The Presence of Non-organ-specific Autoantibodies in Chronic Hepatitis C Treatment-naive Patients

Background: In the patients with hepatitis C virus (HCV) various immune mediated phenomena are described, and non organ specific autoantibodies (NOSAs) in particular are common. The aim of the present study was to investigate the NOSAs prevalence in chronic hepatitis C treatment naive patients. Patients and Methods: Sera of 76 consecutive HCV treatment naive patients were considered to be eligible for this study for evaluation of Antinuclear, antismooth muscle, antimitochondrial, antineutrophil cytoplasmatic and antiliver kidney microsomal antibodies. Criteria of eligibility were serum antiHCV antibody and HCV RNA positivity, chronic inflammation revealed by histological analysis of the liver, genotyping, treatment naive patients, and no have the diagnosis of probable or definite autoimmune hepatitis. Results: Mean chronological age for the 76 patients (44 females and 32 males) was 51.3 years (range: 20 to 67 years). Nineteen patients (25.0%) infected with HCV had detectable levels of NOSAs at before combined antiviral treatment. SMA was present in 16 (21.0%) of 76 patients, ANA in 2 patients (2.6%), and pANCA (perinuclear ANCA) in 1 patients (1.3%). No patient had specimens reactive to AMA, LMK, or cANCA (cytoplasmic ANCA). Conclusions: In this study, we show the NOSAs positivity in chronic hepatitis c treatment naive patients. Assigned to high prevalence of SMA positivity is associated with high METAVIR score, and HCV genotype 1 and 1b, may reflect a release of intracellular antigens at the time of hepatocellular injury triggering immune responses in the form of autoantibody production or a direct infection of immunocytes by the HCV. Keywords: hepatitis C, treatment naive, non organ specific antibodies, chronic liver disease

Cosmetological competence of nail patches in combating onychomycosis-An approach to improve the quality of life

Onychomycosis (Tinea unguium) is said to be the most common cosmetological nail fungal infection. Dermatophyte is a type of fungus that causes this condition. Discoloration and thickening of the nail are found to be the common symptoms of all nail diseases. In this scenario, Onychomycosis is considered as one of the cosmetic problems that leads to cellulitis in adults and diabetic patients. Anatomical structure of the nail and disease manifestations made nail disorders as a difficult endeavor. Onychomycosis is chronic and difficult to eradicate. Many oral antifungal agents are available for the treatment of nail infections. The oral and parenteral administration of antifungal agents can elevate the serum hepatic enzyme levels and causes typical hepatocellular injury within a few weeks of therapy. The goal of this review is to study the role of transungal delivery systems (nail patches) as a promising tool for onychomycosis to encounter the clinical conditions of the patient. Longer therapies and technical treatment methods may frustrate the patients. This novel antifungal therapy helps to avoid the surgical removal of nail for onychomycosis patients. Eradication of issues with Onychomycosis can be achieved by an excellent delivery system with deeper drug release and drug retention in the nail cuticle. Patients who are suffered from onychomycosis are facing embarrassment and disfigurement in the society. So, this newer treatment solution can improve the quality of life of patients.1-3

HiPSC-Derived Hepatocyte-like Cells Can Be Used as a Model for Transcriptomics-Based Study of Chemical Toxicity

Traditional toxicity risk assessment approaches have until recently focussed mainly on histochemical readouts for cell death. Modern toxicology methods attempt to deduce a mechanistic understanding of pathways involved in the development of toxicity, by using transcriptomics and other big data-driven methods such as high-content screening. Here, we used a recently described optimised method to differentiate human induced pluripotent stem cells (hiPSCs) to hepatocyte-like cells (HLCs), to assess their potential to classify hepatotoxic and non-hepatotoxic chemicals and their use in mechanistic toxicity studies. The iPSC-HLCs could accurately classify chemicals causing acute hepatocellular injury, and the transcriptomics data on treated HLCs obtained by TempO-Seq technology linked the cytotoxicity to cellular stress pathways, including oxidative stress and unfolded protein response (UPR). Induction of these stress pathways in response to amiodarone, diclofenac, and ibuprofen, was demonstrated to be concentration and time dependent. The transcriptomics data on diclofenac-treated HLCs were found to be more sensitive in detecting differentially expressed genes in response to treatment, as compared to existing datasets of other diclofenac-treated in vitro hepatocyte models. Hence iPSC-HLCs generated by transcription factor overexpression and in metabolically optimised medium appear suitable for chemical toxicity detection as well as mechanistic toxicity studies.

Complement C5a and Clinical Markers as Predictors of COVID-19 Disease Severity and Mortality in a Multi-Ethnic Population

Coronavirus disease-2019 (COVID-19) was declared as a pandemic by WHO in March 2020. SARS-CoV-2 causes a wide range of illness from asymptomatic to life-threatening. There is an essential need to identify biomarkers to predict disease severity and mortality during the earlier stages of the disease, aiding treatment and allocation of resources to improve survival. The aim of this study was to identify at the time of SARS-COV-2 infection patients at high risk of developing severe disease associated with low survival using blood parameters, including inflammation and coagulation mediators, vital signs, and pre-existing comorbidities. This cohort included 89 multi-ethnic COVID-19 patients recruited between July 14th and October 20th 2020 in Doha, Qatar. According to clinical severity, patients were grouped into severe (n=33), mild (n=33) and asymptomatic (n=23). Common routine tests such as complete blood count (CBC), glucose, electrolytes, liver and kidney function parameters and markers of inflammation, thrombosis and endothelial dysfunction including complement component split product C5a, Interleukin-6, ferritin and C-reactive protein were measured at the time COVID-19 infection was confirmed. Correlation tests suggest that C5a is a predictive marker of disease severity and mortality, in addition to 40 biological and physiological parameters that were found statistically significant between survivors and non-survivors. Survival analysis showed that high C5a levels, hypoalbuminemia, lymphopenia, elevated procalcitonin, neutrophilic leukocytosis, acute anemia along with increased acute kidney and hepatocellular injury markers were associated with a higher risk of death in COVID-19 patients. Altogether, we created a prognostic classification model, the CAL model (C5a, Albumin, and Lymphocyte count) to predict severity with significant accuracy. Stratification of patients using the CAL model could help in the identification of patients likely to develop severe symptoms in advance so that treatments can be targeted accordingly.

Ovothiol-A Isolated from Sea Urchin Eggs Suppress Oxidative Stress, Inflammation, and Dyslipidemia Resulted in Restoration of Liver Activity in Cholestatic Rats

Cholestasis is dropping in bile flow, leading to the intrahepatic bulk of bile acids and other poisonous compounds with the progression of liver pathology, including hepatocellular injury and fibrosis. Ovothiols extracted from sea urchin display unusual antioxidant properties due to the peculiar position of the thiol group on the imidazole ring of histidine. The present study aims to evaluate the anti-fibrotic effect of Ovothiol-A in rats. 28 rats were allocated randomly into 4 groups: Sham, BDL, and BDL + Ovothiol A (500 mg/kg). All rats were treated for 7 days. Oxidative stress biomarkers, liver functions, lipid profile, and histology were all examined. The results revealed that BDL operation induced oxidative stress in rats, which negatively impacted liver functions, as confirmed by the histopathological examination. Ovothiol-A has been shown to lower oxidative stress and enhance lipid profile, resulting in considerable improvements in most biochemical markers. Also, histopathological examination showed an improvement in the liver architecture of the treated group compared to the BDL group. Ovothiol-A protects the liver against toxicity results from cholestasis in rats.

Current and Potential Therapies Targeting Inflammation in NASH

Nonalcoholic steatohepatitis (NASH) is the advanced form of nonalcoholic fatty liver disease (NAFLD). It is characterized by hepatic steatosis, inflammation, hepatocellular injury, and fibrosis. Inflammation plays a key role in the progression of NASH and can be provoked by intrahepatic (e.g., lipotoxicity, immune responses, oxidative stress and cell death) and extrahepatic sources (adipose tissue or gut). The identification of triggers of inflammation is central to understanding the mechanisms in NASH development and progression and in designing targeted therapies that can halt or reverse the disease. In this review, we summarize the current and potential therapies targeting inflammation in NASH.

Hepatotoxicity-Related Adverse Effects of Proton Pump Inhibitors: A Cross-Sectional Study of Signal Mining and Analysis of the FDA Adverse Event Report System Database

Background and Objectives: Mounting evidence demonstrates that proton pump inhibitors (PPIs) are associated with a number of adverse effects. However, the literatures about hepatotoxicity-related adverse effects (HRAEs) of PPIs are mostly case reports and a few clinical studies.Methods: We evaluated the association between PPIs and HAREs using the reporting odd ratio (ROR) for mining the adverse event report signals in the FDA Adverse Event Reporting System (FAERS) database.Results: There were 23,825 reports of PPIs as primary suspect drug or second suspect drug, of which 3,253 reports were HRAEs. The top five HRAE signals caused by PPIs were hepatitis cholestatic, cholestasis, fulminant hepatitis, subacute hepatic failure, and acute hepatitis. We also summarized the signals of the HRAEs caused by each PPI. The simultaneous signals were cholestasis and hepatitis cholestatic. For the cholestasis signal, esomeprazole showed an ROR of 21.556 (95% CI 17.592–26.413); pantoprazole showed the highest ROR of 22.611 (95% CI 17.794–28.733) in the hepatic cholestatic signal; lansoprazole was the only PPI with expression in the coma hepatic signal, with an ROR of 10.424 (95% CI 3.340–32.532). By analyzing the reports of pantoprazole-induced hepatic encephalopathy, we found that patients aged over 65 years and males reported the highest rate. And from the combination of drugs and indications of drugs, no significant results were obtained.Conclusions: The RORs of signals of “cholestasis” were generally higher than those of “hepatocellular injury.” And the signals about “cholestasis” in HRAE caused by PPIs are more reported.

Molecular Markers For Selection of Resistance to Facial Eczema

<p>The disease facial eczema is caused by the fungal metabolite sporidesmin which produces photosensitisation of animals whose liver and biliary tract have been damaged by the toxin. Sporidesmin is produced by the pasture fungus Pithomyces chartarum and affects ruminant animals that graze on contaminated pasture. Previous studies have shown that sporidesmin is metabolised in the liver and have suggested that the toxin is metabolically inactivated by enzymes in the glutathione S-transferase and cytochrome P-450 families. The activities of these enzymes were therefore measured in liver extracts from Romneys that had been selected for resistance or susceptibility to sporidesmin - induced liver damage. Although there were no differences in cytochrome P-450 CO binding spectra or cytochrome c reductase between the selection lines, resistant Romneys had greater nitroanisole O-demethylase activity and this difference was apparently enhanced two days after dosing with sporidesmin. Dose-dependent differences occurred in the absence of major hepatocellular injury suggesting that they reflected changes in enzyme activity rather than changes in tissue mass. Aminopyrine N-demethylase did not vary significantly between the selection lines. Some differences in GSH-dependent metabolism were also observed. Undosed resistant Romneys showed greater GSH-dependent metabolism of sporidesmin in a spectrophotometric assay. It is possible that glutathione S-transferase Mu or Theta isoforms had greater activity in the resistant lines as differences were observed using p-nitrobenzyl chloride and 1,2 epoxy-3-p-nitrophenoxypropanol but not with 1-chloro-2,4-dinitrobenzene or 1,2-dichloro-4-nitrobenzene that are good substrates for these isoforms. 2-D PAGE was applied to the separation of whole homogenate and soluble proteins. Variations in expression of some proteins including GST Mu isoforms were found between the selection lines. Roles of cytochrome P-450 and glutathione S-transferase in the hepatic detoxication of sporidesmin have previously been demonstrated. Results obtained in this study suggest that resistant Romneys may have greater cytochrome P-450 O-demethylase and glutathione S-transferase activities that could be responsible for increased metabolic inactivation of sporidesmin. These differences may in the future be of use in design of DNA probes to enhance detection and selection of facial eczema resistant livestock.</p>

Molecular Markers For Selection of Resistance to Facial Eczema

<p>The disease facial eczema is caused by the fungal metabolite sporidesmin which produces photosensitisation of animals whose liver and biliary tract have been damaged by the toxin. Sporidesmin is produced by the pasture fungus Pithomyces chartarum and affects ruminant animals that graze on contaminated pasture. Previous studies have shown that sporidesmin is metabolised in the liver and have suggested that the toxin is metabolically inactivated by enzymes in the glutathione S-transferase and cytochrome P-450 families. The activities of these enzymes were therefore measured in liver extracts from Romneys that had been selected for resistance or susceptibility to sporidesmin - induced liver damage. Although there were no differences in cytochrome P-450 CO binding spectra or cytochrome c reductase between the selection lines, resistant Romneys had greater nitroanisole O-demethylase activity and this difference was apparently enhanced two days after dosing with sporidesmin. Dose-dependent differences occurred in the absence of major hepatocellular injury suggesting that they reflected changes in enzyme activity rather than changes in tissue mass. Aminopyrine N-demethylase did not vary significantly between the selection lines. Some differences in GSH-dependent metabolism were also observed. Undosed resistant Romneys showed greater GSH-dependent metabolism of sporidesmin in a spectrophotometric assay. It is possible that glutathione S-transferase Mu or Theta isoforms had greater activity in the resistant lines as differences were observed using p-nitrobenzyl chloride and 1,2 epoxy-3-p-nitrophenoxypropanol but not with 1-chloro-2,4-dinitrobenzene or 1,2-dichloro-4-nitrobenzene that are good substrates for these isoforms. 2-D PAGE was applied to the separation of whole homogenate and soluble proteins. Variations in expression of some proteins including GST Mu isoforms were found between the selection lines. Roles of cytochrome P-450 and glutathione S-transferase in the hepatic detoxication of sporidesmin have previously been demonstrated. Results obtained in this study suggest that resistant Romneys may have greater cytochrome P-450 O-demethylase and glutathione S-transferase activities that could be responsible for increased metabolic inactivation of sporidesmin. These differences may in the future be of use in design of DNA probes to enhance detection and selection of facial eczema resistant livestock.</p>