Despite recent advances in the treatment of autoimmune and inflammatory diseases, unmet medical needs in some areas still exist. One of the main therapeutic approaches to alleviate dysregulated inflammation has been to target the activity of kinases that regulate production of inflammatory mediators. Small-molecule kinase inhibitors have the potential for broad efficacy, convenience and tissue penetrance, and thus often offer important advantages over biologics. However, designing kinase inhibitors with target selectivity and minimal off-target effects can be challenging. Nevertheless, immense progress has been made in advancing kinase inhibitors with desirable drug-like properties into the clinic, including inhibitors of JAKs, IRAK4, RIPKs, BTK, SYK and TPL2. This Review will address the latest discoveries around kinase inhibitors with an emphasis on clinically validated autoimmunity and inflammatory pathways.

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Kinase inhibition in autoimmunity and inflammation

https://www.medigraphic.com/pdfs/hepato/ah-2017/ah171h.pdf

Management Strategies for Liver Fibrosis

// Alexander V. Ivanov 1 , Vladimir T. Valuev-Elliston 1 , Daria A. Tyurina 1 , Olga N. Ivanova 1 , Sergey N. Kochetkov 1 , Birke Bartosch 2,3 and Maria G. Isaguliants 4,5 1 Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia 2 Inserm U1052, Cancer Research Center Lyon, University of Lyon, Lyon, France 3 DevWeCan Laboratories of Excellence Network, France 4 Riga Stradins University, Riga, Latvia 5 Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden Correspondence to: Alexander V. Ivanov, email: // Maria G. Isaguliants, email: // Keywords : hepatitis C virus, hepatitis B virus, reactive oxygen species, pathogenesis, carcinogenesis Received : July 22, 2016 Accepted : December 05, 2016 Published : December 11, 2016 Abstract Virally induced liver cancer usually evolves over long periods of time in the context of a strongly oxidative microenvironment, characterized by chronic liver inflammation and regeneration processes. They ultimately lead to oncogenic mutations in many cellular signaling cascades that drive cell growth and proliferation. Oxidative stress, induced by hepatitis viruses, therefore is one of the factors that drives the neoplastic transformation process in the liver. This review summarizes current knowledge on oxidative stress and oxidative stress responses induced by human hepatitis B and C viruses. It focuses on the molecular mechanisms by which these viruses activate cellular enzymes/systems that generate or scavenge reactive oxygen species (ROS) and control cellular redox homeostasis. The impact of an altered cellular redox homeostasis on the initiation and establishment of chronic viral infection, as well as on the course and outcome of liver fibrosis and hepatocarcinogenesis will be discussed The review neither discusses reactive nitrogen species, although their metabolism is interferes with that of ROS, nor antioxidants as potential therapeutic remedies against viral infections, both subjects meriting an independent review.

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Oxidative stress, a trigger of hepatitis C and B virus-induced liver carcinogenesis

In chronic liver diseases, an ongoing hepatocellular injury together with inflammatory reaction results in activation of hepatic stellate cells (HSCs) and increased deposition of extracellular matrix (ECM) termed as liver fibrosis. It can progress to cirrhosis that is characterized by parenchymal and vascular architectural changes together with the presence of regenerative nodules. Even at late stage, liver fibrosis is reversible and the underlying mechanisms include a switch in the inflammatory environment, elimination or regression of activated HSCs and degradation of ECM. While animal models have been indispensable for our understanding of liver fibrosis, they possess several important limitations and need to be further refined. A better insight into the liver fibrogenesis resulted in a large number of clinical trials aiming at reversing liver fibrosis, particularly in patients with non-alcoholic steatohepatitis. Collectively, the current developments demonstrate that reversal of liver fibrosis is turning from fiction to reality.

Reversal of liver fibrosis: From fiction to reality.

Chronic renal and vascular oxidative stress in association with an enhanced inflammatory burden are determinant processes in the development and progression of diabetic complications including cardiovascular disease (CVD), atherosclerosis and diabetic kidney disease (DKD). Persistent hyperglycaemia in diabetes mellitus increases the production of reactive oxygen species (ROS) and activates mediators of inflammation as well as suppresses antioxidant defence mechanisms ultimately contributing to oxidative stress which leads to vascular and renal injury in diabetes. Furthermore, there is increasing evidence that ROS, inflammation and fibrosis promote each other and are part of a vicious connection leading to development and progression of CVD and kidney disease in diabetes.

A causal link between oxidative stress and inflammation in cardiovascular and renal complications of diabetes.

The aim of this study was to assess whether two-years treatment with Pirfenidone influences necroinflammation, fibrosis and steatosis, serum levels of TGF-β1, IL-6, TNF-α and CB1 and CB2 gene expression, in patients with chronic hepatitis C (CHC). Twenty-eight patients out of 34 with CHC virus infection were enrolled in the study and received Pirfenidone (1200 mg/day) for 24 months. Six patients dropped out after 12 months of PFD. Liver biopsies and serum samples were obtained at the beginning and end of treatment. Modified HAI was calculated. CB1 and CB2 gene expression was correlated with fibrosis progression alongside with necroinflammation and steatosis. TGF-β1, IL-6, TNF-α and liver transaminases were measured in serum at two-months intervals. HCV genotype and viral load were also assessed. Quality of life was evaluated by SF36 questionnaires and the prognosis of disease was assessed with Child-Pugh score. The Wilcoxon test matched-pair signed ranks were used to analyze the outcomes. Intention to treat analyses were performed for biochemistry and clinical parameters. At the end of treatment, necroinflammation grading was reduced in an average of 3.2 points in 82% of patients (p < 0.05) and Ishak’s fibrosis stage decreased 2-points average in 67% of patients (p < 0.05). Steatosis decreased in 61% of patients. IL-6 and TGF-β1 serum levels decreased significantly in 93% and 67% of patients (p < 0.05), respectively, while TNF-α diminished in 47% of patients. ALT and AST tended to normalize in 81% of patients; CB2 mRNA levels increased in 86% and CB1 expression diminished in 29% of patients. Both, quality of life and Child-Pugh score improvements were reported in all patients. Pirfenidone for two years benefits CHC patients and improves inflammation, fibrosis and steatosis in higher number of patients as previously shown for 12-months treatment with PFD. Additionally, PFD improved TGFβ1 and IL-6 levels and diminished liver expression of anti-fibrogenic receptor CB2. ClinicalTrials.gov identifier: NCT02161952
 . Protocol Registration Date: 06/11/2014.

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M Guadalupe Sanchez-Parada

Papers

Treatment with pirfenidone for two years decreases fibrosis, cytokine levels and enhances CB2 gene expression in patients with chronic hepatitis C