scholarly journals Impaired Retrograde Transport Due to Lack of TBC1D5 Contributes to the Trafficking Defect of Lysosomal Cathepsins in Ischemic/Hypoxic Cardiomyocytes

2021 ◽  
Vol 8 ◽  
Author(s):  
Lin Cui ◽  
Qiong Zhang ◽  
Yao Huang ◽  
Lei Yang ◽  
Junhui Zhang ◽  
...  
Keyword(s):  
Ischemic Injury ◽  
Retrograde Transport ◽  
Lysosomal Function ◽  
Lysosomal Dysfunction ◽  
Retromer Complex ◽  
Pathological Conditions ◽  
Protein Tag ◽  
Important Regulator ◽  
Shed Light

Lysosomal dysfunction has been found in many pathological conditions, and methods to improve lysosomal function have been reported to be protective against infarcted hearts. However, the mechanisms underlying lysosomal dysfunction caused by ischemic injury are far less well-established. The retromer complex is implicated in the trafficking of cation-independent mannose 6-phosphate receptor (CI-MPR), which is an important protein tag for the proper transport of lysosomal contents and therefore is important for the maintenance of lysosomal function. In this study, we found that the function of retrograde transport in cardiomyocytes was impaired with ischemia/hypoxia (I/H) treatment, which resulted in a decrease in CI-MPR and an abnormal distribution of lysosomal cathepsins. I/H treatment caused a reduction in TBC1D5 and a blockade of the Rab7 membrane cycle, which impeded retromer binding to microtubules and motor proteins, resulting in an impairment of retrograde transport and a decrease in CI-MPR. We also established that TBC1D5 was an important regulator of the distribution of lysosomal cathepsins. Our findings shed light on the regulatory role of retromer in ischemic injury and uncover the regulatory mechanism of TBC1D5 over retromer.

scholarly journals The Role of 5-Lipoxygenase and Leukotrienes in Shock and Ischemia-Reperfusion Injury

2007 ◽  
Vol 7 ◽  
pp. 56-74 ◽  
Author(s):  
Antonietta Rossi ◽  
Carlo Pergola ◽  
Salvatore Cuzzocrea ◽  
Lidia Sautebin
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Biological Activities ◽  
Ischemia Reperfusion ◽  
Targeted Disruption ◽  
Pathological Conditions ◽  
Metabolic Products ◽  
Important Regulator ◽  
Multicellular Organisms

The leukotrienes (LTs) are metabolic products of arachidonic acid via the 5-lipoxygenase (5-LO) pathway. The biological activities of LTs suggest that they are mediators of acute inflammatory and immediate hypersensitivity responses. In particular, the 5-LO activation has been proposed to be an important regulator for pathogenesis in multicellular organisms. The role of LTs in tissue damage, associated with septic and nonseptic shock and ischemia-reperfusion, has been extensively studied by the use of 5-LO inhibitors, receptor antagonists, and mice with a targeted disruption of the 5-LO gene (5-LOKO). In particular, several data indicate that LTs regulate neutrophil trafficking in damaged tissue in shock and ischemia-reperfusion, mainly through the modulation of adhesion molecule expression. This concept may provide new insights into the interpretation of the protective effect of 5-LO inhibition, which may be useful in the therapy of pathological conditions associated with septic and nonseptic shock and ischemia-reperfusion injury.

scholarly journals The long Non-coding RNA Orchestrator of Cancer Axis of Evil Insights into the Multiple Modes of Action of the H19 Gene

2021 ◽  
Vol 01 (1) ◽  
pp. 9-15
Author(s):  
Imad Matouk
Keyword(s):  
Mechanisms Of Action ◽  
Biological Processes ◽  
Rna Molecules ◽  
Pathological Conditions ◽  
Non Coding Rna ◽  
H19 Gene ◽  
Almost All ◽  
Long Non Coding Rna ◽  
Shed Light

Increasing evidence has indicated that the non-coding RNA molecules play central roles in almost all biological processes and many pathological conditions including carcinogenesis. This review focuses on the pathological tumorigenic role of the first discovered long non-coding RNA gene called H19 and its pivotal contribution to the cancer axis of evil. H19 RNA utilizes a variety of mechanisms to perform its pathological function. Some key unanswered questions are presented by the end. Understanding the H19 RNA mechanisms of action will shed light into the class of long non-coding RNA which contains thousands of members mostly with unknown function and will help in delineating the pathological role played by at least some of them.

Abstract 474: Atherosclerotic Macrophages Develop a Progressive Lysosomal Dysfunction that can be Rescued by Induction of a Lysosomal Biogenesis Program

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Roy Emanuel ◽  
Ismail Sergin ◽  
Babak Razani
Keyword(s):  
Atherosclerotic Plaque ◽  
Foam Cell ◽  
Oxidized Ldl ◽  
Membrane Integrity ◽  
Cell Formation ◽  
Foam Cell Formation ◽  
Lysosomal Function ◽  
Lysosomal Dysfunction ◽  
Lipid Species

Recent reports of the proatherogenic phenotype of mice with a macrophage-specific autophagy deficiency has renewed interest in the role of the autophagy-lysosomal system in atherosclerosis. Lysosomes have the unique role of serving to process both exogenous material including the excess of atherogenic lipids and endogenous cargo including dysfunctional proteins and organelles. Surprisingly, little is known about the effect of an atherogenic environment on macrophage lysosomes. To address this, we utilize a variety of complementary techniques to show that oxidized LDL and cholesterol crystals, two of the commonly encountered lipid species in the atherosclerotic plaque, create a profound lysosomal dysfunction in cultured peritoneal macrophages. Disruptions in lysosomal pH, enzyme activity, proteolytic capacity, membrane integrity, and morphology are readily seen when cells are incubated with such lipids. Using flow cytometry to isolate resident tissue macrophages, we show that atherosclerotic plaque macrophages show features of dysfunctional lysosomes, a process that appears to be progressive with advanced plaque formation. These observations lead us to investigate whether stimulation of lysosomal function can ameliorate some of these effects. TFEB is the only known transcription factor that acts as a master regulator of lysosomal biogenesis, although its role in macrophages has not been studied. We show that overexpression of TFEB in cultured macrophages initiates a robust prodegradative response including induction of lysosomal genes and the generation of nascent lysosomes. Interestingly, this response can rescue several deleterious effects seen with atherogenic lipid loading including reductions in the secretion of the proinflammatory cytokine IL-1β and reductions in foam cell formation. Taken together, these data demonstrate that lysosomal function is markedly impaired in atherosclerosis and suggest that induction of a lysosomal biogenesis program can have anti-atherogenic effects.

scholarly journals Rab7a and Mitophagosome Formation

Cells ◽  
2019 ◽  
Vol 8 (3) ◽  
pp. 224 ◽  
Author(s):  
Esther Tan ◽  
Bor Tang
Keyword(s):  
Retrograde Transport ◽  
Small Gtpase ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Autophagosome Formation ◽  
Guanine Nucleotide Exchange ◽  
Gtpase Activating Proteins ◽  
Retromer Complex ◽  
Nucleotide Exchange Factor

The small GTPase, Rab7a, and the regulators of its GDP/GTP-binding status were shown to have roles in both endocytic membrane traffic and autophagy. Classically known to regulate endosomal retrograde transport and late endosome-lysosome fusion, earlier work has indicated a role for Rab7a in autophagosome-lysosome fusion as well as autolysosome maturation. However, as suggested by recent findings on PTEN-induced kinase 1 (PINK1)-Parkin-mediated mitophagy, Rab7a and its regulators are critical for the correct targeting of Atg9a-bearing vesicles to effect autophagosome formation around damaged mitochondria. This mitophagosome formation role for Rab7a is dependent on an intact Rab cycling process mediated by the Rab7a-specific guanine nucleotide exchange factor (GEF) and GTPase activating proteins (GAPs). Rab7a activity in this regard is also dependent on the retromer complex, as well as phosphorylation by the TRAF family-associated NF-κB activator binding kinase 1 (TBK1). Here, we discuss these recent findings and broadened perspectives on the role of the Rab7a network in PINK1-Parkin mediated mitophagy.

scholarly journals The Ins and Outs of Cathepsins: Physiological Function and Role in Disease Management

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1679 ◽  
Author(s):  
Tulasi Yadati ◽  
Tom Houben ◽  
Albert Bitorina ◽  
Ronit Shiri-Sverdlov
Keyword(s):  
Vital Role ◽  
Intracellular Protein ◽  
Pathological Conditions ◽  
Wide Range ◽  
Intracellular Protein Degradation ◽  
Health And Disease ◽  
Lysosomal Proteases ◽  
Shed Light ◽  
Physiological Substrates

Cathepsins are the most abundant lysosomal proteases that are mainly found in acidicendo/lysosomal compartments where they play a vital role in intracellular protein degradation,energy metabolism, and immune responses among a host of other functions. The discovery thatcathepsins are secreted and remain functionally active outside of the lysosome has caused a paradigmshift. Contemporary research has unraveled many versatile functions of cathepsins in extralysosomallocations including cytosol and extracellular space. Nevertheless, extracellular cathepsins are majorlyupregulated in pathological states and are implicated in a wide range of diseases including cancerand cardiovascular diseases. Taking advantage of the dierential expression of the cathepsinsduring pathological conditions, much research is focused on using cathepsins as diagnostic markersand therapeutic targets. A tailored therapeutic approach using selective cathepsin inhibitors isconstantly emerging to be safe and ecient. Moreover, recent development of proteomic-basedapproaches for the identification of novel physiological substrates oers a major opportunity tounderstand the mechanism of cathepsin action. In this review, we summarize the available evidenceregarding the role of cathepsins in health and disease, discuss their potential as biomarkers ofdisease progression, and shed light on the potential of extracellular cathepsin inhibitors as safetherapeutic tools.

scholarly journals Over Fifty Years of Life, Death, and Cannibalism: A Historical Recollection of Apoptosis and Autophagy

2021 ◽  
Vol 22 (22) ◽  
pp. 12466
Author(s):  
Mahmoud Izadi ◽  
Tayyiba Akbar Ali ◽  
Ehsan Pourkarimi
Keyword(s):  
Human Health ◽  
Basic Research ◽  
Clinical Applications ◽  
Biomedical Sciences ◽  
The Past ◽  
Pathological Conditions ◽  
Apoptosis Pathways ◽  
History Of ◽  
Shed Light

Research in biomedical sciences has changed dramatically over the past fifty years. There is no doubt that the discovery of apoptosis and autophagy as two highly synchronized and regulated mechanisms in cellular homeostasis are among the most important discoveries in these decades. Along with the advancement in molecular biology, identifying the genetic players in apoptosis and autophagy has shed light on our understanding of their function in physiological and pathological conditions. In this review, we first describe the history of key discoveries in apoptosis with a molecular insight and continue with apoptosis pathways and their regulation. We touch upon the role of apoptosis in human health and its malfunction in several diseases. We discuss the path to the morphological and molecular discovery of autophagy. Moreover, we dive deep into the precise regulation of autophagy and recent findings from basic research to clinical applications of autophagy modulation in human health and illnesses and the available therapies for many diseases caused by impaired autophagy. We conclude with the exciting crosstalk between apoptosis and autophagy, from the early discoveries to recent findings.

The Role of Zinc in Thyroid Hormones Metabolism

2019 ◽  
Vol 89 (1-2) ◽  
pp. 80-88 ◽  
Author(s):  
Juliana Soares Severo ◽  
Jennifer Beatriz Silva Morais ◽  
Taynáh Emannuelle Coelho de Freitas ◽  
Ana Letícia Pereira Andrade ◽  
Mayara Monte Feitosa ◽  
...  
Keyword(s):  
Thyroid Hormones ◽  
Scientific Evidence ◽  
Thyroid Stimulating Hormone ◽  
Zinc Transporters ◽  
Serum Concentrations ◽  
Metabolic Adaptations ◽  
Serum T3 ◽  
Regulatory Effects ◽  
Shed Light

Abstract. Thyroid hormones play an important role in body homeostasis by facilitating metabolism of lipids and glucose, regulating metabolic adaptations, responding to changes in energy intake, and controlling thermogenesis. Proper metabolism and action of these hormones requires the participation of various nutrients. Among them is zinc, whose interaction with thyroid hormones is complex. It is known to regulate both the synthesis and mechanism of action of these hormones. In the present review, we aim to shed light on the regulatory effects of zinc on thyroid hormones. Scientific evidence shows that zinc plays a key role in the metabolism of thyroid hormones, specifically by regulating deiodinases enzymes activity, thyrotropin releasing hormone (TRH) and thyroid stimulating hormone (TSH) synthesis, as well as by modulating the structures of essential transcription factors involved in the synthesis of thyroid hormones. Serum concentrations of zinc also appear to influence the levels of serum T3, T4 and TSH. In addition, studies have shown that Zinc transporters (ZnTs) are present in the hypothalamus, pituitary and thyroid, but their functions remain unknown. Therefore, it is important to further investigate the roles of zinc in regulation of thyroid hormones metabolism, and their importance in the treatment of several diseases associated with thyroid gland dysfunction.

The Adult as Foe or Friend?: Childism in Guus Kuijer's Criticism and Fiction

2013 ◽  
Vol 6 (2) ◽  
pp. 205-217 ◽  
Author(s):  
Vanessa Joosen
Keyword(s):  
Children's Literature ◽  
Children’S Literature ◽  
Age Groups ◽  
Children's Books ◽  
Children’S Books ◽  
Memorial Award ◽  
Adult Reader ◽  
Shed Light ◽  
Selection Of

Compared to the attention that children's literature scholars have paid to the construction of childhood in children's literature and the role of adults as authors, mediators and readers of children's books, few researchers have made a systematic study of adults as characters in children's books. This article analyses the construction of adulthood in a selection of texts by the Dutch author and Astrid Lindgren Memorial Award winner Guus Kuijer and connects them with Elisabeth Young-Bruehl's recent concept of ‘childism’ – a form of prejudice targeted against children. Whereas Kuijer published a severe critique of adulthood in Het geminachte kind [The despised child] (1980), in his literary works he explores a variety of positions that adults can take towards children, with varying degrees of childist features. Such a systematic and comparative analysis of the way grown-ups are characterised in children's texts helps to shed light on a didactic potential that materialises in different adult subject positions. After all, not only literary and artistic aspects of children's literature may be aimed at the adult reader (as well as the child), but also the didactic aspect of children's books can cross over between different age groups.

Tax evasion in the medical profession An Empirical Study in the General Tax Authority in Iraq

2019 ◽  
Vol 118 (11) ◽  
pp. 80-88
Author(s):  
Ramyar Rzgar Ahmed ◽  
Hawkar Qasim Birdawod ◽  
S. Rabiyathul Basariya
Keyword(s):  
Tax Evasion ◽  
Income Tax ◽  
Medical Profession ◽  
Great Influence ◽  
Tax Law ◽  
Degree Of Confidence ◽  
Medical Professions ◽  
Shed Light

The study dealt with tax evasion in the medical profession, where the problem was the existence of many cases of tax evasion, especially tax evasion in the income tax of medical professions. The aim of the study is to try to shed light on the phenomenon of tax evasion and the role of the tax authority in the development of controls and means that reduce the phenomenon of tax evasion. The most important results of the low level of tax awareness and lack of knowledge of the tax law and the unwillingness to read it and the sense of taxpayers unfairness of the tax all lead to an increase in cases of tax evasion and in suggested tightening control and follow-up on the offices of auditors, through the investigation and auditing The reports of certified accountants and the use of computers for this purpose in order to raise the degree of confidence in these reports and bring them closer to the required truth and coordination and cooperation with the Union of Accountants and Auditors and inform them about each case of violations of the auditors and accountants N because of its great influence in the rejection of the organization of the accounts and not to ratify fake accounts lead to show taxpayers accounts on a non-truth in order to tax evasion.

Dietary Carotenoids in Managing Metabolic Syndrome and Role of PPARs in the Process

2020 ◽  
Vol 16 (6) ◽  
pp. 846-853
Author(s):  
Raghunandan Purohith ◽  
Nagendra P.M. Nagalingaswamy ◽  
Nanjunda S. Shivananju
Keyword(s):  
Metabolic Syndrome ◽  
Dietary Intervention ◽  
Bioactive Constituents ◽  
Dietary Antioxidants ◽  
Predisposing Factor ◽  
Beneficial Effects ◽  
Pathological Conditions ◽  
Established Relationship ◽  
Comprehensive Study

Metabolic syndrome is a collective term that denotes disorder in metabolism, symptoms of which include hyperglycemia, hyperlipidemia, hypertension, and endothelial dysfunction. Diet is a major predisposing factor in the development of metabolic syndrome, and dietary intervention is necessary for both prevention and management. The bioactive constituents of food play a key role in this process. Micronutrients such as vitamins, carotenoids, amino acids, flavonoids, minerals, and aromatic pigment molecules found in fruits, vegetables, spices, and condiments are known to have beneficial effects in preventing and managing metabolic syndrome. There exists a well-established relationship between oxidative stress and major pathological conditions such as inflammation, metabolic syndrome, and cancer. Consequently, dietary antioxidants are implicated in the remediation of these complications. The mechanism of action and targets of dietary antioxidants as well as their effects on related pathways are being extensively studied and elucidated in recent times. This review attempts a comprehensive study of the role of dietary carotenoids in alleviating metabolic syndromewith an emphasis on molecular mechanism-in the light of recent advances.

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