"Let food be thy medicine, and medicine be thy food."

Ground Breaking results confirmed by the HepTech's Anti-Fibrotic study.

"In this study we have fed HCV infected mice an antifibrotic/antioxidant diet and examined their livers after 2 months of infection. The diet consisted of vitamins/cofactors and antioxidants designed to feed into the glutathione homeostasis cycle as well as direct antioxidants such as N-acetyl cysteine. During the course of infection viral titers were measured, and there was no change in mortality or the levels of HCV viral titers associated with the diet. The livers of infected mice on the diet were compared to the livers from infection and age-matched mice transplanted with the same donor liver cells. We found that there was a decrease in lobular inflammation, and an increase in portal inflammation. Notably there was a decrease in the amount of apoptosis as measured by Tunel reactivity in liver sections. There was a decrease in the number of activated stellate cells when liver sections were stained using antibodies specific for smooth muscle actin. Importantly there was a decrease in the amount of collagen I deposited in infected livers as measured by both Mason's tirchrome stain and quantitated using Picro Sirus Red staining. Thus it appears that the fibrosis induced by HCV in mice with chimeric mouse/human livers can be suppressed by an antioxidant diet."

The Chimeric Human Liver Mouse model is cutting-edge scientific technology that represents a significant new development as an animal model used to test the development of new pharmaceutical drugs for the treatment of HCV. This model was developed and patented by doctors Norm Kneteman, David Mercer, and Lorne Tyrrell at the University of Alberta. The chimeric mouse model has been used by a number of the large pharmaceutical houses to test their new candidate antiviral drugs.

HepTech has sponsored testing in this state-of-the art model, the chimeric human liver mouse, to study the eect of new therapies to preventfibrosis before entering clinical trials with their newly-developed products.


The HepTech anti-fibrotic diet reduces the number of TUNEL positive (apoptosis) cells and protects the hepatocyte from inflammation induced cell death.

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The HepTech anti-fibrotic diet reduces the number of TUNEL positive (apoptosis) cells and protects the hepatocyte from inflammation induced cell death.

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The HepTech anti-fibrotic diet dramatically reduces the actual production of collagen bers in the livers of HCV infected human liver Chimeric mice to control levels.

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Damaging liver fibrosis is a major consequence of Hepatitis C Virus (HCV) infection. An estimated 240,000 to 300,000 Canadians and 170 to 200 million people worldwide are chronic carriers of HCV [1,2]. HCV establishes chronic infection in 65–80% of infected individuals [3]. Chronic infection with HCV can lead to chronic active hepatitis, cirrhosis and hepatocellular carcinoma, manifested 10, 20, and 25 years respectively after the initial infection [4]. End-stage liver disease from HCV is the leading indication for liver transplantation in North America and Western Europe, and is continuing to increase [5]. The transplanted liver is universally re-infected and approximately 15% of patients develop HCV related cirrhosis within 2 years after transplantation [6].

When we examined the host response to infection in chimeric mice we found that, similar to patients, there was induction of interferon response genes and changes in expression of genes involved in lipid metabolism. This has been postulated to result in oxidative stress and p53 activation [9,11,12]. In addition, cytokines and chemokines were induced in the human hepatocytes [9]. As seen in liver biopsies from HCV infected patients [9,10], we saw that HCV induced apoptosis in infected chimeric mouse livers, despite the lack of an adaptive immune system in these SCID mice. This is contrary to the popular notion that HCV is a non-cytopathic virus, and that hepatocyte damage during HCV infection is due to HCV-specific adaptive immune responses [13,14]. We saw increased BiP expression in infected cells and increased amounts of BAX at the mitochondria, indicating the induction of ER stress and oxidative stress in HCV infected hepatocytes. However, we saw little translocation of CHOP/GADD153 to the nucleus, indicating the UPR was induced but was not overwhelmed. In hepatocytes, NF-kB is one of the key determinants of whether apoptosis is induced in response to death ligands [15,16,17,18,19,20,21]. Consistent with a key role for NF-kB in the induction of apoptosis, we found that levels of NF-kB were lower in HCV infected cells [10]. Furthermore, consistent with the transcriptional regulation of BCL-xL by NF-kB, we found that levels of BCL-xL were lower in HCV infected cells. We proposed a model in which HCV induces both ER stress and oxidative stress in infected cells, activates pro-apoptotic Bax while preventing induction of anti-apoptotic BCL-xL thus sensitizing HCV infected cells to apoptosis mediated by death receptors and ligands (Figure 1)[10]. Subsequently, it was been found that ER stress is induced in HCV infected patients [22].

chimeric mice [9], stimulated us to examine the chimeric livers of these mice for other indications of HCV induced disease. We found signs of hepatocyte damage and increased inflammation in the parenchyma [10]. This was the first report of a pathologic process occurring in the absence of an adaptive immune response during HCV infection. We stained chimeric livers for collagen, quantified the results and found that HCV infection led to increased fibrosis in chimeric mice infected with HCV as early as 2 months post infection.

2. Shepard CW, Finelli L, Alter MJ (2005) Global epidemiology of hepatitis C virus infection. Lancet Infect Dis 5: 558-567.

4. Di Bisceglie AM, Bonkovsky HL, Chopra S, Flamm S, Reddy RK, et al. (2000) Iron reduction as an adjuvant to interferon therapy in patients with chronic hepatitis C who have previously not responded to interferon: a multicenter, prospective, randomized, controlled trial. Hepatology 32: 135-138.

6. Prieto M, Berenguer M, Rayon JM, Cordoba J, Arguello L, et al. (1999) High incidence of allograft cirrhosis in hepatitis C virus genotype 1b infection following transplantation: relationship with rejection episodes. Hepatology 29: 250-256.

8. Mercer DF, Schiller DE, Elliott JF, Douglas DN, Hao C, et al. (2001) Hepatitis C virus replication in mice with chimeric human livers. Nat Med 7: 927-933.

10. Joyce MA, Walters KA, Lamb SE, Yeh MM, Zhu LF, et al. (2009) HCV induces oxidative and ER stress, and sensitizes infected cells to apoptosis in SCID/Alb-uPA mice. PLoS Pathog 5: e1000291.

12. Qadri I, Iwahashi M, Capasso JM, Hopken MW, Flores S, et al. (2004) Induced oxidative stress and activated expression of manganese superoxide dismutase during hepatitis C virus replication: role of JNK, p38 MAPK and AP-1. Biochem J 378: 919-928.

14. Kanto T, Hayashi N (2006) Immunopathogenesis of hepatitis C virus infection: multifaceted strategies subverting innate and adaptive immunity. Intern Med 45: 183-191.

16. Kim YS, Schwabe RF, Qian T, Lemasters JJ, Brenner DA (2002) TRAIL-mediated apoptosis requires NF-kB inhibition and the mitochondrial permeability transition in human hepatoma cells. Hepatology 36: 1498-1508.

18. Hatano E, Brenner DA (2001) Akt protects mouse hepatocytes from TNF-alpha- and Fas- mediated apoptosis through NK-kappa B activation. Am J Physiol Gastrointest Liver Physiol 281: G1357-1368.

20. Samanta AK, Huang HJ, Bast RC, Jr., Liao WS (2004) Overexpression of MEKK3 confers resistance to apoptosis through activation of NFkappaB. J Biol Chem 279: 7576- 7583.

22. Asselah T, Bieche I, Mansouri A, Laurendeau I, Cazals-Hatem D, et al. (2010) In vivo hepatic endoplasmic reticulum stress in patients with chronic hepatitis C. J Pathol 221: 264- 274.

24. Canbay A, Higuchi H, Bronk SF, Taniai M, Sebo TJ, et al. (2002) Fas enhances fibrogenesis in the bile duct ligated mouse: a link between apoptosis and fibrosis. Gastroenterology 123: 1323-1330.