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1.
Signal Transduct Target Ther ; 5(1): 186, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32883951

RESUMO

Sterol regulatory element binding protein-2 (SREBP-2) is activated by cytokines or pathogen, such as virus or bacteria, but its association with diminished cholesterol levels in COVID-19 patients is unknown. Here, we evaluated SREBP-2 activation in peripheral blood mononuclear cells of COVID-19 patients and verified the function of SREBP-2 in COVID-19. Intriguingly, we report the first observation of SREBP-2 C-terminal fragment in COVID-19 patients' blood and propose SREBP-2 C-terminal fragment as an indicator for determining severity. We confirmed that SREBP-2-induced cholesterol biosynthesis was suppressed by Sestrin-1 and PCSK9 expression, while the SREBP-2-induced inflammatory responses was upregulated in COVID-19 ICU patients. Using an infectious disease mouse model, inhibitors of SREBP-2 and NF-κB suppressed cytokine storms caused by viral infection and prevented pulmonary damages. These results collectively suggest that SREBP-2 can serve as an indicator for severity diagnosis and therapeutic target for preventing cytokine storm and lung damage in severe COVID-19 patients.


Assuntos
Betacoronavirus/patogenicidade , Colesterol/biossíntese , Infecções por Coronavirus/genética , Síndrome da Liberação de Citocina/genética , Interações Hospedeiro-Patógeno/genética , Leucócitos Mononucleares/imunologia , Pneumonia Viral/genética , Proteína de Ligação a Elemento Regulador de Esterol 2/genética , Betacoronavirus/imunologia , Estudos de Casos e Controles , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/mortalidade , Síndrome da Liberação de Citocina/virologia , Regulação da Expressão Gênica , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/imunologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Unidades de Terapia Intensiva , Interleucina-1beta/genética , Interleucina-1beta/imunologia , L-Lactato Desidrogenase/genética , L-Lactato Desidrogenase/imunologia , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/virologia , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/virologia , NF-kappa B/genética , NF-kappa B/imunologia , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/mortalidade , Pneumonia Viral/virologia , Cultura Primária de Células , Pró-Proteína Convertase 9/genética , Pró-Proteína Convertase 9/imunologia , Transdução de Sinais , Proteína de Ligação a Elemento Regulador de Esterol 2/imunologia , Análise de Sobrevida , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
2.
J Toxicol Sci ; 45(9): 559-567, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32879255

RESUMO

Lead is a main threat to human health due to its neurotoxicity and the astrocyte is known to be a common deposit site of lead in vivo. However, the detailed mechanisms related to lead exposure in the astrocytes were unclear. In order to deeply investigate this issue, we used Sprague-Dawley (SD) rats and astrocytes isolated from the hippocampus of SD rats to establish the lead-exposed animal and cell models through treating with lead acetate. The expression levels of GFAP, LC3, and p62 in the rat hippocampus were detected by immunofluorescence and Western blot after lead exposure. The effects of autophagy on lead-exposed astrocytes were studied by further autophagy inhibitor 3-methyladenine (3-MA) induction. Transmission electron microscopy was used to observe autophagosomes in astrocytes after lead acetate treatment, followed by assessing related autophagy protein markers. In addition, some inflammatory cytokines and oxidative stress markers were also evaluated after lead exposure and 3-MA administration. We found that lead exposure induced activation of astrocytes, as evidenced by increased GFAP levels and GFAP-positive staining cells in the rat hippocampus. Moreover, lead exposure induced autophagy in astrocytes, as evidenced by increased LC3II and Beclin 1 protein levels and decreased p62 expression in both the rat hippocampus and astrocytes, and it was confirmed that this autophagy was activated through blocking the downstream Akt/target of the rapamycin (mTOR) pathway in astrocytes. Furthermore, it was shown that treatment of lead acetate increased the release of tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß), and the accumulation of malondialdehyde (MDA) and myeloperoxidase (MPO) in astrocytes, which could be alleviated by further 3-MA induction. Therefore, we conclude that lead exposure can induce the autophagy of astrocytes via blocking the Akt/mTOR pathway, leading to accelerated release of inflammatory factors and oxidative stress indicators in astrocytes.


Assuntos
Astrócitos/metabolismo , Astrócitos/fisiologia , Autofagia/efeitos dos fármacos , Autofagia/genética , Compostos Organometálicos/toxicidade , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Animais , Células Cultivadas , Proteína Glial Fibrilar Ácida/genética , Proteína Glial Fibrilar Ácida/metabolismo , Hipocampo/citologia , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Masculino , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Estresse Oxidativo/genética , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
3.
PLoS One ; 15(8): e0237752, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32817626

RESUMO

Pseudomonas aeruginosa remains a leading cause of nosocomial and serious life-threatening infections, and contributes to increased mortality in immunocompromised individuals. P. aeruginosa infection triggers host immune response and often provokes potent inflammatory mediators, which do not necessarily eradicate the causative pathogen. On the other hand, it causes severe airway damage and eventually decreased lung function. Such unfavorable outcomes of inflammatory injury have necessitated the development of novel effective agents that can combat with P. aeruginosa-mediated inflammation. Herein, we investigated the potential of quercetin in regulating P. aeruginosa-induced inflammation, with particular emphasized on the interleukin-1ß (IL-1ß). Our results showed that quercetin exerted the potent inhibitory activity against the production of IL-1ß in macrophages infected by live P. aeruginosa PAO1, without exhibiting cytotoxicity. According to our settings, such the potent inhibitory activity of quercetin was clearly demonstrated through its ability to efficiently inhibit IL-1ß during P. aeruginosa infection, pre- or even post-infection. In addition, quercetin strongly suppressed MAPK signaling pathway by inhibiting phosphorylation of the p38 MAPK and JNK2, and molecular docking study supported well with this observation. Moreover, quercetin reduced the NLRP3 expression and inhibited the P. aeruginosa-mediated cleavage of caspase-1 as well as mature IL-1ß. These results thus indicated that quercetin inhibition of P. aeruginosa-induced IL-1ß production is mediated by suppressing the initial priming step and by inhibiting the NLRP3 inflammasome activation. Taken together, our findings demonstrated the promising regulatory activity of quercetin against IL-1ß production in P. aeruginosa-infected macrophages, and indicated that quercetin has the potential to be effective as a novel therapeutic agent for treatment of P. aeruginosa-induced inflammation.


Assuntos
Interleucina-1beta/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Infecções por Pseudomonas/tratamento farmacológico , Quercetina/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Linhagem Celular , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamassomos/efeitos dos fármacos , Inflamassomos/genética , Macrófagos/efeitos dos fármacos , Macrófagos/microbiologia , Infecções por Pseudomonas/genética , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/patogenicidade , Transdução de Sinais/efeitos dos fármacos
4.
Medicine (Baltimore) ; 99(31): e21022, 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32756088

RESUMO

Studies have obtained conflicting findings regarding the association between the interleukin-1ß (IL-1ß) +3954 C>T polymorphism and the risk of sepsis. To evaluate the association between the IL-1ß +3954 C>T polymorphism and sepsis risk in Chinese individuals, we conducted a study of 254 sepsis patients and 322 controls. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used for genotyping. We found that the IL-1ß +3954 C>T polymorphism was associated with a reduced risk of sepsis. Subgroup analyses revealed that this significant association was more evident among nonsmokers, nondrinkers, individuals with body mass index <25, and individuals aged ≥60 years. The IL-1ß +3954 C>T polymorphism was also associated with the 28-day mortality rate and severity of sepsis. In summary, the IL-1ß +3954 C>T polymorphism confers a reduced risk of sepsis in Han Chinese. This polymorphism may serve as a marker that predicts patients' susceptibility to sepsis.


Assuntos
Predisposição Genética para Doença/genética , Interleucina-1beta/genética , Polimorfismo de Nucleotídeo Único/genética , Sepse/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Sepse/etiologia
5.
Nat Commun ; 11(1): 3816, 2020 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-32732870

RESUMO

Detection of microbial components such as lipopolysaccharide (LPS) by Toll-like receptor 4 (TLR4) on macrophages induces a robust pro-inflammatory response that is dependent on metabolic reprogramming. These innate metabolic changes have been compared to aerobic glycolysis in tumour cells. However, the mechanisms by which TLR4 activation leads to mitochondrial and glycolytic reprogramming are unknown. Here we show that TLR4 activation induces a signalling cascade recruiting TRAF6 and TBK-1, while TBK-1 phosphorylates STAT3 on S727. Using a genetically engineered mouse model incapable of undergoing STAT3 Ser727 phosphorylation, we show ex vivo and in vivo that STAT3 Ser727 phosphorylation is critical for LPS-induced glycolytic reprogramming, production of the central immune response metabolite succinate and inflammatory cytokine production in a model of LPS-induced inflammation. Our study identifies non-canonical STAT3 activation as the crucial signalling intermediary for TLR4-induced glycolysis, macrophage metabolic reprogramming and inflammation.


Assuntos
Interleucina-1beta/metabolismo , Macrófagos/metabolismo , Fator de Transcrição STAT3/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Linhagem Celular , Células Cultivadas , Expressão Gênica , Glicólise/efeitos dos fármacos , Inflamação/genética , Inflamação/metabolismo , Interleucina-1beta/genética , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Fosforilação , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Fator de Transcrição STAT3/genética , Serina/genética , Serina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Fator 6 Associado a Receptor de TNF/genética , Fator 6 Associado a Receptor de TNF/metabolismo , Receptor 4 Toll-Like/genética
6.
Proc Natl Acad Sci U S A ; 117(26): 15160-15171, 2020 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-32541026

RESUMO

IgG antibodies cause inflammation and organ damage in autoimmune diseases such as systemic lupus erythematosus (SLE). We investigated the metabolic profile of macrophages isolated from inflamed tissues in immune complex (IC)-associated diseases, including SLE and rheumatoid arthritis, and following IgG Fcγ receptor cross-linking. We found that human and mouse macrophages undergo a switch to glycolysis in response to IgG IC stimulation, mirroring macrophage metabolic changes in inflamed tissue in vivo. This metabolic reprogramming was required to generate a number of proinflammatory mediators, including IL-1ß, and was dependent on mTOR and hypoxia-inducible factor (HIF)1α. Inhibition of glycolysis, or genetic depletion of HIF1α, attenuated IgG IC-induced activation of macrophages in vitro, including primary human kidney macrophages. In vivo, glycolysis inhibition led to a reduction in kidney macrophage IL-1ß and reduced neutrophil recruitment in a murine model of antibody-mediated nephritis. Together, our data reveal the molecular mechanisms underpinning FcγR-mediated metabolic reprogramming in macrophages and suggest a therapeutic strategy for autoantibody-induced inflammation, including lupus nephritis.


Assuntos
Reprogramação Celular/fisiologia , Nefrite Lúpica/metabolismo , Animais , Células Cultivadas , Dinoprostona/genética , Dinoprostona/metabolismo , Metabolismo Energético , Regulação da Expressão Gênica , Glicólise/fisiologia , Humanos , Imunoglobulina G/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Rim/citologia , Macrófagos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Espécies Reativas de Oxigênio , Receptores de IgG/genética , Receptores de IgG/metabolismo
7.
Environ Toxicol ; 35(9): 991-997, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32401414

RESUMO

Rheumatoid arthritis (RA) is a systemic autoimmune inflammatory disease, in which the immune system attacks synovial joint tissues. Interleukin (IL)-1ß is a critical proinflammatory cytokine in RA progression. Sphingosine-1-phosphate (S1P), a platelet-derived lysophospholipid mediator, reportedly regulates osteoimmunology. Here, we investigated how S1P mediates IL-1ß expression in osteoblasts. Our analysis of records from the Gene Expression Omnibus (GEO) database demonstrate higher levels of IL-1ß in patients with RA compared with those with osteoarthritis. Stimulation of osteoblasts with S1P concentration dependently increased mRNA and protein expression of IL-1ß. Elevations in IL-1ß mRNA expression induced by S1P were reduced by the small interfering RNA (siRNA) against the S1P1 receptor. S1P also augmented JAK and STAT3 molecular cascades. We also found that JAK and STAT3 inhibitors and their siRNAs antagonized S1P-promoted IL-1ß expression. Our results indicate that S1P promotes the expression of IL-1ß in osteoblasts via the S1P1 receptor and the JAK and STAT3 signaling pathways.


Assuntos
Interleucina-1beta/genética , Janus Quinases/metabolismo , Lisofosfolipídeos/fisiologia , Osteoblastos/metabolismo , Fator de Transcrição STAT3/metabolismo , Esfingosina/análogos & derivados , Artrite Reumatoide/metabolismo , Células Cultivadas , Humanos , Lisofosfolipídeos/farmacologia , Masculino , Osteoartrite/metabolismo , Osteoblastos/efeitos dos fármacos , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Transdução de Sinais/efeitos dos fármacos , Esfingosina/farmacologia , Esfingosina/fisiologia , Receptores de Esfingosina-1-Fosfato/genética
8.
Am J Physiol Endocrinol Metab ; 319(1): E110-E116, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32421368

RESUMO

Statins lower cholesterol and risk of cardiovascular disease. Statins can increase blood glucose and risk of new-onset diabetes. It is unclear why statins can have opposing effects on lipids versus glucose. Statins have cholesterol-independent pleiotropic effects that influence both insulin and glucose control. Statin lowering of isoprenoids required for protein prenylation promotes pancreatic ß-cell dysfunction and adipose tissue insulin resistance. Protein prenylation influences immune function and statin-mediated adipose tissue insulin resistance involves the NLR family pyrin domain-containing 3 (NLRP3) inflammasome and IL-1ß. However, the intracellular cues that statins engage to activate the NLRP3 inflammasome and those responsible for IL-1ß-mediated insulin resistance in adipose tissue have not been identified. We hypothesized that stress kinases or components of the insulin signaling pathway mediated statin-induced insulin resistance. We tested the associations of p38, ERK, JNK, phosphatase, and tensin homolog (PTEN), and mTOR in statin-exposed adipose tissue from WT and IL-1ß-/- mice. We found that statins increased phosphorylation of p38 in WT and IL-1ß-/- mice. Statin activation of p38 upstream of IL-1ß led to priming of this NLRP3 inflammasome effector in macrophages. We found that mTORC1 inhibition with low doses of rapamycin (2 or 20 nM) lowered macrophage priming of IL-1ß mRNA and secretion of IL-1ß caused by multiple statins. Rapamycin (20 nM) or the rapalog everolimus (20 nM) prevented atorvastatin-induced lowering of insulin-mediated phosphorylation of Akt in mouse adipose tissue. These results position p38 and mTOR as mediators of statin-induced insulin resistance in adipose tissue and highlight rapalogs as candidates to mitigate the insulin resistance and glycemic side effects of statins.


Assuntos
Atorvastatina/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inflamassomos/efeitos dos fármacos , Resistência à Insulina , Insulina/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/efeitos dos fármacos , Serina-Treonina Quinases TOR/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/efeitos dos fármacos , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Inflamassomos/metabolismo , Interleucina-1beta/genética , MAP Quinase Quinase 4/efeitos dos fármacos , MAP Quinase Quinase 4/metabolismo , Camundongos , Camundongos Knockout , Proteína Quinase 1 Ativada por Mitógeno/efeitos dos fármacos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/efeitos dos fármacos , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , PTEN Fosfo-Hidrolase/efeitos dos fármacos , PTEN Fosfo-Hidrolase/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
9.
Cardiovasc Ther ; 2020: 8584763, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32426037

RESUMO

Background: Although many studies have been performed to elucidate the molecular mechanisms of heart failure, an effective pharmacological therapy to protect cardiac tissues from severe loss of contractile function associated with heart failure after acute myocardial infarction (MI) has yet to be developed. Methods: We examined the cardioprotective effects of (Z)-2-acetoxy-3-(3,4-dihydroxyphenyl) acrylic acid, a new compound with potent antioxidant and antiapoptotic activities in a rat model of heart failure. (Z)-2-Acetoxy-3-(3,4-dihydroxyphenyl) acrylic acid was systemically delivered to rats 6 weeks after MI at different doses (15, 30, and 60 mg/kg). Cardiac function was assessed by hemodynamic measurements. The expression of proinflammatory cytokines, apoptosis-related molecules, and markers of adverse ventricular remodeling was measured using RT-PCR and Western blot. Results: Treatment with (Z)-2-acetoxy-3-(3,4-dihydroxyphenyl) acrylic acid significantly improved cardiac function, in particular by increasing dP/dt. Simultaneously, the expression of the proinflammatory cytokines TNF-α and IL-1ß was markedly reduced in the treatment group compared with the MI group. In addition, (Z)-2-acetoxy-3-(3,4-dihydroxyphenyl) acrylic acid-treated tissues displayed decreased expression of Bax, caspase-3, and caspase-9 and increased expression of Bcl-2, which was in part due to the promotion of Akt phosphorylation. Conclusion: These data demonstrated that (Z)-2-acetoxy-3-(3,4-dihydroxyphenyl) acrylic acid possesses potent cardioprotective effects against cardiac injury in a rat model of heart failure, which is mediated, at least in part, by suppression of the inflammatory and cell apoptosis responses.


Assuntos
Acrilatos/farmacologia , Anti-Inflamatórios/farmacologia , Apoptose/efeitos dos fármacos , Insuficiência Cardíaca/tratamento farmacológico , Infarto do Miocárdio/complicações , Miócitos Cardíacos/efeitos dos fármacos , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Modelos Animais de Doenças , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Mediadores da Inflamação/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Masculino , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos
10.
Yonsei Med J ; 61(6): 533-541, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32469177

RESUMO

PURPOSE: Ethanol elicits several inflammatory responses and affects the innate immune response. The aim of this study was to identify the mechanism by which ethanol affects uric acid-induced NLR family pyrin domain-containing 3 (NLRP3) inflammasome activation by regulation of aryl hydrocarbon receptor (AhR) and thioredoxin-interacting protein (TXNIP). MATERIALS AND METHODS: Human myeloid leukemia cells (U937 cells) were used to assess the role of ethanol in NLRP3 inflammasome activation induced by monosodium urate (MSU) crystals. Expression of target molecules, such as NLRP3 inflammasome components, AhR, and TXNIP, were measured using quantitative real-time PCR and Western blot analyses. The effect of ethanol-induced TXNIP on the NLRP3 inflammasome was assessed in human macrophages transfected with TXNIP siRNA. RESULTS: U937 cells treated with 100 mM ethanol for 24 h induced NLRP3 and interleukin (IL)-1ß expression. Ethanol increased reactive oxygen species generation in a time- and dose-dependent manner. AhR mRNA expression was downregulated in U937 cells treated with 100 mM ethanol, whereas CYP1A1 mRNA expression increased. Treatment with ethanol increased NLRP3 and IL-1ß mRNA and protein expression in U937 cells exposed to 1.0 mg/mL of MSU crystals for 24 h. TXNIP expression in U937 cells incubated with both 100 mM ethanol and 1.0 mg/mL of MSU crystals was significantly higher than in cells incubated with MSU crystals alone. Treatment with 100mM ethanol for 24 h downregulated NLRP3 and IL-1ß expression in MSU crystal-activated U937 cells transfected with TXNIP siRNA, compared to those with scramble siRNA. CONCLUSION: Ethanol stimulates uric acid-induced NLRP3 inflammasome activation through regression of AhR and upregulation of TXNIP.


Assuntos
Proteínas de Transporte/metabolismo , Etanol/toxicidade , Inflamassomos/metabolismo , Macrófagos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Ácido Úrico/toxicidade , Animais , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Espécies Reativas de Oxigênio/metabolismo , Células U937
11.
PLoS One ; 15(5): e0233096, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32421725

RESUMO

Congenital cytomegalovirus (cCMV) infection is the most common intrauterine infection. A non-specific immune response is the first line of host defense mechanism against human cytomegalovirus (HCMV). There is limited data on associations between Single Nucleotide Polymorphisms (SNPs) in genes involving innate immunity and the risk and clinical manifestation of cCMV infection. The aim of the study was to investigate association between selected SNPs in genes encoding cytokines and cytokine receptors, and predisposition to cCMV infection including symptomatic course of disease and symptoms. A panel of eight SNPs: IL1B rs16944, IL12B rs3212227, IL28B rs12979860, CCL2 rs1024611, DC-SIGN rs735240, TLR2 rs5743708, TLR4 rs4986791, TLR9 rs352140 was analyzed in 233 infants (92 cCMV-infected and 141 healthy controls). Associations between genotyped SNPs and predisposition to cCMV infection and symptoms were analyzed. The association analysis was performed using SNPStats software. No statistically significant association was found between any genotyped SNPs and predisposition to cCMV infection and symptomatic course of disease. In relation to particular symptoms, polymorphism of IL12B rs3212227 was linked to decreased risk of prematurity (OR = 0.37;95%CI,0.14-0.98;p = 0.025), while polymorphism of IL1B rs16944 was linked to reduced risk of splenomegaly (OR = 0.36;95%CI,0.14-0.98; p = 0.034) in infants with cCMV infection. An increased risk of thrombocytopenia was associated with IL28B rs12979860 polymorphism (OR = 2.55;95%CI,1.03-6.32;p = 0.042), while hepatitis was associated with SNP of TLR4rs4986791 (OR = 7.80;95%CI,1.49-40,81; p = 0.024). This is the first study to demonstrate four new associations between SNPs in selected genes (IL1B, IL12B, IL28B, TLR4) and particular symptoms in cCMV disease. Further studies on the role of SNPs in the pathogenesis of cCMV infection and incorporation of selected SNPs in the clinical practice might be considered in the future.


Assuntos
Infecções por Citomegalovirus/genética , Interferons/genética , Interleucina-12/genética , Interleucina-1beta/genética , Polimorfismo de Nucleotídeo Único/genética , Receptor 4 Toll-Like/genética , Adulto , Infecções por Citomegalovirus/virologia , Feminino , Frequência do Gene/genética , Genótipo , Técnicas de Genotipagem , Humanos , Masculino , Trombocitopenia/genética , Trombocitopenia/virologia
12.
Arch Virol ; 165(7): 1599-1609, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32399788

RESUMO

The viral hemorrhage disease caused by grass carp reovirus (GCRV) is a serious contagious disease of grass carp that mainly infects fingerlings and yearlings. Epidemiological studies have shown that GCRV genotype II is currently the prominent genotype. However, little is known about the histopathological characteristics, virus distribution, and expression of immunity-related genes in grass carp infected by GCRV genotype II. In this study, we found that grass carp infected by GCRV genotype II lost appetite, swam alone, and rolled, and their fins, eyes, operculum, oral cavity, abdomen, intestine, and muscles showed pronounced punctate hemorrhage. Congestion, swelling, deformation, thinning of membranes, dilatation and darkened color of nucleoli, cathepsis, erythrocyte infiltration, and vacuole formation were observed in some infected tissues. A qRT-PCR test showed that the 11 genome segments of GCRV had similar expression patterns in different tissues. The S8 segment, with unknown function and no homologous sequences, had the highest expression level, while the most conserved segment, L2, had the lowest expression level. GCRV particles were distributed in different tissues, especially in the intestine. In the infected intestine, the expression of various receptors and adaptor molecules was modulated at different levels. Pro-inflammatory cytokine interleukin-1ß (IL-1ß) expression was 2160.9 times higher than that in the control group. The upregulation of immunity-related genes activated the antiviral immunity pathways. Therefore, the intestine might play a dual role in mediating GCRV infection and the antiviral immune response. This study provides detailed information about the pathogenicity of GCRV and expression of immunity-related genes, laying the foundation for further research on virus control and treatment.


Assuntos
Carpas/virologia , Doenças dos Peixes/genética , Proteínas de Peixes/genética , Infecções por Reoviridae/veterinária , Reoviridae/fisiologia , Animais , Carpas/genética , Carpas/imunologia , Doenças dos Peixes/imunologia , Doenças dos Peixes/patologia , Doenças dos Peixes/virologia , Proteínas de Peixes/imunologia , Genoma Viral , Genótipo , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Reoviridae/genética , Infecções por Reoviridae/genética , Infecções por Reoviridae/imunologia , Infecções por Reoviridae/virologia
13.
Zhonghua Jie He He Hu Xi Za Zhi ; 43(5): 444-449, 2020 May 12.
Artigo em Chinês | MEDLINE | ID: mdl-32450633

RESUMO

Objective: To investigate the relationship between single nucleotide polymorphism (SNP) of IL-1ß gene and susceptibility to tuberculosis. Methods: A case-control study was conducted in Shenzhen Third People's Hospital from January 2012 to December 2014. A total of 1 533 patients with active tuberculosis were enrolled, including 1 432 cases of pulmonary tuberculosis[920 males and 512 females, mean age (37±14) years] and 101 cases of extrapulmonary tuberculosis [60 males and 41 females, mean age (35±13) years]. At the same time, 1 445 healthy controls (882 males and 563 females, mean age (37±20) years) were selected. The genotypes of rs1143627, rs1143623, rs16944 and rs2853550 of IL-1ß gene were detected by time-of-flight mass spectrometry. The allele frequencies of rs1143627 T>C (-31) were compared between patients with pulmonary tuberculosis and those with extrapulmonary tuberculosis. Fifty-three patients with active tuberculosis [male 32, female 21, mean age (37±15) years] were randomly selected, and the correlation between SNP alleles and tuberculosis severity was analyzed before and after treatment. Results: Time-of-flight mass spectrometry effectively detected the genotypes of 4 SNP loci. Among the 4 SNP loci, only the allele frequency of -31 locus was significantly different between the active tuberculosis group and the control group. The allele frequency of rs1143627 T locus in active tuberculosis group was 53.3%(1 634/3 066), which was significantly higher than that in the healthy control group 48.7%(1 407/2 890; OR=1.20, 95%CI=1.09-1.33, P=0.001 6) .The frequencies of the other 3 SNP alleles were not significantly different between the active tuberculosis group and the control group. The frequencies of the other 3 SNP alleles were 59% (1 821/3 066) and 60% (1 732/2 890) for rs1143623 G allele, 51% (1 574/3 066) and 52% (1 499/2 890) for rs16944 G allele, and 64% (1 964/3 066) and 65% (1 875/2 890) for rs2853550 T allele respectively. Stratified analysis showed that the frequency of the -31 T allele in patients with extrapulmonary tuberculosis (62.9%, 127/202) was significantly higher than that in patients with pulmonary tuberculosis (52.6%,1 507/2 864) (OR=1.53; 95% CI=1.13-2.05; P=0.005).The HRCT scores of patients with rs1143627 TT, TC and CC genotypes were 26.6, 13.9 and 13.3 respectively before anti-tuberculosis treatment, and after 2 years of anti-tuberculosis treatment, the HRCT scores of patients with rs1143627 TT, TC and CC genotypes were 14.7, 6.6 and 5.4 respectively, which indicated that TB patients with rs1143627T allele were associated with more severe pulmonary disease. Conclusion: The SNP of IL-1ß-31T>C was associated with susceptibility to active tuberculosis, and T allele was the susceptible gene and individuals carrying T allele were more likely to develop extrapulmonary tuberculosis.


Assuntos
Predisposição Genética para Doença , Interleucina-1beta/genética , Tuberculose/genética , Adolescente , Adulto , Alelos , Estudos de Casos e Controles , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Adulto Jovem
14.
J Pharmacol Sci ; 143(3): 133-140, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32253104

RESUMO

Endogenous noradrenaline (NA) has multiple bioactive functions and, in the central nervous system (CNS), has been implicated in modulating neuroinflammation via ß-adrenergic receptors (ß-ARs). Microglia, resident macrophages in the CNS, have a central role in the brain immune system and have been reported to be activated by NA. However, intracellular signaling mechanisms of the AR-mediated proinflammatory responses of microglia are not fully understood. Using a rapid and stable in vitro reporter assay system to evaluate IL-1ß production in microglial BV2 cells, we found that NA and the ß-AR agonist isoproterenol upregulated the IL-1ß reporter activity. This effect was suppressed by ß-AR antagonists. We further examined the involvement of EPAC (exchange protein directly activated by cAMP) and TPL2 (tumor progression locus 2, MAP3K8) and found that inhibitors for EPAC and TPL2 reduced AR agonist-induced IL-1ß reporter activity. These inhibitors also suppressed NA-induced endogenous Il1b mRNA expression and IL-1ß protein production. Our results suggest that EPAC and TPL2 are involved in ß-AR-mediated IL-1ß production in microglial cells, and extend our understanding of its intracellular signaling mechanism.


Assuntos
Acetilcisteína/análogos & derivados , Eritromicina/análogos & derivados , Interleucina-1beta/metabolismo , MAP Quinase Quinase Quinases/farmacologia , Microglia/metabolismo , Proteínas Proto-Oncogênicas/farmacologia , Acetilcisteína/farmacologia , Agonistas Adrenérgicos beta/farmacologia , Animais , Células Cultivadas , Eritromicina/farmacologia , Expressão Gênica/efeitos dos fármacos , Interleucina-1beta/genética , Isoproterenol/farmacologia , MAP Quinase Quinase Quinases/fisiologia , Camundongos , Norepinefrina/farmacologia , Norepinefrina/fisiologia , Proteínas Proto-Oncogênicas/fisiologia , Receptores Adrenérgicos beta , Transdução de Sinais , Regulação para Cima/efeitos dos fármacos
15.
Am J Physiol Endocrinol Metab ; 318(6): E981-E994, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32315215

RESUMO

Chlamydia trachomatis infection is a primary cause of reproductive tract diseases including infertility. Previous studies showed that this infection alters physiological activities in mouse oviducts. Whether this occurs in the uterus and cervix has never been investigated. This study characterized the physiological activities of the uterine horn and the cervix in a Chlamydia muridarum (Cmu)-infected mouse model at three infection time points of 7, 14, and 21 days postinfection (dpi). Cmu infection significantly decreased contractile force of spontaneous contraction in the cervix (7 and 14 dpi; P < 0.001 and P < 0.05, respectively), but this effect was not observed in the uterine horn. The responses of the uterine horn and cervix to oxytocin were significantly altered by Cmu infection at 7 dpi (P < 0.0001), but such responses were attenuated at 14 and 21 dpi. Cmu infection increased contractile force to prostaglandin (PGF2α) by 53-83% in the uterine horn. This corresponded with the increased messenger ribonucleic acid (mRNA) expression of Ptgfr that encodes for its receptor. However, Cmu infection did not affect contractions of the uterine horn and cervix to PGE2 and histamine. The mRNA expression of Otr and Ptger4 was inversely correlated with the mRNA expression of Il1b, Il6 in the uterine horn of Cmu-inoculated mice (P < 0.01 to P < 0.001), suggesting that the changes in the Otr and Ptger4 mRNA expression might be linked to the changes in inflammatory cytokines. Lastly, this study also showed a novel physiological finding of the differential response to PGE2 in mouse uterine horn and cervix.


Assuntos
Infecções por Chlamydia/fisiopatologia , Chlamydia muridarum , Miométrio/fisiopatologia , Infecções do Sistema Genital/fisiopatologia , Contração Uterina/fisiologia , Útero/fisiopatologia , Animais , Colo do Útero/metabolismo , Colo do Útero/fisiopatologia , Infecções por Chlamydia/genética , Infecções por Chlamydia/imunologia , Infecções por Chlamydia/metabolismo , Citocinas/genética , Dinoprosta/farmacologia , Dinoprostona/farmacologia , Feminino , Regulação da Expressão Gênica , Histamina/farmacologia , Agonistas dos Receptores Histamínicos/farmacologia , Interleucina-1beta/genética , Interleucina-6/genética , Camundongos , Contração Muscular/efeitos dos fármacos , Contração Muscular/fisiologia , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiopatologia , Miométrio/efeitos dos fármacos , Miométrio/metabolismo , Oviductos/patologia , Ocitócicos/farmacologia , RNA Mensageiro/metabolismo , Receptores de Ocitocina/genética , Receptores de Prostaglandina/genética , Receptores de Prostaglandina E Subtipo EP4/genética , Infecções do Sistema Genital/genética , Infecções do Sistema Genital/imunologia , Infecções do Sistema Genital/metabolismo , Contração Uterina/efeitos dos fármacos , Útero/metabolismo
16.
BMC Oral Health ; 20(1): 91, 2020 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-32223750

RESUMO

BACKGROUND: Pulpal inflammation is known to be mediated by multiple signaling pathways. However, whether melatonin plays regulatory roles in pulpal inflammation remains unclear. This study aimed at elucidating an in situ expression of melatonin and its receptors in human pulpal tissues, and the contribution of melatonin on the antagonism of lipopolysaccharide (LPS)-infected pulpal fibroblasts. METHODS: Melatonin expression in pulpal tissues harvested from healthy teeth was investigated by immunohistochemical staining. Its receptors, melatonin receptor 1 (MT1) and melatonin receptor 2 (MT2), were also immunostained in pulpal tissues isolated from healthy teeth and inflamed teeth diagnosed with irreversible pulpitis. Morphometric analysis was subsequently performed. After LPS infection of cultured pulpal fibroblasts, cyclo-oxygenase (COX) and interleukin-1 ß (IL-1 ß) transcripts were examined by using reverse transcription-polymerase chain reaction (RT-PCR). Analysis of mRNA expression was performed to investigate an antagonism of LPS stimulation by melatonin via COX and IL-1 ß induction. Mann-Whitney U test and One-way ANOVA were used for statistical analysis to determine a significance level. RESULTS: Melatonin was expressed in healthy pulpal tissue within the odontoblastic zone, cell-rich zone, and in the pulpal connective tissue. Furthermore, in health, strong MT1 and MT2 expression was distributed similarly in all 3 pulpal zones. In contrast, during disease, expression of MT2 was reduced in inflamed pulpal tissues (P-value< 0.001), but not MT1 (P-value = 0.559). Co-culturing of melatonin with LPS resulted in the reduction of COX-2 and IL-1 ß expression in primary pulpal fibroblasts, indicating that melatonin may play an antagonistic role to LPS infection in pulpal fibroblasts. CONCLUSIONS: Human dental pulp abundantly expressed melatonin and its receptors MT1 and MT2 in the odontoblastic layers and pulpal connective tissue layers. Melatonin exerted antagonistic activity against LPS-mediated COX-2 and IL-1 ß induction in pulpal fibroblasts, suggesting its therapeutic potential for pulpal inflammation and a possible role of pulpal melatonin in an immunomodulation via functional melatonin receptors expressed in dental pulp.


Assuntos
Fibroblastos/metabolismo , Lipopolissacarídeos/efeitos adversos , Melatonina/farmacologia , Pulpite , Humanos , Inflamação , Interleucina-1beta/genética , Prostaglandina-Endoperóxido Sintases/genética , RNA Mensageiro , Reação em Cadeia da Polimerase Via Transcriptase Reversa
17.
Toxicol Appl Pharmacol ; 395: 114980, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32234516

RESUMO

Toluene can be intentionally misused by adolescents to experience psychoactive effects. Toluene has a complex mechanism of action and broad behavioral effects, among which memory impairment is reported consistently. We have previously reported that repeated toluene inhalation (8000 ppm) increases layer 5 prelimbic pyramidal cells' excitability in the medial prefrontal cortex (mPFC) of adolescent rats. Toluene also produces reactive oxygen species (ROS), which activate glial cells. Here, we tested the hypothesis that the anti-inflammatory agent minocycline would decrease toluene's effects because it inhibits NF-κB (nuclear factor enhancer of the kappa light chains of activated B cells) and reduces pro-inflammatory cytokine and ROS production. Our results show that minocycline (50 mg/kg, ip, for 10 days) prevents the hyperexcitability of mPFC neurons observed after repeated 8000 ppm toluene exposure (30 min/day, 2×/day for 10 days). Minocycline prevents toluene-induced hyperexcitability by a mechanism that averts the loss of the slow calcium-dependent potassium current, and normalizes mPFC neurons' firing frequency. These effects are accompanied by significant decreased expression of astrocytes and activated microglia in the mPFC, reduced NLRP3 inflammasome activation and mRNA expression levels of the pro-inflammatory cytokine interleukin 1ß (IL-1ß), as well as increased mRNA expression of the anti-inflammatory cytokine transforming growth factor ß (TGF-ß). Minocycline also prevents toluene-induced memory impairment in adolescent rats in the passive avoidance task and the temporal order memory test in which the mPFC plays a central role. These results show that neuroinflammation produces several effects of repeated toluene administration at high concentrations, and minocycline can significantly prevent them.


Assuntos
Anti-Inflamatórios/administração & dosagem , Transtornos da Memória/prevenção & controle , Minociclina/administração & dosagem , Neurônios/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Tolueno/toxicidade , Administração por Inalação , Animais , Expressão Gênica/efeitos dos fármacos , Abuso de Inalantes , Interleucina-1beta/genética , Masculino , Transtornos da Memória/induzido quimicamente , Proteína 3 que Contém Domínio de Pirina da Família NLR/fisiologia , Neurônios/fisiologia , Córtex Pré-Frontal/patologia , Córtex Pré-Frontal/fisiopatologia , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/antagonistas & inibidores , Tolueno/administração & dosagem , Fator de Crescimento Transformador beta/genética
18.
Ecotoxicol Environ Saf ; 196: 110476, 2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32278143

RESUMO

Several studies have demonstrated that PM2.5 inhalation is associated with an increased risk of cerebrovascular disease (CVD), in which inflammation plays an important role. The mechanisms of this disease are not fully understood to date. Long non-coding RNAs (lncRNAs) are involved in many pathophysiological processes, such as immune responses; however, their functions associated with inflammation are largely unexplored. High-throughput sequencing assay and obtained numerous lncRNAs that altered the expression in response to PM2.5 treatment in HUVECs. NONHSAT247851.1 was also identified, which was significantly up-regulated to control the expression of immune response genes. Mechanistically, the results indicated that NONHSAT247851.1 knockdown reduced the expression of IL1ß. In study, we investigated NONHSAT247851.1 as a promoter in regulating immune response genes via binding with raf-1 to regulate the phosphorylation level of p65 protein in HUVECs. The data collected suggests that NONHSAT247851.1 regulates inflammation via interaction with raf-1 to control the inflammatory expression in PM2.5 exposure.


Assuntos
Poluentes Ambientais/toxicidade , Inflamação/induzido quimicamente , Material Particulado/toxicidade , Proteínas Proto-Oncogênicas c-raf/genética , RNA Longo não Codificante/genética , Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Inflamação/genética , Interleucina-1beta/genética , Proteínas Proto-Oncogênicas c-raf/metabolismo
19.
J Med Life ; 13(1): 50-55, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32341701

RESUMO

The mammalian target of rapamycin is not only a central regulator of lipid metabolism that controls the processes of adipogenesis and lipolysis but also a regulator of the immunometabolism of immune cells that infiltrate adipose tissue. In turn, the level of progression of diabetes is significantly influenced by the Treg subpopulation, the complexity and heterogeneity of which is confirmed by the detection of numerous tissue-specific Tregs, including the so-called VAT Tregs (visceral adipose tissue CD4+Foxp3+ regulatory T cells). Therefore, the purpose of the study was to determine the mRNA expression levels of mTOR, Foxp3, IL1ß, and IL17A genes in rat parapancreatic adipose tissue with experimental streptozotocin-induced diabetes mellitus, with or without metformin administration. The experiments were performed on male Wistar rats with induced diabetes as a result of streptozotocin administration. Molecular genetic studies were performed using real-time reverse transcription-polymerase chain reaction. The development of diabetes caused transcriptional activation of the mammalian target of rapamycin protein kinase gene, as well as increased mRNA expression of the pro-inflammatory cytokines IL1ß and IL17A, but did not affect Foxp3 mRNA expression. The intervention with metformin in diabetic rats inhibited the mammalian target of rapamycin mRNA expression and caused an increase in the transcriptional activity of the Foxp3 gene in parapancreatic adipose tissue.


Assuntos
Tecido Adiposo/patologia , Diabetes Mellitus Experimental/genética , Fatores de Transcrição Forkhead/genética , Metformina/farmacologia , Serina-Treonina Quinases TOR/genética , Transcrição Genética/efeitos dos fármacos , Animais , Diabetes Mellitus Experimental/patologia , Fatores de Transcrição Forkhead/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Masculino , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Wistar , Estreptozocina , Serina-Treonina Quinases TOR/metabolismo
20.
Anticancer Res ; 40(4): 1915-1920, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32234880

RESUMO

BACKGROUND/AIM: New anticancer drugs are usually tested on cancer cells in culture in a standard medium. We stimulated immune polynuclear cells by lipopolysaccharides to obtain an enriched medium (EM) containing inflammatory cytokines more closely reflecting the tumor microenvironment and tested a rhenium-diselenium (Re-diSe) drug in this new model. Concentrations of cytokines were compared with a control medium (CM). MATERIALS AND METHODS: Human-derived breast cancer cells were grown in culture either in CM or EM with or without Re-diSe. Assays of tumor necrosis factor alpha (TNFα), interleukin 6 (IL6), intereukin 1 beta (IL1ß), transforming growth factor-beta (TGFß), insulin growth factor 1 (IGF1) and vascular epidermal growth factor A (VEGFA) were performed by enzyme-linked immunosorbent assays. The production of reactive oxygen species (ROS) was determined by 2,7-dichlorofluorescein test. The cell growth was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide tests. RESULTS: Concentrations of TNFα, IL6 and Il1ß were observed to be significantly higher in EM than in CM. There was no difference for TGFß, IGF1 and VEGFA. The cells were sensitive to Re-diSe, with reduced concentrations of TGFß, IGF1, VEGFA and ROS, but the half-maximal inhibitory concentration was significantly higher in EM than in CM. CONCLUSION: The efficacy of the Re-diSe drug was confirmed in this model of aggressive cancer.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Rênio/farmacologia , Selênio/farmacologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Fator de Crescimento Insulin-Like I/genética , Interleucina-1beta/genética , Interleucina-6/genética , Lipopolissacarídeos/farmacologia , Cultura Primária de Células , Espécies Reativas de Oxigênio , Fator de Crescimento Transformador beta/genética , Microambiente Tumoral/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/genética
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