Diabetes and Vascular Disease: Is It All About Glycemia?

Background: Diabetes is increasing over time, mainly driven by obesity, aging, and urbanization. Classical macro- and microvascular complications represent the final result of a complex interplay involving atherosclerosis at all stages. Methods: In this review, we aim at focusing on current updates in the pathophysiology of vascular disease in diabetes and discussing how new therapies might influence the management of these patients at high cardiovascular risk. Diabetes shows accelerated atherosclerosis with a larger inflammatory cell infiltrate, thus favoring the development of heart failure. ‘Diabetic cardiomyopathy’ perfectly describes a specific ischemia- and hypertension- independent entity due to diabetes-related metabolic alterations on myocardial function. Moreover, platelets from subjects with diabetes display a typical hyperreactivity explaining the stronger adhesion, activation, and aggregation. Additionally, diabetes provokes an exaggerated stimulation of the endothelium, with an increased release of reactive oxygen species and a reduced release of nitric oxide, both key elements of the endothelial dysfunction. Also, the coagulation cascade and leukocytes activate contributing to this pro-thrombotic environment. Neutrophils have been recently recognized to play a pivotal role by releasing neutrophil extracellular traps. Finally, microparticles from platelets, neutrophils or monocytes are detrimental effectors on the vessel wall and are involved both in vascular dysfunction and in thrombotic complications. Conclusion: In light of these findings, the therapeutic management of diabetes needs to be mostly focused on limiting the progression of complications by targeting precise pathophysiological mechanisms rather than the mere glycemic control, which failed to markedly reduce the risk for macrovascular complications and mortality.

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Higher Number of EBI3 Cells in Mucosal Chronic Hyperplastic Candidiasis May Serve to Regulate IL-17-Producing Cells

Journal of Fungi ◽

10.3390/jof7070533 ◽

2021 ◽

Vol 7 (7) ◽

pp. 533

Author(s):

Ailish Williams ◽

Helen Rogers ◽

David Williams ◽

Xiao-Qing Wei ◽

Damian Farnell ◽

...

Keyword(s):

Oral Mucosa ◽

Oral Lichen Planus ◽

Inflammatory Cell ◽

Candida Infection ◽

Inflammatory Cell Infiltrate ◽

T Helper ◽

Cell Infiltrate ◽

High Prevalence ◽

Squamous Cell Papilloma ◽

Oral Lichen

Previous research into the inflammatory cell infiltrate of chronic hyperplastic candidosis (CHC) determined that the immune response is primarily composed of T cells, the majority of which are T helper (CD4+) cells. This present investigation used immunohistochemistry to further delineate the inflammatory cell infiltrate in CHC. Cells profiled were those expressing IL-17A cytokine, EBI3 and IL-12A subunits of the IL-35 cytokine, and FoxP3+ cells. Squamous cell papilloma (with Candida infection) and oral lichen planus tissues served as comparative controls to understand the local immune responses to Candida infection. The results demonstrated that Candida-induced inflammation and immune regulation co-exist in the oral mucosa of CHC and that high prevalence of cells expressing the EBI3 cytokine subunit may play an important role in this regulation. This balance between inflammation and immune tolerance toward invading Candida in the oral mucosa may be critical in determining progress of infection.

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Papular mucinosis: is the inflammatory cell infiltrate neoplastic? The presence of a monotypic plasma cell population demonstrated by in situ hybridization

British Journal of Dermatology ◽

10.1046/j.1365-2133.1996.d01-1024.x ◽

1996 ◽

Vol 135 (3) ◽

pp. 467-470 ◽

Cited By ~ 2

Author(s):

B.J. CLARK ◽

A. MOWAT ◽

M.E. FALLOWFIELD ◽

F.D. LEE

Keyword(s):

In Situ Hybridization ◽

Cell Population ◽

Plasma Cell ◽

Inflammatory Cell ◽

Inflammatory Cell Infiltrate ◽

Cell Infiltrate

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Abstract MP30: Circulating Sars-cov-2 Spike Protein 1 Causes Microarteriolar Oxidative Stress, Endothelial Dysfunction And Enhanced Thromboxane And Endothelin Contractility That Are Prevented By Spironolactone.

Hypertension ◽

10.1161/hyp.78.suppl_1.mp30 ◽

2021 ◽

Vol 78 (Suppl_1) ◽

Author(s):

Dan Wang ◽

Christopher S Wilcox

Keyword(s):

Oxidative Stress ◽

Endothelial Cells ◽

Endothelial Dysfunction ◽

Fluorescence Microscopy ◽

Vascular Dysfunction ◽

Microvascular Complications ◽

Spike Protein ◽

Ros Generation ◽

Intravenous Injections ◽

Novel Model

Introduction and hypothesis: Following bodily entry, the SARS-CoV-2 virus undergoes pulmonary replication with release of circulating viral spike protein 1 (SP1) into the bloodstream. Uptake of SP1 by endothelial cells might provoke vascular dysfunction and thrombosis. We hypothesized that spironolactone could prevent microvascular complications from circulating SP1 in COVID-19. Methods: male C57Bl/6 mice received spironolactone (100 mg · kg -1 · d -1 PO x 3d) or vehicle and intravenous injections of recombinant full-length human SP1 (10 μg per mouse) or vehicle. They were euthanized after 3 days. Mesenteric resistant arterioles (n=4 per group) were dissected and mounted on isometric myographs. Acetylcholine-induced EDRF responses and L-NAME-inhibitable NO generation (DAF-FM fluorescence) were studied in pre-constricted vessels and contraction to endothelin 1 (ET1) or thromboxane (U-46, 619) and ET1-induced ROS (PEG-SOD inhibitable ethidium: dihydroethidium fluorescence) were studied by fluorescence microscopy in other vessels. Results: SP1 reduced acetylcholine-induced EDRF (17 ± 3 vs 27 ± 5 % mean ± sem; P < 0.05) and NO generation (0.21 ± 0.03 vs 0.36 ± 0.04, F 1 /F 0 ; P < 0.05) while increasing contraction to ET1 (10 -7 mol·l -1 : 124 ± 13 vs 89 ± 4 %; P < 0.05) and U-46, 619 (10 -6 mol·l -1 :114± 5 vs 87± 6 %; P < 0.05) and ET1-induced ROS generation(0.30± 0.08 vs 0.09± 0.03; P < 0.05). Spironolactone did not modify any of these responses in vessels from normal mice but prevented all the effects of SP1. Conclusion: these preliminary studies provide a novel model to study COVID-19 vasculopathy. They indicate that spironolactone can provide protection from microvascular oxidative stress, endothelial dysfunction and enhanced contractility and might thereby moderate COVID-19 complications.

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Thrombotic Complications in Inflammatory Bowel Disease

Russian Journal of Gastroenterology Hepatology Coloproctology ◽

10.22416/1382-4376-2019-29-2-23-26 ◽

2019 ◽

Vol 29 (2) ◽

pp. 23-26

Author(s):

A. V. Borota ◽

A. A. Borota ◽

E. V. Onishchenko

Keyword(s):

Inflammatory Bowel Disease ◽

Chronic Inflammation ◽

Bowel Disease ◽

Intestinal Wall ◽

Coagulation Cascade ◽

Coagulation System ◽

Primary Disease ◽

Prevention And Treatment ◽

Thrombotic Complications ◽

Inflammatory Bowel

The risk of thrombotic complications is known to be 3 times higher in patients with inflammatory bowel disease (IBD) than in healthy individuals, with the relative risk being 15 times higher during the periods of relapses. Aim. To study and generalize literature data available on the prevention and treatment of IBD thrombotic complications.Key findings. In the сonditions under study, the presence of chronic inflammation and increased bleeding of the intestinal wall is shown to activate the coagulation system, impair the fibrinolysis system and reduce the activity of natural anticoagulation mechanisms. The concentration of fibrinogen — a protein of the acute inflammation phase — increases significantly. This results in an imbalance of the blood coagulation system with a tendency to hypercoagulation, which significantly increases the risk of thrombotic complications and the disseminated intravascular coagulation syndrome. In turn, the activation of the coagulation cascade may trigger the inflammatory response, which eventually leads to the formation of a vicious circle between chronic inflammation and thrombosis. The pathogenesis of thrombosis in inflammatory colon diseases is a multifactor process, which remains to be understood.Conclusion.The management of patients with IBD in combination with thromboembolic complications requires an individual multidisciplinary approach. Taking into account the pathogenetic factors, the following options are possible in the prevention and treatment of thrombotic complications in IBD: strengthening the basic therapy of the primary disease; administration of prophylactic doses of anticoagulants under dynamic continuous laboratory control in the acute period using the methods of conservative therapy of thrombotic complications (elastic compression of the lower extremities) in the period of exacerbation of the primary disease.

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Uterine Perforation with Omental Prolapse in a Case of Unsafe Abortion

Asian Journal of Medical Sciences ◽

10.3126/ajms.v2i3.4264 ◽

2012 ◽

Vol 2 (3) ◽

pp. 145-147 ◽

Cited By ~ 3

Author(s):

Parinitha S Sangam ◽

Nirmala M Jayakumar ◽

Laxmi V Yaliwal

Keyword(s):

Inflammatory Cell ◽

Past History ◽

Termination Of Pregnancy ◽

Inflammatory Cell Infiltrate ◽

Emergency Laparotomy ◽

Uterine Perforation ◽

Medical Sciences ◽

Medical Termination ◽

Physician Patient ◽

Omental Fat

We report a rare case of prolapsed omentum presenting as mass per vagina in a 24 year old unmarried female following dilatation and curettage for termination of pregnancy by unqualified physician. Patient presented to Obstetrics and gynaecology (OBG) outpatient with bleeding per vagina since 15 days. Per speculum examination showed a greyish yellow mass protruding through cervical os into the vagina. Ultrasonography showed defect in the fundus of uterus. Past history revealed, she had undergone medical termination of pregnancy (MTP) outside at 5th month of gestation by nonallopathic doctor. Emergency laparotomy was done. Histopathologic examination of mass showed omental fat arranged in lobules with mixed inflammatory cell infiltrate. Uterine perforation is a well known complication of induced abortion. Although most uterine perforations at the time of curettage during abortion go unrecognized, serious complications do occur. DOI: http://dx.doi.org/10.3126/ajms.v2i3.4264 Asian Journal of Medical Sciences 2 (2011) 145-147

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Phenotypic and functional characterization of intraepithelial and lamina propria inflammatory cell infiltrate in autoimmune enteropathy.

Frontiers in Immunology ◽

10.3389/conf.fimmu.2013.02.01175 ◽

2013 ◽

Vol 4 ◽

Author(s):

Paroni Moira ◽

Nizzoli Giulia ◽

Abrignani Sergio ◽

Geginat Jeans ◽

Caprioli Flavio

Keyword(s):

Lamina Propria ◽

Inflammatory Cell ◽

Functional Characterization ◽

Inflammatory Cell Infiltrate ◽

Cell Infiltrate ◽

Autoimmune Enteropathy

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Abstract 512: Collagen Homologous Sequence R1R2 Mediates Vascular Remodeling by Decreasing Inflammation and Smooth Muscle Proliferation

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.34.suppl_1.512 ◽

2014 ◽

Vol 34 (suppl_1) ◽

Author(s):

Ting-Hein Lee ◽

Hou-Yu Chiang

Keyword(s):

Smooth Muscle ◽

Vascular Disease ◽

Vascular Remodeling ◽

Vessel Wall ◽

Inflammatory Cell ◽

Vascular Diseases ◽

Inflammatory Cell Infiltration ◽

Collagen I ◽

Cell Infiltration ◽

Ecm Proteins

The extracellular matrix (ECM) is a major constituent of the vessel wall. Except for providing a structural scaffold for cells, ECM controls numerous cellular functions like adhesion, growth, migration and differentiation. The components of ECM are mediated by the interplay between ECM synthesis, deposition, degradation and the interaction between ECM proteins. Vascular remodeling occurs in the vascular diseases and is characterized by endothelial cell activation, inflammatory cell infiltration, smooth muscle cell (SMC) proliferation/migration, and augmented deposition of ECM proteins. Collagen I is the major ECM component in the arterial wall, excess collagen I accumulation may exacerbate the vascular disease by further facilitating SMC proliferation/migration. Therefore, treatments to inhibit excess collagen deposition could provide a remedy for vascular disease. R1R2, a peptide derived from the bacterial adhesin SFS with sequence homology to collagen, is known to inhibit collagen I deposition by inhibiting the binding of fibronectin to collagen. Studies have revealed that R1R2 affects collagen I-dependent cell growth and migration in vitro. However, the in vivo functions of R1R2 during vascular remodeling remain unknown. We hypothesized that R1R2 prevents excess collagen I accumulation and SMC proliferation, resulting in decreased neointimal formation. We induced vascular remodeling by ligating the carotid artery on mice. Delivery of R1R2 was periadventially applied using pluronic gel and evaluated its effects on vascular remodeling, ECM deposition, SMC proliferation and differentiation. Morphometric analysis demonstrated that R1R2 reduced intima-media thickening by 50% compared to the control group. R1R2 treatment also decreased collagen I deposition in the vessel wall and maintained SMC in the contractile phenotype. Interestingly, R1R2 dramatically reduced inflammatory cell infiltration into the vessel by 80% accompanied with decreased VCAM-1 and ICAM-1. In conclusion, our data showed that R1R2 attenuates the vascular remodeling response by decreasing inflammation and SMC proliferation/migration. These studies provide a therapeutic potential of periadventitially delivering R1R2 in treating vascular diseases.

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Therapeutic effects of soluble guanylate cyclase stimulation on pulmonary hemodynamics and emphysema development in guinea pigs chronically exposed to cigarette smoke

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00399.2018 ◽

2019 ◽

Vol 317 (2) ◽

pp. L222-L234 ◽

Cited By ~ 2

Author(s):

Tanja Paul ◽

Isabel Blanco ◽

Daniel Aguilar ◽

Olga Tura-Ceide ◽

Cristina Bonjoch ◽

...

Keyword(s):

Cigarette Smoke ◽

Guanylate Cyclase ◽

Guinea Pigs ◽

Inflammatory Cell ◽

Soluble Guanylate Cyclase ◽

Pulmonary Vasculature ◽

Inflammatory Cell Infiltrate ◽

Therapeutic Effects ◽

Pulmonary Hemodynamics ◽

Vessel Remodeling

We have analyzed the effect of the soluble guanylate cyclase (sGC) stimulator BAY 41-2272 in a therapeutic intervention in guinea pigs chronically exposed to cigarette smoke (CS). The effects of sGC stimulation on respiratory function, pulmonary hemodynamics, airspace size, vessel remodeling, and inflammatory cell recruitment to the lungs were evaluated in animals that had been exposed to CS for 3 mo. CS exposure was continued for an additional 3 mo in half of the animals and withdrawn in the other half. Animals that stopped CS exposure had slightly lower pulmonary artery pressure (PAP) and right ventricle (RV) hypertrophy than those who continued CS exposure, but they did not recover from the emphysema and the inflammatory cell infiltrate. Conversely, oral BAY 41-2272 administration stopped progression or even reversed the CS-induced emphysema in both current and former smokers, respectively. Furthermore, BAY 41-2272 produced a reduction in the RV hypertrophy, which correlated with a decrease in the PAP values. By contrast, the degree of vessel remodeling induced by CS remained unchanged in the treated animals. Functional network analysis suggested perforin/granzyme pathway downregulation as an action mechanism capable of stopping the progression of emphysema after sGC stimulation. The pathway analysis also showed normalization of the expression of cGMP-dependent serine/kinases. In conclusion, in guinea pigs chronically exposed to CS, sGC stimulation exerts beneficial effects on the lung parenchyma and the pulmonary vasculature, suggesting that sGC stimulators might be a potential alternative for chronic obstructive pulmonary disease treatment that deserves further evaluation.

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Enhancing the anticoagulant profile of meizothrombin

BioMolecular Concepts ◽

10.1515/bmc-2018-0016 ◽

2018 ◽

Vol 9 (1) ◽

pp. 169-175 ◽

Cited By ~ 2

Author(s):

Bosko M. Stojanovski ◽

Leslie A. Pelc ◽

Xiaobing Zuo ◽

Nicola Pozzi ◽

Enrico Di Cera

Keyword(s):

Single Molecule ◽

Protein C ◽

Coagulation Cascade ◽

Proteolytic Activation ◽

Single Molecule Fret ◽

Functional Aspects ◽

Active Intermediate ◽

Thrombotic Complications ◽

Gla Domain ◽

Structural Architecture

AbstractMeizothrombin is an active intermediate generated during the proteolytic activation of prothrombin to thrombin in the penultimate step of the coagulation cascade. Structurally, meizothrombin differs from thrombin because it retains the auxiliary Gla domain and two kringles. Functionally, meizothrombin shares with thrombin the ability to cleave procoagulant (fibrinogen), prothrombotic (PAR1) and anticoagulant (protein C) substrates, although its specificity toward fibrinogen and PAR1 is less pronounced. In this study we report information on the structural architecture of meizothrombin resolved by SAXS and single molecule FRET as an elongated arrangement of its individual domains. In addition, we show the properties of a meizothrombin construct analogous to the anticoagulant thrombin mutant W215A/E217A currently in Phase I for the treatment of thrombotic complications and stroke. The findings reveal new structural and functional aspects of meizothrombin that advance our understanding of a key intermediate of the prothrombin activation pathway.

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