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At least 19 recordsLinked to original sources
PubMed1977

Liver protocollagen proline hydroxylase in human liver diseases and experimental liver fibrosis.

Liver protocallagen proline hydroxylase activity (PPH activity) was determined in patients with various liver diseases, CCl4-induced liver fibrosis rats and cholin deficiency (tcd) fatty liver rats. The following results were obtained: Liver PPH activity in patients with chronic hepatitis was higher than that in patients with acute hepatitis, while the activity in patients with liver cirrhosis was much higher than that in patients with chronic hepatitis. The activity was higher in patients with chronic active hepatitis than in those with chronic inactive hepatitis. Patients with active and progressive liver cirrhosis were found to have an especially high PPH activity, in whom the activity reflected well the degree of liver fibrosis. Even though fibrosis in persistent hepatitis was almost negligible or slight, the degree of liver PPH activity in persistent hepatitis was similar to that in liver cirrhosis. Liver PPH activities in CCl4-induced liver fibrosis rats and CD fatty liver rats elevated proportionally to the lapse of time. Whilst liver PPH activity in rats of CD fatty liver without fibrosis in 23 to 31 weeks after the start of the experiment was slightly lower than that in rats of CD fatty liver with fibrosis. But liver PPH activity of the former was considerably higher than that of control rats.

Acute Disease↗
PubMed1975

Studies on the inhibition of experimental liver fibrosis. 2. The mechanism of the inhibition of liver fibrosis of rats due to carbon tetrachloride by elastase.

In the previous experiments, it was demonstrated that high purity elastase extracted from porcine pancreas remarkably inhibits liver fibrosis of rats having chronic liver injury caused by carbon tetrachloride. This time, with the purpose to clarify the mechanism of inhibition of liver fibrosis by elastase, comparative study was made on the activity of lysosomal enzymes by measuring beta-glucuronidase, cathepsin and collagenolytic activity, with the rats administered with elastase and with those untreated, during the period of development of liver fibrosis and the recovery from it. In addition to it, in vitro experiments were made by having elastase act on the substrate comprising mixed collagen of acid soluble and neutral soluble collagens extracted from the skin of guinea pigs and by observing collagen components by disc electrophoresis. With any lysosomal enzymes, no marked difference was noticed between elastase group and non-administered group and thus the possibility of inhibition of liver fibrosis through activation of lysosomal enzyme by elastase was denied. The results of disc electrophoretic observation of the performance of elastase on collagen revealed that beta-component of collagen is disappeared but alpha-component remained. From the above, inhibition of liver fibrosis by elastase may be due to direct affection of elastase to telopeptide portion of collagen.

Animals↗
PubMed2024

Exportin 4 DNA promoter methylation in liver fibrosis.

A role for exportin 4 (XPO4) in the pathogenesis of liver fibrosis was recently identified. We sought to determine changes in hepatic XPO4 promoter methylation levels during liver fibrosis. The quantitative real-time RT-PCR technique was used to quantify the mRNA level of XPO4. Additionally, pyrosequencing was utilized to assess the promoter methylation status of XPO4. The methylation rate of the XPO4 promoter was significantly increased with fibrosis in human and mouse models, while XPO4 mRNA expression negatively correlated with methylation of its promoter. DNA methyltransferases (DNMTs) levels (enzymes that drive DNA methylation) were upregulated in patients with liver fibrosis compared to healthy controls and in hepatic stellate cells upon transforming growth factor beta (TGFβ) stimulation. The DNA methylation inhibitor 5-Aza or specific siRNAs for these DNMTs led to restoration of XPO4 expression. The process of DNA methylation plays a crucial role in the repression of XPO4 transcription in the context of liver fibrosis development.

Animals↗
PubMed1992

[What is reliable in therapy of liver fibrosis?].

Therapy of chronic active liver diseases associated with fibrotic transformation is usually restricted to unspecific antiinflammatory and immunosuppressive agents. However, recent advances in the biochemistry of collagen have allowed to define specific levels of collagen metabolism at which pharmacologic intervention can lead to reduced collagen deposition. The mode of action of some substances which interfere with collagen biosynthesis and degradation is described. However, the efficacy of these agents was tested in vitro exclusively or in animal experiments. Only few agents like colchicine were also studied in clinical trials. Reliable, safe, and specific antifibrotic agents for the clinical management of liver fibrosis do not exist up to now. Advances can be expected, however, from the development of novel inhibitors of prolyl-4-hydroxylase.

Collagen↗
PubMed1992

Hydroxypyridinium collagen cross-links in human liver fibrosis: study of alveolar echinococcosis.

Liver samples from patients with three different types of liver diseases, alveolar echinococcosis (a dense and irreversible fibrosis), hepatocellular carcinoma and alcoholic cirrhosis, were analyzed for their content in hydroxypyridinium cross-links found in mature collagen. We demonstrated the presence of small amounts of pyridinoline in control livers (0.27 +/- 0.06 pmol/pmol of collagen). Pyridinoline content was increased in fibrotic livers, with the highest values found in patients with alveolar echinococcosis (up to 1.33 pmol/pmol of collagen). The deoxy analogue of pyridinoline was not detected in either normal or fibrotic livers. Pyridinoline levels, expressed as picomoles per picomole of collagen, were similar in all patients with carcinoma (0.7 +/- 0.05 pmol/pmol of collagen). They were heterogeneous in patients with alveolar echinococcosis and were particularly high in patients with alcoholic cirrhosis (1.04 +/- 0.11 pmol/pmol of collagen). These results demonstrate for the first time the presence of an hydroxypyridinium cross-link in liver fibrosis and suggest that pyridinoline measurement might be an important criterion in assessing the irreversibility of human liver fibrosis.

Amino Acids↗
PubMed1978

Cystic fibrosis liver sialyltransferase.

The activity of sialytransferase with regard to the glycoprotein substrates asialofetuin and asialo-ovine submaxillary mucin was determined in normal, pathological control, and cystic fibrosis liver homogenates. Cystic fibrosis and pathological livers have about 40% of the average normal specific activity for sialytransferase. Several properties of cystic fibrosis sialytransferase were investigated and compared to those of the normal liver enzyme (Alhadeff et al. 1977). The pH optima curves were similar, but cystic fibrosis sialyltransferase appears to be more thermolabile than the normal liver enzyme. Isoelectric focusing studies revealed that the three most basic forms of sialyltransferase which are found in normal livers are deficient or absent in most cystic fibrosis liver. The data suggest that altered glycoprotein-sialyltransferases may be present in cystic fibrosis livers, probably a secondary effect due to general liver pathology.

Cystic Fibrosis↗
PubMed2026

[Effects and mechanisms of ethanol extract of Salvia miltiorrhiza on liver fibrosis in mice].

To identify clinically advantageous TCMs for anti-hepatic fibrosis and to elucidate the effects and molecular mechanisms of Salvia miltiorrhiza ethanol extract in the intervention of liver fibrosis, this study screened high-frequency anti-hepatic fibrosis TCMs through a review of clinical literature. The S. miltiorrhiza active components, potential targets, and liver fibrosis-related disease targets were obtained using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP), the GeneCards database, and other databases. Gene Ontology(GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analyses were performed on the shared targets between drugs and diseases. Molecular docking was conducted to evaluate the binding affinities between key components and core targets. In animal experiments, male Kunming mice were used to establish a liver fibrosis model induced by carbon tetrachloride(CCl_4). The mice were administered low, medium, and high doses of S. miltiorrhiza ethanol extract by gavage. The liver index, as well as serum aspartate aminotransferase(AST) and alanine aminotransferase(ALT) levels, were measured. Histopathological changes in liver tissue were observed using hematoxylin-eosin(HE) staining and Masson's trichrome staining. Western blot analysis was used to detect the protein expression levels of α-smooth muscle actin(α-SMA), Collagen Ⅰ, and heat shock protein 90 alpha family class A member 1(HSP90AA1) in liver tissue. The results showed that S. miltiorrhiza was the most frequently used TCM in clinical anti-hepatic fibrosis. A total of 65 active components and 135 potential targets were identified, and 109 common targets were obtained by intersecting these with liver fibrosis-related targets. The core targets included tumor protein p53(TP53), serine/threonine protein kinase AKT1(AKT1), Jun proto-oncogene(JUN), signal transducer and activator of transcription 3(STAT3), and HSP90AA1, which were mainly enriched in pathways related to cancer, hepatitis B, and the PI3K-AKT signaling pathway. Molecular docking indicated that the main active components of S. miltiorrhiza bound stably to the core targets, with the strongest binding affinity observed for HSP90AA1. Animal experiments demonstrated that the liver index, serum ALT and AST levels, and the expression of α-SMA, Collagen Ⅰ, and HSP90AA1 in liver tissue were significantly increased in the model group, accompanied by obvious pathological manifestations of fibrosis. Compared with the model group, different dose groups of S. miltiorrhiza ethanol extract reduced the liver index and serum ALT and AST levels to varying degrees, alleviated pathological damage and collagen deposition in liver tissue, and downregulated the protein expression of α-SMA, Collagen Ⅰ, and HSP90AA1. In conclusion, S. miltiorrhiza ethanol extract exerts a significant protective effect on CCl_4-induced liver fibrosis in mice, and its mechanisms may be related to the inhibition of HSP90AA1 expression and the regulation of liver fibrosis-related signaling pathways.

Animals↗
PubMed2025

Newly identified single-nucleotide polymorphism associated with the transition from nonalcoholic fatty liver disease to liver fibrosis: results from a nested case-control study in the UK biobank.

BACKGROUND: Genetic factors may have a significant influence on the likelihood of liver fibrosis in individuals with nonalcoholic fatty liver disease (NAFLD). The present study was conducted to explore how single-nucleotide polymorphism (SNP) impacts the development of fibrosis in those suffering from NAFLD. MATERIALS AND METHODS: Utilizing the UK Biobank dataset, we conducted a nested case-control analysis among NAFLD participants, defining the case group as those with liver fibrosis and cirrhosis during follow-up. For our in vitro investigations, we employed the LX-2 human hepatic stellate cell line. Our procedures included cultivating these cells, employing SAMM50-rs2073080 plasmid techniques to enhance the expression of recently discovered SNPs, and conducting biochemical assays. To quantify gene expression, we used real-time PCR with fluorescence detection. RESULTS: The study analyzed data from 5467 participants (1094 cases and 4373 controls). Genome-wide association analysis identified nine significant loci, including the novel rs2073080 variant, strongly associated with NAFLD-associated hepatic fibrosis. In vitro TGF-β modeling revealed significant upregulation of α-SMA and COL1A1, confirming model effectiveness. Oxidative stress markers like elevated malondialdehyde (MDA) and reduced catalase (CAT) and superoxide dismutase (SOD) levels indicated liver damage in the TGF-β group. SAMM50-rs2073080 was upregulated in the NAFLD-associated fibrosis model. In vitro experiments on LX-2 cells showed that SAMM50-rs2073080 overexpression led to increased fibrosis, as indicated by higher cellular MDA levels and lower CAT and SOD levels, compared to the vector group. CONCLUSION: Our research highlights a significant association of SAMM50-rs2073080 with the progression of NAFLD to hepatic fibrosis, and the in vitro experiments further corroborated these findings.

Humans↗
PubMed1978

Purification and characterization of altered cystic fibrosis liver alpha-L-fucosidase.

alpha-L-Fucosidase (E.C.3.2.4.51) from two cystic fibrosis livers has been purified and characterized. Purification was accomplished by an affinity chromatographic procedure previously used for normal liver alpha-L-fucosidase. Characterization of the two cystic fibrosis alpha-L-fucosidases indicated that they were very similar to normal liver alpha-L-fucosidase with regard to pH optima profiles, Michaelis constants (Km's), subunit structure and antigenicity. However, gas liquid chromatographic analysis revealed altered carbohydrate compositions for both the cystic fibrosis alpha-L-fucosidases. The three major sugars found in normal purified liver alpha-L-fucosidase (mannose, N-acetylglucosamine and sialic acid) were reduced in the cystic fibrosis alpha-L-fucosidases, on average, to 51%, 44% and 32%, respectively, of their normal amounts.

Carbohydrates↗
PubMedDate not supplied

[Pathobiochemistry of organ fibroses. Changes in the connective tissue metabolism in liver fibrosis and in chronic polyarthritis].

Many chronic inflammations of various origin are characterized by an elevated metabolic activity of connective tissue, causing an increased tissue proliferation. The authors first review the more recent methods of analyzing the connective tissue metabolism. Details of changes of this metabolism are described with reference to liver fibrosis and rheumatoid arthritis. First steps of a pathobiochemical diagnosis of activity in organ fibroses are discussed. It seems possible to judge the activity of liver fibrosis by estimating the serum activity of lysosomal glycosidases and serum levels of terminal collagen peptides. Elevated antiprotease serum levels in rheumatoid patients may indicate an inflammatory activity.

Arthritis, Rheumatoid↗
PubMed2024

Super Enhanced Purification of Denatured-Refolded Ubiquitinated Proteins by ThUBD Revealed Ubiquitinome Dysfunction in Liver Fibrosis.

Ubiquitination is crucial for maintaining protein homeostasis and plays a vital role in diverse biological processes. Ubiquitinome profiling and quantification are of great scientific significance. Artificial ubiquitin-binding domains (UBDs) have been widely employed to capture ubiquitinated proteins. The success of this enrichment relies on recognizing native spatial structures of ubiquitin and ubiquitin chains by UBDs under native conditions. However, the use of native lysis conditions presents significant challenges, including insufficient protein extraction, heightened activity of deubiquitinating enzymes and proteasomes in removing the ubiquitin signal, and purification of a substantial number of contaminant proteins, all of which undermine the robustness and reproducibility of ubiquitinomics. In this study, we introduced a novel approach that combines denatured-refolded ubiquitinated sample preparation (DRUSP) with a tandem hybrid UBD for ubiquitinomic analysis. The samples were effectively extracted using strongly denatured buffers and subsequently refolded using filters. DRUSP yielded a significantly stronger ubiquitin signal, nearly three times greater than that of the Control method. Then, eight types of ubiquitin chains were quickly and accurately restored; therefore, they were recognized and enriched by tandem hybrid UBD with high efficiency and no biases. Compared with the Control method, DRUSP showed extremely high efficiency in enriching ubiquitinated proteins, improving overall ubiquitin signal enrichment by approximately 10-fold. Moreover, when combined with ubiquitin chain-specific UBDs, DRUSP had also been proven to be a versatile approach. This new method significantly enhanced the stability and reproducibility of ubiquitinomics research. Finally, DRUSP was successfully applied to deep ubiquitinome profiling of early mouse liver fibrosis with increased accuracy, revealing novel insights for liver fibrosis research.

Animals↗
PubMed2025

Oral semaglutide for weight loss and liver fibrosis in overweight and obesity: A randomized controlled trial.

BACKGROUND AND OBJECTIVES: Obesity is a leading risk factor for fatty liver disease and weight loss has been shown to improve liver parameters. This study evaluates the efficacy of oral semaglutide for weight loss in individuals with overweight or obesity, excluding those with diabetes mellitus. METHODS: A randomized, open-label, controlled trial was conducted at the Asian Institute of Gastroenterology, Hyderabad, from June 2022 to December 2023. Adults (&#x2265;&#x2009;18&#xa0;years) with a body mass index (BMI)&#x2009;&#x2265;&#x2009;30 or&#x2009;&#x2265;&#x2009;27 with comorbidities (pre-diabetes, hypertension, dyslipidemia, obstructive sleep apnea or cardiovascular disease) were randomized into two groups. Both groups received counselling on a reduced-calorie diet and increased physical activity. Group 1 also received oral semaglutide, starting at 3&#xa0;mg/day and titrated to 14&#xa0;mg/day over two to four&#xa0;weeks. The objectives were to assess the effects of semaglutide on weight loss, non-invasive markers of liver fibrosis and cardiometabolic parameters. (ClinicalTrials.gov ID: NCT05442450). RESULTS: Total 116 participants (58 per group) completed the study. At 28&#xa0;weeks, the mean percentage weight reduction was -10.47% (SD 5.3) in the Semaglutide group vs. -2.4% (SD 4.5) in the control group (p&#x2009;<&#x2009;0.001). Semaglutide treatment significantly improved alanine aminotransferase (ALT) (serum glutamic-pyruvic transaminase [SGPT]) levels, along with reductions in the aspartate aminotransferase to platelet ratio index (APRI) score, liver fat content and liver stiffness. However, NFS (NAFLD fibrosis score) and FIB-4 (fibrosis-4 index) did not show significant reductions. Improvements in BMI, waist circumference, HbA1c, fasting insulin and C-reactive protein (CRP) were significantly greater with semaglutide (p&#x2009;<&#x2009;0.001). Total fat mass decreased by 7.3&#xa0;kg vs. 1.74&#xa0;kg (p&#x2009;<&#x2009;0.0001) in controls, while visceral fat ratings dropped by 3.67 vs. 0.6 (p&#x2009;<&#x2009;0.0001). CONCLUSIONS: In adults with overweight or obesity without diabetes, oral semaglutide, combined with dietary and lifestyle modifications, led to significant and clinically meaningful weight loss and metabolic improvements compared to lifestyle modifications alone.

Adult↗
PubMed1978

Lysosomal hydrolases in cystic fibrosis livers.

The specific activity of several lysosomal hydrolases in normal and cystic fibrosis (CF) livers has been investigated. Neuraminidase activity with respect to two natural substrates (fetuin and bovine submaxillary mucin) is normal in CF livers. No significant differences were found between CF and normal livers in 4-methylumbelliferyl-alpha-D-mannosidase specific activities determined at three different pH values (4.3, 5.65 and 6.5) corresponding to lysosomal, golgi and cytosolic components of the enzyme, respectively. The specific activities of p-nitrophenyl-beta-D-mannosidase and 4-methylumbelliferyl-beta-N-acetylglucosaminidase were also both similar in CF and normal livers.

Acetylglucosaminidase↗
PubMed2024

Androgen Effects on Alcohol-induced Liver Fibrosis Are Controlled by a Notch-dependent Epigenetic Switch.

BACKGROUND & AIMS: Alcohol-associated liver disease (ALD) is a major cause of alcohol-related mortality. Sex is an important variable; however, the mechanism behind sex differences is not yet established. METHODS: Kdm5b flox/flox Kdm5c flox male mice were subjected to gonadectomy or sham surgery. Mice were fed a Western diet and 20% alcohol in the drinking water for 18 weeks. To induce knockout, mice received 2&#xa0;&#xd7; 1011 genome copies of AAV8-CMV-Cre or AAV8-control. To test the role of Notch, mice were treated with 10 mg/kg of avagacestat for 4&#xa0;weeks. RESULTS: We found that Kdm5b/Kdm5c knockout promoted alcohol-induced liver disease, whereas gonadectomy abolished this effect, suggesting that male sex hormones promote liver disease in the absence of KDM5 demethylases. In contrast, in the thioacetamide-induced fibrosis model, male sex hormones showed a protective effect regardless of genotype. In human liver disease samples, we found that androgen receptor expression positively correlated with fibrosis levels when KDM5B levels were low and negatively when KDM5B was high, suggesting that a KDM5B-dependent epigenetic state defines the androgen receptor role in liver fibrosis. Using isolated cells, we found that this difference was due to the differential effect of testosterone on hepatic stellate cell activation in the absence or presence of KDM5B/KDM5C. Moreover, this effect was mediated by KDM5-dependent suppression of Notch signaling. In KDM5-deficient mice, Notch3 and Jag1 gene expression was induced, facilitating testosterone-mediated induction of Notch signaling and stellate cell activation. Inhibiting Notch with avagacestat greatly reduced liver fibrosis and abolished the effect of Kdm5b/Kdm5c loss. CONCLUSIONS: Male sex hormone signaling can promote or prevent alcohol-associated liver fibrosis depending on the KDM5-dependent epigenetic state.

Animals↗
PubMed1975

Nephronophthisis and tapetoretinal degeneration associated with liver fibrosis.

A 12 year-old boy was referred because of general weakness, enuresis and pallor which had been present for at least six months. Previously, the child had been hospitalized at the age of five, because of mental retardation and hepatosplenomegaly, for which no cause could be found. He had severe renal insufficiency, with all the hallmarks of nephronophthisis. In addition his vision was very poor and fundoscopy revealed tapetoretinal degeneration. The liver and spleen were grossly enlarged. Liver function was almost completely normal, but histology showed diffuse periportal febrosis with profiferation of the bile ducts. This observation seems to confirm the existence of a new syndrome, associating nephronophthisis and liver fibrosis as described by Boichis and coworkers (1973).

Autopsy↗
PubMed1977

Liver fibrosis of the turkey on rapeseed products.

Sclerosis of the liver accompanied by hydropericardium of long standing was observed in turkeys fed rapeseed products for 16 weeks. Histologically, extensive increases of fibrous tissue composed predominantly of reticular fibres and centrilobular degeneration of parenchymal cells were the main pathological features. Neither prominent fatty degeneration nor the formation of pseudolobules was observed. The birds fed rapeseed products for four and 12 weeks showed continuing occurrence of multiple focal and/or solitary hepatocytic necroses preceding the process of fibrosis in the livers. Glucosinolates and their hydrolytic products were considered the most likely causative factors for the hepatocytic necrosis.

Animal Feed↗