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The Gunpowder Plot
\"Who tried to blow up the King of England? Read this book to find out the answer to this question and more! Discover who the plotters were, why they planned to blow up Parliament, how they were discovered and how we remember the plot today.\"--Back cover.
Book
Hepatic inflammatory responses in liver fibrosis
Chronic liver diseases such as nonalcoholic fatty liver disease (NAFLD) or viral hepatitis are characterized by persistent inflammation and subsequent liver fibrosis. Liver fibrosis critically determines long-term morbidity (for example, cirrhosis or liver cancer) and mortality in NAFLD and nonalcoholic steatohepatitis (NASH). Inflammation represents the concerted response of various hepatic cell types to hepatocellular death and inflammatory signals, which are related to intrahepatic injury pathways or extrahepatic mediators from the gut–liver axis and the circulation. Single-cell technologies have revealed the heterogeneity of immune cell activation concerning disease states and the spatial organization within the liver, including resident and recruited macrophages, neutrophils as mediators of tissue repair, auto-aggressive features of T cells as well as various innate lymphoid cell and unconventional T cell populations. Inflammatory responses drive the activation of hepatic stellate cells (HSCs), and HSC subsets, in turn, modulate immune mechanisms via chemokines and cytokines or transdifferentiate into matrix-producing myofibroblasts. Current advances in understanding the pathogenesis of inflammation and fibrosis in the liver, mainly focused on NAFLD or NASH owing to the high unmet medical need, have led to the identification of several therapeutic targets. In this Review, we summarize the inflammatory mediators and cells in the diseased liver, fibrogenic pathways and their therapeutic implications.Liver inflammation is a key process that orchestrates intrahepatic injury. This Review offers a comprehensive overview of the inflammatory mechanisms of hepatic fibrosis and discusses current advances and therapeutic implications.
Journal Article
Molecular and cellular mechanisms of liver fibrosis and its regression
Chronic liver injury leads to liver inflammation and fibrosis, through which activated myofibroblasts in the liver secrete extracellular matrix proteins that generate the fibrous scar. The primary source of these myofibroblasts are the resident hepatic stellate cells. Clinical and experimental liver fibrosis regresses when the causative agent is removed, which is associated with the elimination of these activated myofibroblasts and resorption of the fibrous scar. Understanding the mechanisms of liver fibrosis regression could identify new therapeutic targets to treat liver fibrosis. This Review summarizes studies of the molecular mechanisms underlying the reversibility of liver fibrosis, including apoptosis and the inactivation of hepatic stellate cells, the crosstalk between the liver and the systems that orchestrate the recruitment of bone marrow-derived macrophages (and other inflammatory cells) driving fibrosis resolution, and the interactions between various cell types that lead to the intracellular signalling that induces fibrosis or its regression. We also discuss strategies to target hepatic myofibroblasts (for example, via apoptosis or inactivation) and the myeloid cells that degrade the matrix (for example, via their recruitment to fibrotic liver) to facilitate fibrosis resolution and liver regeneration.
Chronic liver injury leads to liver inflammation and fibrosis, through which activated myofibroblasts in the liver secrete extracellular matrix proteins that generate the fibrous scar. This Review summarizes studies of the molecular mechanisms underlying liver fibrosis and its reversibility.
Key points
Most chronic liver diseases, such as hepatitis C virus infection or non-alcoholic hepatic steatohepatitis, can progress to liver fibrosis with the formation of a fibrous scar.
Experimental and clinical liver fibrosis regresses with the removal of the aetiological agent or with new therapeutic interventions.
Chronic liver injury leads to activation of hepatic stellate cells, the major source of the fibrous scar in liver fibrosis.
Hepatic stellate cells have four known phenotypes — quiescent, activated, inactivated and senescent — each of which has a critical role in liver fibrosis and its regression.
During regression of liver fibrosis, activated hepatic stellate cells can undergo apoptosis or revert to an inactivated phenotype; the inactivated cells have a phenotype that is similar to but distinct from quiescent hepatic stellate cells.
Macrophages can promote fibrogenesis by the secretion of TGFβ and other agonists, but they also support the regression of fibrosis through the secretion of collagenases that resorb the fibrous scar.
Journal Article
Distinct signatures of gut microbiome and metabolites associated with significant fibrosis in non-obese NAFLD
Nonalcoholic fatty liver disease (NAFLD) is associated with obesity but also found in non-obese individuals. Gut microbiome profiles of 171 Asians with biopsy-proven NAFLD and 31 non-NAFLD controls are analyzed using 16S rRNA sequencing; an independent Western cohort is used for external validation. Subjects are classified into three subgroups according to histological spectra of NAFLD or fibrosis severity. Significant alterations in microbiome diversity are observed according to fibrosis severity in non-obese, but not obese, subjects.
Ruminococcaceae
and
Veillonellaceae
are the main microbiota associated with fibrosis severity in non-obese subjects. Furthermore, stool bile acids and propionate are elevated, especially in non-obese subjects with significant fibrosis. Fibrosis-related
Ruminococcaceae
and
Veillonellaceae
species undergo metagenome sequencing, and four representative species are administered in three mouse NAFLD models to evaluate their effects on liver damage. This study provides the evidence for the role of the microbiome in the liver fibrosis pathogenesis, especially in non-obese subjects.
Nonalcoholic fatty liver disease (NAFLD) is associated with obesity but also found in individuals without obesity. Here, gut microbiome analysis using a biopsy-proven NAFLD cohort reveal distinct signatures of microbiome-metabolites associated with significant fibrosis in patients with NAFLD without obesity.
Journal Article
Targeting metabolic dysregulation for fibrosis therapy
Fibrosis is the abnormal deposition of extracellular matrix, which can lead to organ dysfunction, morbidity, and death. The disease burden caused by fibrosis is substantial, and there are currently no therapies that can prevent or reverse fibrosis. Metabolic alterations are increasingly recognized as an important pathogenic process that underlies fibrosis across many organ types. As a result, metabolically targeted therapies could become important strategies for fibrosis reduction. Indeed, some of the pathways targeted by antifibrotic drugs in development — such as the activation of transforming growth factor-β and the deposition of extracellular matrix — have metabolic implications. This Review summarizes the evidence to date and describes novel opportunities for the discovery and development of drugs for metabolic reprogramming, their associated challenges, and their utility in reducing fibrosis. Fibrotic therapies are potentially relevant to numerous common diseases such as cirrhosis, non-alcoholic steatohepatitis, chronic renal disease, heart failure, diabetes, idiopathic pulmonary fibrosis, and scleroderma.
Journal Article
In search of Sir Thomas Browne : the life and afterlife of the seventeenth century's most inquiring mind
\"Sir Thomas Browne (1605-1682) was an English writer, physician, and philosopher whose work has inspired everyone from Ralph Waldo Emerson to Jorge Luis Borges, Virginia Woolf to Stephen Jay Gould ... Aldersey-Williams sets off not just to tell the story of Browne's life but to champion his skeptical nature and inquiring mind. Mixing botany, etymology, medicine, and literary history, Aldersey-Williams journeys in his hero's footsteps to introduce us to witches, zealots, natural wonders, and fabulous creatures of Browne's time and ours\"-- Provided by publisher.
BOOK
Mechanisms of hepatic stellate cell activation
Key Points
Activation of hepatic stellate cells (HSCs) into proliferative, fibrogenic myofibroblasts is well established as the central driver of hepatic fibrosis in experimental and human liver injury
A panoply of intracellular events and signals in all cellular compartments drive the activated phenotype of HSCs, and many of these represent potential targets for antifibrotic therapies
Extracellular signals converging upon HSCs to promote their activation include those originating from the extracellular matrix and stimuli from resident and infiltrating inflammatory cells
Emerging concepts in HSC activation focus on novel mediators and intracellular signals, as well as drivers of HSC inactivation, which collectively have generated a template for uncovering novel therapeutic targets
Activation of hepatic stellate cells (HSCs) in liver injury is the primary driver of hepatic fibrosis. In this Review, Tsuchida and Friedman detail the varied intracellular and extracellular signalling pathways leading to HSC activation, as well as the role of HSCs in liver fibrosis resolution and as therapeutic targets.
Hepatic fibrosis is a dynamic process characterized by the net accumulation of extracellular matrix resulting from chronic liver injury of any aetiology, including viral infection, alcoholic liver disease and NASH. Activation of hepatic stellate cells (HSCs) — transdifferentiation of quiescent, vitamin-A-storing cells into proliferative, fibrogenic myofibroblasts — is now well established as a central driver of fibrosis in experimental and human liver injury. Yet, the continued discovery of novel pathways and mediators, including autophagy, endoplasmic reticulum stress, oxidative stress, retinol and cholesterol metabolism, epigenetics and receptor-mediated signals, reveals the complexity of HSC activation. Extracellular signals from resident and inflammatory cells including macrophages, hepatocytes, liver sinusoidal endothelial cells, natural killer cells, natural killer T cells, platelets and B cells further modulate HSC activation. Finally, pathways of HSC clearance have been greatly clarified, and include apoptosis, senescence and reversion to an inactivated state. Collectively, these findings reinforce the remarkable complexity and plasticity of HSC activation, and underscore the value of clarifying its regulation in hopes of advancing the development of novel diagnostics and therapies for liver disease.
Journal Article