scholarly journals Chaperone-Mediated Autophagy in the Liver: Good or Bad?

Cells ◽  
2019 ◽  
Vol 8 (11) ◽  
pp. 1308 ◽  
Author(s):  
Srikanta Dash ◽  
Yucel Aydin ◽  
Krzysztof Moroz
Keyword(s):  
Cellular Stress ◽  
Hcv Infection ◽  
Liver Disease Progression ◽  
Cellular Autophagy ◽  
Therapeutic Development ◽  
Metabolic Conditions ◽  
Hepatic Innate Immunity ◽  
Viral Etiologies ◽  
Cellular Components ◽  
Chaperone Mediated Autophagy

Hepatitis C virus (HCV) infection triggers autophagy processes, which help clear out the dysfunctional viral and cellular components that would otherwise inhibit the virus replication. Increased cellular autophagy may kill the infected cell and terminate the infection without proper regulation. The mechanism of autophagy regulation during liver disease progression in HCV infection is unclear. The autophagy research has gained a lot of attention recently since autophagy impairment is associated with the development of hepatocellular carcinoma (HCC). Macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA) are three autophagy processes involved in the lysosomal degradation and extracellular release of cytosolic cargoes under excessive stress. Autophagy processes compensate for each other during extreme endoplasmic reticulum (ER) stress to promote host and microbe survival as well as HCC development in the highly stressed microenvironment of the cirrhotic liver. This review describes the molecular details of how excessive cellular stress generated during HCV infection activates CMA to improve cell survival. The pathological implications of stress-related CMA activation resulting in the loss of hepatic innate immunity and tumor suppressors, which are most often observed among cirrhotic patients with HCC, are discussed. The oncogenic cell programming through autophagy regulation initiated by a cytoplasmic virus may facilitate our understanding of HCC mechanisms related to non-viral etiologies and metabolic conditions such as uncontrolled type II diabetes. We propose that a better understanding of how excessive cellular stress leads to cancer through autophagy modulation may allow therapeutic development and early detection of HCC.

scholarly journals A scientist engineer’s contribution to therapeutic discovery and development

2018 ◽  
Vol 243 (14) ◽  
pp. 1125-1132 ◽  
Author(s):  
Jennifer L Wilson
Keyword(s):  
Drug Development ◽  
Drug Effects ◽  
Deep Understanding ◽  
Empirical Models ◽  
Development Costs ◽  
Therapeutic Development ◽  
Forward Engineering ◽  
Tool Set ◽  
Complex Circuits ◽  
Cellular Components

An engineering perspective views cells as complex circuits that process inputs – drugs, environmental cues – to create complex outcomes – disease, growth, death – and this perspective has immense potential for drug development. Logical rules can describe the features of cells and reductionist approaches have exploited these rules for drug development. In contrast, the reductionist approach serially characterizes cellular components and develops a deep understanding of each component’s specific role. This approach underutilizes the full system of biomolecules relevant to disease pathology and drug effects. An engineering perspective provides the tools to understand and leverage the full extent of biological systems; applying both reverse and forward engineering, a strength of the engineering approach has demonstrated progress in advancing understanding of disease and drug mechanisms. Drug development lacks sufficient engineering specifications, or empirical models, of drug pharmacodynamic effects and future efforts to derive empirical models of drug effects will streamline this development. At this stage of progress, the scientist engineer is uniquely poised to solve problems in therapeutics related to modulating multiple diseases with a single or multiple therapeutic agents and identifying pharmacodynamics biomarkers with knowledge of drug pathways. This article underscores the value of these principles in an age where drug development costs are soaring and finding efficacious therapies is challenging. Impact statement Many untreated diseases are not monogenic and are instead caused by multiple genetic defects. Because of this complexity, computational, logical, and systems understanding will be essential to discovering novel therapies. The scientist engineer is uniquely disposed to use this type of understanding to advance therapeutic discovery. This work highlights benefits of the scientist engineer perspective and underscores the potential impact of these approaches for future therapeutic development. By framing the scientist engineer’s tool set and increasing awareness about this approach, this article stands to impact future therapeutic development efforts in an age of rising development costs and high drug attrition.

scholarly journals Autophagy and Glycative Stress: A Bittersweet Relationship in Neurodegeneration

2021 ◽  
Vol 9 ◽  
Author(s):  
Olga Gómez ◽  
Giuliana Perini-Villanueva ◽  
Andrea Yuste ◽  
José Antonio Rodríguez-Navarro ◽  
Enric Poch ◽  
...  
Keyword(s):  
Protective Role ◽  
Brain Cell ◽  
Cellular Aging ◽  
Brain Physiology ◽  
Proteolytic Pathway ◽  
The Status ◽  
Cell Components ◽  
Metabolic Conditions ◽  
Cellular Components

Autophagy is a fine-tuned proteolytic pathway that moves dysfunctional/aged cellular components into the lysosomal compartment for degradation. Over the last 3 decades, global research has provided evidence for the protective role of autophagy in different brain cell components. Autophagic capacities decline with age, which contributes to the accumulation of obsolete/damaged organelles and proteins and, ultimately, leads to cellular aging in brain tissues. It is thus well-accepted that autophagy plays an essential role in brain homeostasis, and malfunction of this catabolic system is associated with major neurodegenerative disorders. Autophagy function can be modulated by different types of stress, including glycative stress. Glycative stress is defined as a cellular status with abnormal and accelerated accumulation of advanced glycation end products (AGEs). It occurs in hyperglycemic states, both through the consumption of high-sugar diets or under metabolic conditions such as diabetes. In recent years, glycative stress has gained attention for its adverse impact on brain pathology. This is because glycative stress stimulates insoluble, proteinaceous aggregation that is linked to the malfunction of different neuropathological proteins. Despite the emergence of new literature suggesting that autophagy plays a major role in fighting glycation-derived damage by removing cytosolic AGEs, excessive glycative stress might also negatively impact autophagic function. In this mini-review, we provide insight on the status of present knowledge regarding the role of autophagy in brain physiology and pathophysiology, with an emphasis on the cytoprotective role of autophagic function to ameliorate the adverse effects of glycation-derived damage in neurons, glia, and neuron-glia interactions.

scholarly journals The transition in the etiologies of hepatocellular carcinoma-complicated liver cirrhosis in a nationwide survey of Japan

2020 ◽  
Author(s):  
Hirayuki Enomoto ◽  
◽  
Yoshiyuki Ueno ◽  
Yoichi Hiasa ◽  
Hiroki Nishikawa ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cirrhosis ◽  
Viral Hepatitis ◽  
Real Number ◽  
Nationwide Survey ◽  
Hcv Infection ◽  
Annual Number ◽  
The Real ◽  
Number Of Patients ◽  
Viral Etiologies

Abstract Background We recently reported the real-world changes in the etiologies of liver cirrhosis (LC) based on nationwide survey data and assessed the etiologies of LC with hepatocellular carcinoma (HCC). Methods Fifty-five participants from 68 institutions provided data on 23,637 patients with HCC-complicated LC. The changing trends in etiologies were assessed. We further analyzed the data from 29 hospitals that provided the annual number of newly identified HCC-complicated LC patients from 2008 to 2016 (N = 9362) without any missing years and assessed the transition in the real number of newly identified HCC-complicated LC cases. Results In the overall cohort, hepatitis C virus (HCV) infection (60.3%) and hepatitis B virus (HBV) infection (12.9%) were the leading and third-most common causes of HCC-complicated LC in Japan, respectively. HCV infection was found to be the leading cause throughout Japan. The rate of viral hepatitis-related HCC decreased from 85.3 to 64.4%. Among non-viral etiologies, notable increases were observed in nonalcoholic steatohepatitis (NASH)-related HCC (from 1.5 to 7.2%) and alcoholic liver disease (ALD)-related HCC (from 8.5 to 18.6%). Regarding the real number of newly diagnosed patients, the number of patients with viral hepatitis-related HCC decreased, while the number of patients with non-viral HCC, particularly NASH-related HCC, increased. Conclusions Viral hepatitis has remained the main cause of HCC in Japan. However, the decrease in viral hepatitis-related HCC, particularly HCV-related HCC highly contributed to the etiological changes. In addition, the increased incidence of non-viral HCC, particularly NASH-related HCC, was involved in the changing etiologies of HCC-complicated LC in Japan.

scholarly journals RNA Binding Protein HuR Promotes Autophagosome Formation by Regulating Expression of Autophagy-Related Proteins 5, 12, and 16 in Human Hepatocellular Carcinoma Cells

2019 ◽  
Vol 39 (6) ◽  
Author(s):  
Eunbyul Ji ◽  
Chongtae Kim ◽  
Hoin Kang ◽  
Sojin Ahn ◽  
Myeongwoo Jung ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Autophagic Flux ◽  
Autophagosome Formation ◽  
Cellular Autophagy ◽  
Related Proteins ◽  
Cellular Components ◽  
Hcc Cells

ABSTRACT Autophagy is a process of lysosomal self-degradation of cellular components by forming autophagosomes. Autophagosome formation is an essential process in autophagy and is fine-tuned by various autophagy-related gene (ATG) products, including ATG5, ATG12, and ATG16. Although several reports have shown that numerous factors affect multiple levels of gene regulation to orchestrate cellular autophagy, the detailed mechanism of autophagosome formation still needs further investigation. In this study, we demonstrate that the RNA binding protein HuR (human antigen R) performs an essential function in autophagosome formation. We observe that HuR silencing leads to inhibition of autophagosome formation and autophagic flux in liver cells. Ribonucleoprotein immunoprecipitation (RIP) assay allows the identification of ATG5, ATG12, and ATG16 mRNAs as the direct targets of HuR. We further show that HuR mediates the translation of ATG5, ATG12, and ATG16 mRNAs by binding to their 3′ untranslated regions (UTRs). In addition, we show that HuR expression positively correlates with the levels of ATG5 and ATG12 in hepatocellular carcinoma (HCC) cells. Collectively, our results suggest that HuR functions as a pivotal regulator of autophagosome formation by enhancing the translation of ATG5, ATG12, and ATG16 mRNAs and that augmented expression of HuR and ATGs may participate in the malfunction of autophagy in HCC cells.

scholarly journals The Role of Autophagy in Immunity and Autoimmune Diseases / Uloga Autofagije U Imunskom Odgovoru I Autoimunskim Bolestima

2014 ◽  
Vol 15 (4) ◽  
pp. 223-229
Author(s):  
Bojana Simovic Markovic ◽  
Ljubica Vucicevic ◽  
Sanja Bojic ◽  
Vladislav Volarevic
Keyword(s):  
Autoimmune Diseases ◽  
Potential Role ◽  
Current Knowledge ◽  
Inflammatory Diseases ◽  
Physiological Role ◽  
Immune Functions ◽  
Complex Relationships ◽  
Cellular Components ◽  
Chaperone Mediated Autophagy

ABSTRACT Autophagy is a catabolic mechanism in the cell that involves the degradation of unnecessary or dysfunctional cellular components by the lysosomal machinery. Recent studies have indicated that autophagy is a source of autoantigens, thus highlighting its potential role in the pathogenesis of autoimmunity. There are at least three different forms of autophagy: macroautophagy, microautophagy and chaperone-mediated autophagy (CMA). The physiological role of autophagy is to maintain cellular homeostasis by removing long-lived, damaged proteins and dysfunctional organelles and by providing energy. Aberrant autophagy may contribute to chronic inflammatory diseases and autoimmune diseases. An understanding of the complex relationships between autophagy and autophagy-related genes in each autoimmune disease creates the possibility of developing more specific and effective therapeutic strategies. Given the importance of autophagy in immune functions, this review article summarises current knowledge about the role of autophagy in the pathogenesis of autoimmune diseases.

scholarly journals Hepatitis C Virus Evasion from RIG-I-Dependent Hepatic Innate Immunity

2010 ◽  
Vol 2010 ◽  
pp. 1-8 ◽  
Author(s):  
Helene Minyi Liu ◽  
Michael Gale
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Intracellular Signaling ◽  
Innate Immune ◽  
Hcv Infection ◽  
Viral Pathogen ◽  
Infected Hepatocyte ◽  
Interferon Stimulated Genes ◽  
Hepatic Innate Immunity ◽  
Chronic Hcv

Exposure to hepatitis C virus (HCV) usually results in persistent infection that often develops into chronic liver disease. Interferon-alpha (IFN) treatment comprises the foundation of current approved therapy for chronic HCV infection but is limited in overall efficacy. IFN is a major effector of innate antiviral immunity and is naturally produced in response to viral infection when viral pathogen-associated molecular patterns (PAMPs) are recognized as nonself and are bound by cellular pathogen recognition receptors (PRRs), including Toll-like receptors (TLRs) and the RIG-I-like receptors (RLRs). Within hepatocytes, RIG-I is a major PRR of HCV infection wherein PAMP interactions serve to trigger intracellular signaling cascades in the infected hepatocyte to drive IFN production and the expression of interferon-stimulated genes (ISGs). ISGs function to limit virus replication, modulate the immune system, and to suppress virus spread. However, studies of HCV-host interactions have revealed several mechanisms of innate immune regulation and evasion that feature virus control of PRR signaling and regulation of hepatic innate immune programs that may provide a molecular basis for viral persistence.

scholarly journals Association of Toll-Like Receptor 3 Single-Nucleotide Polymorphisms and Hepatitis C Virus Infection

2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
Mashael R. Al-Anazi ◽  
Sabine Matou-Nasri ◽  
Ayman A. Abdo ◽  
Faisal M. Sanai ◽  
Saad Alkahtani ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Liver Disease ◽  
Hepatitis C ◽  
Hcv Infection ◽  
Nucleotide Polymorphisms ◽  
Toll Like Receptor ◽  
Single Nucleotide ◽  
Liver Disease Progression ◽  
Healthy Control ◽  
Arabian Population

Toll-like receptor 3 (TLR3) plays a key role in innate immunity by recognizing pathogenic, double-stranded RNAs. Thus, activation of TLR3 is a major factor in antiviral defense and tumor eradication. Although downregulation of TLR3 gene expression has been mainly reported in patients infected with hepatitis C virus (HCV), the influence of TLR3 genotype on the risk of HCV infection, HCV-related cirrhosis, and/or hepatocellular carcinoma (HCC) remains to be determined. Single-nucleotide polymorphisms (SNPs) within the TLR3 gene and their associations with HCV-related disease risk were investigated in a Saudi Arabian population in this study. Eight TLR3 SNPs were analyzed in 563 patients with HCV, which consisted of 437 patients with chronic HCV infections, 88 with HCV-induced liver cirrhosis, and 38 with HCC. A total of 599 healthy control subjects were recruited to the study. Among the eight TLR3 SNPs studied, the rs78726532 SNP was strongly associated with HCV infection when compared to that in healthy control subjects. The rs5743314 was also strongly associated with HCV-related liver disease progression (cirrhosis and HCC). In summary, these results indicate that distinct genetic variants of TLR3 SNPs are associated with HCV infection and HCV-mediated liver disease progression in the Saudi Arabian population.

scholarly journals Organ system view of the hepatic innate immunity in HCV infection

2016 ◽  
Vol 88 (12) ◽  
pp. 2025-2037 ◽  
Author(s):  
Bo-Ram Bang ◽  
Sandra Elmasry ◽  
Takeshi Saito
Keyword(s):  
Innate Immunity ◽  
Organ System ◽  
Hcv Infection ◽  
System View ◽  
Hepatic Innate Immunity

scholarly journals Autophagy - Adaptive Molecular Mechanisms in Condition of Starvation

2015 ◽  
Vol 52 (3) ◽  
pp. 71-73
Author(s):  
Agnieszka Pedrycz ◽  
Małgorzata Tomasiak ◽  
Beata Cichacz
Keyword(s):  
Cell Nucleus ◽  
Molecular Mechanisms ◽  
Cellular Stress ◽  
Chaperone Mediated Autophagy ◽  
Cellular Organelles

Abstract Autophagy is an extremely old process during which long-lived proteins and cellular organelles are removed by means of lysosomes. Autophagy may be caused by cellular stress mechanisms. Research has proven that autophagy plays a key role in obtaining nutrients and adapting to the conditions of starvation. Owing to this, it takes part in maintaining homeostasis in cytoplasm and cell nucleus. This objective may be achieved through a number of ways. Depending on the manner in which a substrate connects with the lysosome, we can talk about macroautophagy and microautophagy. Additionally, some authors also distinguish a chaperone-mediated autophagy. The article presented below describes molecular mechanisms of each type of autophagy and focuses particularly on macroautophagy, which is the best understood of all the autophagy types.

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