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Biomolecules
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Novel Biomolecules in Neuro-ThromboInflammation
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Novel Biomolecules in Neuro-ThromboInflammation

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Medicine".

Deadline for manuscript submissions: closed (31 May 2021) | Viewed by 21005

Special Issue Editors

Dr. Nicola Maggio

E-Mail Website
Guest Editor
Department of Neurology and Neurosurgery, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
Interests: hippocampus; LTP; synaptic plasticity; memory; stress; behavior
Dr. Efrat Shavit-Stein

E-Mail Website
Guest Editor
Sackler Faculty of Medicine, Tel Aviv University, Ramal Aviv, Israel
Interests: thrombin; coagulation proteins; PAR; inflammation; peripheral nerve function; diabetic peripheral neuropathy; brain trauma; behavior; biochemistry

Special Issue Information

Dear Colleagues,

This Special Issue will focus on neuro-thromboinflammation. Coagulation factors such as thrombin, FXa, and APC, their receptors such as PARs and EPCR, and the inhibitors and inflammatory mediators that affect them are intensively studied in systemic circulation. In recent years, their effects on CNS and PNS function have been getting more and more attention. Their involvement in many physiological and pathophysiological processes has been demonstrated, such as in learning and memory formation, neuro–glia interaction, nerve conduction, myelination, cytotoxicity and cytoprotection, inflammatory diseases, and many other neurological diseases (epilepsy, head trauma, neoplasm, ischemic stroke, etc.). Their tight association with the inflammatory response in the context of CNS and PNS pathologies makes them an important target for pharmacological intervention. Still more data are needed concerning the underlying mechanism that mediates this interaction and modulation. Here, we welcome papers describing recent advances in understanding the neuron-glia-thromboinflammation interaction.

Dr. Nicola Maggio
Dr. Efrat Shavit-Stein
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • thrombin
  • PAR
  • APC
  • EPCR
  • inflammation
  • glia
  • epilepsy
  • stroke
  • learning and memory

Published Papers (7 papers)

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Research

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9 pages, 1559 KiB  
Article
C-KIT Expression in Orbital Cavernous Venous Hemangiomas
by Mizhir Atallah, Natalia Edison, Esther Levi, Irit Elmalah and Daniel Briscoe
Biomolecules 2021, 11(8), 1199; https://doi.org/10.3390/biom11081199 - 12 Aug 2021
Cited by 3 | Viewed by 2164
Abstract
Orbital (slow flow) cavernous venous hemangiomas (OCVH) are the most common benign orbital tumors in adults. The c-KIT is a tyrosine kinase receptor, which is expressed on several types of cells, is thought to play a key role in tumor pathogenesis. The purpose [...] Read more.
Orbital (slow flow) cavernous venous hemangiomas (OCVH) are the most common benign orbital tumors in adults. The c-KIT is a tyrosine kinase receptor, which is expressed on several types of cells, is thought to play a key role in tumor pathogenesis. The purpose of this study was to evaluate the presence of the receptor c-KIT in OCVH. Our retrospective study examined 16 orbital cavernous venous hemangiomas from 16 cases operated on between 2006–2016 at Emek Medical Center. The mean tumor size was 18.4 mm. Symptoms appeared between 6 months and 22 years before operation. All specimens were analyzed for the c-KIT receptor through immunohistochemistry. The c-KIT was expressed by the endothelium in all 16 preparates. Staining was strong in two cases, moderate in six, and weak in eight cases, with no statistically significant correlation between staining and tumor size (p = 0.69) or the symptom duration (p = 0.15). We conclude that c-KIT may play an important role in the pathogenesis of OCVH. This pilot study is significant in that tumor-targeted therapy such as Imatinib Mesylate and Sunitinib may have a role in treating surgically complicated cases located in the orbital apex. A large multicenter collaborative study is necessary to examine the role of c-KIT in OCVH. Full article
(This article belongs to the Special Issue Novel Biomolecules in Neuro-ThromboInflammation)
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11 pages, 1619 KiB  
Article
Treatment of Diabetic Neuropathy with A Novel PAR1-Targeting Molecule
by Efrat Shavit-Stein, Shany Guly Gofrit, Alexandra Gayster, Yotam Teldan, Ariel Ron, Eiman Abu Bandora, Valery Golderman, Orna Gera, Sagi Harnof, Joab Chapman and Amir Dori
Biomolecules 2020, 10(11), 1552; https://doi.org/10.3390/biom10111552 - 13 Nov 2020
Cited by 9 | Viewed by 2215
Abstract
Diabetic peripheral neuropathy (DPN) is a disabling common complication of diabetes mellitus (DM). Thrombin, a coagulation factor, is increased in DM and affects nerve function via its G-protein coupled protease activated receptor 1 (PAR1). Methods: A novel PAR1 modulator (PARIN5) was designed based [...] Read more.
Diabetic peripheral neuropathy (DPN) is a disabling common complication of diabetes mellitus (DM). Thrombin, a coagulation factor, is increased in DM and affects nerve function via its G-protein coupled protease activated receptor 1 (PAR1). Methods: A novel PAR1 modulator (PARIN5) was designed based on the thrombin PAR1 recognition site. Coagulation, motor and sensory function and small fiber loss were evaluated by employing the murine streptozotocin diabetes model. Results: PARIN5 showed a safe coagulation profile and showed no significant effect on weight or glucose levels. Diabetic mice spent shorter time on the rotarod (p < 0.001), and had hypoalgesia (p < 0.05), slow conduction velocity (p < 0.0001) and reduced skin innervation (p < 0.0001). Treatment with PARIN5 significantly improved rotarod performance (p < 0.05), normalized hypoalgesia (p < 0.05), attenuated slowing of nerve conduction velocity (p < 0.05) and improved skin innervation (p <0.0001). Conclusion: PARIN5 is a novel pharmacological approach for prevention of DPN development, via PAR1 pathway modulation. Full article
(This article belongs to the Special Issue Novel Biomolecules in Neuro-ThromboInflammation)
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Review

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15 pages, 1273 KiB  
Review
Protease Activated Receptor 1 and Its Ligands as Main Regulators of the Regeneration of Peripheral Nerves
by Elena Pompili, Valerio De Franchis, Claudia Giampietri, Stefano Leone, Elena De Santis, Francesco Fornai, Lorenzo Fumagalli and Cinzia Fabrizi
Biomolecules 2021, 11(11), 1668; https://doi.org/10.3390/biom11111668 - 10 Nov 2021
Cited by 5 | Viewed by 2096
Abstract
In contrast with the brain and spinal cord, peripheral nerves possess a striking ability to regenerate after damage. This characteristic of the peripheral nervous system is mainly due to a specific population of glial cells, the Schwann cells. Schwann cells promptly activate after [...] Read more.
In contrast with the brain and spinal cord, peripheral nerves possess a striking ability to regenerate after damage. This characteristic of the peripheral nervous system is mainly due to a specific population of glial cells, the Schwann cells. Schwann cells promptly activate after nerve injury, dedifferentiate assuming a repair phenotype, and assist axon regrowth. In general, tissue injury determines the release of a variety of proteases which, in parallel with the degradation of their specific targets, also activate plasma membrane receptors known as protease-activated receptors (PARs). PAR1, the prototypical member of the PAR family, is also known as thrombin receptor and is present at the Schwann cell plasma membrane. This receptor is emerging as a possible regulator of the pro-regenerative capacity of Schwann cells. Here, we summarize the most recent literature data describing the possible contribution of PAR1 and PAR1-activating proteases in regulating the regeneration of peripheral nerves. Full article
(This article belongs to the Special Issue Novel Biomolecules in Neuro-ThromboInflammation)
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21 pages, 2977 KiB  
Review
The Evolving Concept of Neuro-Thromboinflammation for Neurodegenerative Disorders and Neurotrauma: A Rationale for PAR1-Targeting Therapies
by Barry W. Festoff and Chris Dockendorff
Biomolecules 2021, 11(11), 1558; https://doi.org/10.3390/biom11111558 - 21 Oct 2021
Cited by 1 | Viewed by 2354
Abstract
Interest in the role of coagulation and fibrinolysis in the nervous system was active in several laboratories dating back before cloning of the functional thrombin receptor in 1991. As one of those, our attention was initially on thrombin and plasminogen activators in synapse [...] Read more.
Interest in the role of coagulation and fibrinolysis in the nervous system was active in several laboratories dating back before cloning of the functional thrombin receptor in 1991. As one of those, our attention was initially on thrombin and plasminogen activators in synapse formation and elimination in the neuromuscular system, with orientation towards diseases such as amyotrophic lateral sclerosis (ALS) and how clotting and fibrinolytic pathways fit into its pathogenesis. This perspective is on neuro-thromboinflammation, emphasizing this emerging concept from studies and reports over more than three decades. It underscores how it may lead to novel therapeutic approaches to treat the ravages of neurotrauma and neurodegenerative diseases, with a focus on PAR1, ALS, and parmodulins. Full article
(This article belongs to the Special Issue Novel Biomolecules in Neuro-ThromboInflammation)
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15 pages, 1049 KiB  
Review
Role of Purinergic Signalling in Endothelial Dysfunction and Thrombo-Inflammation in Ischaemic Stroke and Cerebral Small Vessel Disease
by Natasha Ting Lee, Lin Kooi Ong, Prajwal Gyawali, Che Mohd Nasril Che Mohd Nassir, Muzaimi Mustapha, Harshal H. Nandurkar and Maithili Sashindranath
Biomolecules 2021, 11(7), 994; https://doi.org/10.3390/biom11070994 - 6 Jul 2021
Cited by 25 | Viewed by 4571
Abstract
The cerebral endothelium is an active interface between blood and the central nervous system. In addition to being a physical barrier between the blood and the brain, the endothelium also actively regulates metabolic homeostasis, vascular tone and permeability, coagulation, and movement of immune [...] Read more.
The cerebral endothelium is an active interface between blood and the central nervous system. In addition to being a physical barrier between the blood and the brain, the endothelium also actively regulates metabolic homeostasis, vascular tone and permeability, coagulation, and movement of immune cells. Being part of the blood–brain barrier, endothelial cells of the brain have specialized morphology, physiology, and phenotypes due to their unique microenvironment. Known cardiovascular risk factors facilitate cerebral endothelial dysfunction, leading to impaired vasodilation, an aggravated inflammatory response, as well as increased oxidative stress and vascular proliferation. This culminates in the thrombo-inflammatory response, an underlying cause of ischemic stroke and cerebral small vessel disease (CSVD). These events are further exacerbated when blood flow is returned to the brain after a period of ischemia, a phenomenon termed ischemia-reperfusion injury. Purinergic signaling is an endogenous molecular pathway in which the enzymes CD39 and CD73 catabolize extracellular adenosine triphosphate (eATP) to adenosine. After ischemia and CSVD, eATP is released from dying neurons as a damage molecule, triggering thrombosis and inflammation. In contrast, adenosine is anti-thrombotic, protects against oxidative stress, and suppresses the immune response. Evidently, therapies that promote adenosine generation or boost CD39 activity at the site of endothelial injury have promising benefits in the context of atherothrombotic stroke and can be extended to current CSVD known pathomechanisms. Here, we have reviewed the rationale and benefits of CD39 and CD39 therapies to treat endothelial dysfunction in the brain. Full article
(This article belongs to the Special Issue Novel Biomolecules in Neuro-ThromboInflammation)
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19 pages, 1063 KiB  
Review
Role of Thrombin in Central Nervous System Injury and Disease
by Nathan A. Shlobin, Meirav Har-Even, Ze’ev Itsekson-Hayosh, Sagi Harnof and Chaim G. Pick
Biomolecules 2021, 11(4), 562; https://doi.org/10.3390/biom11040562 - 12 Apr 2021
Cited by 26 | Viewed by 4227
Abstract
Thrombin is a Na+-activated allosteric serine protease of the chymotrypsin family involved in coagulation, inflammation, cell protection, and apoptosis. Increasingly, the role of thrombin in the brain has been explored. Low concentrations of thrombin are neuroprotective, while high concentrations exert pathological [...] Read more.
Thrombin is a Na+-activated allosteric serine protease of the chymotrypsin family involved in coagulation, inflammation, cell protection, and apoptosis. Increasingly, the role of thrombin in the brain has been explored. Low concentrations of thrombin are neuroprotective, while high concentrations exert pathological effects. However, greater attention regarding the involvement of thrombin in normal and pathological processes in the central nervous system is warranted. In this review, we explore the mechanisms of thrombin action, localization, and functions in the central nervous system and describe the involvement of thrombin in stroke and intracerebral hemorrhage, neurodegenerative diseases, epilepsy, traumatic brain injury, and primary central nervous system tumors. We aim to comprehensively characterize the role of thrombin in neurological disease and injury. Full article
(This article belongs to the Special Issue Novel Biomolecules in Neuro-ThromboInflammation)
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8 pages, 598 KiB  
Review
Monitoring and Modulating Inflammation-Associated Alterations in Synaptic Plasticity: Role of Brain Stimulation and the Blood–Brain Interface
by Maximilian Lenz, Amelie Eichler and Andreas Vlachos
Biomolecules 2021, 11(3), 359; https://doi.org/10.3390/biom11030359 - 26 Feb 2021
Cited by 7 | Viewed by 2632
Abstract
Inflammation of the central nervous system can be triggered by endogenous and exogenous stimuli such as local or systemic infection, trauma, and stroke. In addition to neurodegeneration and cell death, alterations in physiological brain functions are often associated with neuroinflammation. Robust experimental evidence [...] Read more.
Inflammation of the central nervous system can be triggered by endogenous and exogenous stimuli such as local or systemic infection, trauma, and stroke. In addition to neurodegeneration and cell death, alterations in physiological brain functions are often associated with neuroinflammation. Robust experimental evidence has demonstrated that inflammatory cytokines affect the ability of neurons to express plasticity. It has been well-established that inflammation-associated alterations in synaptic plasticity contribute to the development of neuropsychiatric symptoms. Nevertheless, diagnostic approaches and interventional strategies to restore inflammatory deficits in synaptic plasticity are limited. Here, we review recent findings on inflammation-associated alterations in synaptic plasticity and the potential role of the blood–brain interface, i.e., the blood–brain barrier, in modulating synaptic plasticity. Based on recent findings indicating that brain stimulation promotes plasticity and modulates vascular function, we argue that clinically employed non-invasive brain stimulation techniques, such as transcranial magnetic stimulation, could be used for monitoring and modulating inflammation-induced alterations in synaptic plasticity. Full article
(This article belongs to the Special Issue Novel Biomolecules in Neuro-ThromboInflammation)
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