scholarly journals Myocardial Accumulations of Reg3A, Reg3γ and Oncostatin M Are Associated with the Formation of Granulomata in Patients with Cardiac Sarcoidosis

2021 ◽  
Vol 22 (8) ◽  
pp. 4148
Author(s):  
Praveen Gajawada ◽  
Ayse Cetinkaya ◽  
Susanne von Gerlach ◽  
Natalia Kubin ◽  
Heiko Burger ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cardiac Sarcoidosis ◽  
Oncostatin M ◽  
Structural Cell ◽  
Akt Activation ◽  
Highly Active ◽  
Positron Emission ◽  
Developmental Principles ◽  
And Control ◽  
Macrophage Accumulation

Cardiac sarcoidosis (CS) is a poorly understood disease and is characterized by the focal accumulation of immune cells, thus leading to the formation of granulomata (GL). To identify the developmental principles of fatal GL, fluorescence microscopy and Western blot analysis of CS and control patients is presented here. CS is visualized macroscopically by positron emission tomography (PET)/ computed tomography (CT). A battery of antibodies is used to determine structural, cell cycle and inflammatory markers. GL consist of CD68+, CD163+ and CD206+ macrophages surrounded by T-cells within fibrotic areas. Cell cycle markers such as phospho-histone H3, phospho-Aurora and Ki67 were moderately present; however, the phosphorylated ERM (ezrin, radixin and moesin) and Erk1/2 proteins, strong expression of the myosin motor protein and the macrophage transcription factor PU.1 indicate highly active GL. Mild apoptosis is consistent with PI3 kinase and Akt activation. Massive amounts of the IL-1R antagonist reflect a mild activation of stress and inflammatory pathways in GL. High levels of oncostatin M and the Reg3A and Reg3γ chemokines are in accordance with macrophage accumulation in areas of remodeling cardiomyocytes. We conclude that the formation of GL occurs mainly through chemoattraction and less by proliferation of macrophages. Furthermore, activation of the oncostatin/Reg3 axis might help at first to wall-off substances but might initiate the chronic development of heart failure.

scholarly journals Serum Anti-Heart and Anti-Intercalated Disk Autoantibodies: Novel Autoimmune Markers in Cardiac Sarcoidosis

2021 ◽  
Vol 10 (11) ◽  
pp. 2476
Author(s):  
Alida L. P. Caforio ◽  
Anna Baritussio ◽  
Renzo Marcolongo ◽  
Chun-Yan Cheng ◽  
Elena Pontara ◽  
...  
Keyword(s):  
Cardiac Involvement ◽  
Cardiac Sarcoidosis ◽  
Cross Sectional Study ◽  
Cross Sectional ◽  
Cardiac Symptoms ◽  
Positron Emission ◽  
Immune Mediated ◽  
The Usa ◽  
And Control ◽  
Intercalated Disk

Background: Sarcoidosis is an immune-mediated disease. Cardiac involvement, a granulomatous form of myocarditis, is under-recognized and prognostically relevant. Anti-heart autoantibodies (AHAs) and anti-intercalated disk autoantibodies (AIDAs) are autoimmune markers in nonsarcoidosis myocarditis forms. Objective: The aim was to assess serum AHAs and AIDAs as autoimmune markers in cardiac sarcoidosis. Methods: This is a cross-sectional study on AHA and AIDA frequency in: 29 patients (aged 46 ± 12, 20 male) with biopsy-proven extracardiac sarcoidosis and biopsy-proven or clinically suspected and confirmed by 18-fluorodeoxyglucose positron emission tomography and/or cardiovascular magnetic resonance (CMR) cardiac involvement; 30 patients (aged 44 ± 11, 12 male) with biopsy-proven extracardiac sarcoidosis without cardiac involvement (no cardiac symptoms, normal 12-lead electrocardiogram, echocardiography and CMR), and control patients with noninflammatory cardiac disease (NICD) (n = 160), ischemic heart failure (IHF) (n = 141) and normal blood donors (NBDs) (n = 270). Sarcoidosis patients were recruited in two recruiting tertiary centers in the USA and Italy. AHAs and AIDAs were detected by indirect immunofluorescence on the human myocardium and skeletal muscle. Results: AHA and AIDA frequencies were higher in sarcoidosis with cardiac involvement (86%; 62%) than in sarcoidosis without cardiac involvement (0%; 0%), NICD (8%; 4%), IHF (7%; 2%) and NBD (9%; 0%) (p = 0.0001; p = 0.0001, respectively). Sensitivity and specificity for cardiac sarcoidosis were 86% and 92% for positive AHAs and 62% and 98% for positive AIDAs, respectively. AIDAs in cardiac sarcoidosis were associated with a higher number of involved organs (p = 0.04). Conclusions: Serum AHAs and AIDAs provide novel noninvasive diagnostic autoimmune markers for cardiac sarcoidosis.

Porphyrin-lipid nanovesicles (Porphysomes) are effective photosensitizers for photodynamic therapy

Nanophotonics ◽  
2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Keegan Guidolin ◽  
Lili Ding ◽  
Juan Chen ◽  
Brian C. Wilson ◽  
Gang Zheng
Keyword(s):  
Photodynamic Therapy ◽  
Tumor Growth ◽  
Intrinsic Structure ◽  
Therapeutic Applications ◽  
Positron Emission ◽  
Theranostic Agents ◽  
Negative Controls ◽  
And Control ◽  
Complete Tumor

Abstract Porphysomes (PS) are liposome-like nanoparticles comprising pyropheophorbide-conjugated phospholipids that have demonstrated potential as multimodal theranostic agents for applications that include phototherapies, targeted drug delivery and in vivo fluorescence, photoacoustic, magnetic resonance or positron emission imaging. Previous therapeutic applications focused primarily on photothermal therapy (PTT) and suggested that PSs require target-triggered activation for use as photodynamic therapy (PDT) sensitizers. Here, athymic nude mice bearing subcutaneous A549 human lung tumors were randomized into treatment and control groups: PS-PDT at various doses, PS-only and no treatment negative controls, as well as positive controls using the clinical photosensitizer Photofrin. Animals were followed for 30 days post-treatment. PS-PDT at all doses demonstrated a significant tumor ablative effect, with the greatest effect seen with 10 mg/kg PS at a drug-light interval of 24 h. By comparison, negative controls (PS-only, Photofrin-only, and no treatment) showed uncontrolled tumor growth. PDT with Photofrin at 5 mg/kg and PS at 10 mg/kg demonstrated similar tumor growth suppression and complete tumor response rates (15 vs. 25%, p = 0.52). Hence, porphysome nanoparticles are an effective PDT agent and have the additional advantages of multimodal diagnostic and therapeutic applications arising from their intrinsic structure. Porphysomes may also be the first single all-organic agent capable of concurrent PDT and PTT.

scholarly journals Complete heart block in cardiac sarcoidosis reversed by corticosteroid therapy: time course of resolution

2021 ◽  
Vol 14 (3) ◽  
pp. e240834
Author(s):  
Anna Tomdio ◽  
Huzaefah Syed ◽  
Kenneth Ellenbogen ◽  
Jordana Kron
Keyword(s):  
Heart Block ◽  
Time Course ◽  
Cardiac Sarcoidosis ◽  
Complete Heart Block ◽  
Positron Emission ◽  
Av Conduction ◽  
Magnetic Resonance Imaging Mri ◽  
High Level ◽  
Active Inflammation ◽  
Lateral Walls

A 53-year-old man was admitted for recurrent syncope and found to have complete heart block (CHB). Cardiac magnetic resonance imaging MRI) showed extensive patchy late gadolinium enhancement in the apical and lateral walls, consistent with cardiac sarcoidosis (CS) but no scar in the septum. A fluorodeoxyglucose (FDG)–positron emission tomography showed FDG uptake in the septum and basal lateral walls. Imaging suggested active inflammation in the septum affecting atrioventricular (AV) conduction but no irreversible fibrosis. Diagnosis of isolated CS requires a high level of suspicion and multidisciplinary teamwork involving heart failure specialists, electrophysiologists and rheumatologists. After specialist and patient discussion, treatment of the disease was initiated with prednisone 40 mg daily, 11 months after presenting with CHB. Three weeks later, ECG with pacing inhibited showed second-degree AV block Mobitz type II and 4 weeks later, AV conduction recovery. This highlights the importance of immediate therapy in reversing AV conduction abnormalities in CS.

scholarly journals Role for Human SIRT2 NAD-Dependent Deacetylase Activity in Control of Mitotic Exit in the Cell Cycle

2003 ◽  
Vol 23 (9) ◽  
pp. 3173-3185 ◽  
Author(s):  
Sylvia C. Dryden ◽  
Fatimah A. Nahhas ◽  
James E. Nowak ◽  
Anton-Scott Goustin ◽  
Michael A. Tainsky
Keyword(s):  
Cell Cycle ◽  
Protein A ◽  
Proteasome Inhibitors ◽  
26S Proteasome ◽  
Functional Studies ◽  
Cellular Life ◽  
Subsequent Decrease ◽  
Subsequent Degradation ◽  
Phosphorylation Cascade ◽  
And Control

ABSTRACT Studies of yeast have shown that the SIR2 gene family is involved in chromatin structure, transcriptional silencing, DNA repair, and control of cellular life span. Our functional studies of human SIRT2, a homolog of the product of the yeast SIR2 gene, indicate that it plays a role in mitosis. The SIRT2 protein is a NAD-dependent deacetylase (NDAC), the abundance of which increases dramatically during mitosis and is multiply phosphorylated at the G2/M transition of the cell cycle. Cells stably overexpressing the wild-type SIRT2 but not missense mutants lacking NDAC activity show a marked prolongation of the mitotic phase of the cell cycle. Overexpression of the protein phosphatase CDC14B, but not its close homolog CDC14A, results in dephosphorylation of SIRT2 with a subsequent decrease in the abundance of SIRT2 protein. A CDC14B mutant defective in catalyzing dephosphorylation fails to change the phosphorylation status or abundance of SIRT2 protein. Addition of 26S proteasome inhibitors to human cells increases the abundance of SIRT2 protein, indicating that SIRT2 is targeted for degradation by the 26S proteasome. Our data suggest that human SIRT2 is part of a phosphorylation cascade in which SIRT2 is phosphorylated late in G2, during M, and into the period of cytokinesis. CDC14B may provoke exit from mitosis coincident with the loss of SIRT2 via ubiquitination and subsequent degradation by the 26S proteasome.

scholarly journals Netrin-1 in Atherosclerosis: Relationship between Human Macrophage Intracellular Levels and In Vivo Plaque Morphology

Biomedicines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 168
Author(s):  
Susanna Fiorelli ◽  
Nicola Cosentino ◽  
Benedetta Porro ◽  
Franco Fabbiocchi ◽  
Giampaolo Niccoli ◽  
...  
Keyword(s):  
Progressive Increase ◽  
Human Macrophage ◽  
Plaque Morphology ◽  
Artery Disease ◽  
Atherosclerotic Process ◽  
And Function ◽  
And Control ◽  
Macrophage Accumulation

Netrin-1 is a laminin-like protein that plays a pivotal role in cell migration and, according to the site of its release, exerts both pro and anti-atherosclerotic functions. Macrophages, key cells in atherosclerosis, are heterogeneous in morphology and function and different subpopulations may support plaque progression, stabilization, and/or regression. Netrin-1 was evaluated in plasma and, together with its receptor UNC5b, in both spindle and round monocyte-derived macrophages (MDMs) morphotypes from coronary artery disease (CAD) patients and control subjects. In CAD patients, plaque features were detected in vivo by optical coherence tomography. CAD patients had lower plasma Netrin-1 levels and a higher MDMs expression of both protein and its receptor compared to controls. Specifically, a progressive increase in Netrin-1 and UNC5b was evidenced going from controls to stable angina (SA) and acute myocardial infarction (AMI) patients. Of note, spindle MDMs of AMI showed a marked increase of both Netrin-1 and its receptor compared to spindle MDMs of controls. UNC5b expression is always higher in spindle compared to round MDMs, regardless of the subgroup. Finally, CAD patients with higher intracellular Netrin-1 levels showed greater intraplaque macrophage accumulation in vivo. Our findings support the role of Netrin-1 and UNC5b in the atherosclerotic process.

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