Following an injury, the liver embarks on a process that drives the accumulation and reformation of the extracellular matrix, leading to hepatic fibrosis. Type I interferons (IFNs), including IFN-α and IFN-β, play a crucial role in averting chronic liver injury through the activation of IFN-stimulated genes (ISGs), which are instrumental in sculpting adaptive immunity. The role of 2'-5'-oligoadenylate synthase-like protein 1 (OASL1), an antiviral ISG, in the context of liver fibrosis remains to be elucidated. To elicit liver fibrosis, a diet containing 0.1% diethoxycarbonyl-1,4-dihydrocollidine (DDC) and carbon tetrachloride (CCl4) were employed to induce cholestatic- and hepatotoxin-mediated liver fibrosis, respectively. Histological analyses of both models revealed that OASL1-/- mice exhibited reduced liver damage and, consequently, expressed lower levels of fibrotic mediators, notably α-smooth muscle actin. OASL1-/- mice demonstrated significantly elevated IFN-α and IFN-β mRNA levels, regulated by the IFN regulatory factor 7 (IRF7). Additionally, OASL1-/- ameliorated chronic liver fibrosis through the modulation of nuclear factor-κB (NF-κB) signaling. The effect of OASL1 on type I IFN production in acute liver damage was further explored and OASL1-/- mice consistently showed lower alanine transaminase levels and pro-inflammatory cytokines, but IFN-α and IFN-β mRNA levels were upregulated, leading to amelioration of acute liver injury. Additionally, the study discovered that F4/80-positive cells were observed more frequently in OASL1-/- CCl4 acutely treated mice. This implies that there is a significant synergy in the function of macrophages and OASL1 deficiency. These results demonstrate that in instances of liver injury, OASL1 inhibits the production of type I IFN by modulating the NF-κB signaling pathway, thereby worsening disease.

For the first time, based on the expression analysis of a wide range of pro- and anti-fibrotic, pro- and anti-inflammatory, and pro- and anti-apoptotic genes, key markers of endoplasmic reticulum stress (ER-stress), molecular mechanisms for the regulation of fibrosis, and accompanying negative processes caused by thioacetamide (TAA) injections and subsequent injections of selenium-containing nanoparticles and sorafenib have been proposed. We found that selenium nanoparticles of two types (doped with and without sorafenib) led to a significant decrease in almost all pro-fibrotic and pro-inflammatory genes. Sorafenib injections also reduced mRNA expression of pro-fibrotic and pro-inflammatory genes but less effectively than both types of nanoparticles. In addition, it was shown for the first time that TAA can be an inducer of ER-stress, most likely activating the IRE1α and PERK signaling pathways of the UPR, an inducer of apoptosis and pyroptosis. Sorafenib, despite a pronounced anti-apoptotic effect, still did not reduce the expression of caspase-3 and 12 or mitogen-activated kinase JNK1 to control values, which increases the risk of persistent apoptosis in liver cells. After injections of selenium-containing nanoparticles, the negative effects caused by TAA were leveled, causing an adaptive UPR signaling response through activation of the PERK signaling pathway. The advantages of selenium-containing nanoparticles over sorafenib, established in this work, once again emphasize the unique properties of this microelement and serve as an important factor for the further introduction of drugs based on it into clinical practice.

Liver diseases are major causes of morbidity and mortality. Mesenchymal stem cells (MSCs) have immunomodulatory, anti-inflammatory, and antifibrotic effects, so they can be used in the treatment of liver diseases. MSCs co-cultured with diseased liver tissue improve the homing capacity, survival rate, and paracrine effects of the MSCs, as well as the ability to enhance liver function.

This work aimed to study the therapeutic effect of MSCs versus MSCs co-cultured with liver tissue on carbon tetrachloride (CCl4)-induced hepatotoxicity in adult male albino rats.

Twenty adult male albino rats were divided into four equal groups; Group I (control group), Group II received CCl4 intraperitoneally (i.p.), Group III received CCl4 i.p. and then injected with MSCs intravenously (i.v.), and Group IV received CCl4 i.p. and then injected with co-cultured MSCs i.v.

Finally, liver specimens were processed for light microscopy (LM) and electron microscopy (EM). Statistical analysis was carried out to assess histological scoring, area percentage of collagen fibers, number of glial fibrillary acidic protein-positive cells, and biochemical analysis of alanine aminotransferase and aspartate aminotransferase.

Statistical analysis of (histological scoring, area % of collagen fibers, and biochemical analysis) was done by using one-way analysis of variance (ANOVA) test using graphpad software (SanDiego, CA, USA). The means ± standard deviations were used for statistical analysis.

LM of Group II revealed loss of hepatic architecture and diffuse fibrosis with dilated congested blood vessels, bile ductular proliferation, and cellular infiltrations. Vacuolated cytoplasm with or without pyknotic nuclei was observed in addition to micro- and macro-steatosis. EM demonstrated disfigured hepatocytes with abnormal organelles surrounding atypical nucleus. Group III showed restoration of the normal liver architecture with greater extent in Group IV. Statistical analysis confirmed the microscopic findings.

Co-cultured MSCs with diseased liver tissue augmented the therapeutic effects of MSCs in treating hepatotoxicity induced by CCl4 in adult male albino rats.

Nonalcoholic fatty liver disease (NAFLD) is a progressive liver disease that can progress to nonalcoholic steatohepatitis (NASH), NASH-related cirrhosis, and hepatocellular carcinoma (HCC). NAFLD ranges from simple steatosis (or nonalcoholic fatty liver [NAFL]) to NASH as a progressive form of NAFL, which is characterized by steatosis, lobular inflammation, and hepatocellular ballooning with or without fibrosis. Because of the complex pathophysiological mechanism and the heterogeneity of NAFLD, including its wide spectrum of clinical and histological characteristics, no specific therapeutic drugs have been approved for NAFLD. The heterogeneity of NAFLD is closely associated with cellular plasticity, which describes the ability of cells to acquire new identities or change their phenotypes in response to environmental stimuli. The liver consists of parenchymal cells including hepatocytes and cholangiocytes and nonparenchymal cells including Kupffer cells, hepatic stellate cells, and endothelial cells, all of which have specialized functions. This heterogeneous cell population has cellular plasticity to adapt to environmental changes. During NAFLD progression, these cells can exert diverse and complex responses at multiple levels following exposure to a variety of stimuli, including fatty acids, inflammation, and oxidative stress. Therefore, this review provides insights into NAFLD heterogeneity by addressing the cellular plasticity and metabolic adaptation of hepatocytes, cholangiocytes, hepatic stellate cells, and Kupffer cells during NAFLD progression.

Viral hepatitis is associated with high morbidity and mortality. Identification of biological pathways involved in hepatic fibrosis resulting from chronic hepatitis C are essential for better management of patients. Constructing the HCV-human protein interaction network through bioinformatics may enable us to discover diagnostic biological pathways. We investigated to identify dysregulated pathways and gene enrichment based on actin alpha 2 (ACTA2) and glial fibrillar acidic protein (GFAP) interaction network analysis in hepatic fibrosis.

This is an in-silico study conducted at Ziauddin University from March,2019 to September 2019. Enrichment and protein-protein interaction (PPI) network analysis of the identified proteins: GFAP and ACTA2 along with their mapped gene data sets was performed using FunRich version 3.1.3.

Biological pathway grouping showed enrichment of proteins (85.7%) in signalling pathway by epidermal growth factor receptor (EGFR) and Tumor growth factor (TGF)-beta Receptor followed by signaling by PDGF, FGFR and NGF (71.4%) (p < 0.001). SRC, PRKACA, PRKCA and PRKCD were enriched in both EGFR and TGF-beta Signalling pathways.

EGFR and TGF-beta signalling pathways were enriched in liver fibrosis. SRC, PRKACA, PRKCA and PRKCD were enriched and differentially expressed in both EGFR and TGF-beta signalling pathways.

Abnormal expression of microRNA (miR)-219-3p has been widely identified in different tumors. However, whether miR-219-3p is involved in the progression of hepatic fibrosis (HF) has never been explored. The present study showed that compared with healthy controls, the levels of miR-291-3p in peripheral blood were decreased in patients with HF. Furthermore, much lower levels of miR-291-3p were identified in fibrotic liver tissues compared with that of normal liver tissues. Receiver operating characteristic curve analysis showed that the levels of miR-291-3p in peripheral blood may screen patients with HF from healthy controls. Reverse transcription quantitative polymerase chain reaction analysis showed that overexpression of miR-291-3p significantly suppressed the mRNA levels of Snai1, vascular endothelial-specific cadherin (VE-cadherin), Vimentin, transforming growth factor (TGF)-β1, and glial fibrillary acidic protein (GFAP). The protein levels of Snai1, VE-cadherin, Vimentin, TGF-β1, and GFAP were also decreased in hepatic stellate cells transfected with miR-291-3p mimics. Further study indicated that mothers against decapentaplegic homolog 2 (Smad2) was a target gene of miR-291-3p. More importantly, silencing of Smad2 could abolish miR-291-3p inhibition-induced TGF-β1 signaling activation. In summary, reduced peripheral blood miR-291-3p may be involved in the progression of HF via targeting Smad2.

The aim of this study is to investigate the effect of somatostatin (SST) analogue, Octreotide, on some features of liver injury induced by immobilization stress (IS) in adult male albino rats. Eighteen adult male albino rats were randomly divided into three equal groups: control, IS, and Octreotide-treated stressed groups. Octreotide (40 μg/kg body weight, subcutaneously) was administrated twice daily for 8 days during the exposure to IS. Octreotide was found to reduce the IS significantly and induce elevations in the plasma level of corticosterone, liver transaminases, and tumor necrosis factor α (TNF-α) as compared with IS group. Furthermore, Octreotide administration has significantly elevated the decline in the total antioxidant capacities (TAC) and lowered the elevated malondialdehyde (MDA) levels observed with IS in the hepatic tissue. Additionally, Octreotide treatment provided protection against the histopathological changes in the stressed liver in the form of significant reduction in the mean number of degenerated hepatocytes, the area % of collagen fibers, and glial fibrillary acid protein (GFAP) immunostaining with a significant increase in the mean number of normal hepatocytes. In conclusion, stressed rats showed disturbed liver functions and its oxidant-antioxidant status with highly expression hepatic stellate cells (HSCs), which were all improved by Octreotide administration, SST analogue.

Stress affects many organs in addition to the brain, including the liver. We assessed the effects on the liver of blocking N-methyl-d-aspartate (NMDA) glutamate receptors with memantine in acute and repeated restraint stress. Forty-two male albino rats were divided into 7 groups; control, acute restraint stress (ARS), ARS + memantine, repeated restraint stress, repeated restraint + memantine, and positive control groups. We measured serum iron, zinc, alanine transferase and aspartame transferase, hepatic malondialdehyde, tumor necrosis factor-α (TNF-α), glutathione peroxidase, superoxide dismutase, metallothionein content, zinc transporter ZRT/IRT-like protein 14 mRNA expression, and hepcidin expression. We conducted a histopathological evaluation via histological staining and immunostaining for glial fibrillary acidic protein and synaptophysin expression, both of which are markers of hepatic stellate cell (HSC) activation. Both ARS and repeated stress increased markers of hepatic cell injury, oxidative stress, and HSC activation. Blocking NMDA with memantine provided a hepatoprotective effect in acute and repeated restraint stress and decreased hepatic cell injury, oxidative stress, and HSC activation.