scholarly journals Biochemistry, Pathophysiology, and Regulation of Linear Ubiquitination: Intricate Regulation by Coordinated Functions of the Associated Ligase and Deubiquitinase

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2706
Author(s):  
Yasuhiro Fuseya ◽  
Kazuhiro Iwai
Keyword(s):  
Inflammatory Responses ◽  
Current Status ◽  
Deubiquitinating Enzymes ◽  
Therapeutic Approaches ◽  
Catalytic Center ◽  
Ubiquitin System ◽  
Linear Chains ◽  
Ubiquitin Ligase Complex ◽  
Protein Functions ◽  
Chain Type

The ubiquitin system modulates protein functions by decorating target proteins with ubiquitin chains in most cases. Several types of ubiquitin chains exist, and chain type determines the mode of regulation of conjugated proteins. LUBAC is a ubiquitin ligase complex that specifically generates N-terminally Met1-linked linear ubiquitin chains. Although linear ubiquitin chains are much less abundant than other types of ubiquitin chains, they play pivotal roles in cell survival, proliferation, the immune response, and elimination of bacteria by selective autophagy. Because linear ubiquitin chains regulate inflammatory responses by controlling the proinflammatory transcription factor NF-κB and programmed cell death (including apoptosis and necroptosis), abnormal generation of linear chains can result in pathogenesis. LUBAC consists of HOIP, HOIL-1L, and SHARPIN; HOIP is the catalytic center for linear ubiquitination. LUBAC is unique in that it contains two different ubiquitin ligases, HOIP and HOIL-1L, in the same ligase complex. Furthermore, LUBAC constitutively interacts with the deubiquitinating enzymes (DUBs) OTULIN and CYLD, which cleave linear ubiquitin chains generated by LUBAC. In this review, we summarize the current status of linear ubiquitination research, and we discuss the intricate regulation of LUBAC-mediated linear ubiquitination by coordinate function of the HOIP and HOIL-1L ligases and OTULIN. Furthermore, we discuss therapeutic approaches to targeting LUBAC-mediated linear ubiquitin chains.

scholarly journals Small molecules that target the ubiquitin system

2020 ◽  
Vol 48 (2) ◽  
pp. 479-497 ◽  
Author(s):  
Hai Qiu Wu ◽  
David Baker ◽  
Huib Ovaa
Keyword(s):  
Infectious Diseases ◽  
Neurodegenerative Diseases ◽  
Small Molecules ◽  
Small Molecule ◽  
Normal Operation ◽  
Current Status ◽  
Therapeutic Approaches ◽  
Ubiquitin System ◽  
The Individual ◽  
Novel Therapeutic

Eukaryotic life depends upon the interplay between vast networks of signaling pathways composed of upwards of 109–1010 proteins per cell. The integrity and normal operation of the cell requires that these proteins act in a precise spatial and temporal manner. The ubiquitin system is absolutely central to this process and perturbation of its function contributes directly to the onset and progression of a wide variety of diseases, including cancer, metabolic syndromes, neurodegenerative diseases, autoimmunity, inflammatory disorders, infectious diseases, and muscle dystrophies. Whilst the individual components and the overall architecture of the ubiquitin system have been delineated in some detail, how ubiquitination might be successfully targeted, or harnessed, to develop novel therapeutic approaches to the treatment of disease, currently remains relatively poorly understood. In this review, we will provide an overview of the current status of selected small molecule ubiquitin system inhibitors. We will further discuss the unique challenges of targeting this ubiquitous and highly complex machinery, and explore and highlight potential ways in which these challenges might be met.

Oxidative Stress and Atherosclerosis: Its Relationship to Growth Factors, Thrombus Formation and Therapeutic Approaches

1999 ◽  
Vol 82 (S 01) ◽  
pp. 32-37 ◽  
Author(s):  
Karlheinz Peter ◽  
Wolfgang Kübler ◽  
Johannes Ruef ◽  
Thomas K. Nordt ◽  
Marschall S. Runge ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Growth Factors ◽  
Vessel Wall ◽  
Inflammatory Responses ◽  
Plaque Rupture ◽  
Thrombus Formation ◽  
Vascular Lesion ◽  
Coagulation System ◽  
Therapeutic Approaches ◽  
Causative Relationship

SummaryThe initiating event of atherogenesis is thought to be an injury to the vessel wall resulting in endothelial dysfunction. This is followed by key features of atherosclerotic plaque formation such as inflammatory responses, cell proliferation and remodeling of the vasculature, finally leading to vascular lesion formation, plaque rupture, thrombosis and tissue infarction. A causative relationship exists between these events and oxidative stress in the vessel wall. Besides leukocytes, vascular cells are a potent source of oxygen-derived free radicals. Oxidants exert mitogenic effects that are partially mediated through generation of growth factors. Mitogens, on the other hand, are potent stimulators of oxidant generation, indicating a putative self-perpetuating mechanism of atherogenesis. Oxidants influence the balance of the coagulation system towards platelet aggregation and thrombus formation. Therapeutic approaches by means of antioxidants are promising in both experimental and clinical designs. However, additional clinical trials are necessary to assess the role of antioxidants in cardiovascular disease.

scholarly journals Current status of therapeutic approaches and vaccines for SARS-CoV-2

2021 ◽  
Author(s):  
Braira Wahid ◽  
Anam Amir ◽  
Ayesha Ameen ◽  
Muhammad Idrees
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Review Article ◽  
Experimental Designs ◽  
Current Status ◽  
Therapeutic Approaches ◽  
Efficacious Treatment ◽  
Rapid Pace ◽  
Global Health Challenge

SARS-CoV-2, declared a pandemic in March 2020, is the current global health challenge. The global bioburden of this virus is increasing at a rapid pace. Many antiviral drugs and vaccines have been registered for clinical trials because of their inhibitory activity observed in vitro. Currently, five types of vaccines have successfully passed Phase IV clinical trial and are being administered in populations worldwide. A plethora of experimental designs have been proposed worldwide in order to find a safe and efficacious treatment option. Therefore, it is necessary to provide baseline data and information to clinicians and researchers so that they can review the current status of therapeutics and efficacy of already developed vaccines. This review article summarizes all therapeutic options that may help to combat SARS-CoV-2.

Novel Therapeutic Approaches in Sickle Cell Disease

Hematology ◽  
2002 ◽  
Vol 2002 (1) ◽  
pp. 10-34 ◽  
Author(s):  
Mark C. Walters ◽  
Arthur W. Nienhuis ◽  
Elliott Vichinsky
Keyword(s):  
Sickle Cell Disease ◽  
Clinical Application ◽  
Sickle Cell ◽  
Hematopoietic Cell Transplantation ◽  
Pulmonary Complications ◽  
Current Status ◽  
Pulmonary Injury ◽  
Cell Disease ◽  
Therapeutic Approaches ◽  
Novel Treatment

Abstract In this update, selected clinical features of sickle cell disease and their management are reviewed. In addition, the current status of interventions that have curative potential for sickle cell disease is discussed, with particular attention focused on indications, methodology, recent results, and challenges to wider clinical application. In Section I, Dr. Nienhuis describes recent improvements in vector technology, safety, and replacement gene expression that are creating the potential for clinical application of this technology. In Section II, Dr. Vichinsky reviews our current understanding of the pathophysiology and treatment of pulmonary injury in sickle cell disease. The acute and chronic pulmonary complications of sickle cell disease, modulators and predictors of severity, and conventional and novel treatment of these complications are discussed. In Section III, Dr. Walters reviews the current status of hematopoietic cell transplantation for sickle cell disease. Newer efforts to expand its availability by identifying alternate sources of stem cells and by reducing the toxicity of transplantation are discussed.

scholarly journals Gene Therapy for Pancreatic Diseases: Current Status

2018 ◽  
Vol 19 (11) ◽  
pp. 3415 ◽  
Author(s):  
Kenya Kamimura ◽  
Takeshi Yokoo ◽  
Shuji Terai
Keyword(s):  
Pancreatic Cancer ◽  
The Body ◽  
Therapeutic Options ◽  
Current Status ◽  
Endocrine Tumors ◽  
Therapeutic Approaches ◽  
Islet Cell Tumors ◽  
Pancreatic Diseases ◽  
Gene Therapies ◽  
New Strategies

The pancreas is a key organ involved in digestion and endocrine functions in the body. The major diseases of the pancreas include pancreatitis, pancreatic cancer, cystic diseases, pancreatic divisum, islet cell tumors, endocrine tumors, diabetes mellitus, and pancreatic pain induced by these diseases. While various therapeutic methodologies have been established to date, however, the improvement of conventional treatments and establishment of novel therapies are essential to improve the efficacy. For example, conventional therapeutic options, including chemotherapy, are not effective against pancreatic cancer, and despite improvements in the last decade, the mortality rate has not declined and is estimated to become the second cause of cancer-related deaths by 2030. Therefore, continuous efforts focus on the development of novel therapeutic options. In this review, we will summarize the progress toward the development of gene therapies for pancreatic diseases, with an emphasis on recent preclinical studies and clinical trials. We aim to identify new areas for improvement of the current methodologies and new strategies that will lead to safe and effective gene therapeutic approaches in pancreatic diseases.

scholarly journals Targeting STAT3 in Cancer Immunotherapy

2020 ◽  
Vol 19 (1) ◽  
Author(s):  
Sailan Zou ◽  
Qiyu Tong ◽  
Bowen Liu ◽  
Wei Huang ◽  
Yan Tian ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Therapeutic Strategy ◽  
Current Status ◽  
Therapeutic Approaches ◽  
Oncogenic Signaling ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
Oncogenic Signaling Pathways ◽  
Transcription 3 ◽  
Cancerous Cells

Abstract As a point of convergence for numerous oncogenic signaling pathways, signal transducer and activator of transcription 3 (STAT3) is central in regulating the anti-tumor immune response. STAT3 is broadly hyperactivated both in cancer and non-cancerous cells within the tumor ecosystem and plays important roles in inhibiting the expression of crucial immune activation regulators and promoting the production of immunosuppressive factors. Therefore, targeting the STAT3 signaling pathway has emerged as a promising therapeutic strategy for numerous cancers. In this review, we outline the importance of STAT3 signaling pathway in tumorigenesis and its immune regulation, and highlight the current status for the development of STAT3-targeting therapeutic approaches. We also summarize and discuss recent advances in STAT3-based combination immunotherapy in detail. These endeavors provide new insights into the translational application of STAT3 in cancer and may contribute to the promotion of more effective treatments toward malignancies.

scholarly journals Targeting the Ubiquitin System in Glioblastoma

2020 ◽  
Vol 10 ◽  
Author(s):  
Nico Scholz ◽  
Kathreena M. Kurian ◽  
Florian A. Siebzehnrubl ◽  
Julien D. F. Licchesi
Keyword(s):  
Drug Targets ◽  
Ubiquitin Ligases ◽  
Ubiquitin Proteasome System ◽  
Primary Brain Tumor ◽  
E3 Ubiquitin Ligases ◽  
Deubiquitinating Enzymes ◽  
Comprehensive Overview ◽  
Ubiquitin System ◽  
Novel Therapeutic Strategies ◽  
Promising Source

Glioblastoma is the most common primary brain tumor in adults with poor overall outcome and 5-year survival of less than 5%. Treatment has not changed much in the last decade or so, with surgical resection and radio/chemotherapy being the main options. Glioblastoma is highly heterogeneous and frequently becomes treatment-resistant due to the ability of glioblastoma cells to adopt stem cell states facilitating tumor recurrence. Therefore, there is an urgent need for novel therapeutic strategies. The ubiquitin system, in particular E3 ubiquitin ligases and deubiquitinating enzymes, have emerged as a promising source of novel drug targets. In addition to conventional small molecule drug discovery approaches aimed at modulating enzyme activity, several new and exciting strategies are also being explored. Among these, PROteolysis TArgeting Chimeras (PROTACs) aim to harness the endogenous protein turnover machinery to direct therapeutically relevant targets, including previously considered “undruggable” ones, for proteasomal degradation. PROTAC and other strategies targeting the ubiquitin proteasome system offer new therapeutic avenues which will expand the drug development toolboxes for glioblastoma. This review will provide a comprehensive overview of E3 ubiquitin ligases and deubiquitinating enzymes in the context of glioblastoma and their involvement in core signaling pathways including EGFR, TGF-β, p53 and stemness-related pathways. Finally, we offer new insights into how these ubiquitin-dependent mechanisms could be exploited therapeutically for glioblastoma.

scholarly journals MMP-2: is too low as bad as too high in the cardiovascular system?

2018 ◽  
Vol 315 (5) ◽  
pp. H1332-H1340 ◽  
Author(s):  
Eugenio Hardy ◽  
Anette Hardy-Sosa ◽  
Carlos Fernandez-Patron
Keyword(s):  
Inflammatory Responses ◽  
Gene Mutations ◽  
Hypertensive Heart Disease ◽  
Tissue Remodeling ◽  
Therapeutic Effects ◽  
Therapeutic Approaches ◽  
Target Organs ◽  
Extracellular Matrix Components ◽  
Cardiovascular Pathologies ◽  
Matrix Components

Matrix metalloproteinase (MMP)-2 cleaves a broad spectrum of substrates, including extracellular matrix components (responsible for normal tissue remodeling) and cytokines (modulators of the inflammatory response to physiological insults such as tissue damage). MMP-2 expression is elevated in many cardiovascular pathologies (e.g., myocardial infarction, hypertensive heart disease) where tissue remodeling and inflammatory responses are perturbed. Thus, it has generally been assumed that blockade of MMP-2 activity will yield therapeutic effects. Here, we provide a counterargument to this dogma based on 1) preclinical studies on Mmp2-null ( Mmp2−/−) mice and 2) clinical studies on patients with inactivating MMP2 gene mutations. Furthermore, we put forward the hypothesis that, when MMP-2 activity falls below baseline, the bioavailability of proinflammatory cytokines normally cleaved and inactivated by MMP-2 increases, leading to the production of cytokines and cardiac secretion of phospholipase A2activity into the circulation, which stimulate systemic inflammation that perturbs lipid metabolism in target organs. Finally, we suggest that insufficient understanding of the consequences of MMP-2 deficiency remains a major factor in the failure of MMP-2 inhibitor-based therapeutic approaches. This paucity of knowledge precludes our ability to effectively intervene in cardiovascular and noncardiovascular pathologies at the level of MMP-2.

scholarly journals Modern Concepts in Regenerative Therapy for Ischemic Stroke: From Stem Cells for Promoting Angiogenesis to 3D-Bioprinted Scaffolds Customized via Carotid Shear Stress Analysis

2019 ◽  
Vol 20 (10) ◽  
pp. 2574 ◽  
Author(s):  
Annabella Benedek ◽  
Daniel Cernica ◽  
Andras Mester ◽  
Diana Opincariu ◽  
Roxana Hodas ◽  
...  
Keyword(s):  
Stem Cells ◽  
Shear Stress ◽  
Ischemic Stroke ◽  
Therapeutic Angiogenesis ◽  
Current Status ◽  
Regenerative Therapy ◽  
Therapeutic Approaches ◽  
Ischemic Brain ◽  
Promising Tool ◽  
3D Geometry

Ischemic stroke is associated with a tremendous economic and societal burden, and only a few therapies are currently available for the treatment of this devastating disease. The main therapeutic approaches used nowadays for the treatment of ischemic brain injury aim to achieve reperfusion, neuroprotection and neurorecovery. Therapeutic angiogenesis also seems to represent a promising tool to improve the prognosis of cerebral ischemia. This review aims to present the modern concepts and the current status of regenerative therapy for ischemic stroke and discuss the main results of major clinical trials addressing the effectiveness of stem cell therapy for achieving neuroregeneration in ischemic stroke. At the same time, as a glimpse into the future, this article describes modern concepts for stroke prevention, such as the implantation of bioprinted scaffolds seeded with stem cells, whose 3D geometry is customized according to carotid shear stress.

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