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1.
Am Heart J ; 226: 206-213, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32615358

RESUMO

INTRODUCTION: Endurance athletes are at higher risk for developing atrial fibrillation as compared to the general population. The exact mechanism to explain this observation is incompletely understood. Our study aimed to determine whether degree of left atrial fibrosis detected by late gadolinium-enhancement magnetic resonance imaging (LGE-MRI) differed between Masters athletes and non-athlete controls. METHODS: We recruited 20 endurance healthy Masters athletes and 20 healthy control subjects who underwent cardiac MRI. Healthy controls were recruited during screening colonoscopies and Masters athletes were recruited through word of mouth and at competitions. The two groups were age and gender matched. None of the participants were known to have an arrhythmia. Fibrosis, as measured by late gadolinium-enhancement, was measured in each participant by blinded readers. The degree of left atrial fibrosis was compared between the two groups. All participants were recruited from the Salt Lake City region and scanned at the University of Utah healthcare complex. RESULTS: Left ventricular function was normal in all study participants. Left atrial volumes were significantly larger in the athletes (74.2 ml ±â€¯14.4) as compared to the healthy control subjects (60.8 mL ±â€¯21.4) (P = .02). Mean left atrial fibrosis score, reported as a percentage of the LA, was 15.5% ±â€¯5.9 in the athlete cohort compared to 9.6% ±â€¯4.9 in the controls (P = .002). CONCLUSIONS: To our knowledge this is the first study that describes, characterizes and specifically quantifies fibrotic changes within the left atrium of highly trained endurance athletes. Increased atrial fibrosis seen in this population may be an early indicator for endurance athletes at risk of developing atrial arrhythmias.


Assuntos
Treino Aeróbico/efeitos adversos , Átrios do Coração/diagnóstico por imagem , Átrios do Coração/patologia , Imagem por Ressonância Magnética , Adulto , Estudos de Coortes , Meios de Contraste , Treino Aeróbico/métodos , Feminino , Fibrose/diagnóstico por imagem , Fibrose/etiologia , Gadolínio , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Esportes
2.
Restor Neurol Neurosci ; 38(4): 343-354, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32597823

RESUMO

Covid-19 is the acute illness caused by SARS-CoV-2 with initial clinical symptoms such as cough, fever, malaise, headache, and anosmia. After entry into cells, corona viruses (CoV) activate aryl hydrocarbon receptors (AhRs) by an indoleamine 2,3-dioxygenase (IDO1)-independent mechanism, bypassing the IDO1-kynurenine-AhR pathway. The IDO1-kynurenine-AhR signaling pathway is used by multiple viral, microbial and parasitic pathogens to activate AhRs and to establish infections. AhRs enhance their own activity through an IDO1-AhR-IDO1 positive feedback loop prolonging activation induced by pathogens. Direct activation of AhRs by CoV induces immediate and simultaneous up-regulation of diverse AhR-dependent downstream effectors, and this, in turn, results in a "Systemic AhR Activation Syndrome" (SAAS) consisting of inflammation, thromboembolism, and fibrosis, culminating in multiple organ injuries, and death. Activation of AhRs by CoV may lead to diverse sets of phenotypic disease pictures depending on time after infection, overall state of health, hormonal balance, age, gender, comorbidities, but also diet and environmental factors modulating AhRs. We hypothesize that elimination of factors known to up-regulate AhRs, or implementation of measures known to down-regulate AhRs, should decrease severity of infection. Although therapies selectively down-regulating both AhR and IDO1 are currently lacking, medications in clinical use such as dexamethasone may down-regulate both AhR and IDO1 genes, as calcitriol/vitamin D3 may down-regulate the AhR gene, and tocopherol/vitamin E may down-regulate the IDO1 gene. Supplementation of calcitriol should therefore be subjected to epidemiological studies and tested in prospective trials for prevention of CoV infections, as should tocopherol, whereas dexamethasone could be tried in interventional trials. Because lack of physical exercise activates AhRs via the IDO1-kynurenine-AhR signaling pathway increasing risk of infection, physical exercise should be encouraged during quarantines and stay-at-home orders during pandemic outbreaks. Understanding which factors affect gene expression of both AhR and IDO1 may help in designing therapies to prevent and treat humans suffering from Covid-19.


Assuntos
Betacoronavirus/fisiologia , Infecções por Coronavirus/fisiopatologia , Indolamina-Pirrol 2,3,-Dioxigenase/fisiologia , Pandemias , Pneumonia Viral/fisiopatologia , Receptores de Hidrocarboneto Arílico/fisiologia , Poluentes Atmosféricos/efeitos adversos , Calcitriol/uso terapêutico , Infecções por Coronavirus/complicações , Infecções por Coronavirus/tratamento farmacológico , Dexametasona/uso terapêutico , Exercício Físico , Retroalimentação Fisiológica , Feminino , Fibrose/etiologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/biossíntese , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Inflamação/etiologia , Cinurenina/fisiologia , Masculino , Terapia de Alvo Molecular , Insuficiência de Múltiplos Órgãos/etiologia , Trabalho de Parto Prematuro/etiologia , Pneumonia Viral/complicações , Pneumonia Viral/tratamento farmacológico , Gravidez , Complicações Infecciosas na Gravidez/fisiopatologia , Receptores de Hidrocarboneto Arílico/biossíntese , Receptores de Hidrocarboneto Arílico/genética , Transtornos das Sensações/etiologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Tromboembolia/etiologia , Tocoferóis/uso terapêutico
3.
Invest Ophthalmol Vis Sci ; 61(5): 64, 2020 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-32462203

RESUMO

Purpose: To investigate the effect of Gypenosides (Gyps) on the inflammation and fibrosis in orbital fibroblasts (OFs) in Graves ophthalmopathy (GO). Methods: Bioinformatics analyses were performed to identify the enriched genes and signaling pathways related to Gyps function. For ex vivo experiments, OFs were cultured from orbital connective tissues from patients with GO. OF proliferation was estimated by Cell Counting Kit-8 assay. Effects of Gyps treatment on interleukin (IL)-1ß-induced inflammation and transforming growth factor-ß1 (TGF-ß1)-induced fibrosis were evaluated by real-time quantitative PCR (RT-qPCR), enzyme-linked immunosorbent assay (ELISA), and Western blotting. OFs were treated with IL-1ß or TGF-ß1 in the absence or presence of Gyps pretreatment, and the levels of related mRNA or proteins were evaluated by RT-qPCR or ELISA. Results: Eight inflammation-related target genes and nine fibrosis-related target genes were screened out. These genes were mainly enriched in pathways corresponding to inflammation and fibrosis, respectively. IL-1ß-induced upregulation of inflammatory cytokines, and TGF-ß-induced upregulation of fibrotic mediators in OFs were downregulated by Gyps. Moreover, Gyps reduced the activation of Toll like receptors 4/nuclear factor-κ B signaling and TGF-ß1/SMAD2/SMAD4 signaling in GO OFs. Conclusions: Gyps could protect GO-derived OFs against IL-1ß-induced inflammation and TGF-ß1-induced fibrosis. Thus Gyps might have therapeutic potential on inflammation and fibrosis in GO.


Assuntos
Fibroblastos/efeitos dos fármacos , Oftalmopatia de Graves/complicações , Oftalmopatia de Graves/patologia , Inflamação/prevenção & controle , Adulto , Células Cultivadas , Feminino , Fibrose/etiologia , Fibrose/prevenção & controle , Gynostemma , Humanos , Inflamação/etiologia , Masculino , Pessoa de Meia-Idade , Órbita/citologia , Extratos Vegetais/farmacologia , Adulto Jovem
4.
Curr Diab Rep ; 20(6): 19, 2020 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-32277298

RESUMO

PURPOSE OF REVIEW: Fibrocalculous pancreatic diabetes (FCPD) is an uncommon form of diabetes occurring in underprivileged developing countries of the world. We attempt to review the latest evidence on epidemiology, secular trends, etiopathogenic mechanisms, and treatment modalities of FCPD with particular reference to studies from the past decade. RECENT FINDINGS: There has been little new data on FCPD over the past decade even from countries where it was considered to be prevalent. There appears to be a decline in prevalence of the condition of late. There is also some evidence to show that the condition develops due to as yet unknown environmental influences acting on a background of genetic susceptibility. FCPD is a severe form of diabetes and may be a premalignant condition. FCPD deserves more attention than it currently receives, because of its unique clinical features and management strategies, and its propensity to develop pancreatic adenocarcinoma.


Assuntos
Adenocarcinoma/etiologia , Diabetes Mellitus/diagnóstico , Neoplasias Pancreáticas/etiologia , Pancreatite Crônica/diagnóstico , Lesões Pré-Cancerosas/etiologia , Adenocarcinoma/diagnóstico , Calcinose/etiologia , Países em Desenvolvimento , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/etiologia , Diabetes Mellitus/terapia , Fibrose/etiologia , Interação Gene-Ambiente , Predisposição Genética para Doença , Humanos , Neoplasias Pancreáticas/diagnóstico , Pancreatite Crônica/epidemiologia , Pancreatite Crônica/etiologia , Pancreatite Crônica/terapia , Lesões Pré-Cancerosas/diagnóstico , Prevalência , Clima Tropical
5.
Life Sci ; 251: 117644, 2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32259604

RESUMO

AIMS: Electronic cigarette (ECIG) has been used as an alternative to tobacco smoking as it lacks the majority of toxicants found in tobacco smoke. However, the effect of ECIG aerosol inhalation on cardiac health are not well studied. The present study aimed to compare the effects of ECIGs with that of combustible tobacco cigarette (T-Cigs) and waterpipe (WP) smoke on cardiac biomarkers of oxidative stress, inflammation, and fibrosis. MAIN METHODS: Rats were randomized into control (fresh air, n = 12), ECIG aerosol (n = 12), T-Cig smoke (n = 15), or WP (n = 13) smoke conditions in which they were exposed 1 h/daily, 6 day/week for 4 weeks. Cardiac biomarkers of oxidative stress, inflammation, and remodeling were assessed. KEY FINDINGS: Relative to control, significant increase in heart to body weight ratio was observed in all exposed groups. Cardiac endothelin-1 and myeloperoxidase were increased for ECIG and T-Cig. Cardiac nitrite and TBARS were increased in all exposed groups, but activity of superoxide dismutase was increased for ECIG and T-Cig only while glutathione levels increased for ECIG only. No changes were observed for cardiac C-reactive protein and catalase activity. Cardiac fibrosis was observed in all exposed groups coupled with an increase in the transforming growth factor beta protein that was significant for ECIG only. SIGNIFICANCE: ECIG aerosol may promote cardiac alterations in similar manner to tobacco smoke by promoting myocardial oxidative stress and inflammation leading to fibrosis. With regard to cardiac health, exposure to ECIG aerosol and combustible T-Cig smoke may lead to similar adverse outcomes.


Assuntos
Sistemas Eletrônicos de Liberação de Nicotina , Inflamação/etiologia , Miocárdio/patologia , Fumaça/efeitos adversos , Poluição por Fumaça de Tabaco/efeitos adversos , Aerossóis , Animais , Fumar Cigarros/efeitos adversos , Fibrose/etiologia , Inflamação/patologia , Masculino , Estresse Oxidativo , Distribuição Aleatória , Ratos , Ratos Wistar , Vaping/efeitos adversos , Fumar Cachimbo de Água/efeitos adversos
6.
Arch Biochem Biophys ; 685: 108354, 2020 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-32240638

RESUMO

BACKGROUND: Cardiac fibrosis following myocardial infarction (MI) leads to cardiac remodeling and dysfunction. Dysregulation of Smad7 which negatively regulates the profibrotic transforming growth factor-ß1 (TGF-ß1)/Smad signaling promotes cardiac fibrosis. However, the molecular mechanisms underlying TGF-ß1/Smad7 dysregulation remain elusive. Long non-coding RNAs (lncRNAs) are recently emerging as important regulators of cardiac diseases. Here, we report lnc-Ang362 is a novel lncRNA mediating MI-induced fibrosis through TGF-ß1/Smad7 signaling pathway. METHODS AND RESULTS: The MI model was established by artificial coronary artery occlusion in rats. Microarray analysis identified 215 lncRNAs (fold change > 2.0, P < 0.05) differentially expressed between MI hearts and the sham group 4 weeks after MI. Lnc-Ang362 had the highest fold upregulation and the change was validated by reverse transcription polymerase chain reaction. Also, MI caused a marked increase in TGF-ß1 and collagen I/III expression, but significantly downregulated Smad7 expression. Adult rat cardiac fibroblasts (RCFs) treated with TGF-ß1 showed increased lnc-Ang362 expression and decreased Smad7 expression. Moreover, overexpression and knockdown of lnc-Ang362 by small interfering RNAs reduced and increased Smad7 expression, respectively. Importantly, this result was negatively correlated with the expression of collagen I/III in RCFs. Furthermore, the luciferase reporter assays confirmed that Smad7 was a validated lnc-Ang362 target. Further silencing Smad7 attenuated the effects of lnc-Ang362 knockdown on decreasing collagen I/III expression in RCFs. CONCLUSIONS: These results suggested lnc-Ang362 promoted cardiac fibrosis after MI via directly suppressing Smad7, which may decrease the inhibitory feedback regulation of TGF-ß1/Smad signaling pathway. Thus, lnc-Ang362 may be a novel profibrotic lncRNA in the regulation of cardiac fibrosis post MI.


Assuntos
Fibrose/metabolismo , Infarto do Miocárdio/complicações , Miocárdio/metabolismo , RNA Longo não Codificante/metabolismo , Proteína Smad7/metabolismo , Animais , Sequência de Bases , Colágeno/metabolismo , Regulação para Baixo , Fibrose/etiologia , Masculino , Ratos Sprague-Dawley , Fator de Crescimento Transformador beta1/metabolismo , Regulação para Cima
7.
Curr Diab Rep ; 20(6): 16, 2020 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-32221727

RESUMO

PURPOSE OF REVIEW: The aim was to review evidence about diabetes secondary to hereditary pancreatitis, seeking novel diagnostic and treatment features. RECENT FINDINGS: Hereditary pancreatitis (HP) is an autosomal dominant condition, characterized by recurrent episodes of acute pancreatitis, progression to fibrosis, and chronic pancreatitis. Clinical presentation includes diabetes of the exocrine pancreas (DEP). HP prevalence ranges from 0.3 to 0.57 per 100,000 people, with up to 80% of these develop DEP. This condition often requires specific interventions: with regard to metabolic control, metformin is the first choice for those with mild DEP, and for those in advanced disease, insulin is considered the first-line therapy. Insulin analogues and insulin pump therapy are preferred due to the brittle glycemic pattern and risk of hypoglycemia. In case of exocrine insufficiency, pancreatic enzyme replacement therapy is recommended. Pancreatic polypeptide administration is a promising novel treatment feature. DEP due to HP appears to be a misdiagnosed condition. The requirement of specific management demonstrates the importance of this matter; therefore, appropriate recognition and classification are important.


Assuntos
Diabetes Mellitus/genética , Pâncreas Exócrino/patologia , Pancreatite Crônica/genética , Tripsina/genética , Doença Aguda , Carcinoma Ductal Pancreático/etiologia , Quimotripsina/genética , Complicações do Diabetes/complicações , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/fisiopatologia , Diabetes Mellitus/terapia , Insuficiência Pancreática Exócrina/genética , Insuficiência Pancreática Exócrina/fisiopatologia , Insuficiência Pancreática Exócrina/terapia , Fibrose/etiologia , Humanos , Pâncreas Exócrino/fisiopatologia , Neoplasias Pancreáticas/etiologia , Pancreatite Crônica/complicações , Pancreatite Crônica/diagnóstico , Pancreatite Crônica/fisiopatologia , Recidiva , Fatores de Risco , Inibidor da Tripsina Pancreática de Kazal/genética
8.
Clin Sci (Lond) ; 134(6): 609-628, 2020 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-32175563

RESUMO

Diabetic cardiac fibrosis increases ventricular stiffness and facilitates the occurrence of diastolic dysfunction. Retinoid X receptor (RXR) plays an important role in cardiac development and has been implicated in cardiovascular diseases. In the present study, we investigated the effects of RXR agonist treatment on streptozotocin (STZ)-induced diabetic cardiomyopathy (DCM) and the underlying mechanism. Sprague-Dawley (SD) rats induced by STZ injection were treated with either RXR agonist bexarotene (Bex) or vehicle alone. Echocardiography was performed to determine cardiac structure and function. Cardiac fibroblasts (CFs) were treated with high glucose (HG) with or without the indicated concentration of Bex or the RXR ligand 9-cis-retinoic acid (9-cis-RA). The protein abundance levels were measured along with collagen, body weight (BW), blood biochemical indexes and transforming growth factor-ß (TGF-ß) levels. The effects of RXRα down-regulation by RXRα small interfering RNA (siRNA) were examined. The results showed that bexarotene treatment resulted in amelioration of left ventricular dysfunction by inhibiting cardiomyocyte apoptosis and myocardial fibrosis. Immunoblot with heart tissue homogenates from diabetic rats revealed that bexarotene activated liver kinase B1 (LKB1) signaling and inhibited p70 ribosomal protein S6 kinase (p70S6K). The increased collagen levels in the heart tissues of DCM rats were reduced by bexarotene treatment. Treatment of CFs with HG resulted in significantly reduced LKB1 activity and increased p70S6K activity. RXRα mediated the antagonism of 9-cis-RA on HG-induced LKB1/p70S6K activation changes in vitro. Our findings suggest that RXR agonist ameliorates STZ-induced DCM by inhibiting myocardial fibrosis via modulation of the LKB1/p70S6K signaling pathway. RXR agonists may serve as novel therapeutic agents for the treatment of DCM.


Assuntos
Bexaroteno/administração & dosagem , Cardiomiopatias/tratamento farmacológico , Diabetes Mellitus Tipo 1/complicações , Proteínas Serina-Treonina Quinases/metabolismo , Receptores X Retinoide/agonistas , Animais , Cardiomiopatias/etiologia , Cardiomiopatias/genética , Cardiomiopatias/metabolismo , Fibrose/tratamento farmacológico , Fibrose/etiologia , Fibrose/genética , Fibrose/metabolismo , Humanos , Masculino , Proteínas Serina-Treonina Quinases/genética , Ratos , Ratos Sprague-Dawley , Receptores X Retinoide/genética , Receptores X Retinoide/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Estreptozocina
9.
Oxid Med Cell Longev ; 2020: 8076105, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32089781

RESUMO

Diabetes affects a variety of organs such as the kidneys, eyes, and liver, and there is increasing evidence that the lung is also one of the target organs of diabetes and imbalance of Sirt3-mediated stress responses such as inflammation, oxidative stress, apoptosis, autophagy, and ER stress may contribute to diabetic lung fibrosis. Although previous studies have reported that mesenchymal stem cells (MSCs) have beneficial effects on various diabetic complications, the effect and mechanisms of MSCs on diabetes-induced lung injury are not clear. In this study, the STZ-induced diabetes model was constructed in rats, and the effect and potential mechanisms of bone marrow MSCs on diabetic lung fibrosis were investigated. The results revealed that fibrotic changes in the lung were successfully induced in the diabetic rats, while MSCs significantly inhibited or even reversed the changes. Specifically, MSCs upregulated the expression levels of Sirt3 and SOD2 and then activated the Nrf2/ARE signaling pathway, thereby controlling MDA, GSH content, and iNOS and NADPH oxidase subunit p22phox expression levels in the lung tissue. Meanwhile, high levels of Sirt3 and SOD2 induced by MSCs reduced the expression levels of IL-1ß, TNF-α, ICAM-1, and MMP9 by suppressing the NF-κB/HMGB1/NLRP3/caspase-1 signaling pathway, as well as regulating the expression levels of cleaved caspasese-3, Bax, and Bcl2 by upregulating the expression level of P-Akt, thereby inhibiting the apoptosis of the lung tissue. In addition, MSCs also regulated the expression levels of LC3, P62, BiP, Chop, and PERK, thereby enhancing autophagy and attenuating endoplasmic reticulum stress. Taken together, our results suggest that MSCs effectively attenuate diabetic lung fibrosis via adjusting Sirt3-mediated responses, including inflammation, oxidative stress, apoptosis, autophagy, and endoplasmic reticulum stress, providing a theoretical foundation for further exploration of MSC-based diabetic therapeutics.


Assuntos
Fibrose/etiologia , Pulmão/patologia , Células-Tronco Mesenquimais/metabolismo , Sirtuína 3/metabolismo , Animais , Apoptose , Diabetes Mellitus Experimental , Masculino , Camundongos , Coelhos , Ratos , Ratos Sprague-Dawley
10.
Arch Biochem Biophys ; 684: 108306, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32081684

RESUMO

Maternal endotoxemia has been shown to increase renal collagen deposition in the offspring. Renal fibrosis is a hallmark of progressive chronic kidney disease. It was investigated whether maternal reactive oxygen species (ROS) leads to renal fibrosis or exacerbates unilateral ureteral obstruction (UUO)-induced renal fibrosis in the offspring of dams treated with lipopolysaccharide (LPS). Furthermore, it was studied the role of matrix metalloproteinases (MMPs) in these changes. Adults Wistar rats were obtained from dams submitted to LPS administration through the third part of gestation. To evaluate the role of maternal ROS, part of the dams received α-tocopherol simultaneously with LPS. Part of the offspring in each group was submitted to UUO at adulthood when sub-groups were treated with NADPH oxidase inhibitor, apocynin. Maternal LPS administration increased proteinuria, systolic arterial pressure and renal collagen deposition in adult offspring. LPS offspring rats also presented higher MMP-2 activity in parallel to a decreased renal cortical TIMP-2 content. These changes were correlated to increased amounts of TGF-ß1 and NOX2. Maternal α-tocopherol treatment prevented collagen deposition and reduced arterial pressure in adult offspring. α-Tocopherol also inhibited maternal endotoxemia-induced changes in TGF-ß1/NOX2/MMP-2 signaling. UUO led to increased collagen deposition in the contralateral kidneys of LPS offspring, which was correlated to increased NADPH oxidase activity and prevented by NADPH oxidase inhibition. In summary, maternal endotoxemia led to alterations in the TGF-ß1/NOX2/MMP-2 signaling pathway in renal tissue concomitant with collagen deposition, therefore contributing to hypertension in adult offspring.


Assuntos
Colágeno/metabolismo , Endotoxemia/complicações , Nefropatias/etiologia , Rim/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Transdução de Sinais/fisiologia , Animais , Endotoxemia/induzido quimicamente , Matriz Extracelular/metabolismo , Feminino , Fibrose/etiologia , Fibrose/metabolismo , Lipopolissacarídeos , Masculino , Metaloproteinase 2 da Matriz/metabolismo , NADPH Oxidase 2/metabolismo , Gravidez , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta1/metabolismo , Obstrução Ureteral/complicações , Obstrução Ureteral/metabolismo , alfa-Tocoferol/farmacologia
11.
Diabetes Res Clin Pract ; 162: 108093, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32109518

RESUMO

AIMS: This study aimed to detect the effect of angiotensin-converting enzyme (ACE) 2-modified mesenchymal stem cells (MSCs) on glomerular fibrosis in vitro and in vivo and investigate the underlying molecular mechanism. METHODS: MSCs transduced with the ACE2 gene (MSCs-ACE2) were cocultured with glomerular mesangial cells (GMCs) following Ang II stimulation. MSCs-ACE2 were transplanted into streptozotocin-induced diabetic rats. Physical, biochemical and morphological parameters were measured, and fibrotic indicators and renin-angiotensin system (RAS) components in GMCs and kidney tissues were assessed. RESULTS: The transduction efficiency of MSCs was as high as 85%. The modified MSCs secreted soluble ACE2 protein into the culture medium. After transplantation into rats with diabetes, MSCs-ACE2 targeted injured kidneys and enhanced local expression of ACE2. Compared with MSC treatment alone, MSC-ACE2 treatment was superior in reducing albuminuria and improving glomerulosclerosis. In vitro and in vivo, MSCs-ACE2 were more beneficial than MSCs alone in decreasing Ang II and increasing Ang1-7, thereby inhibiting the detrimental effects of Ang II accumulation by downregulating collagen I and fibronectin (FN) expression and inhibiting the transforming growth factor (TGF-ß)/Smad pathway. CONCLUSIONS: MSCs modified with ACE2 therapy have additional benefits to the progression of diabetic nephropathy (DN) by inhibiting renal RAS activation and reducing glomerular fibrosis.


Assuntos
Diabetes Mellitus Experimental/fisiopatologia , Nefropatias Diabéticas/complicações , Fibrose/terapia , Glomérulos Renais/patologia , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/citologia , Peptidil Dipeptidase A/metabolismo , Animais , Fibrose/etiologia , Fibrose/patologia , Glomérulos Renais/metabolismo , Masculino , Células-Tronco Mesenquimais/química , Peptidil Dipeptidase A/genética , Ratos , Ratos Wistar , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo
12.
Rev Med Interne ; 41(5): 325-329, 2020 May.
Artigo em Francês | MEDLINE | ID: mdl-32046868

RESUMO

Fibrogenesis is a universal and ubiquitous process associated with tissue healing. The impairment of tissue homeostasis resulting from the deregulation of numerous cellular actors, under the effect of specific cytokine and pro-oxidative environments can lead to extensive tissue fibrosis, organ dysfunction and significant morbidity and mortality. This situation is frequent in internal medicine, since fibrosis is associated with most organ insufficiencies (i.e. cardiac, renal, or hepatic chronic failures), but also with cancer, a condition with common pathophysiological mechanisms. Finally, fibrosis is a hallmark of numerous systemic autoimmune diseases such as connective tissue disorders (in particular systemic sclerosis), vasculitides, granulomatoses, histiocytoses, and IgG4-associated disease. Although the process leading to tissue fibrosis may be in part irreversible, new pharmacological approaches or cell therapies bring hope in the field of fibrotic conditions.


Assuntos
Fibrose/diagnóstico , Fibrose/etiologia , Fibrose/patologia , Fibrose/terapia , Humanos , Medicina Interna/métodos , Neoplasias/etiologia , Neoplasias/patologia , Estresse Oxidativo/fisiologia , Lesões por Radiação/diagnóstico , Lesões por Radiação/etiologia , Lesões por Radiação/patologia , Radioterapia/efeitos adversos , Fatores de Risco , Transdução de Sinais/fisiologia , Terapias em Estudo/métodos , Terapias em Estudo/tendências
13.
J Knee Surg ; 33(1): 15-21, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30562834

RESUMO

This study aimed to develop a rabbit model of knee contracture in extension and investigate the natural history of motion loss and time-dependent changes in the joint capsule after immobilization. We immobilized the unilateral knee joints of 32 rabbits by maintaining the knee joint in a plaster cast at full extension. Eight rabbits were euthanized at 2, 4, 6, and 8 weeks after casting, respectively, and the lower extremities were disarticulated at the hip joint. Eight control group rabbits that did not undergo immobilization were also examined. We assessed the progression of joint contracture by measuring the joint range of motion, evaluating the histologic alteration of the capsule, and assessing the mRNA levels of transforming growth factor ß1 (TGF-ß1) in the anterior and posterior joint capsules. After 2 weeks of joint immobilization, the knee joint range of motion was limited, the synovial membrane of the suprapatellar and posterior joint capsules was thickened, the collagen deposition was increased, and the mRNA levels of TGF-ß1 were elevated in the anterior and posterior joint capsules. These changes progressed rapidly until 6 weeks of immobilization and may advance slowly after 6 weeks. Joint contracture developed at the early stage of immobilization and progressed over time. The changes in the anterior and posterior joint capsules after joint immobilization may contribute to the limitation in flexion. The elevated mRNA expression of TGF-ß1 may be related to joint capsule fibrosis and may be one of the causes of joint contracture.


Assuntos
Fibrose/patologia , Elevação dos Membros Posteriores/efeitos adversos , Membro Posterior/patologia , Imobilização/efeitos adversos , Cápsula Articular/patologia , Fator de Crescimento Transformador beta1/análise , Animais , Artrometria Articular , Moldes Cirúrgicos/efeitos adversos , Colágeno/biossíntese , Contratura/etiologia , Contratura/metabolismo , Contratura/patologia , Modelos Animais de Doenças , Progressão da Doença , Fibrose/etiologia , Fibrose/metabolismo , Membro Posterior/metabolismo , Membro Posterior/fisiopatologia , Imobilização/métodos , Cápsula Articular/química , Cápsula Articular/metabolismo , Masculino , RNA Mensageiro/análise , Coelhos , Amplitude de Movimento Articular , Membrana Sinovial/química , Membrana Sinovial/metabolismo , Membrana Sinovial/patologia
14.
Biomed Pharmacother ; 121: 109560, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31739160

RESUMO

Radiation-induced fibrosis (RIF) is a severe long-term complication of the normal tissue following radiotherapy. Its prototypical characteristic is the persistent activation of myofibroblasts, resulting in proportion disorder and hyperplasia remodeling of the extracellular matrix comprising collagen. The continuous progress of RIF may contribute to multiple clinical manifestations such as hollow organ stenosis, impaired gaseous diffusion, and loss of tissue compliance significantly affecting the overall quality of daily life in patients with irradiated cancer. Traditionally, the potential mechanism of myofibroblast activation and differentiation has not been elucidated, and the process has been considered as static and irreversible. Recent studies have shown that RIF is a dynamic, multi-step process mediated by many regulated chemokines and cytokines. The RIF process includes release of reactive oxygen species (ROS), microvascular injury, recruitment of inflammatory cells, and activation of myofibroblasts. Numerous signaling pathways are involved in the initiation and progression of RIF, of which SMAD-regulated CTGF expression mediated by TGF-ß1 is referred as the main axis. Current management strategies applied in clinical practice for patients with RIF are only supportive treatments, such as anti-inflammatory therapy using steroids; however, the efficacies achieved by these interventions are limited and unsatisfactory. Therefore, this review explores advances in RIF pathogenesis and anti-fibrosis therapy. We hope to provide clinicians with improved awareness and enormous promise in the management of RIF.


Assuntos
Miofibroblastos/patologia , Lesões por Radiação/patologia , Radioterapia/efeitos adversos , Animais , Fibrose/etiologia , Humanos , Neoplasias/radioterapia , Qualidade de Vida , Lesões por Radiação/terapia , Espécies Reativas de Oxigênio/metabolismo
15.
Eur Radiol ; 30(4): 1986-1996, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31858205

RESUMO

PURPOSE: To evaluate elasticity and perfusion change associated with fibrosis in a rabbit model of unilateral ureter obstruction using shear wave elastography (SWE) and contrast-enhanced ultrasonography (CEUS). METHODS: Complete unilateral ureter obstruction by ligation was performed in the left kidney of 15 rabbits. Renal elasticity on SWE and perfusion change on CEUS at the renal cortex were measured before and after the operation. Histopathological renal fibrosis was quantified by the stained area ratio with Masson trichrome and Picrosirius red using ImageJ analysis. Renal elasticity and perfusion values were compared by the Mann-Whitney U test and Proc Mixed as a function of time. Spearman's correlation was used to analyze differences between imaging values and fibrosis. RESULTS: The duration of imaging follow-up was up to 49 days, with interval imaging performed 1-3 times. Renal elasticity values were higher in obstructed kidneys compared to contralateral kidneys (31.0 kPa vs 16.4 kPa, p < 0.001) and increased according to postoperative time (0.46 kPa/day). With respect to renal fibrosis, SWE values were positively correlated with Masson trichrome (ρ = 0.651, p < 0.001) and Picrosirius red (ρ = 0.514, p = 0.007). Among CEUS parameters, mean transit time was negatively correlated with renal fibrosis by Masson trichrome (ρ = - 0.639, p = 0.001) and Picrosirius red (ρ = - 0.625, p = 0.001). Rise time and time to peak were positively correlated with renal fibrosis. CONCLUSION: Obstructive uropathy resulted in changes to both renal elasticity and perfusion. Renal fibrosis was moderately associated with increased renal cortical stiffness and both delayed and decreased cortical perfusion. KEY POINTS: • Obstructive uropathy causes changes in elasticity and perfusion in a rabbit model. • Renal fibrosis from obstructive uropathy increases renal cortical stiffness, and both delay and decrease cortical perfusion.


Assuntos
Fibrose/diagnóstico , Nefropatias/diagnóstico , Rim/diagnóstico por imagem , Ultrassonografia/métodos , Obstrução Ureteral/diagnóstico , Animais , Modelos Animais de Doenças , Elasticidade , Fibrose/etiologia , Humanos , Rim/fisiopatologia , Nefropatias/etiologia , Nefropatias/fisiopatologia , Coelhos , Obstrução Ureteral/complicações
16.
Klin Monbl Augenheilkd ; 236(12): 1428-1434, 2019 Dec.
Artigo em Alemão | MEDLINE | ID: mdl-31805595

RESUMO

BACKGROUND: The long-term success of fistulating therapies for the treatment of glaucoma is essentially limited by excessive scarring reactions (fibrosis). Cytostatic agents such as mitomycin C can prevent fibrosis, but are often associated with side effects. Specific antifibrotics are not currently in clinical use. Therefore, this study describes a systems biology approach using a dedicated bioinformatics technology platform, with which active substances can be identified and repositioned as antifibrotics. MATERIALS AND METHODS: Differential gene expression data of human Tenon fibroblasts (hTF) were collected from untreated hTF and from hTF stimulated with TGF-ß1 ("fibrotic fibroblasts") by next-generation sequencing (NGS) and were used as the basis for the drug identification process. These data were filtered with the bioinformatic tool "FocusHeuristics". In comparison with the Connectivity Map database, antifibrotic agents were identified. The evaluation of a potentially promising drug as an antifibrotic was performed at hTF by indirect immunofluorescence in vitro. RESULTS: The analysis of the gene expression data led to the identification of several interaction networks of genes or proteins involved in fibrotic processes. One of these networks contains the cytokine bone morphogenic protein 6 (BMP6), interleukin 6 (IL6) and fibroblast growth factor 1 (FGF1). Another relevant network has been identified around the cluster of differentiation 34 (CD34) gene. The comparison of these data with those of the Connectivity Map allowed the identification of an inhibitory drug. Its evaluation in the fibrotic cell culture model in vitro using indirect immunofluorescence led to a significant reduction in the expression of the fibrotic marker proteins fibronectin and alpha-smooth muscle actin (α-SMA), which confirmed the predicted antifibrotic effect. CONCLUSION: Systems biological approaches can be used for the identification of antifibrotic drug candidates for the prevention of postoperative fibrosis and should be transferable by the investigating differential gene expression data of further ocular cells or tissues to other ophthalmological fields of application.


Assuntos
Fibrose , Procedimentos Cirúrgicos Oftalmológicos , Oftalmologia , Biologia de Sistemas , Actinas , Fibroblastos , Fibrose/etiologia , Fibrose/prevenção & controle , Humanos , Mitomicina , Procedimentos Cirúrgicos Oftalmológicos/efeitos adversos , Complicações Pós-Operatórias
17.
PLoS One ; 14(12): e0224457, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31821335

RESUMO

No method has yet been approved for detecting lymphedema fibrosis before its progression. This study assessed the feasibility of computed tomography-based estimation of fibrosis. This observational, cross-sectional study included patients with lymphedema affecting one limb. Three types (maximum, mean, minimum) of computed tomography reticulation indexes were digitally calculated from trans-axial images using absorptive values, and the computed tomography reticulation indexes compared with clinical scales and measurements. Of 326 patients evaluated by at least one of lymphoscintigraphy, bio-electrical impedance, and computed tomography, 24 were evaluated by all three. The mean number of computed tomography scans in these patients was 109. Sixteen patients had breast cancer, seven had gynecologic cancers, and one had primary lymphedema. Mean computed tomography reticulation index (r = 0.52, p < 0.01) and maximal computed tomography reticulation index (r = 0.45, p < 0.05) were significantly associated with time from initial limb swelling to computed tomography. Mean computed tomography reticulation index (r = 0.86, p < 0.01), minimal computed tomography reticulation index (r = 0.79, p < 0.01), and maximal computed tomography reticulation index (r = 0.68, p < 0.01) were significantly associated with International Society of Lymphedema substage. Minimal computed tomography reticulation index correlated with 1-kHz-based bio-electrical impedance ratio (r = -0.46, p < 0.05) and with standardized proximal limb circumference difference ratio (r = 0.45, p < 0.05) of both limbs. Maximal computed tomography reticulation index had a sensitivity of 0.78, specificity of 0.60, and areas under the curve of 0.66 in detecting lymphoscintigraphic stage IV. The algorithm utilizing three-dimensional computed tomography images of epifascial fibrosis may be used as a marker for lymphedema duration, limb swelling, International Society of Lymphedema substage, and interstitial lymphatic fluids of lymphedema. The current approach shows promise in providing an additional method to assist in characterizing and monitoring lymphedema patients.


Assuntos
Algoritmos , Fibrose/diagnóstico , Imageamento Tridimensional/métodos , Linfedema/complicações , Tomografia Computadorizada por Raios X/métodos , Estudos de Coortes , Estudos Transversais , Impedância Elétrica , Estudos de Viabilidade , Feminino , Fibrose/diagnóstico por imagem , Fibrose/etiologia , Humanos , Linfocintigrafia/métodos , Masculino , Pessoa de Meia-Idade
18.
Cell Mol Biol (Noisy-le-grand) ; 65(7): 123-126, 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31880529

RESUMO

The aim of this study is to investigate  the effect of mesenchymal stem cell (MSC)-derived exosomes on diabetes mellitus-induced myocardial injury, and the underlying mechanism. Thirty adult male Sprague Dawley rats were randomly assigned to three groups of ten rats each: normal control group, diabetic control group and MSC exosomes group. Exosomes were isolated from MSCs through gradient ultracentrifugation. With the exception of normal control, diabetes mellitus (DM) was induced in the rats with a single intraperitoneal injection of 30 mg/kg body weight streptozotocin (STZ) in 0.1 mol/L sodium citrate buffer. Rats in MSC exosomes group were intravenously injected with MSC-derived exosomes once a week for 12 weeks. Left ventricular collagen (LVC) level was measured using acid hydrolysis method. Fatty acid transporters (FATPs) and fatty acid beta oxidase (FA-ß-oxidase) were determined using enzyme-linked immunosorbent assay (ELISA). Gene and protein expressions of TGF-ß and Smad2 were determined using real-time quantitative polymerase chain reaction (qRT-PCR) and Western blotting. Flow cytometric analysis and Western blotting revealed positive expression of exosomal specific marker, CD63. The level of LVC was significantly higher in diabetic control group than in normal control group, but was significantly reduced after treatment with MSC-derived exosomes (p < 0.05). The levels of FATPs and FA-ß-oxidase were significantly lower in diabetic control group than in normal control group (p < 0.05). However, treatment with MSC-derived exosomes significantly increased the levels of these proteins (p < 0.05). The levels of expression of TGF-ß1 and Smad2 mRNAs were significantly higher in the diabetic control group than in normal control group, but were significantly reduced after treatment with MSC-derived exosomes (p < 0.05). The expressions of TGF-ß1 and Smad2 proteins were also significantly upregulated in diabetic control group, when compared with normal control group (p < 0.05). However, treatment with MSC-derived exosomes significantly down-regulated the expression of these proteins (p < 0.05). The results obtained in this study indicate that MSC-derived exosomes improve DM-induced myocardial injury and fibrosis via inhibition of TGF-ß1/Smad2 signaling pathway.


Assuntos
Diabetes Mellitus Experimental/complicações , Cardiomiopatias Diabéticas/etiologia , Cardiomiopatias Diabéticas/metabolismo , Exossomos/metabolismo , Fibrose/metabolismo , Células-Tronco Mesenquimais/metabolismo , Proteína Smad2/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Animais , Western Blotting , Diabetes Mellitus Experimental/metabolismo , Exossomos/fisiologia , Fibrose/etiologia , Masculino , Miocárdio/metabolismo , Miocárdio/patologia , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa
19.
Trials ; 20(1): 775, 2019 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-31882012

RESUMO

BACKGROUND: Head and neck cancer (HNC) patients are at high risk for developing lymphedema and fibrosis (LEF) following cancer treatment. Once HNC patients develop LEF, they need to conduct life-long self-care to slow LEF progression and reduce associated symptom burden and functional deficits. Data demonstrate that inadequate LEF self-care may be a potentially remediable issue. The objective of this study is to explore the feasibility and preliminary efficacy of an Information-Motivation-Behavioral (IMB) Skills model-driven self-care program (SCP) to improve LEF management and reduce LEF-related symptom burden and functional impairments. METHODS/DESIGN: This is a three-arm, prospective, randomized controlled clinical trial to compare: Group 1 - Usual Care, Group 2 - Usual Care Plus LEF-SCP, and Group 3 - Usual Care Plus LEF-SCP Plus Follow-Up. Participants will be HNC survivors aged > 18 years of age, who meet predefined inclusion and exclusion criteria. A sample size of 75 participants is targeted. Interventions will be provided by trained staff. The study assessments for all groups will take place at five points: study entry then 3, 6, 9, and 12 months post enrollment. Outcome measures include: (1) feasibility (barriers to implementation, safety, and satisfaction) of the proposed intervention; (2) self-efficacy and adherence to self-care; and (3) preliminary efficacy (LEF progression, symptom burden, and functional status) of the proposed intervention. DISCUSSION: This will be the first study to evaluate the feasibility of a LEF-SCP in the HNC population and its impact on self-efficacy and adherence. Furthermore, it will evaluate the potential benefit of routine follow-up on adherence and fidelity to the self-care protocol. We expect that the trial will provide evidence supporting the feasibility of a LEF self-care program. In addition, we anticipate that preliminary data will support improved outcomes including increased adherence and fidelity, and decreased LEF-associated symptoms. TRIAL REGISTRATION: ClinicalTrials.gov, a service of the US National Institute of Health (NCT03030859). Registered on 22 January 2017.


Assuntos
Neoplasias de Cabeça e Pescoço , Linfedema , Qualidade de Vida , Autocuidado , Adaptação Psicológica , Adulto , Fibrose/etiologia , Fibrose/psicologia , Fibrose/terapia , Neoplasias de Cabeça e Pescoço/complicações , Neoplasias de Cabeça e Pescoço/terapia , Humanos , Linfedema/etiologia , Linfedema/psicologia , Linfedema/terapia , Motivação , Avaliação de Resultados em Cuidados de Saúde , Participação do Paciente , Desempenho Físico Funcional , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa , Autocuidado/métodos , Autocuidado/psicologia , Cooperação e Adesão ao Tratamento
20.
Molecules ; 24(22)2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31752262

RESUMO

Fibrosis is a type of chronic organ failure, resulting in the excessive secretion of extracellular matrix (ECM). ECM protects wound tissue from infection and additional injury, and is gradually degraded during wound healing. For some unknown reasons, myofibroblasts (the cells that secrete ECM) do not undergo apoptosis; this is associated with the continuous secretion of ECM and reduced ECM degradation even during de novo tissue formation. Thus, matrix metalloproteinases (MMPs) are considered to be a potential target of fibrosis treatment because they are the main groups of ECM-degrading enzymes. However, MMPs participate not only in ECM degradation but also in the development of various biological processes that show the potential to treat diseases such as stroke, cardiovascular diseases, and arthritis. Therefore, treatment involving the targeting of MMPs might impede typical functions. Here, we evaluated the links between these MMP functions and possible detrimental effects of fibrosis treatment, and also considered possible approaches for further applications.


Assuntos
Fibrose/etiologia , Fibrose/metabolismo , Metaloproteinases da Matriz/metabolismo , Metaloproteinases da Matriz/farmacologia , Animais , Suscetibilidade a Doenças , Ativação Enzimática , Matriz Extracelular/metabolismo , Fibrose/tratamento farmacológico , Regulação da Expressão Gênica , Humanos , Imunomodulação , Metaloproteinases da Matriz/genética , Metaloproteinases da Matriz/uso terapêutico , Miofibroblastos/metabolismo , Neovascularização Patológica , Especificidade de Órgãos/genética , Proteólise , Cicatrização
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