scholarly journals Inflammatory Mediators in Vascular Disease: Identifying Promising Targets for Intracranial Aneurysm Research

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
David M. Sawyer ◽  
Peter S. Amenta ◽  
Ricky Medel ◽  
Aaron S. Dumont
Keyword(s):  
Intracranial Aneurysm ◽  
Intracranial Aneurysms ◽  
Future Research ◽  
Specific Interactions ◽  
Effector Molecules ◽  
Inflammatory Processes ◽  
And Function ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

Inflammatory processes are implicated in many diseases of the vasculature and have been shown to play a key role in the formation of intracranial aneurysms (IAs). Although the specific mechanisms underlying these processes have been thoroughly investigated in related pathologies, such as atherosclerosis, there remains a paucity of information regarding the immunopathology of IA. Cells such as macrophages and lymphocytes and their effector molecules have been suggested to be players in IA, but their specific interactions and the role of other components of the inflammatory response have yet to be determined. Drawing parallels between the pathogenesis of IA and other vascular disorders could provide a roadmap for developing a mechanistic understanding of the immunopathology of IA and uncovering useful targets for therapeutic intervention. Future research should address the presence and function of leukocyte subsets, mechanisms of leukocyte recruitment and activation, and the role of damage-associated molecular patterns in IA.

Abstract 147: Role of Nicotine in the Development of Intracranial Aneurysm Rupture

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Yoshinobu Kamio ◽  
Hajime Furukawa ◽  
Kimihiko Yokosuka ◽  
Masaaki Korai ◽  
Kazuha Mitsui ◽  
...  
Keyword(s):  
Intracranial Aneurysm ◽  
Tobacco Smoke ◽  
Intracranial Aneurysms ◽  
Aneurysm Rupture ◽  
Alpha7 Nicotinic Acetylcholine Receptor ◽  
Acetate Salt ◽  
Nicotine Receptors ◽  
Aneurysm Wall ◽  
Salt Hypertension

Background: Nicotine is one of main chemicals of tobacco smoke and promotes atherosclerosis and stroke. Tobacco smoke is considered an independent risk factor for intracranial aneurysm formation, growth, and rupture. There are mainly 5 subtypes of nicotine receptors. Roles of alpha7 nicotinic acetylcholine receptor (α7nAChR) in inflammation and vascular remodeling are diverse and context-dependent. Notably, endothelial α7nAChR is considered to mediate nicotine-induced inflammation. Activation of endothelial α7nAChR by nicotine may promote aneurysm rupture by increasing the aneurysm wall inflammation. Using a mouse model of intracranial aneurysm, we examined effects of nicotine in aneurysm rupture. Moreover we investigated potential roles of α7nAChR stimulation by nicotine in the pathophysiology of intracranial aneurysms. Methods: Intracranial aneurysms were induced by a combination of elastase injection into the cerebrospinal fluid and deoxycorticosteron acetate-salt (DOCA-salt) hypertension in male mice. Mice were treated with (1) nicotine (5 mg/kg/day, n=25); (2) saline sc (n=22) for three weeks after aneurysm induction. To investigate the effect of α7nAChR, mice were treated with (1) saline sc + saline ip (n=11); (2) saline sc + α7nAChR antagonist (Methyllycaconitine, MLA 5mg/kg/day) ip (n=13); (3) nicotine (5 mg/kg/day, sc, 28 days) + saline ip (n=18); (4) nicotine sc + MLA ip (n=18). Results: Nicotine alone significantly increased aneurysmal rupture compared with saline treatment (89% vs 46%, p=0.009). While α7nAChR antagonist did not affect the incidence of aneurysm or rupture rates, the α7nAChR antagonist significantly reduced the deleterious effect of nicotine as indicated by the reduction of the rupture rates (41% vs 100%: nicotine sc + MLA ip group vs nicotine sc + saline ip group, p=0.027). Conclusion: Our data indicate the promotion of aneurysm rupture by nicotine may be mediated by its stimulation of alpha7nAChR.

scholarly journals Toll-Like Receptors and Myocardial Inflammation

2011 ◽  
Vol 2011 ◽  
pp. 1-21 ◽  
Author(s):  
Yan Feng ◽  
Wei Chao
Keyword(s):  
Animal Studies ◽  
Myocardial Injury ◽  
Myocardial Inflammation ◽  
Septic Cardiomyopathy ◽  
Toll Like Receptors ◽  
Tlr Signaling ◽  
Animal Data ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

Toll-like receptors (TLRs) are a member of the innate immune system. TLRs detect invading pathogens through the pathogen-associated molecular patterns (PAMPs) recognition and play an essential role in the host defense. TLRs can also sense a large number of endogenous molecules with the damage-associated molecular patterns (DAMPs) that are produced under various injurious conditions. Animal studies of the last decade have demonstrated that TLR signaling contributes to the pathogenesis of the critical cardiac conditions, where myocardial inflammation plays a prominent role, such as ischemic myocardial injury, myocarditis, and septic cardiomyopathy. This paper reviews the animal data on (1) TLRs, TLR ligands, and the signal transduction system and (2) the important role of TLR signaling in these critical cardiac conditions.

scholarly journals Schistosome tegumental ecto-apyrase (SmATPDase1) degrades exogenous pro-inflammatory and pro-thrombotic nucleotides.

2014 ◽  
Author(s):  
Akram A Da'dara ◽  
Rita Bhardwaj ◽  
Yasser MB Ali ◽  
Patrick Skelly
Keyword(s):  
Thrombus Formation ◽  
Functional Characterization ◽  
Host Cells ◽  
Dependent Manner ◽  
Host Immune Responses ◽  
Genes Encoding ◽  
Molecular Patterns ◽  
Parasitic Worms ◽  
Damage Associated Molecular Patterns

Schistosomes are parasitic worms that can survive in the hostile environment of the human bloodstream where they appear refractory to both immune elimination and thrombus formation. We hypothesize that parasite migration in the bloodstream can stress the vascular endothelium causing this tissue to release chemicals alerting responsive host cells to the stress. Such chemicals are called damage associated molecular patterns (DAMPs) and among the most potent is the proinflammatory mediator, adenosine triphosphate (ATP). Furthermore, the ATP derivative ADP is a pro-thrombotic molecule that acts as a strong activator of platelets. Schistosomes are reported to possess at their host interactive tegumental surface a series of enzymes that could, like their homologs in mammals, degrade extracellular ATP and ADP. These are alkaline phosphatase (SmAP), phosphodiesterase (SmNPP-5) and ATP diphosphohydrolase (SmATPDase1). In this work we employ RNAi to knock down expression of the genes encoding these enzymes in the intravascular life stages of the parasite. We then compare the abilities of these parasites to degrade exogenously added ATP and ADP. . We find that only SmATPDase1-suppressed parasites are significantly impaired in their ability to degrade these nucleotides. Suppression of SmAP or SmNPP-5 does not appreciably affect the worms’ ability to catabolize ATP or ADP. These findings are confirmed by the functional characterization of the enzymatically active, full-length recombinant SmATPDase1 expressed in CHO-S cells. The enzyme is a true apyrase; SmATPDase1 degrades ATP and ADP in a cation dependent manner. Optimal activity is seen at alkaline pH. The Km of SmATPDase1 for ATP is 0.4 ±0.02 mM and for ADP, 0.252 ± 0.02 mM. The results confirm the role of tegumental SmATPDase1 in the degradation of the exogenous pro-inflammatory and pro-thrombotic nucleotides ATP and ADP by live intravascular stages of the parasite. By degrading host inflammatory signals like ATP, and pro-thrombotic signals like ADP, these parasite enzymes may minimize host immune responses, inhibit blood coagulation and promote schistosome survival.)

scholarly journals Using Tertiary Sulci to Map the “Cognitive Globe” of Prefrontal Cortex

2021 ◽  
pp. 1-18
Author(s):  
Jacob A. Miller ◽  
Mark D'Esposito ◽  
Kevin S. Weiner
Keyword(s):  
Prefrontal Cortex ◽  
Frontal Lobe ◽  
Spatial Scales ◽  
Structure And Function ◽  
Future Research ◽  
Functional Relationships ◽  
Theoretical Perspectives ◽  
Individual Participant ◽  
And Function

Stuss considered the human prefrontal cortex (pFC) as a “cognitive globe” [Stuss, D. T., & Benson, D. F. Neuropsychological studies of the frontal lobes. Psychological Bulletin, 95, 3–28, 1984] on which functions of the frontal lobe could be mapped. Here, we discuss classic and recent findings regarding the evolution, development, function, and cognitive role of shallow indentations or tertiary sulci in pFC, with the goal of using tertiary sulci to map the “cognitive globe” of pFC. First, we discuss lateral pFC (LPFC) tertiary sulci in classical anatomy and modern neuroimaging, as well as their development, with a focus on those within the middle frontal gyrus. Second, we discuss tertiary sulci in comparative neuroanatomy, focusing on primates. Third, we summarize recent findings showing the utility of tertiary sulci for understanding structural–functional relationships with functional network insights in ventromedial pFC and LPFC. Fourth, we revisit and update unresolved theoretical perspectives considered by C. Vogt and O. Vogt (Allgemeinere ergebnisse unserer hirnforschung. Journal für Psychologie und Neurologie, 25, 279–462, 1919) and F. Sanides (Structure and function of the human frontal lobe. Neuropsychologia, 2, 209–219, 1964) that tertiary sulci serve as landmarks for cortical gradients. Together, the consideration of these classic and recent findings indicate that tertiary sulci are situated in a unique position within the complexity of the “cognitive globe” of pFC: They are the smallest and shallowest of sulci in pFC, yet can offer insights that bridge spatial scales (microns to networks), modalities (functional connectivity to behavior), and species. As such, the map of tertiary sulci within each individual participant serves as a coordinate system specific to that individual on which functions may be further mapped. We conclude with new theoretical and methodological questions that, if answered in future research, will likely lead to mechanistic insight regarding the structure and function of human LPFC.

Abstract 288: High Mobility Group Box 1 (HMGB1) is Involved in the Physiopathology of Post-Cardiac Arrest Syndrome

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_2) ◽  
Author(s):  
Emilie Boissady ◽  
Cynthia El Hedjaj ◽  
Matthias Kohlhauer ◽  
Bijan Ghaleh ◽  
Renaud Tissier
Keyword(s):  
Cardiac Arrest ◽  
High Mobility ◽  
Brain Regions ◽  
Clinical Parameter ◽  
High Mobility Group ◽  
Neurological Dysfunction ◽  
Blood Levels ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

Introduction: After cardiac arrest, a sepsis-like syndrome is observed and contributes to poor prognosis. Hypothesis: This syndrome could be provoked by the massive release of Damage Associated Molecular Patterns (DAMP). Our aim was to investigate the role of the High mobility group box 1 (HMGB1), a well-characterized nuclear DAMP, in an experimental model of cardiac arrest. Methods: Rabbits were anesthetized and submitted to 10 min of ventricular fibrillation. After resuscitation, they either received an administration of the inhibitor of HMGB1 release glycyrrhizin (4 mg/kg i.v.. (GL group, n=6), or saline (5 ml, i.v.; CT group, n=6). Two additional groups received glycyrrhizin (n=4) or saline (n=4) alone without cardiac arrest (Sham groups). Blood samples were withdrawn to evaluate the kinetics of HMGB1 release. After awakening, survival and neurological dysfunction were evaluated during 3 days. Animals were then euthanized and brain histologic damages were assessed (fluorojade-C staining). Results: In the Sham groups, glycyrrhizin did not modify hemodynamic nor clinical parameter as compared to saline. In the CT group, HMGB1 blood levels increased since 30 min after cardiac arrest and remained elevated until the end of the follow-up. This increase in HMGB1 concentrations was significantly attenuated in GL vs CR (18±1 vs 29±5 and ng/ml at 30 min after cardiac arrest, respectively). Neurological dysfunction score or survival were not significantly improved in GL vs CT (e.g., survival = 50 vs 33 % at day 3 in GT vs CT group). However, fluorojade C staining showed a dramatic attenuation of degenerating neurons in GL vs CT groups in all brain regions (e.g., 7±3 vs 32±10 neurons/field in cortex, respectively). Conclusion: HMGB1 played a key role in early inflammation and promoted neuronal death after cardiac arrest. Its inhibition alone does not provide sufficient benefits to improve the clinical outcome. It emphasizes the importance of other contributors, beyond inflammation and neurons cell death. Adjunction of HMGB1 inhibitors to other therapies could still be of interest.

scholarly journals Role of Damage-Associated Molecular Patterns and Uncontrolled Inflammation in Pediatric Sepsis-Induced Multiple Organ Dysfunction Syndrome

2018 ◽  
Vol 08 (01) ◽  
pp. 025-031 ◽  
Author(s):  
Diana Pang ◽  
Dalia Bashir ◽  
Joseph Carcillo ◽  
Trung Nguyen ◽  
Rajesh Aneja ◽  
...  
Keyword(s):  
Organ Dysfunction ◽  
Multiple Organ Dysfunction Syndrome ◽  
Multiple Organ ◽  
Multiple Organ Dysfunction ◽  
Risk Of Death ◽  
Pediatric Sepsis ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns ◽  
Stimulation Of

AbstractThe incidence of multiple organ dysfunction syndrome (MODS) in sepsis varies from 17 to 73% and furthermore, increases the risk of death by 60% when controlled for the number of dysfunctional organs. Several MODS phenotypes exist, each unique in presentation and pathophysiology. Common to the phenotypes is the stimulation of the immune response by pathogen-associated molecular patterns (PAMPs), or danger-associated molecular patterns (DAMPs) causing an unremitting inflammation. Two of the MODS phenotypes are discussed in detail, thrombocytopenia-associated multiple organ failure (TAMOF) and the hyperinflammatory phenotype–macrophage activating syndrome (MAS) and hemophagocytic lymphohistiocytosis (HLH). In the end, we will briefly review the role of mitochondrial dysfunction as a significant contributor to the pathogenesis of MODS.

scholarly journals The Role of Peptide Signals Hidden in the Structure of Functional Proteins in Plant Immune Responses

2019 ◽  
Vol 20 (18) ◽  
pp. 4343 ◽  
Author(s):  
Irina Lyapina ◽  
Anna Filippova ◽  
Igor Fesenko
Keyword(s):  
Immune Responses ◽  
Defense Responses ◽  
Innate Immune ◽  
Functional Protein ◽  
Diverse Range ◽  
Peptide Signals ◽  
Plant Pathogen Interactions ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

Plants have evolved a sophisticated innate immune system to cope with a diverse range of phytopathogens and insect herbivores. Plasma-membrane-localized pattern recognition receptors (PRRs), such as receptor-like kinases (RLK), recognize special signals, pathogen- or damage-associated molecular patterns (PAMPs or DAMPs), and trigger immune responses. A growing body of evidence shows that many peptides hidden in both plant and pathogen functional protein sequences belong to the group of such immune signals. However, the origin, evolution, and release mechanisms of peptide sequences from functional and nonfunctional protein precursors, known as cryptic peptides, are largely unknown. Various special proteases, such as metacaspase or subtilisin-like proteases, are involved in the release of such peptides upon activation during defense responses. In this review, we discuss the roles of cryptic peptide sequences hidden in the structure of functional proteins in plant defense and plant-pathogen interactions.

scholarly journals Evolution of the visual cycle: the role of retinoid-binding proteins

2002 ◽  
Vol 175 (1) ◽  
pp. 75-88 ◽  
Author(s):  
F Gonzalez-Fernandez
Keyword(s):  
Binding Proteins ◽  
Binding Protein ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Future Research ◽  
Visual Cycle ◽  
Hormone Binding ◽  
Evolutionary Context ◽  
And Function

The trafficking of retinoids in the retina represents a model to study soluble hormone-binding proteins in a complex system subject to profound evolutionary adaptations. Although a remarkable illustration of convergent evolution, all visual systems detect light in the same way, that is through the photoisomerization of an 11-cis retinoid to a corresponding trans isomer. What is strikingly different between the systems, is the mechanism by which the 11-cis chromophore is reformed and visual pigment regenerated in a process known as the visual cycle. The variations of the cycle address a problem inherent to retinoids themselves. That is, the properties that make these molecules suited for light detection also account for their susceptibility to oxidative and isomeric degradation, and cellular toxicity. The cycle therefore provides an opportunity to examine the role of soluble hormone-binding proteins within an integrative and evolutionary context. The present review focuses on interphotoreceptor retinoid-binding protein (IRBP), a controversial glycolipoprotein that recruits a protein fold common to Cterminal-processing proteases and the crotonase family. This unorthodox retinoid-binding protein is entrapped in the subretinal compartment of those eyes that translocate visual cycle retinoids between the photoreceptors and the retinal pigment epithelium. Recent studies suggest that we should look beyond a strictly carrier function if we are to appreciate the role of IRBP in the visual cycle. Here we draw lessons from other soluble hormone-binding proteins to anticipate avenues of future research likely to provide insight into the structure and function of IRBP in vision.

scholarly journals Laparoscopy in Emergency: Why Not? Advantages of Laparoscopy in Major Emergency: A Review

Life ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 917
Author(s):  
Giuseppe Ietto ◽  
Francesco Amico ◽  
Giuseppe Pettinato ◽  
Valentina Iori ◽  
Giulio Carcano
Keyword(s):  
Laparoscopic Approach ◽  
High Standard ◽  
Standard Of Care ◽  
Multiple Organ ◽  
Surgical Emergencies ◽  
Grade Of Recommendation ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns ◽  
Organ Dysfunctions

A laparoscopic approach is suggested with the highest grade of recommendation for acute cholecystitis, perforated gastroduodenal ulcers, acute appendicitis, gynaecological disorders, and non-specific abdominal pain (NSAP). To date, the main qualities of laparoscopy for these acute surgical scenarios are clearly stated: quicker surgery, faster recovery and shorter hospital stay. For the remaining surgical emergencies, as well as for abdominal trauma, the role of laparoscopy is still a matter of debate. Patients might benefit from a laparoscopic approach only if performed by experienced teams and surgeons which guarantee a high standard of care. More precisely, laparoscopy can limit damage to the tissue and could be effective for the reduction of the overall amount of cell debris, which is a result of the intensity with which the immune system reacts to the injury and the following symptomatology. In fact, these fragments act as damage-associated molecular patterns (DAMPs). DAMPs, as well as pathogen associated molecular patterns (PAMPs), are recognised by both surface and intracellular receptors of the immune cells and activate the cascade which, in critically ill surgical patients, is responsible for a deranged response. This may result in the development of progressive and multiple organ dysfunctions, manifesting with acute respiratory distress syndrome (ARDS), coagulopathy, liver dysfunction and renal failure. In conclusion, none of the emergency surgical scenarios preclude laparoscopy, provided that the surgical tactic could ensure sufficient cleaning of the abdomen in addition to resolving the initial tissue damage caused by the “trauma”.

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