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1.
Polymers (Basel) ; 13(19)2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34641146

RESUMO

Delta (δ) and epsilon (ε) co-crystalline forms of syndiotactic polystyrene with a carboxylic acid guest were obtained by sorption of liquid hexanoic acid in syndiotactic polystyrene films exhibiting delta and epsilon nanoporous-crystalline forms. The characterization study is facilitated by axially stretched syndiotactic polystyrene films, used both for polarized FTIR spectra and for WAXD fiber patterns. Particularly informative are two carbonyl-stretching FTIR peaks, attributed to monomeric and dimeric hexanoic acid. The dichroism of these carbonyl peaks indicates that both delta and epsilon phases are able to include hexanoic acid as isolated guest molecules, while only the epsilon phase is also able to include dimeric hexanoic acid molecules in its crystalline channels. The inclusion of both isolated and dimeric hexanoic acid species in the epsilon form crystalline channels produces extremely fast hexanoic acid uptakes by syndiotactic polystyrene epsilon form films.

2.
Front Cell Dev Biol ; 9: 695114, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34527667

RESUMO

Dysregulation of the Notch pathway is implicated in the pathophysiology of cardiovascular diseases (CVDs), but, as of today, therapies based on the re-establishing the physiological levels of Notch in the heart and vessels are not available. A possible reason is the context-dependent role of Notch in the cardiovascular system, which would require a finely tuned, cell-specific approach. MicroRNAs (miRNAs) are short functional endogenous, non-coding RNA sequences able to regulate gene expression at post-transcriptional levels influencing most, if not all, biological processes. Dysregulation of miRNAs expression is implicated in the molecular mechanisms underlying many CVDs. Notch is regulated and regulates a large number of miRNAs expressed in the cardiovascular system and, thus, targeting these miRNAs could represent an avenue to be explored to target Notch for CVDs. In this Review, we provide an overview of both established and potential, based on evidence in other pathologies, crosstalks between miRNAs and Notch in cellular processes underlying atherosclerosis, myocardial ischemia, heart failure, calcification of aortic valve, and arrhythmias. We also discuss the potential advantages, as well as the challenges, of using miRNAs for a Notch-based approach for the diagnosis and treatment of the most common CVDs.

3.
Biomedicines ; 9(8)2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34440201

RESUMO

Endothelial dysfunction characterizes every aspect of the so-called cardiovascular continuum, a series of events ranging from hypertension to the development of atherosclerosis and, finally, to coronary heart disease, thrombus formation, myocardial infarction, and heart failure. Endothelial dysfunction is the main prognostic factor for the progression of vascular disorders, which responds to drug intervention and lifestyle changes. Virtually all of the drugs used to prevent cardiovascular disorders, such as long-used and new antilipidemic agents and inhibitors of angiotensin enzyme (ACEi), exert an important effect on the endothelium. Endothelial dysfunction is a central feature of coronavirus disease -19 (COVID-19), and it is now clear that life-risk complications of the disease are prompted by alterations of the endothelium induced by viral infection. As a consequence, the progression of COVID-19 is worse in the subjects in whom endothelial dysfunction is already present, such as elderly, diabetic, obese, and hypertensive patients. Importantly, circulating biomarkers of endothelial activation and injury predict the severity and mortality of the disease and can be used to evaluate the efficacy of treatments. The purpose of this review is to provide updates on endothelial function by discussing its clinical relevance in the cardiovascular continuum, the latest insights from molecular and cellular biology, and their implications for clinical practice, with a focus on new actors, such as the Notch signaling and emerging therapies for cardiovascular disease.

4.
Life Sci Alliance ; 4(9)2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34226277

RESUMO

Here, we recorded serum proteome profiles of 33 severe COVID-19 patients admitted to respiratory and intensive care units because of respiratory failure. We received, for most patients, blood samples just after admission and at two more later time points. With the aim to predict treatment outcome, we focused on serum proteins different in abundance between the group of survivors and non-survivors. We observed that a small panel of about a dozen proteins were significantly different in abundance between these two groups. The four structurally and functionally related type-3 cystatins AHSG, FETUB, histidine-rich glycoprotein, and KNG1 were all more abundant in the survivors. The family of inter-α-trypsin inhibitors, ITIH1, ITIH2, ITIH3, and ITIH4, were all found to be differentially abundant in between survivors and non-survivors, whereby ITIH1 and ITIH2 were more abundant in the survivor group and ITIH3 and ITIH4 more abundant in the non-survivors. ITIH1/ITIH2 and ITIH3/ITIH4 also showed opposite trends in protein abundance during disease progression. We defined an optimal panel of nine proteins for mortality risk assessment. The prediction power of this mortality risk panel was evaluated against two recent COVID-19 serum proteomics studies on independent cohorts measured in other laboratories in different countries and observed to perform very well in predicting mortality also in these cohorts. This panel may not be unique for COVID-19 as some of the proteins in the panel have previously been annotated as mortality markers in aging and in other diseases caused by different pathogens, including bacteria.


Assuntos
COVID-19/sangue , COVID-19/mortalidade , Proteoma/metabolismo , Índice de Gravidade de Doença , Idoso , COVID-19/virologia , Estudos de Coortes , Feminino , Hospitalização , Humanos , Imunoglobulinas/sangue , Masculino , SARS-CoV-2/fisiologia , Sobreviventes
5.
Polymers (Basel) ; 13(10)2021 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-34068379

RESUMO

Poly(ʟ-lactide) (PLLA) films, even of high thickness, exhibiting co-crystalline and crystalline α phases with their chain axes preferentially perpendicular to the film plane (c⊥ orientation) have been obtained. This c⊥ orientation, unprecedented for PLLA films, can be achieved by the crystallization of amorphous films as induced by low-temperature sorption of molecules being suitable as guests of PLLA co-crystalline forms, such as N,N-dimethylformamide, cyclopentanone or 1,3-dioxolane. This kind of orientation is shown and quantified by two-dimensional wide-angle X-ray diffraction (2D-WAXD) patterns, as taken with the X-ray beam parallel to the film plane (EDGE patterns), which present all the hk0 arcs centered on the meridian. PLLA α-form films, as obtained by low-temperature guest-induced crystallization, also exhibit high transparency, being not far from those of the starting amorphous films.

6.
Nephron ; 145(4): 428-444, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33910203

RESUMO

BACKGROUND/AIM: Necrotizing crescentic glomerulonephritis (GN) associated with anti-neutrophil cytoplasmic antibodies (ANCA) against myeloperoxidase (MPO) is a devastating disease that quickly progresses to kidney failure. Current therapies are broadly immunosuppressive and associated with adverse effects. We wanted to set up a model that could be suitable for testing narrowly targeted therapies. METHODS: The model was constructed in male Wistar Kyoto rats through injections of human MPO (hMPO) and pertussis toxin, followed by a sub-nephritogenic dose of sheep anti-rat glomerular basement membrane (GBM) serum to boost the disease. Rats were monitored for 35 days. Rats given hMPO alone, saline, or human serum albumin with or without anti-GBM serum were also studied. RESULTS: Rats receiving hMPO developed circulating anti-hMPO and anti-rat MPO antibodies. Challenging hMPO-immunized rats with the anti-GBM serum led to more glomerular neutrophil infiltration and MPO release, and severe haematuria, heavy proteinuria, and higher blood urea nitrogen than hMPO alone. Pauci-immune GN developed with crescents, affecting 25% of glomeruli. The majority of crescents were fibrocellular. Necrotizing lesions and Bowman capsule ruptures were detected. Cells double positive for claudin-1 (a marker of parietal epithelial cells [PECs]) and neural cell adhesion molecule (NCAM; progenitor PECs) were present in crescents. Double staining for NCAM and Ki-67 established proliferative status of progenitor PECs. Podocyte damage was associated with endothelial and GBM changes by electron microscopy. Monocyte/macrophages and CD4+ and CD8+ T cells accumulated in glomeruli and the surrounding area and in the tubulointerstitium. Lung haemorrhage also manifested. CONCLUSION: This model reflects histological lesions of human ANCA-associated rapidly progressive GN and may be useful for investigating new therapies.

7.
Clin Epigenetics ; 13(1): 79, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33858475

RESUMO

BACKGROUND: Diagnostic biomarkers for detecting chronic obstructive pulmonary disease (COPD) in acute coronary syndrome (ACS) patients are not available. SERPINA1, coding for the most potent circulating anti-inflammatory protein in the lung, has been found to be differentially methylated in blood cells from COPD patients. This study aimed to investigate the methylation profile of SERPINA1 in blood cells from ACS patients, with (COPD+) or without COPD (COPD-). METHODS: Blood samples were from 115 ACS patients, including 30 COPD+ and 85 COPD- according to lung function phenotype, obtained with spirometry. DNA treated with sodium bisulfite was PCR-amplified at SERPINA1 promoter region. Methylation analysis was carried out by sequencing the PCR products. Lymphocytes count in ACS patients was recorded at hospital admission and discharge. RESULTS: SERPINA1 was hypermethylated in 24/30 (80%) COPD+ and 48/85 (56.5%) COPD- (p < 0.05). Interestingly, at hospital discharge, lymphocytes count was higher in COPD- patients carrying SERPINA1 hypermethylated (1.98 × 103 ± 0.6 cell/µl) than in COPD- carrying SERPINA1 hypomethylated (1.7 × 103 ± 0.48 cell/µl) (p < 0.05). CONCLUSIONS: SERPINA1 is hypermethylated in blood cells from COPD+ patients. COPD- carrying SERPINA1 hypermethylated and high lymphocytes count may be at risk of COPD development. Therefore, SERPINA1 hypermethylation may represent a potential biomarker for predicting COPD development in ACS patients.

9.
Front Immunol ; 12: 648004, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33767713

RESUMO

Background: Deficient interferon responses have been proposed as one of the relevant mechanisms prompting severe manifestations of COVID-19. Objective: To evaluate the interferon (IFN)-α levels in a cohort of COVID-19 patients in relation to severity, evolution of the clinical manifestations and immune/inflammatory profile. Methods: This is prospective study recruiting consecutive hospitalized patients with respiratory failure associated with SARS-COV-2 infection and matched controls. After enrollment, patients were assessed every 7 ± 2 days for additional 2 consecutive visits, for a total of 21 days. The severity of the clinical condition was ranked based on the level of respiratory support required. At each time-point blood samples were obtained to assess immune cells and mediators by multiplex immunoassay. Results: Fifty-four COVD-19 and 11 control patients matched for severity were enrolled. At recruitment, lower levels of blood IFN-α were found in COVID-19 patients compared to controls (3.8-fold difference, p < 0.01). Improvements in COVID-19 severity were paralleled by a significant increase of blood IFN-α levels. A significant increase in blood IFN-α was found over the study period in survivors (70% of the study population). A similar trend was found for blood IFN-ß with IFN-ß levels below the threshold of detectability in a substantial proportion of subjects. Significantly higher values of blood lymphocytes and lower levels of IL-10 were found at each time point in patients who survived compared to patients who died. In patients who clinically improved and survived during the study, we found an inverse association between IL-10 and IFN-α levels. Conclusion: The study identifies a blood immune profile defined by deficient IFN-α levels associated with increased IL-10 expression in patients progressing to severe/life threatening COVID-19 conditions, suggesting the involvement of immunological pathways that could be target of pharmacological intervention. Clinical Trial Registration: ClinicalTrials.gov identifier NCT04343053.


Assuntos
COVID-19/sangue , Mediadores da Inflamação/sangue , Interferon-alfa/sangue , Idoso , Biomarcadores/sangue , COVID-19/diagnóstico , COVID-19/imunologia , COVID-19/virologia , Estudos de Casos e Controles , Feminino , Hospitalização , Interações Hospedeiro-Patógeno , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , SARS-CoV-2/imunologia , SARS-CoV-2/patogenicidade , Índice de Gravidade de Doença
10.
Crit Care ; 25(1): 74, 2021 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-33608030

RESUMO

BACKGROUND: Biomarkers can be used to detect the presence of endothelial and/or alveolar epithelial injuries in case of ARDS. Angiopoietin-2 (Ang-2), soluble intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion protein-1 (VCAM-1), P-selectin and E-selectin are biomarkers of endothelial injury, whereas the receptor for advanced glycation end-products (RAGE) reflects alveolar epithelial injury. The aims of this study were to evaluate whether the plasma concentration of the above-mentioned biomarkers was different 1) in survivors and non-survivors of COVID-19-related ARDS and 2) in COVID-19-related and classical ARDS. METHODS: This prospective study was performed in two COVID-19-dedicated Intensive Care Units (ICU) and one non-COVID-19 ICU at Ferrara University Hospital. A cohort of 31 mechanically ventilated patients with COVID-19 ARDS and a cohort of 11 patients with classical ARDS were enrolled. Ang-2, ICAM-1, VCAM-1, P-selectin, E-selectin and RAGE were determined with a bead-based multiplex immunoassay at three time points: inclusion in the study (T1), after 7 ± 2 days (T2) and 14 ± 2 days (T3). The primary outcome was to evaluate the plasma trend of the biomarker levels in survivors and non-survivors. The secondary outcome was to evaluate the differences in respiratory mechanics variables and gas exchanges between survivors and non-survivors. Furthermore, we compared the plasma levels of the biomarkers at T1 in patients with COVID-19-related ARDS and classical ARDS. RESULTS: In COVID-19-related ARDS, the plasma levels of Ang-2 and ICAM-1 at T1 were statistically higher in non-survivors than survivors, (p = 0.04 and p = 0.03, respectively), whereas those of P-selectin, E-selectin and RAGE did not differ. Ang-2 and ICAM-1 at T1 were predictors of mortality (AUROC 0.650 and 0.717, respectively). At T1, RAGE and P-selectin levels were higher in classical ARDS than in COVID-19-related ARDS. Ang-2, ICAM-1 and E-selectin were lower in classical ARDS than in COVID-19-related ARDS (all p < 0.001). CONCLUSIONS: COVID-19 ARDS is characterized by an early pulmonary endothelial injury, as detected by Ang-2 and ICAM-1. COVID-19 ARDS and classical ARDS exhibited a different expression of biomarkers, suggesting different pathological pathways. Trial registration NCT04343053 , Date of registration: April 13, 2020.


Assuntos
Biomarcadores/análise , Lesão Pulmonar/diagnóstico , Respiração Artificial/efeitos adversos , Idoso , Antígenos de Neoplasias/análise , Antígenos de Neoplasias/sangue , Área Sob a Curva , COVID-19/sangue , COVID-19/prevenção & controle , Estudos de Coortes , Selectina E/análise , Selectina E/sangue , Feminino , Humanos , Unidades de Terapia Intensiva/organização & administração , Unidades de Terapia Intensiva/estatística & dados numéricos , Molécula 1 de Adesão Intercelular/análise , Molécula 1 de Adesão Intercelular/sangue , Lesão Pulmonar/sangue , Lesão Pulmonar/fisiopatologia , Masculino , Pessoa de Meia-Idade , Proteínas Quinases Ativadas por Mitógeno/análise , Proteínas Quinases Ativadas por Mitógeno/sangue , Selectina-P/análise , Selectina-P/sangue , Estudos Prospectivos , Curva ROC , Respiração Artificial/normas , Respiração Artificial/estatística & dados numéricos , Síndrome do Desconforto Respiratório/sangue , Síndrome do Desconforto Respiratório/fisiopatologia , Versicanas/análise , Versicanas/sangue , Proteínas de Transporte Vesicular/análise , Proteínas de Transporte Vesicular/sangue
11.
Platelets ; 32(4): 560-567, 2021 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-33270471

RESUMO

The aim of this study (NCT04343053) is to investigate the relationship between platelet activation, myocardial injury, and mortality in patients affected by Coronavirus disease 2019 (COVID-19). Fifty-four patients with respiratory failure due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection were enrolled as cases. Eleven patients with the same clinical presentation, but negative for SARS-CoV-2 infection, were included as controls. Blood samples were collected at three different time points (inclusion [T1], after 7 ± 2 days [T2] and 14 ± 2 days [T3]). Platelet aggregation by light transmittance aggregometry and the circulating levels of soluble CD40 ligand (sCD40L) and P-selectin were measured. Platelet biomarkers did not differ between cases and controls, except for sCD40L which was higher in COVID-19 patients (p = .003). In COVID-19 patients, P-selectin and sCD40L levels decreased from T1 to T3 and were higher in cases requiring admission to intensive care unit (p = .004 and p = .008, respectively). Patients with myocardial injury (37%), as well as those who died (30%), had higher values of all biomarkers of platelet activation (p < .05 for all). Myocardial injury was an independent predictor of mortality. In COVID-19 patients admitted to hospital for respiratory failure, heightened platelet activation is associated with severity of illness, myocardial injury, and mortality.ClinicalTrials.gov number: NCT04343053.


Assuntos
Plaquetas/metabolismo , COVID-19 , Traumatismos Cardíacos , Miocárdio , Insuficiência Respiratória , SARS-CoV-2/metabolismo , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Ligante de CD40/sangue , COVID-19/sangue , COVID-19/mortalidade , COVID-19/patologia , Feminino , Traumatismos Cardíacos/sangue , Traumatismos Cardíacos/mortalidade , Traumatismos Cardíacos/patologia , Traumatismos Cardíacos/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Miocárdio/metabolismo , Miocárdio/patologia , Selectina-P/sangue , Agregação Plaquetária , Insuficiência Respiratória/sangue , Insuficiência Respiratória/mortalidade , Insuficiência Respiratória/patologia , Insuficiência Respiratória/virologia
12.
Int J Mol Sci ; 21(23)2020 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-33255450

RESUMO

Calcific aortic valve disease (CAVD) is the result of maladaptive fibrocalcific processes leading to a progressive thickening and stiffening of aortic valve (AV) leaflets. CAVD is the most common cause of aortic stenosis (AS). At present, there is no effective pharmacotherapy in reducing CAVD progression; when CAVD becomes symptomatic it can only be treated with valve replacement. Inflammation has a key role in AV pathological remodeling; hence, anti-inflammatory therapy has been proposed as a strategy to prevent CAVD. Cyclooxygenase 2 (COX-2) is a key mediator of the inflammation and it is the target of widely used anti-inflammatory drugs. COX-2-inhibitor celecoxib was initially shown to reduce AV calcification in a murine model. However, in contrast to these findings, a recent retrospective clinical analysis found an association between AS and celecoxib use. In the present study, we investigated whether variations in COX-2 expression levels in human AVs may be linked to CAVD. We extracted total RNA from surgically explanted AVs from patients without CAVD or with CAVD. We found that COX-2 mRNA was higher in non-calcific AVs compared to calcific AVs (0.013 ± 0.002 vs. 0.006 ± 0.0004; p < 0.0001). Moreover, we isolated human aortic valve interstitial cells (AVICs) from AVs and found that COX-2 expression is decreased in AVICs from calcific valves compared to AVICs from non-calcific AVs. Furthermore, we observed that COX-2 inhibition with celecoxib induces AVICs trans-differentiation towards a myofibroblast phenotype, and increases the levels of TGF-ß-induced apoptosis, both processes able to promote the formation of calcific nodules. We conclude that reduced COX-2 expression is a characteristic of human AVICs prone to calcification and that COX-2 inhibition may promote aortic valve calcification. Our findings support the notion that celecoxib may facilitate CAVD progression.


Assuntos
Estenose da Valva Aórtica/tratamento farmacológico , Valva Aórtica/patologia , Calcinose/tratamento farmacológico , Ciclo-Oxigenase 2/genética , Inflamação/tratamento farmacológico , Fator de Crescimento Transformador beta/genética , Idoso , Idoso de 80 Anos ou mais , Animais , Valva Aórtica/efeitos dos fármacos , Estenose da Valva Aórtica/genética , Estenose da Valva Aórtica/patologia , Apoptose/efeitos dos fármacos , Calcinose/genética , Calcinose/patologia , Celecoxib/administração & dosagem , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamação/genética , Inflamação/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , RNA Mensageiro/genética
13.
Kidney Med ; 2(6): 804-809, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33319205

RESUMO

In recent years, kidney functional magnetic resonance imaging (MRI) has seen great advances, with several cross-sectional studies demonstrating correlations between MRI biomarkers and glomerular filtration rate. However, the potential of MRI to monitor response to therapy in kidney disease remains undescribed. In this case report, a man in his 40s with drug-resistant membranous nephropathy was addressed to ofatumumab therapy. He underwent kidney biopsy before and 2 years after treatment and repeat non-contrast-enhanced MRI of the kidney every 6 months. An age- and sex-matched healthy volunteer was included as a normal control. The patient showed a striking positive immunologic response to therapy. Repeat MRI of the kidney documented progressive kidney functional recovery, with a significant widespread increase in kidney diffusivity, assessed using diffusion-weighted imaging, paralleling the increase in glomerular filtration rate and regression of albuminuria. Renal blood flow and ultrafiltration coefficient, assessed using phase-contrast MRI, significantly increased, suggesting an increase in filtration fraction. This case report provides the first clinical evidence in support of MRI of the kidney as a tool to noninvasively monitor pathophysiologic changes occurring in response to treatment. Although kidney biopsy remains critical for diagnosis, functional MRI of the kidney has promise for monitoring disease progression and response to therapy.

14.
Biomedicines ; 8(12)2020 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-33322648

RESUMO

(1)Background: Chronic heart failure (CHF) contributes to the overall burden of cardiovascular disease. Early identification of at-risk individuals may facilitate the targeting of precision therapies. Plasma microRNAs are promising circulating biomarkers for their implications with cardiac pathologies. In this pilot study, we investigate the possible exploitability of circulating micro-RNAs (miRNAs) to track chronic heart failure (CHF) occurrence, and progression from NYHA class I to IV. (2)Methods: We screened 367 microRNAs using TaqMan microRNA Arrays in plasma samples from healthy controls (HC) and CHF NYHA-class I-to-IV patients (5/group). Validation was performed by singleplex assays on 10 HC and 61 CHF subjects. Differences in the expression of validated microRNAs were evaluated through analysis of covariance (ANCOVA). Associations between N-terminal pro-BNP (NT-proBNP), left ventricular end-diastolic volume (LVEDV) or peak oxygen uptake (VO2 peak) and plasma microRNA were assessed by multivariable linear regression analysis. (3)Results: Twelve microRNAs showed higher expression in CHF patients vs. HC. Seven microRNAs were associated with NT-proBNP concentration; of these, miR-423-5p was also an independent predictor of LVEDV. Moreover, miR-499-5p was a predictor of the VO2 peak. Finally, a cluster of 5 miRNAs discriminated New York Heart Association (NYHA) class-I from HC subjects. (4)Conclusions: Our data suggest that circulating miRNAs have the potential to serve as pathophysiology-based markers of HF status and progression, and as indicators of pre-symptomatic individuals.

15.
Polymers (Basel) ; 12(10)2020 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-33080828

RESUMO

Films exhibiting co-crystalline (CC) phases between a polymer host and low-molecular-mass guest molecules are relevant for many applications. As is usual for semi-crystalline polymers, axially oriented films can give relevant information on the crystalline structure, both by Wide Angle X-ray diffraction fiber patterns and by polarized Fourier-transform infrared spectroscopy. Axially oriented CC phases of poly(2,6-dimethyl-1,4-phenylene)oxide (PPO) with 1,3,5-trimethylbenzene (mesitylene) can be simply obtained by the stretching of CC PPO films. In fact, due to the plasticization effect of this highly boiling guest, PPO orientation can occur in a stretching temperature range (170-175 °C) nearly 50 °C lower than that generally needed for PPO films (220-230 °C). This low stretching temperature range allows avoidance of polymer oxidation, as well as formation of the mesomorphic dense γ PPO phase. Axially oriented CC phases of PPO with toluene, i.e., with a more volatile guest, can be instead obtained by the stretching (in the same low temperature range: 170-175 °C) of CC PPO blend films with polystyrene.

16.
Front Cell Dev Biol ; 8: 550543, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33015055

RESUMO

SERine Protein INhibitor-A1 (SERPINA1) is an inducible blood cell gene coding for alpha1-antitrypsin (AAT), a plasma protease inhibitor whose circulating levels are raised during inflammation, infection and advanced pregnancy. DNA methylation has been suggested to play a role in SERPINA1 gene expression regulation in peripheral blood mononuclear cells (PBMCs). The methylation status of SERPINA1 in PBMCs is unknown. The aim of this study was to evaluate the methylation profile of the SERPINA1 promoter in PBMC. To this purpose PBMCs and serum were collected from healthy subjects (HS) (n = 75), including blood donors (BD) (n = 25), pregnant women at early pregnancy (EP) (n = 25), i.e., within the first trimester, and pregnant women at late pregnancy (LP) (n = 25), i.e., at the third trimester. DNA from PBMCs was treated with sodium bisulfite and PCR amplified for SERPINA1 gene promoter, followed by sequencing analyses. AAT serum levels were determined by ELISA test. SERPINA1 was found hypermethylated in 58.7% of HS. The prevalence of SERPINA1 hypermethylation was significantly higher in BD (68%) and EP (88%) than in LP (20%) (p < 0.01). The median serum AAT concentration was 1.07, 0.63, and 3.15 mg/ml in BD, EP, and LP, respectively (p < 0.05, BD and EP vs LP). This study indicates, for the first time, that SERPINA1 gene promoter is differentially methylated in PBMCs from HS. Likely, modulation of the methylation may be a novel epigenetic regulator mechanism of AAT expression in the PBMC of HS. Therefore, SERPINA1 gene promoter methylation may represent an epigenetic biomarker of PBMCs in healthy subjects.

17.
J Clin Med ; 9(8)2020 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-32748835

RESUMO

Some random mutations can confer a selective advantage to a hematopoietic stem cell. As a result, mutated hematopoietic stem cells can give rise to a significant proportion of mutated clones of blood cells. This event is known as "clonal hematopoiesis." Clonal hematopoiesis is closely associated with age, and carriers show an increased risk of developing blood cancers. Clonal hematopoiesis of indeterminate potential is defined by the presence of clones carrying a mutation associated with a blood neoplasm without obvious hematological malignancies. Unexpectedly, in recent years, it has emerged that clonal hematopoiesis of indeterminate potential carriers also have an increased risk of developing cardiovascular disease. Mechanisms linking clonal hematopoiesis of indeterminate potential to cardiovascular disease are only partially known. Findings in animal models indicate that clonal hematopoiesis of indeterminate potential-related mutations amplify inflammatory responses. Consistently, clinical studies have revealed that clonal hematopoiesis of indeterminate potential carriers display increased levels of inflammatory markers. In this review, we describe progress in our understanding of clonal hematopoiesis in the context of cancer, and we discuss the most recent findings linking clonal hematopoiesis of indeterminate potential and cardiovascular diseases.

18.
JCI Insight ; 5(13)2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32641585

RESUMO

The epithelial filtration slit is a crucial component of the glomerular capillary membrane, which is essential for maintaining glomerular filtration function. Though chronic kidney diseases are an immense clinical problem, the mechanisms through which structural alterations reduce glomerular water filtration have not yet been understood completely. To investigate the mechanisms underlying filtration function loss, we studied rats with spontaneously occurring progressive kidney disease, either treated with angiotensin II antagonist or untreated, combining high-resolution electron microscopy of the glomerular capillary wall with theoretical water filtration modeling. Under pathological conditions, epithelial filtration pores and the extension of the subpodocyte space were larger than in normal controls. Numerical analyses indicated that these ultrastructural changes increased hydraulic resistance of the glomerular capillary wall by extending coverage of the filtration barrier by the subpodocyte space, with the changes in hydrodynamic forces acting on podocytes likely being responsible for their detachment. Angiotensin II inhibition normalized the subpodocyte space's hydraulic resistance, restored mechanical podocyte load, and preserved CD151-α3 integrin complex assembly, improving podocyte adherence and survival. Our results show that ultrastructural changes in podocytes are major determinants of the hydraulic resistance of the glomerular capillary wall and highlight the mechanism of podocyte loss in kidney disease progression, as well as the mechanisms underlying angiotensin II inhibition.


Assuntos
Capilares/ultraestrutura , Glomérulos Renais/ultraestrutura , Rim/ultraestrutura , Permeabilidade , Animais , Rim/patologia , Nefropatias/patologia , Masculino , Microscopia Eletrônica/métodos , Podócitos/patologia , Proteinúria/patologia , Ratos , Ultrafiltração/métodos
19.
Basic Res Cardiol ; 115(3): 31, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32274570

RESUMO

From January 2020, coronavirus disease (COVID-19) originated in China has spread around the world. The disease is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The presence of myocarditis, cardiac arrest, and acute heart failure in COVID-19 patients suggests the existence of a relationship between SARS-CoV-2 infection and cardiac disease. The Notch signalling is a major regulator of cardiovascular function and it is also implicated in several biological processes mediating viral infections. In this report we discuss the possibility to target Notch signalling to prevent SARS-CoV-2 infection and interfere with the progression of COVID-19- associated heart and lungs disease.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/fisiopatologia , Cardiopatias/tratamento farmacológico , Cardiopatias/etiologia , Pneumopatias/tratamento farmacológico , Pneumopatias/etiologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/fisiopatologia , Receptores Notch/antagonistas & inibidores , Proteína ADAM17/antagonistas & inibidores , Enzima de Conversão de Angiotensina 2 , Betacoronavirus/efeitos dos fármacos , COVID-19 , China , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Progressão da Doença , Furina/metabolismo , Parada Cardíaca/etiologia , Parada Cardíaca/patologia , Cardiopatias/patologia , Cardiopatias/fisiopatologia , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/patologia , Humanos , Interleucina-6/imunologia , Pneumopatias/patologia , Pneumopatias/fisiopatologia , Miocardite/etiologia , Miocardite/patologia , Pandemias , Peptidil Dipeptidase A/deficiência , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Receptores Notch/metabolismo , SARS-CoV-2 , Transdução de Sinais/efeitos dos fármacos
20.
Int J Mol Sci ; 21(5)2020 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-32106619

RESUMO

Ticagrelor is a powerful P2Y12 inhibitor with pleiotropic effects in the cardiovascular system. Consistently, we have reported that in patients with stable coronary artery disease (CAD) and concomitant chronic obstructive pulmonary disease (COPD) who underwent percutaneous coronary intervention (PCI), 1-month treatment with ticagrelor was superior in improving biological markers of endothelial function, compared with clopidogrel. The objective of this study was to investigate the mechanisms underlying these beneficial effects of ticagrelor by conducting molecular analyses of RNA isolated from peripheral blood cells of these patients. We determined mRNAs levels of markers of inflammation and oxidative stress, such as RORγt (T helper 17 cells marker), FoxP3 (regulatory T cells marker), NLRP3, ICAM1, SIRT1, Notch ligands JAG1 and DLL4, and HES1, a Notch target gene. We found that 1-month treatment with ticagrelor, but not clopidogrel, led to increased levels of SIRT1 and HES1 mRNAs. In patients treated with ticagrelor or clopidogrel, we observed a negative correlation among changes in both SIRT1 and HES1 mRNA and serum levels of Epidermal Growth Factor (EGF), a marker of endothelial dysfunction found to be reduced by ticagrelor treatment in our previous study. In conclusion, we report that in stable CAD/COPD patients ticagrelor positively regulates HES1 and SIRT1, two genes playing a protective role in the context of inflammation and oxidative stress. Our observations confirm and expand previous studies showing that the beneficial effects of ticagrelor in stable CAD/COPD patients may be, at least in part, mediated by its capacity to reduce systemic inflammation and oxidative stress.


Assuntos
Células Sanguíneas/efeitos dos fármacos , Doença da Artéria Coronariana/metabolismo , Inibidores da Agregação Plaquetária/farmacologia , Doença Pulmonar Obstrutiva Crônica/metabolismo , Sirtuína 1/genética , Ticagrelor/farmacologia , Fatores de Transcrição HES-1/genética , Células Sanguíneas/metabolismo , Células Cultivadas , Fator de Crescimento Epidérmico/genética , Fator de Crescimento Epidérmico/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores Notch/genética , Receptores Notch/metabolismo , Transdução de Sinais , Sirtuína 1/metabolismo , Fatores de Transcrição HES-1/metabolismo
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