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Schistosomiasis is a serious parasitic infection caused by Schistosoma. The parasite deposits eggs in the host liver, causing inflammation that activates hepatic stellate cells (HSCs), which leads to liver fibrosis. Currently, there is no effective therapy for liver fibrosis; thus, treatments are urgently needed. Therefore, in the present study, mice infected with Schistosoma japonicum were treated with JQ-1, a small-molecule bromodomain inhibitor with reliable anti-tumor and anti-inflammatory activities. The fibrotic area of the liver measured by computer-assisted morphometric analysis and the expression levels of the cytoskeletal protein alpha smooth muscle actin (α-SMA) and of collagen assessed by quantitative PCR, Western blot and immunohistochemistry were significantly decreased in the liver following JQ-1 treatment compared with vehicle-treated controls. Total RNA was extracted from the liver of JQ-1-treated Schistosoma-infected mice for RNA-sequencing analysis. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses indicated that JQ-1 affected biological processes and the expression of cellular components known to play key roles in the transdifferentiation of HSCs to myofibroblasts. In vitro treatment with JQ-1 of JS-1 cells, a mouse HSC line, indicated that JQ-1 significantly inhibited JS-1 proliferation but had no effect on JS-1 activity, senescence, or apoptosis. Western blot results showed that JQ-1 inhibited the expression levels of phosphorylated JAK2 and phosphorylated STAT3 without altering expression levels of these non-phosphorylated proteins. Taken together, these findings suggested that JQ-1 treatment ameliorated S. japonicum egg-induced liver fibrosis, at least in part, by suppressing HSC activation and proliferation through the inhibition of JAK2/STAT3 signaling. These results lay a foundation for the development of novel approaches to treat and control liver fibrosis caused by S. japonicum., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Nitric oxide (NO), a recently discovered free radical, is overproduced in liver cirrhosis. Hepatitis C virus (HCV) might increase NO levels via increased inducible NO synthase (iNOS). This work was carried out to study the effect of HCV-induced liver cirrhosis on NO levels among Egyptian patients. The study included 46 patients with liver cirrhosis, and 30 healthy individuals of matched age and sex. NO levels determined as the stable endproduct nitrate, showed a statistically significant increase among patients compared to the control group (P < 0.001). Furthermore, NO levels increased proportionally with the severity of liver cirrhosis as assessed by Child's classification (P < 0.05). Moreover, schistosomial infection enhanced NO levels in cirrhotic patients with HCV infection compared to non-bilharzial patients (P < 0.001). Polymerase chain reaction (PCR) and branched DNA assays were used for detection of HCV RNA positivity, and measurement of the virus load, respectively. Both showed a positive correlation with the NO levels (P < 0.001). At a nitrate cutoff value of 70 micromol/L, the sensitivity and specificity were 83.0% and 73.0%, respectively. Chi square analysis showed a significant correlation between ALT levels and both HCV RNA positivity by polymerase chain reaction (PCR) (P < 0.02), and virus load (P<0.05). Interestingly enough, there was a significant positive correlation between HCV RNA and schistosomal antibody titer as measured by hemaglutination inhibition assay (HAI) (P < 0.05). The data presented in this report indicated an association between NO levels and the development and progression of liver cirrhosis. Furthermore, the findings obtained from this study demonstrated that schistomiasis is an important risk factor involved in enhancement of NO levels and virus replication. The latter may aggravate liver cell injury and hence the development of cirrhosis.

Plasma total lipid phosphorus, individual phospholipid fractions, free and esterified cholesterol, triglycerides and nonesterified fatty acids were fractionated by thin-layer chromatography and determined in bilharzial hepatic fibrosis patients (57 cases) and normal controls (25 cases). Significant diminutions were encountered in the total and the individual phospholipids, especially the lysolecithin fraction in the 3 groups of patients studied. Total and esterified cholesterol and triglycerides showed significant decreases, especially in moderate and late cases. NEFA, on the other hand, did not reveal any change from normal level in either moderate, late or mixed cases. Such findings may be attributed to malabsorption, lack of energy, insufficiency of required precursors as well as impaired synthesis by the liver.

Serum and urinary RNase activity was determined in 15 normal children and in 52 children in various clinical stages of schistosomal hepatic fibrosis. The activity of serum RNase was compared with that of serum GOT, GPT and AP. The activity of serum and urinary RNase in the different schistosomal groups was significantly higher than in healthy children. The elevated levels of serum and urinary RNase activity were possibly due to malnutrition with tissue catabolism, zinc-deficiency and liver cell injury. Treatment with Astiban and protein-rich diet resulted in a significant decrease in serum and urinary RNase activity and an in significant drop in serum GOT, GPT and AP. Serum and urinary RNase appear to be more sensitive indices for evaluating the early metabolic disturbances in schistosomal patients than GOT, GPT or AP. Our findings also showed that the severity of cases could be graded according to the level of urinary RNase.

The activity of procollagen prolyl hydroxylase was measured in fibrotic liver obtained from mice with hepatosplenic schistosomiasis, an animal model of the most prevalent form of human liver fibrosis. Measurable activity of prolyl hydroxylase in fibrotic liver supernatants was 47-fold higher than that of normal liver. The effect of prolyl hydroxylase inhibition on collagen synthesis in fibrotic liver slices was studied, using 8,9-dihydroxy-7-methyl benzo[b]quinolizinium bromide (GPA 1734). This compound was shown in other systems to inhibit prolyl and lysyl hydroxylations by iron chelation at concentrations which did not affect total protein synthesis. The formation of nondialyzable labelled hydroxyproline was inhibited by GPA 1734, 40, 70 and 95% at 30, 50 and 100 micrometer, respectively. Incorporation of proline into total liver protein was unaffected at 30 and 50 micrometer, but was inhibited 20% at 100 micrometer GPA 1734. Underhydroxylated collagen synthesized by liver slices with GPA 1734 was extracted with neutral salt solution and was subsequently hydroxylated with partially-purified prolyl hydroxylase to the same extent as control material synthesized in the absence of GPA 1734.