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Clinical Gastroenterology and... Jul 2023Chronic liver disease (CLD) and its associated complications (cirrhosis and liver cancer) cause significant mortality, morbidity, and economic burden. Published data... (Review)
Review
Chronic liver disease (CLD) and its associated complications (cirrhosis and liver cancer) cause significant mortality, morbidity, and economic burden. Published data from the World Health Organization and/or the Global Burden of Disease show that the burden of CLD is large and increasing, primarily owing to the increasing burden of nonalcoholic fatty liver disease and alcohol-related liver disease (ALD). Middle Eastern, Northern African, and Asian regions of the globe are most affected by hepatitis B and hepatitis C virus. Furthermore, Middle Eastern and North African regions also are affected by nonalcoholic fatty liver disease, and Eastern European, West African, and Central Asian regions are affected by ALD. In this context, the rate of increase for cirrhosis is highest in the Middle East, as well as in middle high and high sociodemographic index (SDI) regions. On the other hand, the highest SDI countries are experiencing increasing rates of hepatocellular carcinoma (HCC). Assessing HCC burden based on country and etiology shows that China, Korea, India, Japan, and Thailand have the highest hepatitis B virus-related HCC cases, while China, Japan, and the United States have the highest hepatitis C virus-related HCC cases. Additionally, the United States has the highest ALD-related HCC cases, while India, the United States, and Thailand have the highest nonalcoholic steatohepatitis-related HCC cases. Although the burden of CLD is increasing globally, regions of the world are impacted differently as a result of a number of sociodemographic factors.
Topics: Humans; United States; Carcinoma, Hepatocellular; Liver Neoplasms; Non-alcoholic Fatty Liver Disease; Liver Cirrhosis; Hepatitis C
PubMed: 37121527
DOI: 10.1016/j.cgh.2023.04.015 -
Trends in Cell Biology Sep 2023Autophagy is an intracellular degradation pathway that recycles subcellular components to maintain metabolic homeostasis. NAD is an essential metabolite that... (Review)
Review
Autophagy is an intracellular degradation pathway that recycles subcellular components to maintain metabolic homeostasis. NAD is an essential metabolite that participates in energy metabolism and serves as a substrate for a series of NAD-consuming enzymes (NADases), including PARPs and SIRTs. Declining levels of autophagic activity and NAD represent features of cellular ageing, and consequently enhancing either significantly extends health/lifespan in animals and normalises metabolic activity in cells. Mechanistically, it has been shown that NADases can directly regulate autophagy and mitochondrial quality control. Conversely, autophagy has been shown to preserve NAD levels by modulating cellular stress. In this review we highlight the mechanisms underlying this bidirectional relationship between NAD and autophagy, and the potential therapeutic targets it provides for combatting age-related disease and promoting longevity.
Topics: Animals; NAD; Longevity; Energy Metabolism; NAD+ Nucleosidase; Autophagy
PubMed: 36878731
DOI: 10.1016/j.tcb.2023.02.004 -
Current Opinion in Neurology Oct 2023The purpose of this review is to summarise the recent developments in trial readiness, natural history studies, and interventional clinical trials for Becker muscular... (Review)
Review
PURPOSE OF REVIEW
The purpose of this review is to summarise the recent developments in trial readiness, natural history studies, and interventional clinical trials for Becker muscular dystrophy (BMD).
RECENT FINDINGS
As several treatment concepts have claimed to convert patients with Duchenne muscular dystrophy (DMD) into a BMD phenotype, BMD itself has moved into the focus of clinical research. Natural history studies have helped to better characterize patients with BMD and the disease is now a target for interventional trials. In parallel, there have been advances in diagnostics and in the development of preclinical models.
SUMMARY
Despite increased collaborative efforts to improve trial readiness amongst patients with BMD, there is still a lack of long-term natural history data, and the broad spectrum of disease severity remains a challenge for well designed clinical trials.
Topics: Humans; Muscular Dystrophy, Duchenne; Phenotype; Research Design
PubMed: 37591308
DOI: 10.1097/WCO.0000000000001191 -
Frontiers in Molecular Biosciences 2023
PubMed: 38028532
DOI: 10.3389/fmolb.2023.1287885 -
Nature Reviews. Gastroenterology &... Oct 2023Nonalcoholic steatohepatitis (NASH) might soon become the leading cause of end-stage liver disease and indication for liver transplantation worldwide. Fibrosis severity... (Review)
Review
Nonalcoholic steatohepatitis (NASH) might soon become the leading cause of end-stage liver disease and indication for liver transplantation worldwide. Fibrosis severity is the only histological predictor of liver-related morbidity and mortality in NASH identified to date. Moreover, fibrosis regression is associated with improved clinical outcomes. However, despite numerous clinical trials of plausible drug candidates, an approved antifibrotic therapy remains elusive. Increased understanding of NASH susceptibility and pathogenesis, emerging human multiomics profiling, integration of electronic health record data and modern pharmacology techniques hold enormous promise in delivering a paradigm shift in antifibrotic drug development in NASH. There is a strong rationale for drug combinations to boost efficacy, and precision medicine strategies targeting key genetic modifiers of NASH are emerging. In this Perspective, we discuss why antifibrotic effects observed in NASH pharmacotherapy trials have been underwhelming and outline potential approaches to improve the likelihood of future clinical success.
Topics: Humans; Non-alcoholic Fatty Liver Disease; Liver; Liver Cirrhosis; Liver Transplantation; End Stage Liver Disease
PubMed: 37268740
DOI: 10.1038/s41575-023-00796-x -
Neuroscience and Biobehavioral Reviews Jul 2023Despite decades of research, we do not definitively know how people sometimes see things that are not there. Eight models of complex visual hallucinations have been... (Review)
Review
Despite decades of research, we do not definitively know how people sometimes see things that are not there. Eight models of complex visual hallucinations have been published since 2000, including Deafferentation, Reality Monitoring, Perception and Attention Deficit, Activation, Input, and Modulation, Hodological, Attentional Networks, Active Inference, and Thalamocortical Dysrhythmia Default Mode Network Decoupling. Each was derived from different understandings of brain organisation. To reduce this variability, representatives from each research group agreed an integrated Visual Hallucination Framework that is consistent with current theories of veridical and hallucinatory vision. The Framework delineates cognitive systems relevant to hallucinations. It allows a systematic, consistent, investigation of relationships between the phenomenology of visual hallucinations and changes in underpinning cognitive structures. The episodic nature of hallucinations highlights separate factors associated with the onset, persistence, and end of specific hallucinations suggesting a complex relationship between state and trait markers of hallucination risk. In addition to a harmonised interpretation of existing evidence, the Framework highlights new avenues of research, and potentially, new approaches to treating distressing hallucinations.
Topics: Humans; Hallucinations; Brain; Attention Deficit Disorder with Hyperactivity
PubMed: 37141962
DOI: 10.1016/j.neubiorev.2023.105208 -
Drugs Sep 2023Pyoderma gangrenosum is a rare neutrophilic dermatosis that leads to exceedingly painful ulcerations of the skin. Although the exact pathogenesis is not yet fully... (Review)
Review
Pyoderma gangrenosum is a rare neutrophilic dermatosis that leads to exceedingly painful ulcerations of the skin. Although the exact pathogenesis is not yet fully understood, various auto-inflammatory phenomena with increased neutrophil granulocyte activity have been demonstrated. Despite the limited understanding of the pathogenesis, it is no longer a diagnosis of exclusion, as it can now be made on the basis of validated scoring systems. However, therapy remains a major multidisciplinary challenge. Various immunosuppressive and immunomodulatory therapies are available for the treatment of affected patients. In addition, concomitant topical pharmacologic therapy, wound management and pain control should always be addressed. Corticosteroids and/or cyclosporine remain the systemic therapeutics of choice for most patients. However, in recent years, there has been an increasing number of studies on the positive effects of biologic therapies such as inhibitors of tumour necrosis factor-α; interleukin-1, interleukin-17, interleukin-23 or complement factor C5a. Biologics have now become the drug of choice in certain scenarios, particularly in patients with underlying inflammatory comorbidities, and are increasingly used at an early stage in the disease rather than in therapy refractory patients.
Topics: Humans; Pyoderma Gangrenosum; Skin; Pain Management; Biological Products; Cyclosporine
PubMed: 37610614
DOI: 10.1007/s40265-023-01931-3 -
Science (New York, N.Y.) Sep 2023Murine intraepithelial γδ T cells include distinct tissue-protective cells selected by epithelial butyrophilin-like (BTNL) heteromers. To determine whether this...
Murine intraepithelial γδ T cells include distinct tissue-protective cells selected by epithelial butyrophilin-like (BTNL) heteromers. To determine whether this biology is conserved in humans, we characterized the colonic γδ T cell compartment, identifying a diverse repertoire that includes a phenotypically distinct subset coexpressing T cell receptor Vγ4 and the epithelium-binding integrin CD103. This subset was disproportionately diminished and dysregulated in inflammatory bowel disease, whereas on-treatment CD103γδ T cell restoration was associated with sustained inflammatory bowel disease remission. Moreover, CD103Vγ4cell dysregulation and loss were also displayed by humans with germline BTNL3/BTNL8 hypomorphism, which we identified as a risk factor for penetrating Crohn's disease (CD). Thus, BTNL-dependent selection and/or maintenance of distinct tissue-intrinsic γδ T cells appears to be an evolutionarily conserved axis limiting the progression of a complex, multifactorial, tissue-damaging disease of increasing global incidence.
Topics: Animals; Humans; Mice; Butyrophilins; Colon; Crohn Disease; Inflammatory Bowel Diseases; Receptors, Antigen, T-Cell, gamma-delta; T-Lymphocyte Subsets; Intestinal Mucosa
PubMed: 37708268
DOI: 10.1126/science.adh0301 -
Journal of Hepatology Aug 2023The progression of non-alcoholic steatohepatitis (NASH) to fibrosis and hepatocellular carcinoma (HCC) is aggravated by auto-aggressive T cells. The gut-liver axis...
BACKGROUND & AIMS
The progression of non-alcoholic steatohepatitis (NASH) to fibrosis and hepatocellular carcinoma (HCC) is aggravated by auto-aggressive T cells. The gut-liver axis contributes to NASH, but the mechanisms involved and the consequences for NASH-induced fibrosis and liver cancer remain unknown. We investigated the role of gastrointestinal B cells in the development of NASH, fibrosis and NASH-induced HCC.
METHODS
C57BL/6J wild-type (WT), B cell-deficient and different immunoglobulin-deficient or transgenic mice were fed distinct NASH-inducing diets or standard chow for 6 or 12 months, whereafter NASH, fibrosis, and NASH-induced HCC were assessed and analysed. Specific pathogen-free/germ-free WT and μMT mice (containing B cells only in the gastrointestinal tract) were fed a choline-deficient high-fat diet, and treated with an anti-CD20 antibody, whereafter NASH and fibrosis were assessed. Tissue biopsy samples from patients with simple steatosis, NASH and cirrhosis were analysed to correlate the secretion of immunoglobulins to clinicopathological features. Flow cytometry, immunohistochemistry and single-cell RNA-sequencing analysis were performed in liver and gastrointestinal tissue to characterise immune cells in mice and humans.
RESULTS
Activated intestinal B cells were increased in mouse and human NASH samples and licensed metabolic T-cell activation to induce NASH independently of antigen specificity and gut microbiota. Genetic or therapeutic depletion of systemic or gastrointestinal B cells prevented or reverted NASH and liver fibrosis. IgA secretion was necessary for fibrosis induction by activating CD11b+CCR2+F4/80+CD11c-FCGR1+ hepatic myeloid cells through an IgA-FcR signalling axis. Similarly, patients with NASH had increased numbers of activated intestinal B cells; additionally, we observed a positive correlation between IgA levels and activated FcRg+ hepatic myeloid cells, as well the extent of liver fibrosis.
CONCLUSIONS
Intestinal B cells and the IgA-FcR signalling axis represent potential therapeutic targets for the treatment of NASH.
IMPACT AND IMPLICATIONS
There is currently no effective treatment for non-alcoholic steatohepatitis (NASH), which is associated with a substantial healthcare burden and is a growing risk factor for hepatocellular carcinoma (HCC). We have previously shown that NASH is an auto-aggressive condition aggravated, amongst others, by T cells. Therefore, we hypothesized that B cells might have a role in disease induction and progression. Our present work highlights that B cells have a dual role in NASH pathogenesis, being implicated in the activation of auto-aggressive T cells and the development of fibrosis via activation of monocyte-derived macrophages by secreted immunoglobulins (e.g., IgA). Furthermore, we show that the absence of B cells prevented HCC development. B cell-intrinsic signalling pathways, secreted immunoglobulins, and interactions of B cells with other immune cells are potential targets for combinatorial NASH therapies against inflammation and fibrosis.
Topics: Humans; Mice; Animals; Non-alcoholic Fatty Liver Disease; Carcinoma, Hepatocellular; Liver Neoplasms; Mice, Inbred C57BL; Liver; Fibrosis; Liver Cirrhosis; Mice, Transgenic; Microbiota; Immunoglobulin A; Disease Models, Animal; Diet, High-Fat
PubMed: 37224925
DOI: 10.1016/j.jhep.2023.04.037