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PURPOSE: A variety of pathologic conditions may increase oxidative stress in semen resulting in structural modifications to spermozoa's plasma membrane that interfere with sperm motility, morphology, and count. Antioxidants are currently being marketed to treat male infertility. In semen, antioxidants may decrease oxidative stress and potentially improve sperm parameters. In this narrative, mini-review we evaluated the effectiveness of antioxidants in infertility. METHODS: This mini-review of the current literature has been carried out through searching of the PubMed and Google scholar databases. RESULTS AND CONCLUSIONS: The literature review suggests that there is evidence that oral antioxidants such as selenium, carnitine, zinc, coenzymeQ10, vitamins E and C, etc. alone or in combinations, improve sperm count, motility, morphology as well as pregnancy rates in infertile men with idiopathic oligoasthenospermia. Unfortunately, most of these studies are poorly designed, limited by sample size, varying in dosage, differing in primary end points, and most notably lacking live birth data. Importantly, large randomized, well-designed, placebo-controlled trials are needed.
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Antioxidantes , Infertilidade Masculina , Gravidez , Feminino , Masculino , Humanos , Antioxidantes/uso terapêutico , Sêmen , Motilidade dos Espermatozoides , Espermatozoides/metabolismo , Infertilidade Masculina/tratamento farmacológico , Infertilidade Masculina/metabolismo , Contagem de EspermatozoidesRESUMO
Virus-induced lung injury is associated with loss of pulmonary epithelial-endothelial tight junction integrity. While the alveolar-capillary membrane may be an indirect target of injury, viruses may interact directly and/or indirectly with miRs to augment their replication potential and evade the host antiviral defense system. Here, we expose how the influenza virus (H1N1) capitalizes on host-derived interferon-induced, microRNA (miR)-193b-5p to target occludin and compromise antiviral defenses. Lung biopsies from patients infected with H1N1 revealed increased miR-193b-5p levels, marked reduction in occludin protein, and disruption of the alveolar-capillary barrier. In C57BL/6 mice, the expression of miR-193b-5p increased, and occludin decreased, 5-6 days post-infection with influenza (PR8). Inhibition of miR-193b-5p in primary human bronchial, pulmonary microvascular, and nasal epithelial cells enhanced antiviral responses. miR-193b-deficient mice were resistant to PR8. Knockdown of occludin, both in vitro and in vivo, and overexpression of miR-193b-5p reconstituted susceptibility to viral infection. miR-193b-5p inhibitor mitigated loss of occludin, improved viral clearance, reduced lung edema, and augmented survival in infected mice. Our results elucidate how the innate immune system may be exploited by the influenza virus and how strategies that prevent loss of occludin and preserve tight junction function may limit susceptibility to virus-induced lung injury.
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Vírus da Influenza A Subtipo H1N1 , Influenza Humana , Lesão Pulmonar , MicroRNAs , Humanos , Animais , Camundongos , Influenza Humana/complicações , Influenza Humana/genética , Influenza Humana/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Ocludina/genética , Ocludina/metabolismo , Lesão Pulmonar/metabolismo , Junções Íntimas/metabolismo , Carga Viral , Vírus da Influenza A Subtipo H1N1/genética , Camundongos Endogâmicos C57BL , AntiviraisRESUMO
Acute Respiratory Distress Syndrome (ARDS) is characterized by lung inflammation and increased membrane permeability, which represents the leading cause of mortality in ICUs. Mechanical ventilation strategies are at the forefront of supportive approaches for ARDS. Recently, an increasing understanding of RNA biology, function, and regulation, as well as the success of RNA vaccines, has spurred enthusiasm for the emergence of novel RNA-based therapeutics. The most common types of RNA seen in development are silencing (si)RNAs, antisense oligonucleotide therapy (ASO), and messenger (m)RNAs that collectively account for 80% of the RNA therapeutics pipeline. These three RNA platforms are the most mature, with approved products and demonstrated commercial success. Most recently, miRNAs have emerged as pivotal regulators of gene expression. Their dysregulation in various clinical conditions offers insights into ARDS pathogenesis and offers the innovative possibility of using microRNAs as targeted therapy. This review synthesizes the current state of the literature to contextualize the therapeutic potential of miRNA modulation. It considers the potential for miR-based therapeutics as a nuanced approach that incorporates the complexity of ARDS pathophysiology and the multifaceted nature of miRNA interactions.
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MicroRNAs , Pneumonia , Síndrome do Desconforto Respiratório , Humanos , MicroRNAs/genética , Síndrome do Desconforto Respiratório/tratamento farmacológico , Pneumonia/complicações , Respiração Artificial/efeitos adversosRESUMO
Although mesenchymal stromal (stem) cell (MSC) administration attenuates sepsis-induced lung injury in pre-clinical models, the mechanism(s) of action and host immune system contributions to its therapeutic effects remain elusive. We show that treatment with MSCs decreased expression of host-derived microRNA (miR)-193b-5p and increased expression of its target gene, the tight junctional protein occludin (Ocln), in lungs from septic mice. Mutating the Ocln 3' untranslated region miR-193b-5p binding sequence impaired binding to Ocln mRNA. Inhibition of miR-193b-5p in human primary pulmonary microvascular endothelial cells prevents tumour necrosis factor (TNF)-induced decrease in Ocln gene and protein expression and loss of barrier function. MSC-conditioned media mitigated TNF-induced miR-193b-5p upregulation and Ocln downregulation in vitro When administered in vivo, MSC-conditioned media recapitulated the effects of MSC administration on pulmonary miR-193b-5p and Ocln expression. MiR-193b-deficient mice were resistant to pulmonary inflammation and injury induced by lipopolysaccharide (LPS) instillation. Silencing of Ocln in miR-193b-deficient mice partially recovered the susceptibility to LPS-induced lung injury. In vivo inhibition of miR-193b-5p protected mice from endotoxin-induced lung injury. Finally, the clinical significance of these results was supported by the finding of increased miR-193b-5p expression levels in lung autopsy samples from acute respiratory distress syndrome patients who died with diffuse alveolar damage.
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Lesão Pulmonar Aguda , MicroRNAs , Sepse , Lesão Pulmonar Aguda/terapia , Animais , Terapia Baseada em Transplante de Células e Tecidos , Células Endoteliais , Humanos , Camundongos , MicroRNAs/genética , Sepse/complicações , Sepse/terapiaRESUMO
Sepsis is a complicated multi-system disorder characterized by a dysregulated host response to infection. Despite substantial progress in the understanding of mechanisms of sepsis, translation of these advances into clinically effective therapies remains challenging. Mesenchymal Stromal Cells (MSCs) possess immunomodulatory properties that have shown therapeutic promise in preclinical models of sepsis. The therapeutic effects of MSCs may vary depending on the source and type of these cells. In this comparative study, the gene expression pattern and surface markers of bone marrow-derived MSCs (BM-MSCs) and umbilical cord-derived MSCs (UC-MSCs) as well as their therapeutic effects in a clinically relevant mouse model of polymicrobial sepsis, cecal ligation and puncture (CLP), were investigated. The results showed remarkable differences in gene expression profile, surface markers and therapeutic potency in terms of enhancing survival and pro/anti-inflammatory responses between the two MSC types. BM-MSCs improved survival concomitant with an enhanced systemic bacterial clearance and improved inflammatory profile post CLP surgery. Despite some improvement in the inflammatory profile of the septic animals, treatment with UC-MSCs did not enhance survival or bacterial clearance. Overall, the beneficial therapeutic effects of BM-MSCs over UC-MSCs may likely be attributed to their pro-inflammatory function, and to some extent anti-inflammatory features, reflected in their gene expression pattern enhancing macrophage polarization to M1/M2 phenotypes resulting in a balanced pro- and anti-inflammatory response against polymicrobial sepsis.
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Células da Medula Óssea/citologia , Transplante de Medula Óssea , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Sepse/terapia , Animais , Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Transplante de Medula Óssea/métodos , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Imunofenotipagem , Masculino , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/imunologia , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Sepse/genética , Sepse/imunologia , Sepse/patologiaRESUMO
ABSTRACT: Accumulating evidence indicates that heat shock proteins (HSPs) may represent a suitable biomarker to predict atrial fibrillation (AF). We investigated the relation of circulating serum HSP70 (sHSP70) with inflammatory cytokines and recurrence of symptomatic recent onset AF (ROAF). We enrolled 90 patients with ROAF (the duration from onset of symptoms ≤24 hours) and 30 controls. Patients received amiodarone for cardioversion and rhythm control. The association of serum HSP70, serum interleukin-2 (sIL-2), and serum interleukin-4 (sIL-4) with the presence of cardioversion and AF recurrence within a year was investigated. Toll-like receptor 4 (TLR4) signaling dependence for IL-2 and IL-4 induction in response to stimulation with HSP70 was tested in rat aortic vascular smooth muscle cell cultures. Patients had higher sHSP70 and sIL-2 and lower sIL-4 compared with controls. Serum HSP70 was independently associated with ROAF (P = 0.005) and correlated with sIL-2 (r = 0.494, P < 0.001) and sIL-4 (r = -0.550, P < 0.001). By 48 hours, 71 of the 90 patients were cardioverted, with noncardioverted patients having higher sHSP70 and sIL-2 and lower sIL-4, which were the only independent factors associated with cardioversion. AF recurred in 38 of the 71 cardioverted patients in 1 year. A cutoff value of sHSP70 ≥0.65 ng/mL and sIL-2 ≥0.21 pg/mL was the only independent factor associated with AF recurrence (hazard ratio: 3.311, 95% confidence interval: 1.503-7.293, P = 0.003 and hazard ratio: 3.144, 95% confidence interval: 1.341-7.374, P = 0.008, respectively). The exposure of smooth muscle cell to HSP70 in vitro increased the expression of IL-2 (5×) and IL-4 (1.5×) through TLR4-dependent and receptor-independent mechanisms. In conclusion, sHSP70 and sIL-2 might constitute a prognostic tool for determining the cardioversion and recurrence likelihood in ROAF.
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Fibrilação Atrial/terapia , Cardioversão Elétrica , Hipertensão Essencial/complicações , Proteínas de Choque Térmico HSP70/sangue , Idoso , Animais , Fibrilação Atrial/sangue , Fibrilação Atrial/etiologia , Fibrilação Atrial/fisiopatologia , Biomarcadores/sangue , Pressão Sanguínea , Estudos de Casos e Controles , Células Cultivadas , Cardioversão Elétrica/efeitos adversos , Hipertensão Essencial/sangue , Hipertensão Essencial/fisiopatologia , Feminino , Frequência Cardíaca , Humanos , Mediadores da Inflamação/sangue , Interleucina-2/sangue , Interleucina-4/sangue , Masculino , Pessoa de Meia-Idade , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Estudos Prospectivos , Ratos , Ratos Sprague-Dawley , Recidiva , Indução de Remissão , Transdução de Sinais , Fatores de Tempo , Receptor 4 Toll-Like/metabolismo , Resultado do TratamentoRESUMO
DJ-1 was originally identified as an oncogene product while mutations of the gene encoding DJ-1/PARK7 were later associated with a recessive form of Parkinson's disease. Its ubiquitous expression and diversity of function suggest that DJ-1 is also involved in mechanisms outside the central nervous system. In the last decade, the contribution of DJ-1 to the protection from ischemia-reperfusion injury has been recognized and its involvement in the pathophysiology of cardiovascular disease is attracting increasing attention. This review describes the current and gaps in our knowledge of DJ-1, focusing on its role in regulating cardiovascular function. In parallel, we present original data showing an association between increased DJ-1 expression and antiapoptotic and anti-inflammatory markers following cardiac and vascular surgical procedures. Future studies should address DJ-1's role as a plausible novel therapeutic target for cardiovascular disease.
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Coração/fisiopatologia , Traumatismo por Reperfusão Miocárdica , Miocárdio , Proteína Desglicase DJ-1/metabolismo , Animais , Biomarcadores/metabolismo , Humanos , Inflamação/metabolismo , Inflamação/patologia , Inflamação/fisiopatologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miocárdio/metabolismo , Miocárdio/patologiaRESUMO
We determined whether plasma concentrations of the receptor for advanced glycation end products (RAGE) and the soluble (s) form of RAGE (sRAGE) in healthy individuals and patients with type 2 diabetes (T2D) modulate vascular remodeling. Healthy individuals and patients with T2D were divided into two age groups: young = <35 years old or middle-aged (36-64 years old) and stratified based on normal glucose tolerance (NGT), impaired (IGT), and T2D. Plasma titers of sRAGE, the RAGE ligands, AGEs, S100B, S100A1, S100A6, and the apoptotic marker Fas ligand Fas(L) were measured by enzyme-linked immunosorbent assay (ELISA). The apoptotic potential of the above RAGE ligands and sRAGE were assessed in cultured adult rat aortic smooth muscle cells (ASMC). In NGT individuals, aging increased the circulating levels of AGEs and S100B and decreased sRAGE, S100A1 and S100A6. Middle-aged patients with T2D presented higher levels of circulating S100B, AGEs and FasL, but lower levels of sRAGE, S100A1 and S100A6 than individuals with NGT or IGT. Treatment of ASMC with either AGEs or S100B at concentrations detected in T2D patients increased markers of inflammation and apoptosis. Responses attenuated by concomitant administration of sRAGE. In middle-aged patients with T2D, lower circulating plasma levels of sRAGE may limit decoy and exogenous trapping of deleterious pro-apoptotic/pro-inflammatory RAGE ligands AGEs and S100B, increasing the risk for diabetic complications.
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Apoptose , Diabetes Mellitus Tipo 2/sangue , Ligantes , Receptor para Produtos Finais de Glicação Avançada/sangue , Receptor para Produtos Finais de Glicação Avançada/química , Adulto , Fatores Etários , Idoso , Animais , Antropometria , Proteínas de Ciclo Celular/metabolismo , Células Cultivadas , Endotélio Vascular/metabolismo , Proteína Ligante Fas/metabolismo , Feminino , Teste de Tolerância a Glucose , Humanos , Inflamação , Masculino , Pessoa de Meia-Idade , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso , Ratos , Proteína A6 Ligante de Cálcio S100/metabolismo , Subunidade beta da Proteína Ligante de Cálcio S100/metabolismo , Proteínas S100/metabolismo , Transdução de Sinais , Receptor fas/metabolismoRESUMO
The calcium binding protein S100B has been implicated in diabetic neuronal and vascular complications but has not been examined in the development of diabetes. S100B knock out (S100B KO) and wild-type (WT) mice were injected with 40â¯mg/kg body weight streptozotocin (STZ) for 5 days. Blood and pancreatic tissue samples were obtained to examine islet structure and function, the profile of glucose and insulin and expression of glucose transporter 2 (Glut2), S100B and its receptor, the receptor for advanced glycation end products (RAGE). Primary islet ß-cells cultures from WT mice were used to test the apoptotic potential of S100B. S100B KO mice were resistant to STZ induced-diabetes with lower urine volume, food and water intake compared to WT mice. S100B increased in the WT islet following diabetes but did not co-localize with beta or peri-islet Schwann cells but with CD3â¯+â¯T lymphocytes. S100B KO mice exhibited enhanced glucose tolerance, insulin sensitivity, prevented ß-cell destruction and functional impairment in response to STZ treatment. S100B deficiency was associated with decreased Glut2 and RAGE. In primary ß-cell cultures from WT mice, S100B induced reactive oxygen species (ROS) and RAGE-dependent apoptosis. In the STZ diabetic animal model, abrogation of S100B enhances insulin sensitivity and reduces pancreatic islet, and ß-cell destruction. S100B may be a promising target for pharmacological interventions aimed at repressing diabetes.
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Diabetes Mellitus Experimental/metabolismo , Subunidade beta da Proteína Ligante de Cálcio S100/metabolismo , Animais , Apoptose/efeitos dos fármacos , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Modelos Animais de Doenças , Glucose/metabolismo , Transportador de Glucose Tipo 2/metabolismo , Insulina/metabolismo , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/metabolismo , Masculino , Camundongos , Camundongos Knockout , Espécies Reativas de Oxigênio/metabolismo , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Estreptozocina/farmacologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismoRESUMO
Atrial fibrillation (AF) following on-pump coronary artery bypass grafting (CABG) is a common condition associated with increased morbidity and mortality. We investigated the possibility that miRs may play a contributory role in postoperative AF and associated apoptosis. A total of 42 patients (31 males and 11 females, mean age 65.0⯱â¯1.3â¯years) with sinus rhythm and without a history of AF were prospectively enrolled. We examined the levels of the muscle-specific miRs 1 and 133A and markers of apoptosis including TUNEL staining, caspase-3 activation, Bcl2 and Bax mRNAs in right atrial appendage (RAA) biopsies and blood plasma taken before aortic cross-clamping and after reperfusion. After reperfusion, indices of apoptosis increased the RAA. There was no change in tissue or plasma miR -1 and -133A levels compared to pre CABG. However, in patients who postoperatively developed AF (nâ¯=â¯14, 7 males and 7 females), compared to patients that remained in SR (nâ¯=â¯28, 24 males and 4 females) post CABG, tissue miR-1 increased whereas miR-133A decreased and negatively correlated with RAA apoptosis. Mechanistically, overexpression of miR-133A inhibited hypoxia-induced rat neonatal cardiomyocyte apoptosis and phosphorylated pro-survival Akt, responses abolished by a miR-133A antisense inhibitor oligonucleotide or by pre-treatment with an Akt inhibitor. In postoperative AF, differential regulation of pro- and anti-apoptotic miRs-1 and -133A respectively in the RAA, may contribute to postoperative apoptosis. These results provide new insights into molecular mechanisms of postoperative AF with potential therapeutic implications.
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Apêndice Atrial/patologia , Fibrilação Atrial/genética , MicroRNAs/genética , Idoso , Apoptose/genética , Apêndice Atrial/metabolismo , Fibrilação Atrial/sangue , Fibrilação Atrial/etiologia , Fibrilação Atrial/patologia , Biópsia , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Diferenciação Celular/genética , Ponte de Artéria Coronária/efeitos adversos , Feminino , Regulação da Expressão Gênica/genética , Átrios do Coração/metabolismo , Átrios do Coração/patologia , Humanos , Masculino , MicroRNAs/sangueRESUMO
Heat shock proteins (HSPs) play an important role in the cellular adaptation to stress, a requisite for cell survival. The aortic wall appears to be a target for increased expression of HSPs during surgical stress. We aimed to define the expression and function of aortic HSP70 in 31 patients with normal ascending thoracic aortic diameter who underwent aortic valve replacement due to aortic valve stenosis and in 35 patients with dilated ascending thoracic aorta who underwent replacement of an ascending thoracic aortic aneurysm. To elucidate responsible signaling mechanisms we used an in vitro model of rat hypoxic aortic vascular smooth muscle cell (AVSMC) cultures. We demonstrated an increase in AVSMC HSP70 and an attenuation of the apoptotic markers (TUNEL-positive nuclei, caspase-3 activity, Bax/Bcl2 ratio) in aortic wall tissue specimens from both aortic valve stenosis and ascending thoracic aortic aneurysm patients on ß1 blockade with metoprolol. In vitro, metoprolol treatment of hypoxic rat AVSMCs increased nitric oxide (NO) production, induced heat shock factor 1 transport to the nucleus, upregulated HSP70, decreased p53 phosphorylation and attenuated apoptosis. Blockade of NO production, resulted in decreased HSP70 and prevented the metoprolol-induced anti-apoptotic response of hypoxic AVSMCs. We demonstrate an anti-apoptotic effect of metoprolol dependent on NO-induced HSP70 expression, and thus augmentation of HSP70 expression should be considered as a therapeutic approach to limit apoptosis in the human ascending thoracic aorta of patients undergoing cardiac surgery.
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Antagonistas de Receptores Adrenérgicos beta 1/farmacologia , Apoptose/efeitos dos fármacos , Proteínas de Choque Térmico HSP70/metabolismo , Metoprolol/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Idoso , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/metabolismo , Aorta Torácica/patologia , Aneurisma da Aorta Torácica/metabolismo , Aneurisma da Aorta Torácica/patologia , Proteínas Reguladoras de Apoptose/metabolismo , Estudos de Casos e Controles , Células Cultivadas , Feminino , Fatores de Transcrição de Choque Térmico/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Óxido Nítrico/metabolismo , Fosforilação , Estudos Prospectivos , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismoRESUMO
The capacity of imatinib mesylate to reverse established pulmonary arterial hypertension (PAH) has been attributed to a reduction in pulmonary arterial muscularization via inhibition of platelet-derived growth factor receptor-ß on vascular smooth muscle cells. However, there is also a significant immunomodulatory component to the action of imatinib that may account for its efficacy in PAH. We found that monocrotaline-induced pulmonary hypertension was associated with a significant decrease in pulmonary natural killer (NK) cells and T lymphocytes and the accumulation of macrophages in the lungs of F344 rats. The prevention of pulmonary hypertension by imatinib blocked these changes in pulmonary leukocyte content and induced elevations in pulmonary interferon-γ, tumor necrosis factor α, and IL-10, corresponding to the enhanced activity of splenic NK cells ex vivo. Treatment with anti-asialo GM1 antiserum (ASGM1), which ablated circulating NK cells and depleted T cells, eliminated the therapeutic benefit of imatinib. ASGM1-treated animals also exhibited significant pulmonary arteriolar muscularization in response to monocrotaline challenge compared with immunocompetent controls despite daily imatinib administration to both groups. In the athymic rat, imatinib decreased right ventricular hypertrophy and pulmonary arteriolar muscularization in monocrotaline-challenged animals versus saline-treated controls but did not prevent pulmonary macrophage accumulation or the development of pulmonary hypertension. These data demonstrate that the immunomodulatory effects of imatinib are critical to its therapeutic action in experimental PAH.
Assuntos
Benzamidas/uso terapêutico , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/patologia , Linfócitos/metabolismo , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Benzamidas/farmacologia , Citocinas/metabolismo , Modelos Animais de Doenças , Hipertensão Pulmonar/induzido quimicamente , Hipertrofia Ventricular Direita/patologia , Mesilato de Imatinib , Imunomodulação/efeitos dos fármacos , Contagem de Leucócitos , Depleção Linfocítica , Linfócitos/efeitos dos fármacos , Masculino , Monocrotalina , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Piperazinas/farmacologia , Pirimidinas/farmacologia , Ratos , Ratos Endogâmicos F344 , Ratos NusRESUMO
BACKGROUND: This study addresses the expression of the glycosylated proteins known as advanced glycation end products (AGEs), the calcium binding protein S100B and the apoptotic parameters cytochome c and caspase-3 activity in peripheral lymphocyte cytosolic extracts from a sample of bipolar disorder (BD) patients and healthy (control) subjects. METHODS: Cross-sectional study of 35 patients with a clinical diagnosis of bipolar disease (10 euthymic, 12 depressed, 13 manic) and 10 healthy control subjects. Lymphocytes were used as a surrogate model in BD diagnosis and treatment. AGEs and S100B in lymphocyte cell extracts were measured by commercially available enzyme-linked immunosorbent assay. RESULTS: AGEs were lower in all BD patients compared to healthy subjects. Depressed patients had approximately two-fold higher S100B levels compared to healthy subjects. Manic and depressed BD patients had increased superoxide dismutase mRNA levels. Apoptosis as measured by BAX/Bcl2 ratio, cytochrome c release, caspase-3 activity was increased in manic and depressed patients compared to healthy subjects. In the depressed patients, S100B levels correlated with cytochrome c release. CONCLUSIONS: In conclusion, our study shows decreased AGEs and increased S100B levels and caspase down-stream apoptosis in peripheral lymphocytes of BD patients that may underlie disease etiopathogenesis.
Assuntos
Apoptose , Transtorno Bipolar/sangue , Transtorno Bipolar/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Linfócitos/metabolismo , Linfócitos/patologia , Subunidade beta da Proteína Ligante de Cálcio S100/metabolismo , Adulto , Idoso , Transtorno Bipolar/patologia , Feminino , Produtos Finais de Glicação Avançada/análise , Humanos , Masculino , Pessoa de Meia-Idade , Subunidade beta da Proteína Ligante de Cálcio S100/análise , Adulto JovemRESUMO
BACKGROUND AND AIMS: The multi-ligand receptor for advanced glycation end products (RAGE) and its ligands AGEs and S100/calgranulin proteins are important mediators of inflammation and oxidative stress whereas the soluble form of RAGE (sRAGE) by acting as a decoy and the antioxidant PARK7/DJ-1 exert antiatherogenic effects. We examined whether sRAGE and its ligands AGEs, S100A8/A9, S100B, S100A12 and DJ-1 are associated with the presence of angiographic coronary artery disease (CAD) in asymptomatic patients with and without diabetes. METHODS AND RESULTS: Plasma levels of RAGE ligands, sRAGE and DJ-1 were determined in 50 patients with angiographically proven CAD and in 50 age-matched healthy controls. In the whole cohort, lower levels of sRAGE and higher levels of interleukin-6 (IL-6), the RAGE ligands S100B, S100A12 and the AGEs/sRAGE ratio were associated with CAD. In patients without diabetes (n = 72), lower levels of sRAGE and DJ-1 and higher levels of IL-6 and AGEs/sRAGE ratio were associated with CAD. In multivariable analysis, AGEs/sRAGE ratio was an independent predictor of CAD both in the whole cohort (p = 0.034, OR = 1.247, [95%CI: 1.024, 1.0519]) and in the subgroup of patients without diabetes (p = 0.021, OR = 1.363, 95%CI [1.048, 1.771]) on top of established cardiovascular risk factors. CONCLUSION: Alterations in plasma RAGE axis inflammatory mediators are associated with atherosclerosis, and higher levels of AGEs/sRAGE ratio are independently associated with CAD in asymptomatic patients and may act as a novel biomarker for predicting CAD. DJ-1 emerges as promising marker of oxidative stress in CAD patients without diabetes, a finding that deserves further study.
Assuntos
Doença da Artéria Coronariana , Diabetes Mellitus , Humanos , Proteína S100A12 , Ligantes , Interleucina-6 , Inflamação , Proteínas S100 , Receptor para Produtos Finais de Glicação Avançada , Biomarcadores , Produtos Finais de Glicação Avançada , Estresse OxidativoRESUMO
Asthma is a heterogeneous disease, characterized by chronic inflammation and oxidative stress of the airways. Several inflammatory pathways including activation of the receptor for advanced glycation end products (RAGE) have been described in the course of the disease. DJ-1 is a redox-sensitive protein with multifaceted roles in mast cell homeostasis and an emerging role in the pathogenesis of asthma. Moreover, cardiac function abnormalities have been described via echocardiography in patients with asthma. The main aim of this study was to investigate the plasma levels of RAGE, its ligands and DJ-1 in asthmatic patients pre- and post-treatment along with echocardiographic indices of cardiovascular function. The study population was divided into two groups. Group A included 13 patients with newly diagnosed bronchial asthma who were free of treatment for at least two weeks and Group B included 12 patients without asthma. An echocardiography examination was performed on all patients. The plasma levels of RAGE, its ligands (AGEs, S100A12, S100B, S100A8/A9), the interleukins (IL-6, IL-1ß) and DJ-1 were measured. No differences were noted among the two groups for baseline characteristics and echocardiographic indices of cardiac function. In Group A, 31% suffered from mild asthma, 54% from moderate asthma and 15% from severe asthma. Plasma levels of IL-6, AGEs and AGE/RAGE ratio were increased and those of S100A12 and DJ-1 were decreased in asthmatics. Pharmacotherapy with corticosteroids/ß2-agonists decreased IL-6, and AGEs, and increased DJ-1. In search of novel approaches in diagnosing and treating patients with asthma, S100A12, ratio AGE/sRAGE, and DJ-1 in addition to IL-6 may prove to be useful tools.
Assuntos
Asma , Proteína S100A12 , Humanos , Ligantes , Interleucina-6 , Receptor para Produtos Finais de Glicação Avançada , Produtos Finais de Glicação Avançada , Asma/diagnóstico por imagem , Asma/tratamento farmacológico , EcocardiografiaRESUMO
Coronary artery ectasia (CAE) is defined as abnormal dilation of a coronary artery with a diameter exceeding that of adjacent normal arterial segment by >1.5 times. CAE is a pathological entity of the coronary arteries and characterized as a variant of coronary atherosclerosis. CAE frequently coexists with coronary artery disease (CAD). While inflammation appears to be involved, the pathophysiology of CAE remains unclear. Damage-associated molecular patterns (DAMPs), defined as endogenous molecules released from stressed or damaged tissue, are deemed as alarm signals by the innate immune system. Inflammatory agents can generate DAMPs and DAMPs can create a pro-inflammatory state. In a prospective cross-sectional study, we enrolled 29 patients with CAE and non-obstructive CAD, 19 patients with obstructive CAD without CAE, and 14 control subjects with normal (control) coronary arteries age- and sex-matched with the CAE patients, to investigate the differential expression of plasma DAMPs. Patients with CAE and non-obstructive CAD had increased plasma levels of the DAMPs S100B, S100A12, HMGB1, and HSP70, the DAMPs receptor TLR4, and miR328a-3p compared to CAD and controls. Plasma levels of the mir328a-3p target the protective soluble form of the DAMPs receptor for advanced glycation end products (sRAGE), and the antioxidant DJ-1 was decreased in both CAE and CAD compared to controls. In an in vitro human umbilical vein endothelial cells model, circulating levels of S100B, HMGB1, HSP70 as well as CAE patient plasma induced inflammatory responses. The differential expression of the DAMPs S100B, HSP70, HMGB1, and their receptors TLR4 and sRAGE in CAE versus CAD makes them attractive novel biomarkers as therapeutic targets and therapeutics.
Assuntos
Doença da Artéria Coronariana , Proteína HMGB1 , Humanos , Proteína HMGB1/genética , Dilatação Patológica , Angiografia Coronária , Estudos Prospectivos , Estudos Transversais , Células Endoteliais/patologia , Receptor 4 Toll-Like/genética , AlarminasRESUMO
Oxidative stress is considered one of the early underlying contributors of sepsis-induced myocardial depression. DJ-1, also known as PARK7, has a well-established role as an antioxidant. We have previously shown, in a clinically relevant model of polymicrobial sepsis, DJ-1 deficiency improved survival and bacterial clearance by decreasing ROS production. In the present study, we investigated the role of DJ-1 in sepsis-induced myocardial depression. Here we compared wildtype (WT) with DJ-1 deficient mice at 24 and 48 h after cecal ligation and puncture (CLP). In WT mice, DJ-1 was increased in the myocardium post-CLP. DJ-1 deficient mice, despite enhanced inflammatory and oxidative responses, had an attenuated hypertrophic phenotype, less apoptosis, improved mitochondrial function, and autophagy, that was associated with preservation of myocardial function and improved survival compared to WT mice post-CLP. Collectively, these results identify DJ-1 as a regulator of myocardial function and as such, makes it an attractive therapeutic target in the treatment of early sepsis-induced myocardial depression.
RESUMO
Post-infarct remodeling is associated with the upregulation of the receptor for advanced glycation end products (RAGE), the induction of its ligand the calcium binding protein S100B and the release of the potent endothelial-cell specific mitogen vascular endothelial growth factor (VEGF). To determine a possible functional interaction between S100B, RAGE and VEGF we stimulated rat neonatal cardiac myocyte cultures transfected with either RAGE or a dominant-negative cytoplasmic deletion mutant of RAGE with S100B for 48 h. Under baseline conditions, cardiac myocytes express low levels of RAGE and VEGF and secrete VEGF in the medium as measured by ELISA. In RAGE overexpressing myocytes, S100B (100 nM) resulted in increases in VEGF mRNA, VEGF protein, VEGF secretion, and activation of the transcription factor NF-κB. Pre-treatment of RAGE overexpressing myocytes with the NF-κB inhibitor caffeic acid phenethyl ester inhibited increases in VEGF mRNA, VEGF protein and VEGF in the medium by S100B. In myocytes expressing dominant-negative RAGE, S100B did not induce VEGF mRNA, VEGF protein, VEGF secretion or NF-κB activation. In culture, rat neonatal and adult cardiac fibroblasts undergo phenotypic transition to myofibroblasts. Treatment of neonatal and adult myofibroblasts with VEGF (10 ng/mL) induces VEGFR-2 (flk-1/KDR) tyrosine kinase phosphorylation, ERK1/2 phosphorylation and myofibroblast proliferation. Together these data demonstrate that secreted VEGF by cardiac myocytes in response to S100B via RAGE ligation induces myofibroblast proliferation potentially contributing to scar formation observed in infarcted myocardium. This article is part of a Special Issue entitled "Local Signaling in Myocytes".
Assuntos
Miócitos Cardíacos/metabolismo , Miofibroblastos/efeitos dos fármacos , Fatores de Crescimento Neural/metabolismo , Receptores Imunológicos/metabolismo , Proteínas S100/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Proliferação de Células/efeitos dos fármacos , Fibroblastos/citologia , Fibroblastos/metabolismo , Hemodinâmica/fisiologia , Humanos , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/fisiopatologia , Miofibroblastos/citologia , NF-kappa B/metabolismo , Fatores de Crescimento Neural/sangue , Fosforilação/efeitos dos fármacos , Cultura Primária de Células , Ratos , Ratos Sprague-Dawley , Receptor para Produtos Finais de Glicação Avançada , Receptores Imunológicos/genética , Subunidade beta da Proteína Ligante de Cálcio S100 , Proteínas S100/sangue , Transdução de Sinais/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/sangue , Fator A de Crescimento do Endotélio Vascular/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Remodelação VentricularRESUMO
Among different proposed pathophysiological mechanisms, redox imbalance has been suggested to be a potential contributor in the pathogenesis of schizophrenia. DJ-1 is a redox-sensitive protein that has been shown to have neuroprotective function in the brain in Parkinson's disease and other neurodegenerative diseases. However, a role for DJ-1 in schizophrenia is unknown. Bioinformatic analysis suggested that microRNA (miR)-203a-3p could target the 3' untranslated region (UTR) of DJ-1. In whole blood and blood-derived exosomes of 11 first episode antipsychotic naïve schizophrenia patients, DJ-1 protein and mRNA demonstrated decreased DJ-1 mRNA and protein and increased miR203a-3p levels compared to healthy controls. In whole blood, antipsychotic monotherapy with olanzapine for 6 weeks increased DJ-1 and attenuated miR203a-3p levels, whereas in blood derived exosomes, olanzapine returned DJ-1 and miR203a-3p to levels seen healthy controls. Consistent with this finding, we showed that human umbilical vein endothelial cells (HUVACs) transfected with a DJ-1-3' UTR luciferase reporter construct displayed reduced gene expression when subjected to the oxidative stressor H2O2. Transfection of a miR203a-3p mimic into HUVACs reduced DJ-1-3 'UTR reporter gene expression, while transfection of an anti miR-203a-3p prevented the H2O2-induced downregulation of the reporter gene. We conclude that miR-203a-3p is an essential mediator of oxidative stress in schizophrenia via its ability to target the 3' UTR of DJ-1 and antipsychotic monotherapy restores DJ-1 antioxidant levels by regulating miR203a-3p expression. miR-203a-3p and DJ-1 might represent attractive targets for the treatment of pathologies such as schizophrenia that has underlying oxidative stress.
Assuntos
MicroRNAs , Olanzapina/uso terapêutico , Proteína Desglicase DJ-1/sangue , Esquizofrenia , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Humanos , Peróxido de Hidrogênio , Estudos Longitudinais , MicroRNAs/sangue , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genéticaRESUMO
The ongoing coronavirus disease 2019 (COVID-19) pandemic has had a widespread impact on individuals' mental health through indirect psychological and social mechanisms, related to factors such as fear of infection or death, social isolation, lack of social support and financial instability. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has also been associated with the development or recurrence of neuropsychiatric symptoms, both during the acute phase, as well as during the post-acute 'long-COVID' phase. In addition to the COVID-19 survivors with a mental health history that are at a high risk of experiencing a range of neuropsychiatric symptoms following resolution of acute COVID-19, there is accumulating evidence that a diagnosis of COVID-19 may also be associated with new-onset neuropsychiatric morbidity among survivors without pre-existing mental health disorders. In particular, studies investigating the incidence of post-acute neuropsychiatric sequelae, based mostly on retrospective cohort study designs and data from national health registries, have reported the development of new-onset manifestations, including depression, anxiety, psychotic symptoms, sleep disturbances and fatigue. Nevertheless, when COVID-19 survivors were compared with SARS-CoV-2-negative controls and especially survivors of other disorders (such as influenza), the findings regarding the risk of incident neuropsychiatric manifestations varied among studies. While there is evidence of an association between SARS-CoV-2 infection and the subsequent occurrence of new-onset neuropsychiatric symptoms, especially among patients with increased disease severity, further research using methodological approaches less susceptible to confounding bias is required to establish causal relationships.