05; Fig. 1D), worsened in one patient (7%), and remained stable in seven patients (40%). The improvement in inflammation and piecemeal activity after treatment with losartan was significant http://www.selleckchem.com/products/Imatinib-Mesylate.html (P < 0.05 for both; Table 4). In contrast, lobular inflammation did not change in nine patients (65%, not significant; Table 4), improved in three patients (21%), and worsened in two patients (14%). Patients with improvement in liver fibrosis or inflammation were not different regarding age, gender, body mass index, duration of infection, baseline serum viral load, baseline liver tests, degree of activation of the systemic RAS at baseline, or treatment compliance. Moreover, the degree of activation of the systemic RAS following treatment with losartan was not different between responder and nonresponder patients.

Changes in hepatic gene expression of fibrosis-related genes after treatment with oral losartan. We first analyzed hepatic gene expression in patients with CHC compared with normal livers (n = 6). Most candidate genes were differentially expressed in livers with CHC compared with control livers. Gene expression of extracellular proteins (��1 chains of procollagen type I and type IV), major fibrogenic (TGF-��1, ACE-1 and 2) and proinflammatory mediators (TNF-��) as well as regulators of matrix degradation (MMP-2, TIMP-1, and ut-PA) were upregulated in livers of patients with chronic HCV infection. In contrast, genes mainly expressed by hepatocytes (i.e., cytochrome P-450 2E1) and AT1 receptors were downregulated in CHC livers compared with normal livers.

These findings are in agreement with previous reports on hepatic gene expression in patients with CHC (2, 36). Components of the NOX complex (NOX-4, Rac-1, and Rac-2) were upregulated in livers with chronic HCV infection. We performed an unsupervised hierarchical clustering of normal livers and patients with chronic HCV infection according to the expression profile of the selected genes. On the basis of similarity in gene expression profiles, this procedure adequately clustered livers from patients with CHC and normal livers in two different groups (Fig. 2). Fig. 2. Unsupervised hierarchical clustering of normal (NORM) livers (n = 6) and patients with chronic hepatitis C (HCV) before treatment with oral losartan (n = 14) according to the expression profile of the selected genes.

Following treatment with losartan for 18 mo, there was a significant reduction in the expression of nine Anacetrapib genes (Table 5). Importantly, four of these genes are known to be involved in liver fibrogenesis and were upregulated at baseline compared with normal livers. Expression of procollagen ��1(I) and ��1(IV), two major extracellular proteins in the fibrotic liver, decreased in the majority of patients after AT1 receptor blockade. Procollagen ��1(I) decreased in 11 patients with a mean reduction of ?31% (P < 0.05 vs. baseline).