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1.
Neurobiol Dis ; 168: 105716, 2022 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-35367629

RESUMO

The distinction between glial painful and protective pathways is unclear and the possibility to finely modulate the system is lacking. Focusing on painful neuropathies, we studied the role of interleukin 1α (IL-1α), an alarmin belonging to the larger family of damage-associated molecular patterns endogenously secreted to restore homeostasis. The treatment of rat primary neurons with increasing doses of the neurotoxic anticancer drug oxaliplatin (0.3-100µM, 48 h) induced the release of IL-1α. The knockdown of the alarmin in neurons leads to their higher mortality when co-cultured with astrocytes. This toxicity was related to increased extracellular ATP and decreased release of transforming growth factor ß1, mostly produced by astrocytes. In a rat model of neuropathy induced by oxaliplatin, the intrathecal treatment with IL-1α was able to reduce mechanical and thermal hypersensitivity both after acute injection (100 ng and 300 ng) and continuous infusion (100 and 300 ng/die-1). Ex vivo analysis on spinal purified astrocyte processes (gliosomes) and nerve terminals (synaptosomes) revealed the property of IL-1α to reduce the endogenous glutamate release induced by oxaliplatin. This protective effect paralleled with an increased number of GFAP-positive cells in the spinal cord, suggesting the ability of IL-1α to evoke a positive, conservative astrocyte phenotype. Endogenous IL-1α induced protective signals in the cross-talk between neurons and astrocytes. Exogenously administered in rats, IL-1α prevented neuropathic pain in the presence of spinal glutamate decrease and astrocyte activation.


Assuntos
Antineoplásicos , Neuralgia , Alarminas/efeitos adversos , Alarminas/metabolismo , Animais , Antineoplásicos/efeitos adversos , Astrócitos/metabolismo , Ácido Glutâmico/metabolismo , Hiperalgesia/metabolismo , Interleucina-1alfa/efeitos adversos , Interleucina-1alfa/metabolismo , Neuralgia/metabolismo , Neurônios/metabolismo , Oxaliplatina/toxicidade , Ratos , Ratos Sprague-Dawley , Medula Espinal/metabolismo
2.
Yakugaku Zasshi ; 139(10): 1235-1241, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31582606

RESUMO

Reactive oxygen species (ROS) are highly reactive molecules generated during mitochondrial respiration and under various environmental stresses, and cause damage to DNA, proteins, and lipids, which is linked to a wide variety of pathologies. However, recent studies have revealed the physiological importance of ROS as signaling molecules, which play crucial roles in the maintenance of cellular functions and homeostasis. According to the extent and duration of ROS generation, ROS-mediated oxidation-reduction (redox) signaling (ROS signaling) is tightly regulated by various molecules and post-translational modifications (PTMs), for inducing appropriate cellular responses. Dysregulation of ROS signaling causes cellular malfunctions, which are also linked to various diseases, such as cancer, neurodegeneration and inflammatory diseases. In this review, we focus on a ROS-responsive protein kinase apoptosis signal-regulating kinase 1 (ASK1) that belongs to the mitogen-activated protein (MAP) kinase kinase kinase (MAP3K) family, and activates the c-jun N-terminal kinase (JNK) and p38 MAP kinase pathways, which consequently induces various cellular responses, including apoptosis and inflammation. Here, we introduce a novel regulatory mechanism and the pathophysiological significance of ASK1 activation. We found that an E3 ubiquitin ligase TRIM48 orchestrates fine-tuning of ROS-induced ASK1 activation mediated by multiple types of PTMs, including ubiquitination, methylation, and phosphorylation. We also found that trans-fatty acids (TFAs) enhance ROS-dependent ASK1 activation induced by extracellular ATP, a damage-associated molecular pattern (DAMP), and thereby promotes apoptosis, which possibly contributes to the pathogenesis of TFA-related diseases including atherosclerosis. Thus, this review provides recent advances in the study of ROS signaling, especially ROS-ASK1 signaling pathway.


Assuntos
Apoptose , Aterosclerose/etiologia , Inflamação/etiologia , MAP Quinase Quinase Quinase 5/fisiologia , Neoplasias/etiologia , Doenças Neurodegenerativas/etiologia , Espécies Reativas de Oxigênio , Transdução de Sinais/fisiologia , Ubiquitina-Proteína Ligases/fisiologia , Trifosfato de Adenosina , Alarminas/efeitos adversos , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , MAP Quinase Quinase Quinase 5/metabolismo , Metilação , Oxirredução , Fosforilação , Processamento de Proteína Pós-Traducional , Espécies Reativas de Oxigênio/metabolismo , Ácidos Graxos trans/efeitos adversos , Ubiquitinação , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
3.
Can J Physiol Pharmacol ; 97(3): 206-212, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30485131

RESUMO

Inflammation is known to be associated with placental dysfunction and pregnancy complications. Infections are well known to be a cause of inflammation but they are frequently undetectable in pregnancy complications. More recently, the focus has been extended to inflammation of noninfectious origin, namely caused by endogenous mediators known as "damage-associated molecular patterns (DAMPs)" or alarmins. In this manuscript, we review the mechanism by which inflammation, sterile or infectious, can alter the placenta and its function. We discuss some classical DAMPs, such as uric acid, high mobility group box 1 (HMGB1), cell-free fetal deoxyribonucleic acid (DNA) (cffDNA), S100 proteins, heat shock protein 70 (HSP70), and adenosine triphosphate (ATP) and their impact on the placenta. We focus on the main placental cells (i.e., trophoblast and Hofbauer cells) and describe the placental response to, and release of, DAMPs. We also covered the current state of knowledge about the role of DAMPs in pregnancy complications including preeclampsia, fetal growth restriction, preterm birth, and stillbirth and possible therapeutic strategies to preserve placental function.


Assuntos
Alarminas/efeitos adversos , Alarminas/metabolismo , Inflamação/etiologia , Relações Materno-Fetais/fisiologia , Doenças Placentárias/etiologia , Complicações na Gravidez/etiologia , Animais , Feminino , Humanos , Inflamação/metabolismo , Placenta/metabolismo , Doenças Placentárias/metabolismo , Gravidez , Complicações na Gravidez/metabolismo
4.
Jpn J Ophthalmol ; 61(5): 415-422, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28725984

RESUMO

PURPOSE: Dying cells release endogenous molecules known as alarmins that signal danger to surrounding tissue. We investigated the effects of necrotic cell-derived alarmins on cytokine expression and barrier function in human corneal epithelial cells. METHODS: The release of interleukin (IL)-6 and IL-8 from immortalized human corneal epithelial (HCE) cells in culture was measured with enzyme-linked immunosorbent assays. The abundance of IL-6 and 8 mRNAs was quantitated by reverse transcription and real-time polymerase chain reaction analysis. Barrier function of HCE cells was evaluated by measurement of transepithelial electrical resistance (TER). The subcellular localization of the p65 subunit of the transcription factor NF-κB was determined by immunofluorescence analysis, and phosphorylation of the endogenous NF-κB inhibitor IκBα was examined by immunoblot analysis. RESULTS: A necrotic cell supernatant prepared from HCE cells induced the up-regulation of IL-6 and 8 expression at both mRNA and protein levels as well as reduced TER in intact HCE cells. Among alarmins tested, only IL-1α (not IL-33 or HMGB1) mimicked these effects of the necrotic cell supernatant. Furthermore, IL-1 receptor antagonist (IL-1RA) and neutralizing antibodies to IL-1α (but not those to IL-1ß) each attenuated the effects of the necrotic cell supernatant. Exposure of HCE cells to the necrotic cell supernatant also induced the phosphorylation and degradation of IκBα as well as translocation of the p65 subunit of NF-κB to the nucleus. CONCLUSION: IL-1α released from necrotic corneal epithelial cells may trigger inflammatory responses at the ocular surface, including cytokine production and barrier disruption.


Assuntos
Doenças da Córnea/genética , Epitélio Corneano/metabolismo , Regulação da Expressão Gênica , Interleucina-1alfa/genética , Interleucina-6/genética , Interleucina-8/genética , RNA/genética , Alarminas/efeitos adversos , Células Cultivadas , Doenças da Córnea/induzido quimicamente , Doenças da Córnea/metabolismo , Citocinas/biossíntese , Citocinas/genética , Impedância Elétrica , Ensaio de Imunoadsorção Enzimática , Epitélio Corneano/patologia , Humanos , Immunoblotting , Interleucina-1alfa/biossíntese , Interleucina-6/biossíntese , Interleucina-8/biossíntese , Necrose/genética , Necrose/metabolismo , Necrose/patologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa
5.
J Trauma Acute Care Surg ; 82(6): 1023-1029, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28301393

RESUMO

BACKGROUND: Massive transfusions are accompanied by an increased incidence of a particularly aggressive and lethal form of acute lung injury (delayed transfusion-related acute lung injury) which occurs longer than 24 hours after transfusions. In light of recent reports showing that mitochondrial (mt)DNA damage-associated molecular patterns (DAMPs) are potent proinflammatory mediators, and that their abundance in the sera of severely injured or septic patients is predictive of clinical outcomes, we explored the idea that mtDNA DAMPs are present in transfusion products and are associated with the occurrence of delayed transfusion-related acute lung injury. METHODS: We prospectively enrolled fourteen consecutive severely injured patients that received greater than three units of blood transfusion products and determined if the total amount of mtDNA DAMPs delivered during transfusion correlated with serum mtDNA DAMPs measured after the last transfusion, and whether the quantity of mtDNA DAMPs in the serum-predicted development of acute respiratory distress syndrome (ARDS). RESULTS: We found detectable levels of mtDNA DAMPs in packed red blood cells (3 ± 0.4 ng/mL), fresh frozen plasma (213.7 ± 65 ng/mL), and platelets (94.8 ± 69.2), with the latter two transfusion products containing significant amounts of mtDNA fragments. There was a linear relationship between the mtDNA DAMPs given during transfusion and the serum concentration of mtDNA fragments (R = 0.0.74, p < 0.01). The quantity of mtDNA DAMPs in serum measured at 24 hours after transfusion predicted the occurrence of ARDS (9.9 ± 1.4 vs. 3.3 ± 0.9, p < 0.01). CONCLUSION: These data show that fresh frozen plasma and platelets contain large amounts of extracellular mtDNA, that the amount of mtDNA DAMPs administered during transfusion may be a determinant of serum mtDNA DAMP levels, and that serum levels of mtDNA DAMPs after multiple transfusions may predict the development of ARDS. Collectively, these findings support the idea that mtDNA DAMPs in transfusion products significantly contribute to the incidence of ARDS after massive transfusions. LEVEL OF EVIDENCE: Prognostic study, level II; therapeutic study, level II.


Assuntos
Alarminas/efeitos adversos , Dano ao DNA , DNA Mitocondrial/metabolismo , Síndrome do Desconforto Respiratório/etiologia , Reação Transfusional , Adulto , Alarminas/sangue , Plaquetas/química , DNA Mitocondrial/sangue , Feminino , Humanos , Masculino , Plasma/química , Estudos Prospectivos , Ferimentos e Lesões/terapia
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