An overview of the α4β1 integrin and the potential therapeutic role of its antagonists

2021 ◽  
Vol 28 ◽  
Author(s):  
Elenilze F. B. Ferreira ◽  
Luciane B. Silva ◽  
Josiane V. Cruz ◽  
Pedro H. F. Araújo ◽  
Njogu M. Kimani ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Monoclonal Antibody ◽  
Extracellular Matrix ◽  
Inflammatory Responses ◽  
Cellular Responses ◽  
Tumour Invasion ◽  
Potential Therapeutic Role ◽  
Integrin Antagonists ◽  
Inside Out

: This article presents a simplified view of integrins with emphasis on the α4 (α4β1/VLA-4) integrin. Integrins are heterodimeric proteins expressed on the cell surface of leukocytes that participate in a wide variety of functions, such as survival, growth, differentiation, migration, inflammatory responses, tumour invasion, among others. When the extracellular matrix is degraded or deformed, cells are forced to undergo responsive changes that influence remodelling during physiological and pathological events. Integrins recognize these changes and trigger a series of cellular responses, forming a physical connection between the interior and the outside of the cell. The communication of integrins through the plasma membrane occurs in both directions, from the extracellular to the intracellular (outside-in) and from the intracellular to the extracellular (inside-out). Integrins are valid targets for antibodies and small molecule antagonists. One example is the monoclonal antibody natalizumab, marketed under the name of TYSABRI®, used in the treatment of recurrent multiple sclerosis, which inhibits the adhesion of α4 integrin to its counter-receptor. α4β1 Integrin antagonists are summarized here and their utility as therapeutics discussed.

Natalizumab for the treatment of highly active MS: risks and benefits

2019 ◽  
Vol 1 (8) ◽  
pp. 382-387
Author(s):  
Nicola Daykin
Keyword(s):  
Multiple Sclerosis ◽  
Monoclonal Antibody ◽  
Patient Safety ◽  
Gold Standard ◽  
Risk Profile ◽  
Risks And Benefits ◽  
Highly Active ◽  
History Of ◽  
The Uk

This article discusses the history of natalizumab (Tysabri), the first monoclonal antibody used to treat multiple sclerosis. It reviews how the drug's difficult beginnings and controversial past has changed the treatment is monitored treatment. The article looks at the role of clinicians in maintaining patient safety, the benefits and risk profile of this treatment, and ways of optimising practice to provide gold standard nationalised natalizumab services throughout the UK.

Role of endotoxin in intestinal reperfusion-induced expression of E-selectin

1999 ◽  
Vol 276 (2) ◽  
pp. G479-G484 ◽  
Author(s):  
Philippe Bauer ◽  
Janice M. Russell ◽  
D. Neil Granger
Keyword(s):  
Monoclonal Antibody ◽  
Cell Adhesion Molecule ◽  
Inflammatory Responses ◽  
Enteric Bacteria ◽  
Ischemia And Reperfusion ◽  
Induced Expression ◽  
Antibody Technique ◽  
Dose Dependent ◽  
Endothelial Cell Adhesion

Products of enteric bacteria, including endotoxin [lipopolysaccharide (LPS)], have been implicated in the acute inflammatory responses elicited by ischemia and reperfusion (I/R) of the small intestine. The objective of this study was to assess the contribution of LPS to the increased E-selectin expression observed in the intestinal vasculature after I/R. The dual radiolabeled monoclonal antibody technique was used in LPS-sensitive (C3HeB/FeJ) and LPS-insensitive (C3H/HeJ) mice that were exposed to either exogenous LPS or to gut I/R (45 min ischemia, 5 h reperfusion). LPS elicited a dose-dependent (0.5–50 μg LPS/animal) increase in E-selectin expression (at 3 h) in LPS-sensitive mice, whereas LPS-insensitive mice were largely unresponsive. E-selectin expression was increased fivefold by I/R in the small bowel of both LPS-sensitive and -insensitive mice. These results indicate that, although exogenous LPS is capable of eliciting profound dose-dependent increases in E-selectin expression, endogenous LPS does not contribute significantly to I/R-induced expression of this endothelial cell adhesion molecule.

scholarly journals Nanostructures Control the Hepatocellular Responses to a Cytotoxic Agent “Cisplatin”

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Shimaa A. Abdellatef ◽  
Riho Tange ◽  
Takeshi Sato ◽  
Akihiko Ohi ◽  
Toshihide Nabatame ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Chemotherapeutic Agent ◽  
Chromatin Condensation ◽  
Cellular Responses ◽  
Flat Surfaces ◽  
Flat Substrate ◽  
Cells Cultured

In drug discovery programs, the alteration betweenin vivoandin vitrocellular responses to drug represents one of the main challenges. Since the variation in the native extracellular matrix (ECM) betweenin vivoand 2Din vitroconditions is one of the key reasons for such discrepancies, thus the utilization of substrate that likely mimics ECM characteristics (topography, stiffness, and chemical composition) is needed to overcome such problem. Here, we investigated the role of substrate nanotopography as one of the major determinants of hepatic cellular responses to a chemotherapeutic agent “cisplatin.” We studied the substratum induced variations in cisplatin cytotoxicity; a higher cytotoxic response to cisplatin was observed for cells cultured on the nanopattern relative to a flat substrate. Moreover, the nanofeatures with grating shapes that mimic the topography of major ECM protein constituents (collagen) induced alterations in the cellular orientation and chromatin condensation compared to flat surfaces. Accordingly, the developments of biomimetic substrates with a particular topography could have potentials in drug development analyses to reflect more physiological mimicry conditionsin vitro.

An Update on Monoclonal Antibody Therapies in Multiple Sclerosis

2007 ◽  
Vol 20 (2) ◽  
pp. 167-180 ◽  
Author(s):  
Bilal A. Choudry ◽  
Jane W. Chan
Keyword(s):  
Multiple Sclerosis ◽  
Monoclonal Antibody ◽  
Complex Disease ◽  
Adult Population ◽  
Interferon Β ◽  
Immunomodulatory Agents ◽  
Inflammatory Reactions ◽  
Life Threatening ◽  
Young Adult Population

Multiple sclerosis (MS) is a complex disease that causes a great deal of disability, especially in the young adult population. There have been several immunomodulatory agents that have been approved by the Food and Drug Administration for MS, including glatiramer acetate, interferon-β 1a and -β 1b, mitoxantrone, and corticosteroids. The effectiveness of these therapies has not been optimal, and drugs, such as monoclonal antibodies, that more selectively target the pathogenetic process of MS have been sought. These agents have their own intrinsic limitations such as systemic inflammatory reactions, induction of neutralizing antiantibodies, and even life-threatening infectious processes. The agent that has been in the forefront of the discussion is natalizumab, a monoclonal antibody (mAb) against α 4 integrin, which shows much promise in suppressing MS activity. However, 3 individuals treated with natalizumab developed a life-threatening infection, progressive multifocal leukoencephalopathy. This article reviews the role of mAbs in the treatment of MS, particularly their advantages over other drugs and their limitations, which have to be overcome for these agents to be at the forefront in the treatment of MS.

scholarly journals Role of Monoclonal Antibody "Alemtuzumab" in the Treatment of Multiple Sclerosis

Cureus ◽  
2021 ◽  
Author(s):  
Sadia Nosher ◽  
Sehrish Fuad ◽  
Nupur Mishra ◽  
Zaid A Alrashid ◽  
Bindu Rathod ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Monoclonal Antibody

scholarly journals MicroRNAs and Multiple Sclerosis

2011 ◽  
Vol 2011 ◽  
pp. 1-27 ◽  
Author(s):  
Kemal Ugur Tufekci ◽  
Meryem Gulfem Oner ◽  
Sermin Genc ◽  
Kursad Genc
Keyword(s):  
Multiple Sclerosis ◽  
Immune Responses ◽  
Inflammatory Responses ◽  
Current Knowledge ◽  
Expression Patterns ◽  
Mirna Biogenesis ◽  
Disease Marker ◽  
Organ Specific ◽  
And Function

MicroRNAs (miRNAs) have recently emerged as a new class of modulators of gene expression. miRNAs control protein synthesis by targeting mRNAs for translational repression or degradation at the posttranscriptional level. These noncoding RNAs are endogenous, single-stranded molecules approximately 22 nucleotides in length and have roles in multiple facets of immunity, from regulation of development of key cellular players to activation and function in immune responses. Recent studies have shown that dysregulation of miRNAs involved in immune responses leads to autoimmunity. Multiple sclerosis (MS) serves as an example of a chronic and organ-specific autoimmune disease in which miRNAs modulate immune responses in the peripheral immune compartment and the neuroinflammatory process in the brain. For MS, miRNAs have the potential to serve as modifying drugs. In this review, we summarize current knowledge of miRNA biogenesis and mode of action and the diverse roles of miRNAs in modulating the immune and inflammatory responses. We also review the role of miRNAs in autoimmunity, focusing on emerging data regarding miRNA expression patterns in MS. Finally, we discuss the potential of miRNAs as a disease marker and a novel therapeutic target in MS. Better understanding of the role of miRNAs in MS will improve our knowledge of the pathogenesis of this disease.

The Potential Therapeutic Role of the HMGB1-TLR Pathway in Epilepsy

2020 ◽  
Vol 21 ◽  
Author(s):  
Shu Wang ◽  
Yuguang Guan ◽  
Tianfu Li
Keyword(s):  
Neurological Disorders ◽  
Clinical Evidence ◽  
Inflammatory Responses ◽  
High Mobility ◽  
Toll Like Receptor ◽  
Treatment Of Epilepsy ◽  
Important Target ◽  
Potential Therapeutic Role ◽  
Neuro Inflammation

: Epilepsy is one of the most common serious neurological disorders, affecting over 70 million people world-wide. For treatment of epilepsy, antiepileptic drugs (AEDs) and surgeries are widely used. However, drug resistance and adverse effects indicate the need to develop targeted AEDs based on further exploration of the epileptogenic mechanism. Currently, many efforts have been made elucidate to the neuro inflammation theory in epileptogenesis, which may show potentialin treatment of epilepsy. In this respect, an important target protein, high mobility group box 1 (HMGB1), has received increased attention and has been developed rapidly. HMGB1 is expressed in various eukaryotic cells and localized in the cell nucleus. When HMGB1is released by injuries or diseases, it participates in inflammation. Recent studies suggest that HMGB1 via Toll-like receptor (TLR) pathways can trigger inflammatory responses and play an important role in epilepsy. In addition, studies of HMGB1 have shown its potential in treatment of epilepsy.Herein, the authors analyzedthe experimental and clinical evidence of the HMGB1-TLR pathway in epilepsy to summarize the theory of epileptogenesis and provideinsights into antiepileptic therapy in this novel field.

A Systematic Review on the Role of Arachidonic Acid Pathway in Multiple Sclerosis

2020 ◽  
Vol 19 ◽  
Author(s):  
Malvina Hoxha ◽  
Erila Spahiu ◽  
Emanuela Prendi ◽  
Bruno Zappacosta
Keyword(s):  
Multiple Sclerosis ◽  
Systematic Review ◽  
Arachidonic Acid ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Lox Inhibitors ◽  
Acid Pathway ◽  
Arachidonic Acid Pathway

Background & Objective: Multiple sclerosis (MS) is an inflammatory neurodegenerative disease characterized by destruction of oligodendrocytes, immune cell infiltration and demyelination. Inflammation plays a significant role in MS, and the inflammatory mediators such as eicosanoids, leukotrienes, superoxide radicals are involved in pro-inflammatory responses in MS. In this systematic review we tried to define and discuss all the findings of in vivo animal studies and human clinical trials on the potential association between arachidonic acid (AA) pathway and multiple sclerosis. Methods: A systematic literature search across Pubmed, Scopus, Embase and Cochrane database was conducted. This systematic review was performed according to PRISMA guidelines. Results: A total of 146 studies were included, of which 34 were conducted in animals, 58 in humans, and 60 studies reported the role of different compounds that target AA mediators or their corresponding enzymes/ receptors, and can have a therapeutic effect in MS. These results suggest that eicosanoids have significant roles in experimental autoimmune encephalomyelitis (EAE) and MS. The data from animal and human studies elucidated that PGI2, PGF2α, PGD2, isoprostanes, PGE2, PLA2, LTs are increased in MS. PLA2 inhibition modulates the progression of the disease. PGE1 analogues can be a useful option in the treatment of MS. Conclusions: All studies reported the beneficial effects of COX and LOX inhibitors in MS. The hybrid compounds, such as COX-2 inhibitors/TP antagonists and 5-LOX inhibitors can be an innovative approach for multiple sclerosis treatment. Future work in MS should shed light in synthesizing new compounds targeting arachidonic acid pathway.

scholarly journals Role of Toll-Like Receptors in Neuroimmune Diseases: Therapeutic Targets and Problems

2021 ◽  
Vol 12 ◽  
Author(s):  
Haixia Li ◽  
Shan Liu ◽  
Jinming Han ◽  
Shengxian Li ◽  
Xiaoyan Gao ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Immune Responses ◽  
Inflammatory Responses ◽  
Inflammatory Factors ◽  
Neuromyelitis Optica Spectrum Disorder ◽  
Toll Like Receptors ◽  
Adaptive Immune Responses ◽  
Adaptive Immune ◽  
Partial Activation

Toll-like receptors (TLRs) are a class of proteins playing a key role in innate and adaptive immune responses. TLRs are involved in the development and progression of neuroimmune diseases via initiating inflammatory responses. Thus, targeting TLRs signaling pathway may be considered as a potential therapy for neuroimmune diseases. However, the role of TLRs is elusive and complex in neuroimmune diseases. In addition to the inadequate immune response of TLRs inhibitors in the experiments, the recent studies also demonstrated that partial activation of TLRs is conducive to the production of anti-inflammatory factors and nervous system repair. Exploring the mechanism of TLRs in neuroimmune diseases and combining with developing the emerging drug may conquer neuroimmune diseases in the future. Herein, we provide an overview of the role of TLRs in several neuroimmune diseases, including multiple sclerosis, neuromyelitis optica spectrum disorder, Guillain-Barré syndrome and myasthenia gravis. Emerging difficulties and potential solutions in clinical application of TLRs inhibitors will also be discussed.

scholarly journals An “Outside-In” and “Inside-Out” Consideration of Complement in the Multiple Sclerosis Brain: Lessons From Development and Neurodegenerative Diseases

2021 ◽  
Vol 14 ◽  
Author(s):  
B. Paul Morgan ◽  
Jennifer L. Gommerman ◽  
Valeria Ramaglia
Keyword(s):  
Multiple Sclerosis ◽  
Complement System ◽  
Traumatic Injury ◽  
Complement Components ◽  
Synaptic Circuits ◽  
New Findings ◽  
The Central Nervous System ◽  
The Complement System ◽  
Inside Out

The last 15 years have seen an explosion of new findings on the role of complement, a major arm of the immune system, in the central nervous system (CNS) compartment including contributions to cell migration, elimination of synapse during development, aberrant synapse pruning in neurologic disorders, damage to nerve cells in autoimmune diseases, and traumatic injury. Activation of the complement system in multiple sclerosis (MS) is typically thought to occur as part of a primary (auto)immune response from the periphery (the outside) against CNS antigens (the inside). However, evidence of local complement production from CNS-resident cells, intracellular complement functions, and the more recently discovered role of early complement components in shaping synaptic circuits in the absence of inflammation opens up the possibility that complement-related sequelae may start and finish within the brain itself. In this review, the complement system will be introduced, followed by evidence that implicates complement in shaping the developing, adult, and normal aging CNS as well as its contribution to pathology in neurodegenerative conditions. Discussion of data supporting “outside-in” vs. “inside-out” roles of complement in MS will be presented, concluded by thoughts on potential approaches to therapies targeting specific elements of the complement system.

Sign in / Sign up

Export Citation Format

Share Document