There is, I think, something ethereal about i —the square root of minus one. I remember first hearing about it at school. It seemed an odd beast at that time—an intruder hovering on the edge of reality.

Usually familiarity dulls this sense of the bizarre, but in the case of i it was the reverse: over the years the sense of its surreal nature intensified. It seemed that it was impossible to write mathematics that described the real world in …

I and i

Oxidative stress is a reflection of the imbalance between the production of reactive oxygen species (ROS) and the scavenging capacity of the antioxidant system. Excessive ROS, generated from various endogenous oxidative biochemical enzymes, interferes with the normal function of liver-specific cells and presumably plays a role in the pathogenesis of liver fibrosis. Once exposed to harmful stimuli, Kupffer cells (KC) are the main effectors responsible for the generation of ROS, which consequently affect hepatic stellate cells (HSC) and hepatocytes. ROS-activated HSC undergo a phenotypic switch and deposit an excessive amount of extracellular matrix that alters the normal liver architecture and negatively affects liver function. Additionally, ROS stimulate necrosis and apoptosis of hepatocytes, which causes liver injury and leads to the progression of end-stage liver disease. In this review, we overview the role of ROS in liver fibrosis and discuss the promising therapeutic interventions related to oxidative stress. Most importantly, novel drugs that directly target the molecular pathways responsible for ROS generation, namely, mitochondrial dysfunction inhibitors, endoplasmic reticulum stress inhibitors, NADPH oxidase (NOX) inhibitors, and Toll-like receptor (TLR)-affecting agents, are reviewed in detail. In addition, challenges for targeting oxidative stress in the management of liver fibrosis are discussed.

Targeting Oxidative Stress for the Treatment of Liver Fibrosis.

https://ris.utwente.nl/ws/files/30085981/1_s2.0_S0169409X17301072_main.pdf

Drug targeting to myofibroblasts: Implications for fibrosis and cancer

Chronic liver diseases represent a global health problem due to their high prevalence worldwide and the limited available curative treatment options. They can result from various causes, both infectious and noninfectious diseases. The application of nanoparticle (NP) systems has emerged as a rapidly evolving area of interest for the safe delivery of various drugs and nucleic acids for chronic liver diseases. This review presents the pathogenesis, diagnosis and the emerging nanoparticulate systems used in the treatment of chronic liver diseases caused by liver fibrosis. Activated hepatic stellate cell (HSC) is considered to be the main mechanism for liver fibrosis. Ultrasonography and magnetic resonance imaging techniques are widely used noninvasive diagnostic methods for hepatic fibrosis. A variety of nanoparticulate systems are mainly focused on targeting HSC in the treatment of hepatic fibrosis. As early liver fibrosis is reversible by current NP therapy, it is being studied in preclinical as well as clinical trials. Among various nanoparticulate systems, inorganic NPs, liposomes and nanomicelles have been widely studied due to their distinct properties to deliver drugs as well as other therapeutic moieties. Liposomal NPs in clinical trials is considered to be a milestone in the treatment of hepatic fibrosis. Currently, NP therapy for liver fibrosis is updating fast, and hopefully, it can be the future remedy for liver fibrosis.

/pdf/nanoparticles-for-the-treatment-of-liver-fibrosis-2q3nijd89l.pdf

Nanoparticles for the treatment of liver fibrosis.

Chronic liver diseases, characterized by an excessive accumulation of extracellular matrix (ECM) resulting in scar tissue formation, are a growing health problem causing increasing morbidity and mortality worldwide. Currently, therapeutic options for tissue fibrosis are severely limited, and organ transplantation is the only treatment for the end-stage liver diseases. During liver damage, injured hepatocytes release proinflammatory factors resulting in the recruitment and activation of immune cells that activate quiescent hepatic stellate cells (HSCs). Upon activation, HSCs transdifferentiate into highly proliferative, migratory, contractile and ECM-producing myofibroblasts. The disrupted balance between ECM deposition and degradation leads to the formation of scar tissue referred to as fibrosis. This balance can be restored either by reducing ECM deposition (by inhibition of HSCs activation and proliferation) or enhancing ECM degradation (by increased expression of matrix metalloproteinases (MMPs)). MMPs play an important role in ECM remodeling and represent an interesting target for therapeutic drug discovery. In this review, we present the current knowledge about ECM remodeling and role of the different MMPs in liver diseases. MMP expression patterns in different stages of liver diseases have also been reviewed to determine their role as biomarkers. Finally, we highlight MMPs as promising therapeutic targets for the resolution of liver diseases.

Matrix Metalloproteinases as Potential Biomarkers and Therapeutic Targets in Liver Diseases.

Hepatic fibrosis, characterized by excessive accumulation of extracellular matrix (ECM) proteins leading to liver dysfunction, is a growing cause of mortality worldwide. Hepatocellular damage owing to liver injury leads to the release of profibrotic factors from infiltrating inflammatory cells that results in the activation of hepatic stellate cells (HSCs). Upon activation, HSCs undergo characteristic morphological and functional changes and are transformed into proliferative and contractile ECM-producing myofibroblasts. Over recent years, a number of therapeutic strategies have been developed to inhibit hepatocyte apoptosis, inflammatory responses, and HSCs proliferation and activation. Preclinical studies have yielded numerous targets for the development of antifibrotic therapies, some of which have entered clinical trials and showed improved therapeutic efficacy and desirable safety profiles. Furthermore, advancements have been made in the development of noninvasive markers and techniques for the accurate disease assessment and therapy responses. Here, we focus on the clinical developments attained in the field of targeted antifibrotics for the treatment of liver fibrosis, for example, small molecule drugs, antibodies, and targeted drug conjugate. We further briefly highlight different noninvasive diagnostic technologies and will provide an overview about different therapeutic targets, clinical trials, endpoints, and translational efforts that have been made to halt or reverse the progression of liver fibrosis.

/pdf/clinical-advancements-in-the-targeted-therapies-against-dcl76qjjvf.pdf

Clinical Advancements in the Targeted Therapies against Liver Fibrosis.

/pdf/engineered-relaxin-as-theranostic-nanomedicine-to-diagnose-12n1k7l0fj.pdf

Beata P. Nagórniewicz

Papers

Clinical Advancements in the Targeted Therapies against Liver Fibrosis.

Engineered Relaxin as theranostic nanomedicine to diagnose and ameliorate liver cirrhosis