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New Concepts on Reversibility and Targeting of Liver Fibrosis; A Review Article.

ABSTRACT: Currently, liver fibrosis and its complications are regarded as critical health problems. With the studies showing the reversible nature of liver fibrogenesis, scientists have focused on understanding the underlying mechanism of this condition in order to develop new therapeutic strategies. Although hepatic stellate cells are known as the primary cells responsible for liver fibrogenesis, studies have shown contributing roles for other cells, pathways, and molecules in the development of fibrosis depending on the etiology of liver fibrosis. Hence, interventions could be directed in the proper way for each type of liver diseases to better address this complication. There are two main approaches in clinical reversion of liver fibrosis; eliminating the underlying insult and targeting the fibrosis process, which have variable clinical importance in the treatment of this disease. In this review, we present recent concepts in molecular pathways of liver fibrosis reversibility and their clinical implications.

SUBMITTER: Ebrahimi H

PROVIDER: S-EPMC6119836 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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New Concepts on Reversibility and Targeting of Liver Fibrosis; A Review Article.

Ebrahimi Hedyeh H Naderian Mohammadreza M Sohrabpour Amir Ali AA

Middle East journal of digestive diseases 20180614 3

Currently, liver fibrosis and its complications are regarded as critical health problems. With the studies showing the reversible nature of liver fibrogenesis, scientists have focused on understanding the underlying mechanism of this condition in order to develop new therapeutic strategies. Although hepatic stellate cells are known as the primary cells responsible for liver fibrogenesis, studies have shown contributing roles for other cells, pathways, and molecules in the development of fibrosis ...[more]

PMID: 30186577

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Project description:γ-aminobutyric acid type A receptors (GABAARs) are the major mediators of synaptic inhibition in the brain. Aberrant GABAAR activity or regulation is observed in various neurodevelopmental disorders, neurodegenerative diseases and mental illnesses, including epilepsy, Alzheimer's and schizophrenia. Benzodiazepines, anesthetics and other pharmaceutics targeting these receptors find broad clinical use, but their inherent lack of receptor subtype specificity causes unavoidable side effects, raising a need for new or adjuvant medications. In this review article, we introduce a new strategy to modulate GABAeric signaling: targeting the intracellular protein interactors of GABAARs. Of special interest are scaffolding, anchoring and supporting proteins that display high GABAAR subtype specificity. Recent efforts to target gephyrin, the major intracellular integrator of GABAergic signaling, confirm that GABAAR-associated proteins can be successfully targeted through diverse molecules, including recombinant proteins, intrabodies, peptide-based probes and small molecules. Small-molecule artemisinins and peptides derived from endogenous interactors, that specifically target the universal receptor binding site of gephyrin, acutely affect synaptic GABAAR numbers and clustering, modifying neuronal transmission. Interference with GABAAR trafficking provides another way to modulate inhibitory signaling. Peptides blocking the binding site of GABAAR to AP2 increase the surface concentration of GABAAR clusters and enhance GABAergic signaling. Engineering of gephyrin binding peptides delivered superior means to interrogate neuronal structure and function. Fluorescent peptides, designed from gephyrin binders, enable live neuronal staining and visualization of gephyrin in the post synaptic sites with submicron resolution. We anticipate that in the future, novel fluorescent probes, with improved size and binding efficiency, may find wide application in super resolution microscopy studies, enlightening the nanoscale architecture of the inhibitory synapse. Broader studies on GABAAR accessory proteins and the identification of the exact molecular binding interfaces and affinities will advance the development of novel GABAAR modulators and following in vivo studies will reveal their clinical potential as adjuvant or stand-alone drugs.

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New Concepts on Reversibility and Targeting of Liver Fibrosis; A Review Article.

Publications

New Concepts on Reversibility and Targeting of Liver Fibrosis; A Review Article.

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