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1.
Int J Mol Sci ; 22(16)2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34445357

RESUMO

The biological activities of interleukins, a group of circulating cytokines, are linked to the immuno-pathways involved in many diseases. Mounting evidence suggests that interleukin-1ß (IL-1ß) plays a significant role in the pathogenesis of various types of hypertension. In this review, we summarized recent findings linking IL-1ß to systemic arterial hypertension, pulmonary hypertension, and gestational hypertension. We also outlined the new progress in elucidating the potential mechanisms of IL-1ß in hypertension, focusing on it's regulation in inflammation, vascular smooth muscle cell function, and extracellular remodeling. In addition, we reviewed recent studies that highlight novel findings examining the function of non-coding RNAs in regulating the activity of IL-1ß and its associated proteins in the setting of hypertension. The information collected in this review provides new insights into understanding the pathogenesis of hypertension and could lead to the discovery of new anti-hypertensive therapies to combat this highly prevalent disease.


Assuntos
Hipertensão/etiologia , Interleucina-1beta/fisiologia , Animais , Matriz Extracelular/patologia , Matriz Extracelular/fisiologia , Feminino , Regulação da Expressão Gênica , Humanos , Hipertensão/patologia , Hipertensão/fisiopatologia , Hipertensão Induzida pela Gravidez/etiologia , Hipertensão Induzida pela Gravidez/patologia , Hipertensão Induzida pela Gravidez/fisiopatologia , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/patologia , Hipertensão Pulmonar/fisiopatologia , Inflamação/complicações , Inflamação/fisiopatologia , Interleucina-1beta/genética , Músculo Liso Vascular/fisiopatologia , Gravidez , RNA não Traduzido/fisiologia , Remodelação Vascular/fisiologia
2.
Int J Mol Sci ; 22(15)2021 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-34360779

RESUMO

Pro-inflammatory cytokines promote cellular iron-import through enhanced divalent metal transporter-1 (DMT1) expression in pancreatic ß-cells, consequently cell death. Inhibition of ß-cell iron-import by DMT1 silencing protects against apoptosis in animal models of diabetes. However, how alterations of signaling networks contribute to the protective action of DMT1 knock-down is unknown. Here, we performed phosphoproteomics using our sequential enrichment strategy of mRNA, protein, and phosphopeptides, which enabled us to explore the concurrent molecular events in the same set of wildtype and DMT1-silenced ß-cells during IL-1ß exposure. Our findings reveal new phosphosites in the IL-1ß-induced proteins that are clearly reverted by DMT1 silencing towards their steady-state levels. We validated the levels of five novel phosphosites of the potential protective proteins using parallel reaction monitoring. We also confirmed the inactivation of autophagic flux that may be relevant for cell survival induced by DMT1 silencing during IL-1ß exposure. Additionally, the potential protective proteins induced by DMT1 silencing were related to insulin secretion that may lead to improving ß-cell functions upon exposure to IL-1ß. This global profiling has shed light on the signal transduction pathways driving the protection against inflammation-induced cell death in ß-cells after DMT1 silencing.


Assuntos
Apoptose/imunologia , Autofagia/imunologia , Proteínas de Transporte de Cátions/deficiência , Técnicas de Silenciamento de Genes , Células Secretoras de Insulina/imunologia , Interleucina-1beta/imunologia , Interleucina-6/imunologia , Transdução de Sinais/imunologia , Animais , Apoptose/genética , Autofagia/genética , Proteínas de Transporte de Cátions/imunologia , Interleucina-1beta/genética , Interleucina-6/genética , Camundongos , Transdução de Sinais/genética
3.
J Trop Pediatr ; 67(3)2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34363079

RESUMO

BACKGROUND: The severity of Helicobacter pylori infection is determined by the interplay between bacterial virulence, host genetic and environmental factors. This study aimed to identify interleukin-1 beta (IL-1ß) and interleukin receptor antagonist (IL-1RN) gene polymorphisms and their associations with H. pylori infection, and severity of chronic gastritis in Egyptian children. METHODS: A case control study was conducted on 100 children (50 H. pylori positive and 50 controls). Genotyping of IL-1ß-31 gene was done by PCR-CTPP (confronting two-pair primers), of IL-1ß-511 was performed using allele specific PCR, and investigation of the variable number tandem repeat polymorphism of the IL-1RN gene was done by PCR. RESULTS: The genotype C/T of IL1ß-511 was the predominant genotype (36/50; 72%) among H. pylori positive cases (p ≤ 0.001). The presence of C/T genotype at position 511 of IL1ß was associated with increased risk of infection with H. pylori (p ≤ 0.001, odds ratio = 6.612) and with more severe disease (p = 0.004, odds ratio = 8.333). No association of IL-1ß-31 or IL-1RN gene polymorphisms with H. pylori infection or with risk of severe gastric diseases was found. Children who carry two polymorphisms are almost four times at risk for development of H. pylori infection (p = 0.026, odds ratio = 3.937). CONCLUSIONS: Polymorphism at position -511 of IL1ß gene is associated with increased risk of H. pylori infection as well as of severe corpus gastric disease in Egyptian children. This population should be considered a high-risk group, which needs regular gastric endoscopic surveillance, and should be target for H. pylori eradication. Lay summaryThe genotype C/T of IL1ß-511 gene was the predominant genotype (36/50; 72%) among H. pylori positive children. Polymorphism at position -511 of IL1ß gene is associated with increased risk of Helicobacter pylori infection as well as of severe corpus gastric disease in Egyptian children. No association of IL-1ß-31 or IL-1RN gene polymorphisms with H. pylori infection or with risk of severe gastric diseases in Egyptian children.


Assuntos
Gastrite , Infecções por Helicobacter , Proteína Antagonista do Receptor de Interleucina 1/genética , Interleucina-1beta , Estudos de Casos e Controles , Criança , Gastrite/genética , Gastrite/microbiologia , Predisposição Genética para Doença , Genótipo , Infecções por Helicobacter/epidemiologia , Helicobacter pylori , Humanos , Interleucina-1beta/genética , Polimorfismo Genético
4.
Molecules ; 26(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34361797

RESUMO

Carpesium divaricatum Sieb. & Zucc., a traditional medicinal plant used as an inflammation-relieving remedy, is a rich source of terpenoids. At least 40 germacrane-type sesquiterpene lactones, representatives of four different structural groups, were isolated from the plant. Cytotoxicity against cancer cells in vitro is the most frequently described biological activity of the compounds. However, little is known about the selectivity of the cytotoxic effect. The anti-inflammatory activity of the germacranolides is also poorly documented. The objective of the present study was to assess the cytotoxic activity of selected C. divaricatum germacranolides-derivatives of 4,5,8,9-tetrahydroxy-3-oxo-germacran-6,12-olide towards cancer and normal cell lines (including cells of different p53 status). Moreover, to assess the anti-inflammatory effect of the compounds, the release of four proinflammatory cytokines/chemokines (IL-1ß, IL-8, TNF-α and CCL2) by lipopolysaccharide-stimulated human neutrophils was measured by ELISA. The investigated sesquiterpene lactones demonstrated nonselective activity towards prostate cancer (Du145 and PC3) and normal prostate epithelial cells (PNT2) as well as against melanoma cells (A375 and HTB140) and keratinocytes (HaCaT). Cytotoxic activity against osteosarcoma cells was independent of their p53 status. In sub-cytotoxic concentrations (0.5-2.5 µM) the studied compounds significantly decreased cytokine/chemokine release by lipopolysaccharide-stimulated human leukocytes.


Assuntos
Anti-Inflamatórios/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Asteraceae/química , Citotoxinas/farmacologia , Sesquiterpenos de Germacrano/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/classificação , Anti-Inflamatórios/isolamento & purificação , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/classificação , Antineoplásicos Fitogênicos/isolamento & purificação , Asteraceae/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Quimiocina CCL2/genética , Quimiocina CCL2/imunologia , Citotoxinas/química , Citotoxinas/classificação , Citotoxinas/isolamento & purificação , Doxorrubicina/farmacologia , Regulação Neoplásica da Expressão Gênica , Humanos , Concentração Inibidora 50 , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Interleucina-8/genética , Interleucina-8/imunologia , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Neutrófilos/citologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Componentes Aéreos da Planta/química , Componentes Aéreos da Planta/metabolismo , Extratos Vegetais/química , Plantas Medicinais , Polônia , Cultura Primária de Células , Sesquiterpenos de Germacrano/química , Sesquiterpenos de Germacrano/classificação , Sesquiterpenos de Germacrano/isolamento & purificação , Transdução de Sinais , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/imunologia
5.
Molecules ; 26(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34361744

RESUMO

Korean red pine (Pinus densiflora) belongs to the Genus Pinus, and its bark contains a great amount of naturally occurring phenolic compounds. Until now, few studies have been conducted to assess the neuroprotective effects of Pinus densiflora bark extract against brain ischemic injury. The aim of this study was to investigate the neuroprotective effects of pre-treatment with the extract in the hippocampus following 5-min transient forebrain ischemia in gerbils. Furthermore, this study examined the anti-inflammatory effect as a neuroprotective mechanism of the extract. Pinus densiflora bark was extracted by pure water (100 °C), and this extract was quantitatively analyzed and contained abundant polyphenols, flavonoids, and proanthocyanidins. The extract (25, 50, and 100 mg/kg) was orally administered once a day for seven days before the ischemia. In the gerbil hippocampus, death of the pyramidal neurons was found in the subfield cornu ammonis 1 (CA1) five days after the ischemia. This death was significantly attenuated by pre-treatment with 100 mg/kg, not 25 or 50 mg/kg, of the extract. The treatment with 100 mg/kg of the extract markedly inhibited the activation of microglia (microgliosis) and significantly decreased the expression of pro-inflammatory cytokines (interleukin 1ß and tumor necrosis factor α). In addition, the treatment significantly increased anti-inflammatory cytokines (interleukin 4 and interleukin 13). Taken together, this study clearly indicates that pre-treatment with 100 mg/kg of Pinus densiflora bark extract in gerbils can exert neuroprotection against brain ischemic injury by the attenuation of neuroinflammatory responses.


Assuntos
Anti-Inflamatórios/farmacologia , Isquemia Encefálica/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Pinus/química , Prosencéfalo/efeitos dos fármacos , Animais , Anti-Inflamatórios/química , Isquemia Encefálica/genética , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Flavonoides/química , Flavonoides/farmacologia , Expressão Gênica/efeitos dos fármacos , Gerbillinae , Hipocampo/metabolismo , Hipocampo/patologia , Inflamação , Interleucina-13/agonistas , Interleucina-13/genética , Interleucina-13/metabolismo , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-4/agonistas , Interleucina-4/genética , Interleucina-4/metabolismo , Masculino , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Fármacos Neuroprotetores/química , Casca de Planta/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Polifenóis/química , Polifenóis/farmacologia , Proantocianidinas/química , Proantocianidinas/farmacologia , Prosencéfalo/metabolismo , Prosencéfalo/patologia , Células Piramidais/efeitos dos fármacos , Células Piramidais/metabolismo , Células Piramidais/patologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
6.
Zool Res ; 42(5): 633-636, 2021 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-34423606

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiologic agent responsible for the global coronavirus disease 2019 (COVID-19) pandemic. Numerous studies have demonstrated that cardiovascular disease may affect COVID-19 progression. In the present study, we investigated the effect of hypertension on viral replication and COVID-19 progression using a hypertensive mouse model infected with SARS-CoV-2. Results revealed that SARS-CoV-2 replication was delayed in hypertensive mouse lungs. In contrast, SARS-CoV-2 replication in hypertensive mice treated with the antihypertensive drug captopril demonstrated similar virus replication as SARS-CoV-2-infected normotensive mice. Furthermore, antihypertensive treatment alleviated lung inflammation induced by SARS-CoV-2 replication (interleukin (IL)-1ß up-regulation and increased immune cell infiltration). No differences in lung inflammation were observed between the SARS-CoV-2-infected normotensive mice and hypertensive mice. Our findings suggest that captopril treatment may alleviate COVID-19 progression but not affect viral replication.


Assuntos
Anti-Hipertensivos/uso terapêutico , COVID-19/complicações , Captopril/uso terapêutico , Hipertensão/complicações , Pneumopatias/tratamento farmacológico , SARS-CoV-2 , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Anti-Hipertensivos/farmacologia , Captopril/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/complicações , Inflamação/tratamento farmacológico , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Pneumopatias/etiologia , Pneumopatias/virologia , Camundongos , Replicação Viral/efeitos dos fármacos
7.
Arterioscler Thromb Vasc Biol ; 41(9): 2509-2511, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34261329
8.
Aging (Albany NY) ; 13(13): 17227-17236, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34198264

RESUMO

Osteoarthritis (OA) and rheumatoid arthritis (RA) are two of the most common types of arthritis. Both are characterized by the infiltration of a number of proinflammatory cytokines into the joint microenvironment. miRNAs play critical roles in the disease processes of arthritic disorders. However, little is known about the effects of miRNAs on critical inflammatory cytokine production with OA and RA progression. Here, we found higher levels of proinflammatory cytokines including interleukin 1 beta (IL-1ß), interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) in human OA and RA synovial fibroblasts (SFs) compared with normal SFs. Searches of open-source microRNA (miRNA) software determined that miR-let-7c-5p and miR-149-5p interfere with IL-1ß, IL-6 and TNF-α transcription; levels of all three proinflammatory cytokines were lower in human OA and RA patients compared with normal controls. Anti-inflammatory agents dexamethasone, celecoxib and indomethacin reduced proinflammatory cytokine production by promoting the expression of miR-let-7c-5p and miR-149-5p. Similarly, ibuprofen and methotrexate also enhanced miR-let-7c-5p and miR-149-5p expression in human SFs. The evidence suggests that increasing miR-let-7c-5p and miR-149-5p expression is a novel strategy for OA and RA.


Assuntos
Artrite Reumatoide/genética , Artrite Reumatoide/metabolismo , Citocinas/biossíntese , Citocinas/genética , Fibroblastos/metabolismo , MicroRNAs/genética , Osteoartrite/genética , Osteoartrite/metabolismo , Membrana Sinovial/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Fibroblastos/efeitos dos fármacos , Humanos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , MicroRNAs/biossíntese , Membrana Sinovial/citologia , Membrana Sinovial/efeitos dos fármacos , Fator de Necrose Tumoral alfa
9.
Commun Biol ; 4(1): 865, 2021 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-34257370

RESUMO

A single-nucleotide polymorphism of neutrophil cytosolic factor 1 (Ncf1), leading to an impaired generation of reactive oxygen species (ROS), is a causative genetic factor for autoimmune disease. To study a possible tumor protection effect by the Ncf1 mutation in a manner dependent on cell types, we used experimental mouse models of lung colonization assay by B16F10 melanoma cells. We observed fewer tumor foci in Ncf1 mutant mice, irrespective of αßT, γδT, B-cell deficiencies, or of a functional Ncf1 expression in CD68-positive monocytes/macrophages. The susceptibility to tumor colonization was restored by the human S100A8 (MRP8) promoter directing a functional Ncf1 expression to granulocytes. This effect was associated with an increase of both ROS and interleukin 1 beta (IL-1ß) production from lung neutrophils. Moreover, neutrophil depletion by anti-Ly6G antibodies increased tumor colonization in wild type but failed in the Ncf1 mutant mice. In conclusion, tumor colonization is counteracted by ROS-activated and IL-1ß-secreting tissue neutrophils.


Assuntos
Regulação Neoplásica da Expressão Gênica , NADPH Oxidases/genética , Neoplasias/genética , Neutrófilos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Animais , Calgranulina A/genética , Calgranulina A/metabolismo , Linhagem Celular Tumoral , Humanos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Pulmão/metabolismo , Pulmão/patologia , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , NADPH Oxidases/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Polimorfismo de Nucleotídeo Único
10.
Aging (Albany NY) ; 13(13): 17690-17706, 2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-34237707

RESUMO

Inflammation and extracellular matrix (ECM) degradation have been implicated in the pathological process of osteoarthritis (OA). α-Cyperone is the main active component of the traditional Chinese medicine Cyperus rotundus L. In this study, we found that α-Cyperone abolished the IL-1ß-induced production of inflammatory cytokines in isolated rat chondrocytes, such as cyclooxygenase-2 (COX-2), tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6) and inducible nitric oxide synthase (iNOS), in a dose-dependent manner (0.75, 1.5 or 3 µM). Also, the results showed that α-Cyperone downregulated the expression of metalloproteinases (MMPs) and thrombospondin motifs 5 (ADAMTS5), and upregulated the expression of type-2 collagen. Mechanistically, molecular docking tests revealed that α-Cyperone stably and effectively binds to p65, p38, extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK). α-Cyperone inhibited NF-κB activation by blocking its nuclear transfer, and decreasing the phosphorylation of mitogen-activated protein kinase (MAPKs). In addition, in vivo studies based on a mouse model of arthritis showed that α-Cyperone prevented the development of osteoarthritis. Therefore, α-Cyperone may be a potential anti-OA drug.


Assuntos
Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Matriz Extracelular/efeitos dos fármacos , Inflamação/tratamento farmacológico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , NF-kappa B/efeitos dos fármacos , Naftalenos/farmacologia , Naftalenos/uso terapêutico , Osteoartrite/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Animais , Condrócitos/efeitos dos fármacos , Cyperus , Regulação para Baixo , Matriz Extracelular/patologia , MAP Quinases Reguladas por Sinal Extracelular , Regulação da Expressão Gênica/efeitos dos fármacos , Interleucina-1beta/biossíntese , Interleucina-1beta/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Osteoartrite/patologia , Osteoartrite/prevenção & controle , Ratos
11.
J Photochem Photobiol B ; 221: 112243, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34217028

RESUMO

Due to their capacity to differentiate into the chondrogenic lineage, adipose-derived stromal/stem cells (ASC) are a promising source of therapeutically relevant cells for cartilage tissue regeneration. Their differentiation potential, however, varies between patients. In our study, we aim to stimulate ASC towards a more reliable chondrogenic phenotype using photobiomodulation (PBM). LED devices of either blue (475 nm), green (516 nm) or red (635 nm) light were used to treat human ASC from donors of varying chondrogenic potential. The treatment was applied either once during the 2D expansion phase or repeatedly during the 3D differentiation phase. Chondrogenic differentiation was assessed via pellet size, GAG/DNA content, histology and gene expression analysis. Reactions to PBM were found to be wavelength-dependent and more pronounced when the treatment was applied during expansion. Donors were assigned to responder categories according to their response to the treatment during expansion, whereby good responders were mainly donors with low intrinsic chondrogenic potential. Exposed to light, they revealed a particularly high relative increase in pellet size (more than twice the size of untreated controls after red light PBM), intense collagen type II immunostaining (low/absent in untreated controls) and activation of otherwise absent COL2A1 expression. Conversely, on a donor with high intrinsic chondrogenic potential, light had adverse effects. When applied with shorter wavelengths (blue, green), it led to reduced pellet size, GAG/DNA content and collagen type II immunostaining. However, when PBM was applied in 3D, the same donor was the only one to react with increased differentiation to all three wavelengths. We were able to demonstrate that PBM can be used to enhance or hamper chondrogenesis of ASC, and that success depends on treatment parameters and intrinsic cellular potential. The improvement of chondrogenesis in donors with low intrinsic potential highlights PBM as potent tool for cell-based cartilage regeneration. Its cost-effectiveness and ease of use make for an attractive treatment option to enhance the performance of ASC in cartilage tissue engineering.


Assuntos
Diferenciação Celular/efeitos da radiação , Condrogênese/efeitos da radiação , Luz , Tecido Adiposo/citologia , Técnicas de Cultura de Células , Células Cultivadas , Colágeno Tipo II/genética , Colágeno Tipo II/metabolismo , Regulação para Baixo/efeitos da radiação , Humanos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Regulação para Cima/efeitos da radiação
12.
Immunity ; 54(7): 1463-1477.e11, 2021 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-34115964

RESUMO

Acute respiratory distress syndrome (ARDS), an inflammatory condition with high mortality rates, is common in severe COVID-19, whose risk is reduced by metformin rather than other anti-diabetic medications. Detecting of inflammasome assembly in post-mortem COVID-19 lungs, we asked whether and how metformin inhibits inflammasome activation while exerting its anti-inflammatory effect. We show that metformin inhibited NLRP3 inflammasome activation and interleukin (IL)-1ß production in cultured and alveolar macrophages along with inflammasome-independent IL-6 secretion, thus attenuating lipopolysaccharide (LPS)- and SARS-CoV-2-induced ARDS. By targeting electron transport chain complex 1 and independently of AMP-activated protein kinase (AMPK) or NF-κB, metformin blocked LPS-induced and ATP-dependent mitochondrial (mt) DNA synthesis and generation of oxidized mtDNA, an NLRP3 ligand. Myeloid-specific ablation of LPS-induced cytidine monophosphate kinase 2 (CMPK2), which is rate limiting for mtDNA synthesis, reduced ARDS severity without a direct effect on IL-6. Thus, inhibition of ATP and mtDNA synthesis is sufficient for ARDS amelioration.


Assuntos
Trifosfato de Adenosina/metabolismo , DNA Mitocondrial/biossíntese , Inflamassomos/efeitos dos fármacos , Metformina/farmacologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Pneumonia/prevenção & controle , Animais , COVID-19/metabolismo , COVID-19/prevenção & controle , Citocinas/genética , Citocinas/metabolismo , DNA Mitocondrial/metabolismo , Humanos , Inflamassomos/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Lipopolissacarídeos/toxicidade , Metformina/uso terapêutico , Camundongos , Núcleosídeo-Fosfato Quinase/metabolismo , Pneumonia/metabolismo , Síndrome do Desconforto Respiratório/induzido quimicamente , Síndrome do Desconforto Respiratório/prevenção & controle , SARS-CoV-2/patogenicidade
13.
Front Immunol ; 12: 623610, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093519

RESUMO

Severe cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) strongly hampered the broad clinical applicability of chimeric antigen receptor T cell (CAR-T) therapy. Vascular endothelial activation has been suggested to contribute to the development of CRS and ICANS after CAR-T therapy. However, therapeutic strategies targeting endothelial dysfunction during CAR-T therapy have not been well studied yet. Here, we found that tumor necrosis factor α (TNFα) produced by CAR-T cells upon tumor recognition and interleukin 1ß (IL1ß) secreted by activated myeloid cells were the main cytokines in inducing endothelial activation. Therefore, we investigated the potential effectiveness of TNFα and IL1ß signaling blockade on endothelial activation in CAR-T therapy. The blockade of TNFα and IL1ß with adalimumab and anti-IL1ß antibody respectively, as well as the application of focal adhesion kinase (FAK) inhibitor, effectively ameliorated endothelial activation induced by CAR-T, tumor cells, and myeloid cells. Moreover, adalimumab and anti-IL1ß antibody exerted synergistic effect on the prevention of endothelial activation induced by CAR-T, tumor cells, and myeloid cells. Our results indicate that TNFα and IL1ß blockade might have therapeutic potential for the treatment of CAR-T therapy-associated CRS and neurotoxicity.


Assuntos
Adalimumab/farmacologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Imunoterapia Adotiva , Interleucina-1beta/antagonistas & inibidores , Células Mieloides/efeitos dos fármacos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T/efeitos dos fármacos , Inibidores do Fator de Necrose Tumoral/farmacologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Antígenos CD19/genética , Antígenos CD19/imunologia , Antígenos CD19/metabolismo , Linhagem Celular Tumoral , Técnicas de Cocultura , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/metabolismo , Síndrome da Liberação de Citocina/prevenção & controle , Células HEK293 , Células Endoteliais da Veia Umbilical Humana/imunologia , Humanos , Imunoterapia Adotiva/efeitos adversos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Células Mieloides/imunologia , Células Mieloides/metabolismo , Síndromes Neurotóxicas/imunologia , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/prevenção & controle , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
14.
Mol Cell Biol ; 41(9): e0044920, 2021 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-34124933

RESUMO

A desynchronized circadian rhythm in tumors is coincident with aberrant inflammation and dysregulated metabolism. As their interrelationship in cancer etiology is largely unknown, we investigated the link among the three in glioma. The tumor metabolite lactate-mediated increase in the proinflammatory cytokine interleukin-1ß (IL-1ß) was concomitant with elevated levels of the core circadian regulators Clock and Bmal1. Small interfering RNA (siRNA)-mediated knockdown of Bmal1 and Clock decreased (i) lactate dehydrogenase A (LDHA) and IL-1ß levels and (ii) the release of lactate and proinflammatory cytokines. Lactate-mediated deacetylation of Bmal1 and its interaction with Clock regulate IL-1ß levels and vice versa. Site-directed mutagenesis and luciferase reporter assays indicated the functionality of E-box sites on LDHA and IL-1ß promoters. Sequential chromatin immunoprecipitation (ChIP-re-ChIP) revealed that lactate-IL-1ß cross talk positively affects the corecruitment of Clock-Bmal1 to these E-box sites. Clock-Bmal1 enrichment was accompanied by decreased H3K9me3 and increased H3K9ac and RNA polymerase II (Pol II) occupancy. The lactate-IL-1ß-Clock (LIC) loop positively regulated the expression of genes associated with the cell cycle, DNA damage, and cytoskeletal organization involved in glioma progression. TCGA (The Cancer Genome Atlas) data analysis suggested the presence of lactate-IL-1ß cross talk in other cancers. The responsiveness of stomach and cervical cancer cells to lactate inhibition followed the same trend as that exhibited by glioma cells. In addition, components of the LIC loop were found to be correlated with (i) patient survival, (ii) clinically actionable genes, and (iii) anticancer drug sensitivity. Our findings provide evidence for potential cancer-specific axis wiring of IL-1ß and LDHA through Clock-Bmal1, the outcome of which is to fuel an IL-1ß-lactate autocrine loop that drives proinflammatory and oncogenic signals.


Assuntos
Fatores de Transcrição ARNTL/metabolismo , Relógios Circadianos , Glioma/metabolismo , Homeostase , Interleucina-1beta/metabolismo , Ácido Láctico/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Relógios Circadianos/efeitos dos fármacos , Relógios Circadianos/genética , Citocinas/metabolismo , Progressão da Doença , Elementos E-Box/genética , Epigênese Genética/efeitos dos fármacos , Redes Reguladoras de Genes/efeitos dos fármacos , Glioma/tratamento farmacológico , Glioma/genética , Glioma/patologia , Homeostase/efeitos dos fármacos , Humanos , Mediadores da Inflamação/metabolismo , Interleucina-1beta/genética , Lactato Desidrogenase 5/genética , Lactato Desidrogenase 5/metabolismo , Regiões Promotoras Genéticas , Análise de Sobrevida
15.
Ecotoxicol Environ Saf ; 221: 112448, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34174739

RESUMO

Atmospheric PM2.5 can induce airway inflammation and mucin secretion. MUC5B is required for airway defense. However, the research on the role of MUC5B in airway inflammation induced by atmospheric PM2.5 remains limited. This study was designed to explore the role of MUC5B in airway inflammation induced by atmospheric PM2.5. In vivo, Wistar rats were exposed to 0, 1.5, 7.5, 37.5 mg/ kg PM2.5 saline suspension via intratracheal instillation. HE staining and AB-PAS staining were used to observe the airway inflammation and goblet cell hyperplasia. In vitro, normal A549 cells and MUC5B-knockdown A549 cells were exposed to 0, 100, 200 and 400 µg/mL PM2.5 for 6 h, 12 h, 24 h and 48 h. ELISA was used to measure the levels of TNF-α and IL-1ß in serum and bronchoalveolar lavage fluid of rats and in cell culture. Real time-PCR and ELISA were used to quantify the mRNA and protein levels of MUC5B in trachea and lung of rats and in A549 cells. PM2.5 could cause the infiltration of inflammatory cells and increase the mucus secretions and goblet cell metaplasia. MUC5B is related to rats' airway inflammation induced by PM2.5. A549 cells exposed to PM2.5 in higher concentration and longer time, the protein level of MUC5B was significantly increased, while the levels of IL-1ß, TNF-α and MUC5B mRNA were significantly decreased. Compared with normal A549 cells, the levels of IL-1ß and TNF-α were significantly higher in Muc5b-knockdown cells. Atmospheric PM2.5 can induce airway inflammation and mucin secretion. MUC5B played a critical role in controlling the inflammatory response induced by PM2.5.


Assuntos
Inflamação/metabolismo , Mucina-5B/metabolismo , Material Particulado/toxicidade , Células A549 , Animais , Líquido da Lavagem Broncoalveolar/química , Feminino , Humanos , Interleucina-1beta/sangue , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Pulmão/metabolismo , Masculino , Mucina-5B/genética , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
16.
Mol Med Rep ; 24(2)2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34132373

RESUMO

Coronavirus disease 2019 (COVID­19), caused by the severe acute respiratory syndrome coronavirus­2 (SARS­CoV­2), led to an outbreak of viral pneumonia in December 2019. The present study aimed to investigate the host inflammatory response signature­caused by SARS­CoV­2 in human corneal epithelial cells (HCECs). The expression level of angiotensin­converting enzyme 2 (ACE2) in the human cornea was determined via immunofluorescence. In vitro experiments were performed in HCECs stimulated with the SARS­CoV­2 spike protein. Moreover, the expression levels of ACE2, IL­8, TNF­α, IL­6, gasdermin D (GSDMD) and IL­1ß in HCECs were detected using reverse transcription­quantitative PCR and/or western blotting. It was identified that ACE2 was expressed in normal human corneal epithelium and HCECs cultured in vitro. Furthermore, the expression levels of IL­8, TNF­α and IL­6 in HCECs were decreased following SARS­CoV­2 spike protein stimulation, while the expression levels of GSDMD and IL­1ß were increased. In conclusion, the present results demonstrated that the SARS­CoV­2 spike protein suppressed the host inflammatory response and induced pyroptosis in HCECs. Therefore, blocking the ACE2 receptor in HCECs may reduce the infection rate of COVID­19.


Assuntos
Epitélio Corneano/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Adulto , Idoso , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/metabolismo , Células Cultivadas , Córnea/citologia , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Células Epiteliais/virologia , Epitélio Corneano/virologia , Feminino , Humanos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Pessoa de Meia-Idade , Proteínas de Ligação a Fosfato/genética , Proteínas de Ligação a Fosfato/metabolismo , Piroptose , Glicoproteína da Espícula de Coronavírus/genética , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima
17.
Nat Commun ; 12(1): 3964, 2021 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-34172720

RESUMO

The regulation of bone vasculature by chronic diseases, such as heart failure is unknown. Here, we describe the effects of myocardial infarction and post-infarction heart failure on the bone vascular cell composition. We demonstrate an age-independent loss of type H endothelium in heart failure after myocardial infarction in both mice and humans. Using single-cell RNA sequencing, we delineate the transcriptional heterogeneity of human bone marrow endothelium, showing increased expression of inflammatory genes, including IL1B and MYC, in ischemic heart failure. Endothelial-specific overexpression of MYC was sufficient to induce type H bone endothelial cells, whereas inhibition of NLRP3-dependent IL-1ß production partially prevented the post-myocardial infarction loss of type H vasculature in mice. These results provide a rationale for using anti-inflammatory therapies to prevent or reverse the deterioration of bone vascular function in ischemic heart disease.


Assuntos
Osso e Ossos/irrigação sanguínea , Células Endoteliais/patologia , Insuficiência Cardíaca/fisiopatologia , Infarto do Miocárdio/fisiopatologia , Idoso , Animais , Osso e Ossos/fisiopatologia , Estudos de Casos e Controles , Células Endoteliais/metabolismo , Feminino , Furanos/farmacologia , Genes myc , Insuficiência Cardíaca/etiologia , Células-Tronco Hematopoéticas/patologia , Humanos , Indenos/farmacologia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pessoa de Meia-Idade , Infarto do Miocárdio/complicações , Infarto do Miocárdio/genética , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Sulfonamidas/farmacologia
18.
Nat Commun ; 12(1): 3655, 2021 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-34135341

RESUMO

RNA in extracellular vesicles (EVs) are uptaken by cells, where they regulate fundamental cellular functions. EV-derived mRNA in recipient cells can be translated. However, it is still elusive whether "naked nonvesicular extracellular mRNA" (nex-mRNA) that are not packed in EVs can be uptaken by cells and, if so, whether they have any functions in recipient cells. Here, we show the entrance of nex-mRNA in the nucleus, where they exert a translation-independent function. Human nex-interleukin-1ß (IL1ß)-mRNA outside cells proved to be captured by RNA-binding zinc finger CCCH domain containing protein 12D (ZC3H12D)-expressing human natural killer (NK) cells. ZC3H12D recruited to the cell membrane binds to the 3'-untranslated region of nex-IL1ß-mRNA and transports it to the nucleus. The nex-IL1ß-mRNA in the NK cell nucleus upregulates antiapoptotic gene expression, migration activity, and interferon-γ production, leading to the killing of cancer cells and antimetastasis in mice. These results implicate the diverse actions of mRNA.


Assuntos
Núcleo Celular/metabolismo , Espaço Extracelular/metabolismo , RNA Mensageiro/metabolismo , Regiões 3' não Traduzidas , Animais , Antineoplásicos/farmacologia , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Meios de Cultivo Condicionados/metabolismo , Endorribonucleases/metabolismo , Humanos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Células Matadoras Naturais/metabolismo , Camundongos , Ligação Proteica , RNA Mensageiro/genética , RNA Mensageiro/farmacologia , Proteínas de Ligação a RNA/metabolismo
19.
Int J Mol Sci ; 22(10)2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-34063554

RESUMO

Acute lung injury (ALI) afflicts approximately 200,000 patients annually and has a 40% mortality rate. The COVID-19 pandemic has massively increased the rate of ALI incidence. The pathogenesis of ALI involves tissue damage from invading microbes and, in severe cases, the overexpression of inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß). This study aimed to develop a therapy to normalize the excess production of inflammatory cytokines and promote tissue repair in the lipopolysaccharide (LPS)-induced ALI. Based on our previous studies, we tested the insulin-like growth factor I (IGF-I) and BTP-2 therapies. IGF-I was selected, because we and others have shown that elevated inflammatory cytokines suppress the expression of growth hormone receptors in the liver, leading to a decrease in the circulating IGF-I. IGF-I is a growth factor that increases vascular protection, enhances tissue repair, and decreases pro-inflammatory cytokines. It is also required to produce anti-inflammatory 1,25-dihydroxyvitamin D. BTP-2, an inhibitor of cytosolic calcium, was used to suppress the LPS-induced increase in cytosolic calcium, which otherwise leads to an increase in proinflammatory cytokines. We showed that LPS increased the expression of the primary inflammatory mediators such as toll like receptor-4 (TLR-4), IL-1ß, interleukin-17 (IL-17), TNF-α, and interferon-γ (IFN-γ), which were normalized by the IGF-I + BTP-2 dual therapy in the lungs, along with improved vascular gene expression markers. The histologic lung injury score was markedly elevated by LPS and reduced to normal by the combination therapy. In conclusion, the LPS-induced increases in inflammatory cytokines, vascular injuries, and lung injuries were all improved by IGF-I + BTP-2 combination therapy.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/metabolismo , Anilidas/farmacologia , Citocinas/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Fator de Crescimento Insulin-Like I/farmacologia , Tiadiazóis/farmacologia , Lesão Pulmonar Aguda/patologia , Lesão Pulmonar Aguda/virologia , Anilidas/uso terapêutico , Animais , COVID-19/complicações , Cálcio/metabolismo , Canais de Cálcio/metabolismo , Citocinas/genética , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica/genética , Imuno-Histoquímica , Fator de Crescimento Insulin-Like I/metabolismo , Fator de Crescimento Insulin-Like I/uso terapêutico , Interferon gama/genética , Interferon gama/metabolismo , Interleucina-17/genética , Interleucina-17/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Lipopolissacarídeos/toxicidade , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Tiadiazóis/uso terapêutico , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
20.
Int J Mol Sci ; 22(9)2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-34066976

RESUMO

Heterotypic interactions between newly transformed cells and normal surrounding cells define tumor's fate in incipient carcinomas. Once homeostasis has been lost, normal resident fibroblasts become carcinoma-associated fibroblasts, conferring protumorogenic properties on these normal cells. Here we describe the IL1ß-mediated interplay between cancer cells and normal colonic myofibroblasts (NCFs), which bestows differential sensitivity to cytotoxic drugs on tumor cells. We used NCFs, their conditioned media (CM), and cocultures with tumor cells to characterize the IL1ß-mediated crosstalk between both cell types. We silenced IL1ß in tumor cells to demonstrate that such cells do not exert an influence on NCFs inflammatory phenotype. Our results shows that IL1ß is overexpressed in cocultured tumor cells. IL1ß enables paracrine signaling in myofibroblasts, converting them into inflammatory-CAFs (iCAF). IL1ß-stimulated-NCF-CM induces migration and differential sensitivity to oxaliplatin in colorectal tumor cells. Such chemoprotective effect has not been evidenced for TGFß1-driven NCFs. IL1ß induces the loss of a myofibroblastic phenotype in NCFs and acquisition of iCAF traits. In conclusion, IL1ß-secreted by cancer cells modify surrounding normal fibroblasts to confer protumorogenic features on them, particularly tolerance to cytotoxic drugs. The use of IL1ß-blocking agents might help to avoid the iCAF traits acquisition and consequently to counteract the protumorogenic actions these cells.


Assuntos
Fibroblastos Associados a Câncer/metabolismo , Colo/patologia , Neoplasias Colorretais/tratamento farmacológico , Inflamação/patologia , Interleucina-1beta/metabolismo , Transdução de Sinais , Fibroblastos Associados a Câncer/patologia , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Interleucina-1beta/genética , Fenótipo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Interleucina-1/metabolismo , Ensaio Tumoral de Célula-Tronco
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