scholarly journals Till Death Do Us Part—The Multifaceted Role of Platelets in Liver Diseases

2021 ◽  
Vol 22 (6) ◽  
pp. 3113
Author(s):  
Marion Mussbacher ◽  
Laura Brunnthaler ◽  
Anja Panhuber ◽  
Patrick Starlinger ◽  
Alice Assinger
Keyword(s):  
Liver Diseases ◽  
Environmental Changes ◽  
Current Knowledge ◽  
Circulatory System ◽  
Fine Tuning ◽  
Therapeutic Interventions ◽  
Alcoholic Fatty Liver ◽  
Cellular Mediators ◽  
Shed Light

Platelets are tightly connected with the liver, as both their production and their clearance are mediated by the liver. Platelets, in return, participate in a variety of liver diseases, ranging from non-alcoholic fatty liver diseases, (viral) hepatitis, liver fibrosis and hepatocellular carcinoma to liver regeneration. Due to their versatile functions, which include (1) regulation of hemostasis, (2) fine-tuning of immune responses and (3) release of growth factors and cellular mediators, platelets quickly adapt to environmental changes and modulate disease development, leading to different layers of complexity. Depending on the (patho)physiological context, platelets exert both beneficial and detrimental functions. Understanding the precise mechanisms through which platelet function is regulated at different stages of liver diseases and how platelets interact with various resident and non-resident liver cells helps to draw a clear picture of platelet-related therapeutic interventions. Therefore, this review summarizes the current knowledge on platelets in acute and chronic liver diseases and aims to shed light on how the smallest cells in the circulatory system account for changes in the (patho)physiology of the second largest organ in the human body.

Effects of Maternal Obesity and Gestational Diabetes Mellitus on the Placenta: Current Knowledge and Targets for Therapeutic Interventions

2020 ◽  
Vol 19 (2) ◽  
pp. 176-192
Author(s):  
Samantha Bedell ◽  
Janine Hutson ◽  
Barbra de Vrijer ◽  
Genevieve Eastabrook
Keyword(s):  
Diabetes Mellitus ◽  
Gestational Diabetes ◽  
Gestational Diabetes Mellitus ◽  
Maternal Obesity ◽  
Environmental Changes ◽  
Current Knowledge ◽  
Therapeutic Interventions ◽  
Placental Development ◽  
Exchange Site ◽  
And Function

: Obesity and gestational diabetes mellitus (GDM) are becoming more common among pregnant women worldwide and are individually associated with a number of placenta-mediated obstetric complications, including preeclampsia, macrosomia, intrauterine growth restriction and stillbirth. The placenta serves several functions throughout pregnancy and is the main exchange site for the transfer of nutrients and gas from mother to fetus. In pregnancies complicated by maternal obesity or GDM, the placenta is exposed to environmental changes, such as increased inflammation and oxidative stress, dyslipidemia, and altered hormone levels. These changes can affect placental development and function and lead to abnormal fetal growth and development as well as metabolic and cardiovascular abnormalities in the offspring. This review aims to summarize current knowledge on the effects of obesity and GDM on placental development and function. Understanding these processes is key in developing therapeutic interventions with the goal of mitigating these effects and preventing future cardiovascular and metabolic pathology in subsequent generations.

scholarly journals Targeting Autophagy to Counteract Obesity-Associated Oxidative Stress

Antioxidants ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 102
Author(s):  
Federico Pietrocola ◽  
José Manuel Bravo-San Pedro
Keyword(s):  
Oxidative Stress ◽  
Oxygen Species ◽  
Alcoholic Fatty Liver ◽  
Redox Biology ◽  
Obesity Therapy ◽  
Treatment Of Obesity ◽  
Novel Therapeutic Strategies ◽  
Alcoholic Fatty Liver Disease ◽  
Shed Light

Reactive oxygen species (ROS) operate as key regulators of cellular homeostasis within a physiological range of concentrations, yet they turn into cytotoxic entities when their levels exceed a threshold limit. Accordingly, ROS are an important etiological cue for obesity, which in turn represents a major risk factor for multiple diseases, including diabetes, cardiovascular disorders, non-alcoholic fatty liver disease, and cancer. Therefore, the implementation of novel therapeutic strategies to improve the obese phenotype by targeting oxidative stress is of great interest for the scientific community. To this end, it is of high importance to shed light on the mechanisms through which cells curtail ROS production or limit their toxic effects, in order to harness them in anti-obesity therapy. In this review, we specifically discuss the role of autophagy in redox biology, focusing on its implication in the pathogenesis of obesity. Because autophagy is specifically triggered in response to redox imbalance as a quintessential cytoprotective mechanism, maneuvers based on the activation of autophagy hold promises of efficacy for the prevention and treatment of obesity and obesity-related morbidities.

scholarly journals The Role of Oxidative Stress in NAFLD–NASH–HCC Transition—Focus on NADPH Oxidases

Biomedicines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 687
Author(s):  
Daniela Gabbia ◽  
Luana Cannella ◽  
Sara De De Martin
Keyword(s):  
Oxidative Stress ◽  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Current Knowledge ◽  
Mechanisms Of Action ◽  
Nadph Oxidases ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Fatty Liver Disease

A peculiar role for oxidative stress in non-alcoholic fatty liver disease (NAFLD) and its transition to the inflammatory complication non-alcoholic steatohepatitis (NASH), as well as in its threatening evolution to hepatocellular carcinoma (HCC), is supported by numerous experimental and clinical studies. NADPH oxidases (NOXs) are enzymes producing reactive oxygen species (ROS), whose abundance in liver cells is closely related to inflammation and immune responses. Here, we reviewed recent findings regarding this topic, focusing on the role of NOXs in the different stages of fatty liver disease and describing the current knowledge about their mechanisms of action. We conclude that, although there is a consensus that NOX-produced ROS are toxic in non-neoplastic conditions due to their role in the inflammatory vicious cycle sustaining the transition of NAFLD to NASH, their effect is controversial in the neoplastic transition towards HCC. In this regard, there are indications of a differential effect of NOX isoforms, since NOX1 and NOX2 play a detrimental role, whereas increased NOX4 expression appears to be correlated with better HCC prognosis in some studies. Further studies are needed to fully unravel the mechanisms of action of NOXs and their relationships with the signaling pathways modulating steatosis and liver cancer development.

scholarly journals The Protective Role of Butyrate against Obesity and Obesity-Related Diseases

Molecules ◽  
2021 ◽  
Vol 26 (3) ◽  
pp. 682
Author(s):  
Serena Coppola ◽  
Carmen Avagliano ◽  
Antonio Calignano ◽  
Roberto Berni Canani
Keyword(s):  
Metabolic Diseases ◽  
Environmental Changes ◽  
Short Chain Fatty Acids ◽  
Protective Role ◽  
Health Concern ◽  
Predisposing Factor ◽  
Alcoholic Fatty Liver ◽  
Beneficial Effects ◽  
The Individual

Worldwide obesity is a public health concern that has reached pandemic levels. Obesity is the major predisposing factor to comorbidities, including type 2 diabetes, cardiovascular diseases, dyslipidemia, and non-alcoholic fatty liver disease. The common forms of obesity are multifactorial and derive from a complex interplay of environmental changes and the individual genetic predisposition. Increasing evidence suggest a pivotal role played by alterations of gut microbiota (GM) that could represent the causative link between environmental factors and onset of obesity. The beneficial effects of GM are mainly mediated by the secretion of various metabolites. Short-chain fatty acids (SCFAs) acetate, propionate and butyrate are small organic metabolites produced by fermentation of dietary fibers and resistant starch with vast beneficial effects in energy metabolism, intestinal homeostasis and immune responses regulation. An aberrant production of SCFAs has emerged in obesity and metabolic diseases. Among SCFAs, butyrate emerged because it might have a potential in alleviating obesity and related comorbidities. Here we reviewed the preclinical and clinical data that contribute to explain the role of butyrate in this context, highlighting its crucial contribute in the diet-GM-host health axis.

scholarly journals Mitochondrial Mechanisms of Apoptosis and Necroptosis in Liver Diseases

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Qingfei Chu ◽  
Xinyu Gu ◽  
Qiuxian Zheng ◽  
Jing Wang ◽  
Haihong Zhu
Keyword(s):  
Cell Death ◽  
Liver Cirrhosis ◽  
Liver Disease ◽  
Programmed Cell Death ◽  
Liver Diseases ◽  
Current Knowledge ◽  
Therapeutic Strategies ◽  
Cellular Energetics ◽  
Liver Cell Death

In addition to playing a pivotal role in cellular energetics and biosynthesis, mitochondrial components are key operators in the regulation of cell death. In addition to apoptosis, necrosis is a highly relevant form of programmed liver cell death. Differential activation of specific forms of programmed cell death may not only affect the outcome of liver disease but may also provide new opportunities for therapeutic intervention. This review describes the role of mitochondria in cell death and the mechanism that leads to chronic liver hepatitis and liver cirrhosis. We focus on mitochondrial-driven apoptosis and current knowledge of necroptosis and discuss therapeutic strategies for targeting mitochondrial-mediated cell death in liver diseases.

scholarly journals Metabolic Hallmarks of Hepatic Stellate Cells in Liver Fibrosis

Cells ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 24 ◽  
Author(s):  
Olga Khomich ◽  
Alexander V. Ivanov ◽  
Birke Bartosch
Keyword(s):  
Liver Disease ◽  
Liver Fibrosis ◽  
Hepatic Stellate Cells ◽  
Current Knowledge ◽  
Stellate Cells ◽  
Central Carbon Metabolism ◽  
Regenerative Process ◽  
Therapeutic Interventions ◽  
Alcoholic Fatty Liver ◽  
Liver Functions

Liver fibrosis is a regenerative process that occurs after injury. It is characterized by the deposition of connective tissue by specialized fibroblasts and concomitant proliferative responses. Chronic damage that stimulates fibrogenic processes in the long-term may result in the deposition of excess matrix tissue and impairment of liver functions. End-stage fibrosis is referred to as cirrhosis and predisposes strongly to the loss of liver functions (decompensation) and hepatocellular carcinoma. Liver fibrosis is a pathology common to a number of different chronic liver diseases, including alcoholic liver disease, non-alcoholic fatty liver disease, and viral hepatitis. The predominant cell type responsible for fibrogenesis is hepatic stellate cells (HSCs). In response to inflammatory stimuli or hepatocyte death, HSCs undergo trans-differentiation to myofibroblast-like cells. Recent evidence shows that metabolic alterations in HSCs are important for the trans-differentiation process and thus offer new possibilities for therapeutic interventions. The aim of this review is to summarize current knowledge of the metabolic changes that occur during HSC activation with a particular focus on the retinol and lipid metabolism, the central carbon metabolism, and associated redox or stress-related signaling pathways.

Non-alcoholic fatty liver diseases: from role of gut microbiota to microbial-based therapies

2019 ◽  
Vol 39 (4) ◽  
pp. 613-627 ◽  
Author(s):  
Hamed Ebrahimzadeh Leylabadlo ◽  
Reza Ghotaslou ◽  
Hossein Samadi Kafil ◽  
Mohammad Mehdi Feizabadi ◽  
Seyed Yaghoub Moaddab ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Fatty Liver ◽  
Liver Diseases ◽  
Alcoholic Fatty Liver

scholarly journals Caveolin-1 Deficiency Protects Mice Against Carbon Tetrachloride-Induced Acute Liver Injury Through Regulating Polarization of Hepatic Macrophages

2021 ◽  
Vol 12 ◽  
Author(s):  
Ziheng Yang ◽  
Jie Zhang ◽  
Yan Wang ◽  
Jing Lu ◽  
Quan Sun
Keyword(s):  
Carbon Tetrachloride ◽  
Liver Injury ◽  
Liver Diseases ◽  
Acute Liver Injury ◽  
Mrna Levels ◽  
Alcoholic Fatty Liver ◽  
Caveolin 1 ◽  
Hepatic Macrophages ◽  
M1 Phenotype

Polarization of hepatic macrophages plays a crucial role in the injury and repair processes of acute and chronic liver diseases. However, the underlying molecular mechanisms remain elusive. Caveolin-1 (Cav1) is the structural protein of caveolae, the invaginations of the plasma membrane. It has distinct functions in regulating hepatitis, cirrhosis, and hepatocarcinogenesis. Given the increasing number of cases of liver cancer, nonalcoholic steatohepatitis, and non-alcoholic fatty liver disease worldwide, investigations on the role of Cav1 in liver diseases are warranted. In this study, we aimed to investigate the role of Cav1 in the pathogenesis of acute liver injury. Wild-type (WT) and Cav1 knockout (KO) mice (Cav1tm1Mls) were injected with carbon tetrachloride (CCl4). Cav1 KO mice showed significantly reduced degeneration, necrosis, and apoptosis of hepatocytes and decreased level of alanine transaminase (ALT) compared to WT mice. Moreover, Cav1 was required for the recruitment of hepatic macrophages. The analysis of the mRNA levels of CD86, tumor necrosis factor (TNF), and interleukin (IL)-6, as well as the protein expression of inducible nitric oxide synthase (iNOS), indicated that Cav1 deficiency inhibited the polarization of hepatic macrophages towards the M1 phenotype in the injured liver. Consistent with in vivo results, the expressions of CD86, TNF, IL-6, and iNOS were significantly downregulated in Cav1 KO macrophages. Also, fluorescence-activated cell sorting (FACS) analysis showed that the proportion of M1 macrophages was significantly decreased in the liver tissues obtained from Cav1 KO mice following CCl4 treatment. In summary, our results showed that Cav1 deficiency protected mice against CCl4-induced acute liver injury by regulating polarization of hepatic macrophages. We provided direct genetic evidence that Cav1 expressed in hepatic macrophages contributed to the pathogenesis of acute liver injury by regulating the polarization of hepatic macrophages towards the M1 phenotype. These findings suggest that Cav1 expressed in macrophages may represent a potential therapeutic target for acute liver injury.

Emerging Role of Interleukins for the Assessment and Treatment of Liver Diseases

2021 ◽  
Vol 21 ◽  
Author(s):  
Aaliya L. Ali ◽  
Namrata P. Nailwal ◽  
Gaurav M. Doshi
Keyword(s):  
Hepatocellular Carcinoma ◽  
Clinical Trial ◽  
Liver Disease ◽  
Alcoholic Liver Disease ◽  
Liver Diseases ◽  
Clinical Trial Data ◽  
Trial Data ◽  
Alcoholic Fatty Liver ◽  
Assessment And Treatment

Background: The most common liver diseases are fibrosis, alcoholic liver disease, non-alcoholic fatty disease, viral hepatitis, and hepatocellular carcinoma. These liver diseases account for approximately 2 million deaths per year worldwide, with cirrhosis accounting for 2.1% of the worldwide burden. The most widely used liver function tests for diagnosis are alanine transaminase, aspartate transaminase, serum proteins, serum albumin, and serum globulins, whereas antivirals and corticosteroids have been proven to be useful for the treatment of liver diseases. A major disadvantage of these diagnostic measures is the lack of specificity to a particular tissue or cell type, as these enzymes are common to one or more tissues. The major adverse effect of current treatment methods is drug resistance. To overcome these issues, interleukins have been investigated. The balance of these interleukins determines the outcome of an immune response. Interleukins are considered interesting therapeutic targets for the treatment of liver diseases. In this review, we summarize the current state of knowledge regarding interleukins in the diagnosis, treatment, and pathogenesis of different acute and chronic liver diseases. Objective: To understand the role of interleukins in the assessment and treatment of different types of liver diseases. Methods: A literature search was conducted using PubMed, Science Direct, and NCBI with the following keywords: Interleukins, Acute Liver Failure, Alcoholic Liver Disease, Non-Alcoholic Fatty Liver Disease, Liver Fibrosis, Hepatocellular Carcinoma, Inflammation, Liver injury, Hepatoprotective effect. Clinical trial data on these interleukins have been searched on Clinicaltrials.gov. Results: Existing literature and preclinical and clinical trial data demonstrate that interleukins play a crucial role in the pathogenesis of liver diseases. Conclusion: Our findings indicate that IL-1, IL-6, IL-10, IL-17, IL-22, IL-35, and IL-37 are involved in the progression and control of various liver conditions via the regulation of cell signaling pathways. However, further investigation on the involvement of these interleukins is necessary for their use as a targeted therapy in liver diseases.

Epitranscriptomic modifications in acute myeloid leukemia: m6A and 2′-O-methylation as targets for novel therapeutic strategies

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Cornelius Pauli ◽  
Michael Kienhöfer ◽  
Stefanie Göllner ◽  
Carsten Müller-Tidow
Keyword(s):  
Acute Myeloid Leukemia ◽  
Ribosomal Rna ◽  
Myeloid Leukemia ◽  
Current Knowledge ◽  
Therapeutic Strategies ◽  
Therapeutic Interventions ◽  
Rna Modifications ◽  
Novel Therapeutic Strategies ◽  
Acute Myeloid

Abstract Modifications of RNA commonly occur in all species. Multiple enzymes are involved as writers, erasers and readers of these modifications. Many RNA modifications or the respective enzymes are associated with human disease and especially cancer. Currently, the mechanisms how RNA modifications impact on a large number of intracellular processes are emerging and knowledge about the pathogenetic role of RNA modifications increases. In Acute Myeloid Leukemia (AML), the N 6-methyladenosine (m6A) modification has emerged as an important modulator of leukemogenesis. The writer proteins METTL3 and METTL14 are both involved in AML pathogenesis and might be suitable therapeutic targets. Recently, close links between 2′-O-methylation (2′-O-me) of ribosomal RNA and leukemogenesis were discovered. The AML1-ETO oncofusion protein which specifically occurs in a subset of AML was found to depend on induction of snoRNAs and 2′-O-me for leukemogenesis. Also, NPM1, an important tumor suppressor in AML, was associated with altered snoRNAs and 2′-O-me. These findings point toward novel pathogenetic mechanisms and potential therapeutic interventions. The current knowledge and the implications are the topic of this review.

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