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1.
Med Sci (Paris) ; 36(10): 886-892, 2020 Oct.
Artigo em Francês | MEDLINE | ID: mdl-33026331

RESUMO

Age-related macular degeneration (AMD) is a complex, highly heritable, multifactorial disease caused by the interplay of age and genetic and environmental risk factors. No treatment has yet been found to treat the slowly progressing atrophic form of AMD. All forms of AMD are invariably associated with an accumulation of mononuclear phagocytes (MP) in the subretinal space, a family of cells that include inflammatory and resident macrophages. We here present an overview of the inflammatory process occurring in AMD and discuss the origin of MPs and the consequences of their accumulation in the subretinal space. Finally, we will review the role played by the established risk factors for AMD to promote the switch from beneficial inflammation in early stage to a deleterious inflammation in the advanced stage of the disease.


Assuntos
Inflamação/complicações , Degeneração Macular/etiologia , Olho/imunologia , Olho/metabolismo , Olho/patologia , Humanos , Privilégio Imunológico/fisiologia , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Mediadores da Inflamação/fisiologia , Degeneração Macular/epidemiologia , Degeneração Macular/imunologia , Degeneração Macular/metabolismo , Fatores de Risco
2.
Neurologia ; 35(4): 245-251, 2020 May.
Artigo em Inglês, Espanhol | MEDLINE | ID: covidwho-178369

RESUMO

INTRODUCTION: SARS-CoV-2 was first detected in December 2019 in the Chinese city of Wuhan and has since spread across the world. At present, the virus has infected over 1.7 million people and caused over 100 000 deaths worldwide. Research is currently focused on understanding the acute infection and developing effective treatment strategies. In view of the magnitude of the epidemic, we conducted a speculative review of possible medium- and long-term neurological consequences of SARS-CoV-2 infection, with particular emphasis on neurodegenerative and neuropsychiatric diseases of neuroinflammatory origin, based on the available evidence on neurological symptoms of acute SARS-CoV-2 infection. DEVELOPMENT: We systematically reviewed the available evidence about the pathogenic mechanisms of SARS-CoV-2 infection, the immediate and lasting effects of the cytokine storm on the central nervous system, and the consequences of neuroinflammation for the central nervous system. CONCLUSIONS: SARS-CoV-2 is a neuroinvasive virus capable of triggering a cytokine storm, with persistent effects in specific populations. Although our hypothesis is highly speculative, the impact of SARS-CoV-2 infection on the onset and progression of neurodegenerative and neuropsychiatric diseases of neuroinflammatory origin should be regarded as the potential cause of a delayed pandemic that may have a major public health impact in the medium to long term. Cognitive and neuropsychological function should be closely monitored in COVID-19 survivors.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/complicações , Síndrome da Liberação de Citocina/etiologia , Citocinas/fisiologia , Transtornos Mentais/etiologia , Doenças Neurodegenerativas/etiologia , Pandemias , Pneumonia Viral/complicações , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/fisiopatologia , Síndrome da Liberação de Citocina/fisiopatologia , Síndrome da Liberação de Citocina/psicologia , Progressão da Doença , Humanos , Sistema Imunitário/fisiopatologia , Sistema Imunitário/virologia , Inflamação , Mediadores da Inflamação/fisiologia , Transtornos Mentais/epidemiologia , Modelos Imunológicos , Modelos Neurológicos , Doenças Neurodegenerativas/epidemiologia , Neuroimunomodulação/fisiologia , Pneumonia Viral/epidemiologia , Pneumonia Viral/fisiopatologia , Saúde Pública , Fatores de Tempo
3.
Neurologia ; 35(4): 245-251, 2020 May.
Artigo em Inglês, Espanhol | MEDLINE | ID: covidwho-71976

RESUMO

INTRODUCTION: SARS-CoV-2 was first detected in December 2019 in the Chinese city of Wuhan and has since spread across the world. At present, the virus has infected over 1.7 million people and caused over 100 000 deaths worldwide. Research is currently focused on understanding the acute infection and developing effective treatment strategies. In view of the magnitude of the epidemic, we conducted a speculative review of possible medium- and long-term neurological consequences of SARS-CoV-2 infection, with particular emphasis on neurodegenerative and neuropsychiatric diseases of neuroinflammatory origin, based on the available evidence on neurological symptoms of acute SARS-CoV-2 infection. DEVELOPMENT: We systematically reviewed the available evidence about the pathogenic mechanisms of SARS-CoV-2 infection, the immediate and lasting effects of the cytokine storm on the central nervous system, and the consequences of neuroinflammation for the central nervous system. CONCLUSIONS: SARS-CoV-2 is a neuroinvasive virus capable of triggering a cytokine storm, with persistent effects in specific populations. Although our hypothesis is highly speculative, the impact of SARS-CoV-2 infection on the onset and progression of neurodegenerative and neuropsychiatric diseases of neuroinflammatory origin should be regarded as the potential cause of a delayed pandemic that may have a major public health impact in the medium to long term. Cognitive and neuropsychological function should be closely monitored in COVID-19 survivors.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/complicações , Síndrome da Liberação de Citocina/etiologia , Citocinas/fisiologia , Transtornos Mentais/etiologia , Doenças Neurodegenerativas/etiologia , Pandemias , Pneumonia Viral/complicações , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/fisiopatologia , Síndrome da Liberação de Citocina/fisiopatologia , Síndrome da Liberação de Citocina/psicologia , Progressão da Doença , Humanos , Sistema Imunitário/fisiopatologia , Sistema Imunitário/virologia , Inflamação , Mediadores da Inflamação/fisiologia , Transtornos Mentais/epidemiologia , Modelos Imunológicos , Modelos Neurológicos , Doenças Neurodegenerativas/epidemiologia , Neuroimunomodulação/fisiologia , Pneumonia Viral/epidemiologia , Pneumonia Viral/fisiopatologia , Saúde Pública , Fatores de Tempo
4.
Neurologia ; 35(4): 245-251, 2020 May.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-32364119

RESUMO

INTRODUCTION: SARS-CoV-2 was first detected in December 2019 in the Chinese city of Wuhan and has since spread across the world. At present, the virus has infected over 1.7 million people and caused over 100 000 deaths worldwide. Research is currently focused on understanding the acute infection and developing effective treatment strategies. In view of the magnitude of the epidemic, we conducted a speculative review of possible medium- and long-term neurological consequences of SARS-CoV-2 infection, with particular emphasis on neurodegenerative and neuropsychiatric diseases of neuroinflammatory origin, based on the available evidence on neurological symptoms of acute SARS-CoV-2 infection. DEVELOPMENT: We systematically reviewed the available evidence about the pathogenic mechanisms of SARS-CoV-2 infection, the immediate and lasting effects of the cytokine storm on the central nervous system, and the consequences of neuroinflammation for the central nervous system. CONCLUSIONS: SARS-CoV-2 is a neuroinvasive virus capable of triggering a cytokine storm, with persistent effects in specific populations. Although our hypothesis is highly speculative, the impact of SARS-CoV-2 infection on the onset and progression of neurodegenerative and neuropsychiatric diseases of neuroinflammatory origin should be regarded as the potential cause of a delayed pandemic that may have a major public health impact in the medium to long term. Cognitive and neuropsychological function should be closely monitored in COVID-19 survivors.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/complicações , Síndrome da Liberação de Citocina/etiologia , Citocinas/fisiologia , Transtornos Mentais/etiologia , Doenças Neurodegenerativas/etiologia , Pandemias , Pneumonia Viral/complicações , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/fisiopatologia , Síndrome da Liberação de Citocina/fisiopatologia , Síndrome da Liberação de Citocina/psicologia , Progressão da Doença , Humanos , Sistema Imunitário/fisiopatologia , Sistema Imunitário/virologia , Inflamação , Mediadores da Inflamação/fisiologia , Transtornos Mentais/epidemiologia , Modelos Imunológicos , Modelos Neurológicos , Doenças Neurodegenerativas/epidemiologia , Neuroimunomodulação/fisiologia , Pneumonia Viral/epidemiologia , Pneumonia Viral/fisiopatologia , Saúde Pública , Fatores de Tempo
5.
Medicine (Baltimore) ; 99(14): e19054, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32243356

RESUMO

Lung adenocarcinoma (LUAD), a form of lung cancer, is reported to cause first and second-order cancer morbidity to men and women in China, respectively. We assessed the mRNA expression of GJB2 in LUAD patients in our study, based on data acquired from the cancer genome atlas (TCGA) and so as to increase further knowledge into the biological pathways involved in LUAD pathogenesis related to GJB2.Information on gene expression and comparing clinical data were recognized and downloaded from TCGA. Gene set enrichment analysis (GSEA) created an arranged list of all genes is indicated by their connection with GJB2 expression.Our study cohort included 265 (54.5%) female and 221 (36.0%) male patients. The scatter plot and paired plot showed the difference of GJB2 expression between normal and tumor samples (P < .01). Overall survival (OS) analysis demonstrated that LUAD with GJB2 -high had a more terrible prognosis than that with GJB2 -low (P < .01). Multivariate analysis with the cox proportional hazards model indicated that the expression of Cx26 (HR: 1.00; 95%CI: 1.00-1.01; P = .041) and stage (HR: 1.95; 95%CI: 1.23-3.09; P = .003) were independent prognostic factors for patients with LUAD. The GSEA results showed that cytosolic DNA sensing pathway, apoptosis, cytokine-cytokine receptor interaction, natural killer cell mediated cytotoxicity, regulation of actin cytoskeleton, toll-like receptor signaling pathway, small cell lung cancer and pathways in cancer are differentially enriched in GJB2 high expression phenotype.Our study confirmed the significantly high levels of Cx26 expression in LUAD patients with several observed clinical features. GJB2 may be a potentially useful prognostic molecular biomarker of bad survival in LUAD, while further experimental ought to be performed to demonstrate the biologic effect of GJB2.


Assuntos
Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Conexinas/biossíntese , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Adenocarcinoma de Pulmão/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Apoptose/fisiologia , Biomarcadores Tumorais , Bases de Dados Genéticas , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Mediadores da Inflamação/fisiologia , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , RNA Mensageiro/biossíntese , Transdução de Sinais/fisiologia , Carcinoma de Pequenas Células do Pulmão/patologia , Análise de Sobrevida
6.
Orthopade ; 48(11): 911-916, 2019 Nov.
Artigo em Alemão | MEDLINE | ID: mdl-31531702

RESUMO

Inflammatory rheumatic diseases are often associated with secondary osteoporosis, as many inflammatory messengers can interfere with bone metabolism and adversely affect it. In addition to a decrease in densitometric bone density, remodeling occurs in the trabecular bone, which can lead to a disturbed microarchitecture and increase the risk of fracture.Central to this is the close integration of bone metabolism and the immune system. Proinflammatory cytokines play an important role not only in the inflammatory process, but also as mediators of bone resorption because they stimulate osteoclastogenesis and induce further signal transduction cascades with negative influence on the bone. The understanding gained in recent years of the underlying immunological processes has led to the development of new and targeted treatment approaches.


Assuntos
Reabsorção Óssea/imunologia , Citocinas/fisiologia , Osteoporose , Doenças Reumáticas/imunologia , Remodelação Óssea , Reabsorção Óssea/metabolismo , Humanos , Mediadores da Inflamação/fisiologia , Osteoblastos/fisiologia , Osteoclastos/fisiologia , Doenças Reumáticas/metabolismo
7.
J Orthop Res ; 37(12): 2575-2582, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31378986

RESUMO

Subacromial impingement is associated with a spectrum of disorders-including rotator cuff disease-but their relationship is complex. We have established a novel murine model of subacromial impingement to study supraspinatus tendinopathy. The purpose of this study was to evaluate changes in gene expression in this murine shoulder impingement model to further elucidate the mechanisms underlying the development of tendinopathy. Twenty-eight C57BL/6 mice were used in this study. All mice underwent bilateral surgery with insertion of a small metal clip in the subacromial space or a sham procedure. The supraspinatus tendons underwent histological analyses, biomechanical testing, and RNA extraction for multiplex gene expression analysis (NanoString, Seattle, WA). Histology demonstrated increased cellularity and disorganized collagen fibers of the supraspinatus tendon in the clip impingement group. Mean load to failure (5.20 vs. 1.50 N, p < 0.001) and mean stiffness (4.95 vs. 1.47 N/mm, p < 0.001) were lower in the impingement group than the sham group. NanoString analyses revealed 111 differentially expressed genes (DEGs) between the impingement and sham groups. DEGs of interest included Mmp3 (expression ratio [ER]: 2.68, p = 0.002), Tgfb1 (ER: 1.76, p = 0.01), Col3a1 (ER: 1.66, p = 0.03), and Tgfbr2 (ER: 1.53, p = 0.01). Statement of clinical significance: We identified 111 DEGs that may contribute to the development of tendinopathy in this model. Further studies of these specific genes will allow identification of their roles in the initiation and regulation of tendon damage, and their potential to serve as novel therapeutic targets in the treatment of rotator cuff disease. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2575-2582, 2019.


Assuntos
Mediadores da Inflamação/fisiologia , Síndrome de Colisão do Ombro/metabolismo , Tendinopatia/etiologia , Animais , Fenômenos Biomecânicos , Modelos Animais de Doenças , Masculino , Metaloproteinases da Matriz/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Tendões/patologia
8.
Nat Rev Immunol ; 19(12): 747-760, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31409920

RESUMO

Platelets are small anucleate cellular fragments that are released by megakaryocytes and safeguard vascular integrity through a process termed 'haemostasis'. However, platelets have important roles beyond haemostasis as they contribute to the initiation and coordination of intravascular immune responses. They continuously monitor blood vessel integrity and tightly coordinate vascular trafficking and functions of multiple cell types. In this way platelets act as 'patrolling officers of the vascular highway' that help to establish effective immune responses to infections and cancer. Here we discuss the distinct biological features of platelets that allow them to shape immune responses to pathogens and tumour cells, highlighting the parallels between these responses.


Assuntos
Plaquetas/fisiologia , Infecções/imunologia , Neoplasias/imunologia , Animais , Humanos , Mediadores da Inflamação/fisiologia , Neoplasias/irrigação sanguínea , Células Neoplásicas Circulantes , Trombopoese , Microambiente Tumoral , Vasculite/imunologia
9.
Adv Exp Med Biol ; 1165: 381-406, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31399975

RESUMO

Renal inflammation is the initial, healthy response to renal injury. However, prolonged inflammation promotes the fibrosis process, which leads to chronic pathology and eventually end-stage kidney disease. There are two major sources of inflammatory cells: first, bone marrow-derived leukocytes that include neutrophils, macrophages, fibrocytes and mast cells, and second, locally activated kidney cells such as mesangial cells, podocytes, tubular epithelial cells, endothelial cells and fibroblasts. These activated cells produce many profibrotic cytokines and growth factors that cause accumulation and activation of myofibroblasts, and enhance the production of the extracellular matrix. In particular, activated macrophages are key mediators that drive acute inflammation into chronic kidney disease. They produce large amounts of profibrotic factors and modify the microenvironment via a paracrine effect, and they also transdifferentiate to myofibroblasts directly, although the origin of myofibroblasts in the fibrosing kidney remains controversial. Collectively, understanding inflammatory cell functions and mechanisms during renal fibrosis is paramount to improving diagnosis and treatment of chronic kidney disease.


Assuntos
Mediadores da Inflamação/fisiologia , Nefropatias/fisiopatologia , Rim/patologia , Transdiferenciação Celular , Fibrose , Humanos , Leucócitos/citologia , Macrófagos/citologia , Miofibroblastos/citologia
11.
Adv Exp Med Biol ; 1127: 181-194, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31140179

RESUMO

Despite the progress made over the last decades to understand the mechanisms underlying tissue damage and neurological deficits after neurotrauma, there are currently no effective treatments in the clinic. It is well accepted that the inflammatory response in the CNS after injury exacerbates tissue loss and functional impairments. Unfortunately, the use of potent anti-inflammatory drugs, such as methylprednisolone, fails to promote therapeutic recovery and also gives rise to several undesirable side effects related to immunosuppression. The injury-induced inflammatory response is complex, and understanding the mechanisms that regulate this inflammation is therefore crucial in the quest to develop effective treatments. Bioactive lipids have emerged as potent molecules in controlling the initiation, coordination, and resolution of inflammation and in promoting tissue repair and recovery of homeostasis. These bioactive lipids are produced by cells involved in the inflammatory response, and their defective synthesis leads to persistent chronic inflammation, tissue damage, and fibrosis. The present chapter discusses recent evidence for the role of some of these bioactive lipids, in particular, eicosanoid and pro-resolving lipid mediators, in the regulation of inflammation after neurotrauma and highlights the therapeutic potential of some of these lipids in enhancing neurological outcomes after CNS injuries.


Assuntos
Mediadores da Inflamação/fisiologia , Inflamação , Lipídeos/fisiologia , Traumatismos do Sistema Nervoso , Eicosanoides/fisiologia , Humanos
12.
J Adv Nurs ; 75(10): 2236-2245, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31115064

RESUMO

AIMS: (a) Determine relationships among stress exposure, inflammation, and neurodevelopment in very preterm infants and determine the mediated effect of inflammation on the relationship between stress exposure and neurodevelopment; (b) describe cytokine trajectories following birth and determine the effect of stress exposure on these trajectories; and (c) examine relationships between stress exposure and chronic stress responses in very preterm infants. DESIGN: Non-experimental, repeated measures. METHODS: Very preterm infants born 28-31 weeks post menstrual age will be enrolled. Cumulative stress exposure over the first 14 days of life will be measured using the Neonatal Infant Stressor Scale. Blood will be collected weekly for the quantification of cytokines. Neurodevelopment will be assessed using the Neurobehavioral Assessment of the Preterm Infant and hair for quantification of hair cortisol will be collected at 35 weeks post menstrual age. Multiple linear regression and conditional process analysis will be used to analyse the relationships among stress exposure, inflammation and neurodevelopment. Linear mixed models will be used to determine inflammatory trajectories over time. IRB approval for the study was received May 2017, and funding from the National Institute of Nursing Research was awarded July 2017. DISCUSSION: This study will determine the extent to which inflammation mediates the relationship between stress exposure and neurodevelopment. Interventions to attenuate inflammation in preterm infants may improve outcomes. IMPACT: Determining the potentially modifiable mediators of stress exposure and neurodevelopment in preterm infants is critical to improving long-term outcomes.


Assuntos
Desenvolvimento Infantil/fisiologia , Recém-Nascido Prematuro/crescimento & desenvolvimento , Mediadores da Inflamação/fisiologia , Estresse Fisiológico/fisiologia , Feminino , Humanos , Recém-Nascido , Masculino
13.
EMBO J ; 38(11)2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31028084

RESUMO

Alternatively activated M2 macrophages play an important role in maintenance of tissue homeostasis by scavenging dead cells, cell debris and lipoprotein aggregates via phagocytosis. Using proteomics, we investigated how alternative activation, driven by IL-4, modulated the phagosomal proteome to control macrophage function. Our data indicate that alternative activation enhances homeostatic functions such as proteolysis, lipolysis and nutrient transport. Intriguingly, we identified the enhanced recruitment of the TAK1/MKK7/JNK signalling complex to phagosomes of IL-4-activated macrophages. The recruitment of this signalling complex was mediated through K63 polyubiquitylation of the macrophage scavenger receptor 1 (MSR1). Triggering of MSR1 in IL-4-activated macrophages leads to enhanced JNK activation, thereby promoting a phenotypic switch from an anti-inflammatory to a pro-inflammatory state, which was abolished upon MSR1 deletion or JNK inhibition. Moreover, MSR1 K63 polyubiquitylation correlated with the activation of JNK signalling in ovarian cancer tissue from human patients, suggesting that it may be relevant for macrophage phenotypic shift in vivo Altogether, we identified that MSR1 signals through JNK via K63 polyubiquitylation and provides evidence for the receptor's involvement in macrophage polarization.


Assuntos
Inflamação , Interleucina-4/farmacologia , Proteínas Quinases JNK Ativadas por Mitógeno/fisiologia , Ativação de Macrófagos , Receptores Depuradores Classe A/agonistas , Receptores Depuradores Classe A/genética , Animais , Polaridade Celular/efeitos dos fármacos , Polaridade Celular/genética , Células Cultivadas , Feminino , Humanos , Inflamação/induzido quimicamente , Inflamação/genética , Inflamação/metabolismo , Mediadores da Inflamação/fisiologia , Lipólise/efeitos dos fármacos , Lipólise/genética , Lipoproteínas LDL/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Ativação de Macrófagos/genética , Macrófagos/efeitos dos fármacos , Macrófagos/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fagocitose/efeitos dos fármacos , Fagocitose/genética , Polissacarídeos/farmacologia , Processamento de Proteína Pós-Traducional/genética , Células RAW 264.7 , Receptores Depuradores Classe A/química , Receptores Depuradores Classe A/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Ubiquitinação/genética
14.
J Affect Disord ; 250: 249-259, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30870775

RESUMO

BACKGROUND: Major depressive disorder (MDD) is a complex and heterogeneous disorder in which clinical symptoms can widely differ among patients. Neurovegetative symptoms, i.e. decreased or increased appetite, changes in body weight and sleep disturbances, described as 'melancholic' or 'atypical' features of a depressive episode, are the most variable symptoms among patients with MDD. We hypothesized biomarkers differences underlying this neurovegetative variability in major depression. METHODS: We systematically reviewed, according to the PRISMA guidelines, the role of specific metabolic, hormonal and inflammatory biomarkers in drug-free MDD patients, that could have neurobiological effects on appetite, weight regulation and circadian rhythms, influencing eating behaviour and sleep patterns. All studies regarding the co-occurrence of disturbed sleep and appetite were examined. RESULTS: Besides the well-known leptin and ghrelin, other biomarkers such as BDNF, VEGF, NPY, orexin, and the recent discovered nesfatin-1 seem to be involved in neurovegetative changes in depressive disorders playing a role in the regulation of affective states, stress reactions and sleep patterns. Interestingly, based on the existing evidence, ghrelin, orexin and nesfatin-1 could be linked both to sleep and appetite regulation in depressed patients. LIMITATIONS: Heterogeneous studies with low sample size. CONCLUSIONS: Despite the wide heterogeneity of results, studies on biomarkers of appetite and sleep in MDD are an interesting field of research to explain the neurobiological substrates of depressive symptoms that deserve further investigation.


Assuntos
Apetite/fisiologia , Biomarcadores/metabolismo , Transtorno Depressivo Maior/fisiopatologia , Metabolismo Energético/fisiologia , Hormônios/fisiologia , Mediadores da Inflamação/fisiologia , Sono/fisiologia , Transtorno Depressivo Maior/psicologia , Humanos
15.
Biochem Pharmacol ; 165: 4-16, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30826327

RESUMO

Osteoarthritis (OA) is the most common joint disorder and a leading cause of disability. Current treatments for OA can improve symptoms but do not delay the progression of disease. In the last years, much effort has been devoted to developing new treatments for OA focused on pain control, inflammatory mediators or degradation of articular tissues. Although promising results have been obtained in ex vivo studies and animal models of OA, few of these agents have completed clinical trials. Available clinical data support the interest of nerve growth factor as a target in pain control as well as the disease-modifying potential of inhibitors of Wnt signaling or catabolic enzymes such as aggrecanases and cathepsin K, and anabolic strategies like fibroblast growth factor-18 or cellular therapies. Carefully controlled studies in patients selected according to OA phenotypes and with a long follow-up will help to confirm the relevance of these new approaches as emerging therapeutic treatments in OA.


Assuntos
Osteoartrite/tratamento farmacológico , Animais , Citocinas/fisiologia , Humanos , Mediadores da Inflamação/fisiologia , Canais Iônicos/fisiologia , Transplante de Células-Tronco Mesenquimais , Fator de Crescimento Neural/antagonistas & inibidores , Fator de Crescimento Neural/fisiologia , Transdução de Sinais/fisiologia , Via de Sinalização Wnt/fisiologia
16.
Oncogene ; 38(25): 4932-4947, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30804456

RESUMO

Colorectal cancer (CRC) has long been known for its tight association with chronic inflammation, thought to play a key role in tumor onset and malignant progression through the modulation of cancer stemness. However, the underlying molecular and cellular mechanisms are still largely elusive. Here we show that the IL-6/STAT3 inflammatory signaling axis induces the deacetylation of FRA1 at the Lys-116 residue located within its DNA-binding domain. The HDAC6 deacetylase underlies this key modification leading to the increase of FRA1 transcriptional activity, the subsequent transactivation of NANOG expression, and the acquisition of stem-like cellular features. As validated in a large (n = 123) CRC cohort, IL-6 secretion was invariably accompanied by increased FRA1 deacetylation at K116 and an overall increase in its protein levels, coincident with malignant progression and poor prognosis. Of note, combined treatment with the conventional cytotoxic drug 5-FU together with Tubastatin A, a HDAC6-specific inhibitor, resulted in a significant in vivo synergistic inhibitory effect on tumor growth through suppression of CRC stemness. Our results reveal a novel transcriptional and posttranslational regulatory cross-talk between inflammation and stemness signaling pathways that underlie self-renewal and maintenance of CRC stem cells and promote their malignant behavior. Combinatorial treatment aimed at the core regulatory mechanisms downstream of IL-6 may offer a novel promising approach for CRC treatment.


Assuntos
Acetiltransferases/metabolismo , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Interleucina-6/farmacologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Acetilação/efeitos dos fármacos , Animais , Neoplasias Colorretais/genética , Feminino , Células HEK293 , Células HT29 , Humanos , Mediadores da Inflamação/farmacologia , Mediadores da Inflamação/fisiologia , Interleucina-6/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células-Tronco Neoplásicas/patologia , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Processamento de Proteína Pós-Traducional/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
17.
J Med Chem ; 62(6): 2916-2927, 2019 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-30798607

RESUMO

Ca2+-independent phospholipase A2 (GVIA iPLA2) has gained increasing interest recently as it has been recognized as a participant in biological processes underlying diabetes development and autoimmune-based neurological disorders. The development of potent GVIA iPLA2 inhibitors is of great importance because only a few have been reported so far. We present a novel class of GVIA iPLA2 inhibitors based on the ß-lactone ring. This functionality in combination with a four-carbon chain carrying a phenyl group at position-3 and a linear propyl group at position-4 of the lactone ring confers excellent potency. trans-3-(4-Phenylbutyl)-4-propyloxetan-2-one (GK563) was identified as being the most potent GVIA iPLA2 inhibitor ever reported ( XI(50) 0.0000021, IC50 1 nM) and also one that is 22 000 times more active against GVIA iPLA2 than GIVA cPLA2. It was found to reduce ß-cell apoptosis induced by proinflammatory cytokines, raising the possibility that it can be beneficial in countering autoimmune diseases, such as type 1 diabetes.


Assuntos
Apoptose/efeitos dos fármacos , Células Secretoras de Insulina/efeitos dos fármacos , Lactonas/farmacologia , Inibidores de Fosfolipase A2/farmacologia , Fosfolipases A2 Independentes de Cálcio/antagonistas & inibidores , Animais , Apoptose/fisiologia , Citocinas/fisiologia , Desenho de Fármacos , Humanos , Mediadores da Inflamação/fisiologia , Lactonas/química , Inibidores de Fosfolipase A2/química , Inibidores de Fosfolipase A2/metabolismo , Fosfolipases A2 Independentes de Cálcio/metabolismo , Relação Estrutura-Atividade
18.
J Leukoc Biol ; 106(1): 133-146, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30645013

RESUMO

Cold-inducible RNA-binding protein (CIRP) was discovered 2 decades ago while studying the mechanism of cold stress adaptation in mammals. Since then, the role of intracellular CIRP (iCIRP) as a stress-response protein has been extensively studied. Recently, extracellular CIRP (eCIRP) was discovered to also have an important role, acting as a damage-associated molecular pattern, raising critical implications for the pathobiology of inflammatory diseases. During hemorrhagic shock and sepsis, inflammation triggers the translocation of CIRP from the nucleus to the cytosol and its release to the extracellular space. eCIRP then induces inflammatory responses in macrophages, neutrophils, lymphocytes, and dendritic cells. eCIRP also induces endoplasmic reticulum stress and pyroptosis in endothelial cells by activating the NF-κB and inflammasome pathways, and necroptosis in macrophages via mitochondrial DNA damage. eCIRP works through the TLR4-MD2 receptors. Studies with CIRP-/- mice reveal protection against inflammation, implicating eCIRP to be a novel drug target. Anti-CIRP Ab or CIRP-derived small peptide may have effective therapeutic potentials in sepsis, acute lung injury, and organ ischemia/reperfusion injuries. The current review focuses on the pathobiology of eCIRP by emphasizing on signal transduction machineries, leading to discovering novel therapeutic interventions targeting eCIRP in various inflammatory diseases.


Assuntos
Inflamação/etiologia , Proteínas de Ligação a RNA/fisiologia , Alarminas/fisiologia , Animais , Estresse do Retículo Endoplasmático , Humanos , Inflamação/tratamento farmacológico , Mediadores da Inflamação/fisiologia , Neutrófilos/fisiologia , Proteínas de Ligação a RNA/antagonistas & inibidores , Transdução de Sinais , Receptor 4 Toll-Like/fisiologia
19.
J Strength Cond Res ; 33(2): 502-513, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28277426

RESUMO

de Freitas, VH, Ramos, SP, Bara-Filho, MG, Freitas, DGS, Coimbra, DR, Cecchini, R, Guarnier, FA, and Nakamura, FY. Effect of cold water immersion performed on successive days on physical performance, muscle damage, and inflammatory, hormonal, and oxidative stress markers in volleyball players. J Strength Cond Res 33(2): 502-513, 2019-The aim of this study was to investigate the effects of daily cold water immersion (CWI) on physical performance, muscle damage, and inflammatory, hormonal, and oxidative stress markers in volleyball. Six players were submitted to CWI and six players to a placebo, during 5 training days. Thigh circumference, squat jump, and agility were measured on the first, third, and sixth days. On the first and sixth days, blood and saliva were collected for analysis of oxidative stress, muscle damage, and inflammatory and hormonal levels. Muscle soreness and countermovement jump were quantified daily. The physical performance comparisons did not present differences and the only between group comparison with a large effect size (ES = -1.39) was in Δ% between day 1 and day 2 for countermovement jump. Delayed onset muscle soreness and creatine kinase increased in both groups and the ESs of between group comparisons of Δ% between moments were not more than moderate. Thigh circumference increased only in the placebo group (p = 0.04) and the ES of the between group comparisons of Δ% between moments was large (1.53). No differences were found in oxidative stress, or inflammatory markers. Cortisol decreased only in the CWI-group (p ≤ 0.05) and the ESs of the between group comparisons of Δ% between moments of the testosterone to cortisol ratio (-1.94) and insulin-like growth-1 (-1.34) were large. Despite the positive effects of daily CWI on muscle edema and hormonal status, the limited effects of CWI on performance, muscle damage, inflammation markers, and reactive oxygen species mediators signal the unimportance of the daily practice of this recovery method in volleyball players.


Assuntos
Desempenho Atlético/fisiologia , Temperatura Baixa , Músculo Esquelético/fisiologia , Voleibol/fisiologia , Água , Adulto , Biomarcadores , Creatina Quinase/sangue , Humanos , Imersão , Mediadores da Inflamação/fisiologia , Masculino , Mialgia/fisiopatologia , Estresse Oxidativo/fisiologia , Esteroides/metabolismo , Adulto Jovem
20.
Auton Neurosci ; 216: 72-86, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30503161

RESUMO

Neuroinflammation is produced by local or systemic alterations and mediated mainly by glia, affecting the activity of various neural circuits including those involved in breathing rhythm generation and control. Several pathological conditions, such as sudden infant death syndrome, obstructive sleep apnea and asthma exert an inflammatory influence on breathing-related circuits. Consequently breathing (both resting and ventilatory responses to physiological challenges), is affected; e.g., responses to hypoxia and hypercapnia are compromised. Moreover, inflammation can induce long-lasting changes in breathing and affect adaptive plasticity; e.g., hypoxic acclimatization or long-term facilitation. Mediators of the influences of inflammation on breathing are most likely proinflammatory molecules such as cytokines and prostaglandins. The focus of this review is to summarize the available information concerning the modulation of the breathing function by inflammation and the cellular and molecular aspects of this process. I will consider: 1) some clinical and experimental conditions in which inflammation influences breathing; 2) the variety of experimental approaches used to understand this inflammatory modulation; 3) the likely cellular and molecular mechanisms.


Assuntos
Mediadores da Inflamação/fisiologia , Inflamação/fisiopatologia , Respiração , Animais , Humanos , Modelos Neurológicos
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