytokines and Reverses Hepatic Fibrosis in Chronic Murine Schistosomiasis

Hilton

Dutra

Rocha

et al. 2014

Antimicrob Agents Chemother

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In chronic schistosomiasis, hepatic fibrosis is linked to the portal hypertension that causes morbidity in Schistosoma mansoni infection. Silymarin (SIL) is a hepatoprotective and antioxidant medicament largely prescribed against liver diseases that has previously been shown to prevent fibrosis during acute murine schistosomiasis. Here we employed silymarin to try to reverse established hepatic fibrosis in chronic schistosomiasis. Silymarin or vehicle was administered to BALB/c mice every 48 h, starting on the 40th (80 days of treatment), 70th (50 days), or 110th (10 days) day postinfection (dpi). All mice were sacrificed and analyzed at 120 dpi. Treatment with silymarin reduced liver weight and granuloma sizes, reduced the increase in alanine aminotransferase and aspartate aminotransferase levels, and reduced the established hepatic fibrosis (assessed by hydroxyproline contents and picrosirius staining). Treatment with silymarin also reduced the levels of interleukin-13 (IL-13) in serum and increased the gamma interferon (IFN-␥)/IL-13 ratio. There was a linear correlation between IL-13 levels in serum and hydroxyproline hepatic content in both infected untreated and SIL-treated mice, with decreased IL-13 levels corresponding to decreased hydroxyproline hepatic contents. Treatment with either SIL or N-acetylcysteine reduced both proliferation of fibroblast cell lines and basal/IL-13-induced production of collagen I, indicating that besides inhibiting IL-13 production during infection, SIL antioxidant properties most likely contribute to inhibition of collagen production downstream of IL-13. These results show that silymarin interferes with fibrogenic cytokines, reduces established fibrosis, and inhibits downstream effects of IL-13 on fibrogenesis, indicating the drug as a safe and cheap treatment to liver fibrotic disease in schistosomiasis. Schistosomiasis is a chronic disease of high prevalence and wide distribution around the world (1) caused by worms that parasitize the vascular system. The morbidity in schistosomiasis is associated with the arrival of worm eggs to the liver and the stimulation of a granulomatous reaction (2). Chronic liver pathology is closely associated to the nature of the host inflammatory response. The immunological progression of this disease is frequently divided in distinct phases: prepostural acute Th1 phase, postural acute Th2 phase, and chronic Th2 downmodulated phase (3). The control of this Th response throughout the chronic phase may be associated with the reduction of morbidity in schistosomiasis. During acute murine infection, administration of antioxidant drugs such as curcumin (4), resveratrol (5), n-acetylcysteine (6), artemether (7), and silymarin (8) is used to reduce morbidity and prevent hepatic fibrosis. The reversal of established hepatic fibrosis at the chronic stage is directly linked to the portal hypertension, the major cause of morbidity in Schistosoma mansoni infection, and was not attained in any of these previous works. Currently, there is no medical treatmen...

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Section: Discussionmentioning

confidence: 99%

Silymarin Reduces Profibrogenic Cytokines and Reverses Hepatic Fibrosis in Chronic Murine Schistosomiasis

Hilton

Dutra

Rocha

et al. 2014

Antimicrob Agents Chemother

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“…vitro and in prevention of fibrosis in vivo in a mouse model of schistosomiasis (9,15), showed a significant increase in release of AP (Fig. 3) and PGI (Fig.…”

Section: Resultsmentioning

confidence: 96%

“…Use of both AP and PGI as measures of drug effects on cestodes has been mostly limited to E. multilocularis (15), There are limitations in their general use. Both are pathogens of humans, and accidental injection may be infectious.…”

Section: Discussionmentioning

confidence: 99%

“…The widespread use and availability of these drugs in most regions of endemicity and their relatively low toxicity make them attractive new anticestode drugs. Imatinib, a tyrosine kinase inhibitor, has been previously demonstrated to have activity in vitro against Schistosoma mansoni, which encodes a tyrosine kinase in its genome (9,15). This drug has also been reported to have activity against the filarial parasite Brugia malayi (S. Bennuru, Laboratory of Parasitic Diseases, NIAID, personal communication).…”

Section: Discussionmentioning

confidence: 99%

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Quantitative Screening for Anticestode Drugs Based on Changes in Baseline Enzyme Secretion by Taenia crassiceps

Mahanty

Madrid²,

Nash

2013

Antimicrob Agents Chemother

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Neurocysticercosis (NCC), an infection of the brain with the larval stage of the Taenia solium tapeworm, is responsible for an estimated one-third of adult-onset epilepsy cases in regions of the world where it is endemic. Currently, anthelmintic drugs used for treatment of NCC are only partially effective, and there is, therefore, a pressing need for new therapeutic agents. Discovery of new anthelmintics with activity against T. solium has been limited by the lack of suitable sensitive assays that allow highthroughput screening. Using an in vitro culture system with Taenia crassiceps metacestodes, we demonstrate that changes in secretion of parasite-associated alkaline phosphatase (AP) and phosphoglucose isomerase (PGI) can be used to detect and quantify anthelmintic effects of praziquantel (PZQ), a drug with activity against T. solium. We applied two enzyme release assays to screen for anti-T. crassiceps activity in nonconventional antiparasitic drugs and demonstrate that nitazoxanide and artesunate induced release of both AP and PGI in differing time-and dose-related patterns. Furthermore, imatinib, a tyrosine kinase inhibitor previously reported to have parasiticidal activity against Schistosoma mansoni, also induced release of both AP and PGI in a dose-dependent manner, similar in pattern to that observed with the other anthelmintics. We also evaluated release of ATP into cyst supernatants as an indicator of drug effects but did not see any differences between treated and untreated cysts. These data provide the basis for rapid and quantitative screening assays for testing for anthelmintic activity in candidate anticestode agents.

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“…In a Schistosoma mansoni-injected model, the preventive and curative effects of liver fibrosis were evaluated by using antioxidants such as resveratrol, curcumin, and N-acetylcysteine (NAC); results indicated that curcumin had potent anti-fibrotic activity in both suppressing and reversing fibrosis, whereas resveratrol had a beneficial effect only in suppressing fibrosis (El-Agamy et al 2011). In BDL-and CCl4-or TAAtreated rats, NAC prevented liver fibrogenesis associated with decreased oxidative stress in the liver (Nissar et al 2013;Yang et al 2008).…”

Section: Down-regulating Myofibroblast Activation and Ecm Productionmentioning

confidence: 99%

Strategies to prevent and reverse liver fibrosis in humans and laboratory animals

Chen

Wang

2015

Arch Toxicol

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Liver fibrosis results from chronic damage to the liver in conjunction with various pathways and is mediated by a complex microenvironment. Based on clinical observations, it is now evident that fibrosis is a dynamic, bidirectional process with an inherent capacity for recovery and remodeling. The major mechanisms involved in liver fibrosis include the repetitive injury of hepatocytes, the activation of the inflammatory response after injury stimulation, and the activation and proliferation of hepatic stellate cells (HSCs), which represents the major extracellular matrix (ECM)-producing cells, stimulated by hepatocyte injury and inflammation. The microenvironment in the liver is synergistically regulated abnormal ECM deposition, scar formation, angiogenesis, and fibrogenesis. Moreover, recent studies have clarified novel mechanism in fibrosis such as epigenetic regulation of HSCs, the leptin and PPARγ pathways, the coagulation system, and even autophagy. Uncovering the mechanisms of liver fibrogenesis provides a basis to develop potential therapies to reverse and treat the fibrotic response, thereby improving the outcomes of patients with chronic liver disease. Although both scientific and clinical challenges remain, emerging studies attempt to reveal the ideal anti-fibrotic drug that could be easily delivered to the liver with high specificity and low toxicity. This review highlights the mechanisms, including novel pathways underlying fibrogenesis that may be translated into preventive and treatment strategies, reviews both current and novel agents that target specific pathways or multiple targets, and discusses novel drug delivery systems such as nanotechnology that can be applied in the treatment of liver fibrosis. In addition, we also discuss some current treatment strategies that are being applied in animal models and in clinical trials.

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Prevention and treatment of Schistosoma mansoni-induced liver fibrosis in mice

Cited by 31 publications

References 50 publications

Silymarin Reduces Profibrogenic Cytokines and Reverses Hepatic Fibrosis in Chronic Murine Schistosomiasis

Silymarin Reduces Profibrogenic Cytokines and Reverses Hepatic Fibrosis in Chronic Murine Schistosomiasis

Quantitative Screening for Anticestode Drugs Based on Changes in Baseline Enzyme Secretion by Taenia crassiceps

Strategies to prevent and reverse liver fibrosis in humans and laboratory animals

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