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1.
Biochemistry (Mosc) ; 86(6): 693-703, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34225592

RESUMO

Differential effect of the neonatal proinflammatory stress (NPS) on the development of neuroinflammation in the hippocampus and induction of the depressive-like behavior in juvenile and adult male and female rats was studied. NPS induction by bacterial lipopolysaccharide in the neonatal period upregulated expression of the Il6 and Tnf mRNAs accompanied by the development of depressive-like behavior in the adult male rats. NPS increased expression of the mRNAs for fractalkine and its receptor in the ventral hippocampus of the juvenile male rats, but did not affect expression of mRNAs for the proinflammatory cytokines and soluble form of fractalkine. NPS downregulated expression of fractalkine mRNA in the dorsal hippocampus of juvenile males. No significant effects of NPS were found in the female rats. Therefore, the NPS induces long-term changes in the expression of neuroinflammation-associated genes in different regions of the hippocampus, which ultimately leads to the induction of neuroinflammation and development of depressive-like behavior in male rats.


Assuntos
Quimiocina CX3CL1/genética , Depressão/etiologia , Hipocampo/metabolismo , Inflamação/metabolismo , Interleucina-6/genética , Fator de Necrose Tumoral alfa/genética , Animais , Animais Recém-Nascidos , Receptor 1 de Quimiocina CX3C/genética , Depressão/genética , Depressão/metabolismo , Depressão/fisiopatologia , Feminino , Regulação da Expressão Gênica , Hipocampo/patologia , Hipocampo/fisiopatologia , Inflamação/induzido quimicamente , Inflamação/genética , Lipopolissacarídeos/toxicidade , Masculino , Ratos , Caracteres Sexuais
2.
Int J Med Microbiol ; 311(5): 151515, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34146956

RESUMO

Listeria monocytogenes (Lm) can lead to high mortality rates relative to other foodborne pathogens. Lm-induced inflammation is partly characterized by macrophage activation. Long non-coding RNAs (lncRNAs) have important roles in various biological processes. However, it is unknown how lncRNAs regulate the host response to Lm infection. To identify the role of lncRNA in Lm infection, we used in vitro and in vivo models. We found that lincRNA-Cox2 was highly expressed in Lm-infected RAW264.7 cells. LincRNA-Cox2 knockdown resulted in reduced proinflammatory cytokines, apoptosis, migration ability and enhanced phagocytosis of Lm. LincRNA-Cox2 knockdown also reduced the phosphorylation of Janus kinase 3 (JAK3) and signal transducer and activator of transcription (STAT3) and the nuclear translocation of nuclear factor (NF)-κB P65, which are known to be involved in inflammatory responses. Experimentally inhibiting the protein and phosphorylation levels of STAT3 resulted in reduced proinflammatory cytokines and enhanced phagocytosis of Lm by the RAW264.7 cells. Our research suggests that lincRNA-Cox2 plays important roles in inflammation, the phagocytic function and cell migration ability of RAW264.7 cells by activating interleukin (IL)-6/JAK3/STAT3 signaling, and lincRNA-Cox2 also regulates NF-κB P65 nuclear translocation. Our research provides new insights into the regulatory role of lincRNA-Cox2 in Lm infection.


Assuntos
Listeria monocytogenes , RNA Longo não Codificante , Interleucina-6/genética , Janus Quinase 3 , NF-kappa B , RNA Longo não Codificante/genética
3.
Artigo em Inglês | MEDLINE | ID: mdl-34073132

RESUMO

The present study attempted to investigate whether concerted contributions of significant risk variables, pro-inflammatory markers, and candidate genes translate into a predictive marker for knee osteoarthritis (KOA). The present study comprised 279 confirmed osteoarthritis patients (Kellgren and Lawrence scale >2) and 287 controls. Twenty SNPs within five genes (CRP, COL1A1, IL-6, VDR, and eNOS), four pro-inflammatory markers (interleukin-6 (IL-6), interleuin-1 beta (IL-1ß), tumor necrosis factor alpha (TNF-α), and high sensitivity C-reactive protein (hsCRP)), along with significant risk variables were investigated. A receiver operating characteristic (ROC) curve was used to observe the predictive ability of the model for distinguishing patients with KOA. Multivariable logistic regression analysis revealed that higher body mass index (BMI), triglycerides (TG), poor sleep, IL-6, IL-1ß, and hsCRP were independent predictors for KOA after adjusting for the confounding from other risk variables. Four susceptibility haplotypes for the risk of KOA, AGT, GGGGCT, AGC, and CTAAAT, were observed within CRP, IL-6, VDR, and eNOS genes, which showed their impact in recessive ß(SE): 2.11 (0.76), recessive ß(SE): 2.75 (0.59), dominant ß(SE): 1.89 (0.52), and multiplicative modes ß(SE): 1.89 (0.52), respectively. ROC curve analysis revealed the model comprising higher values of BMI, poor sleep, IL-6, and IL-1ß was predictive of KOA (AUC: 0.80, 95%CI: 0.74-0.86, p< 0.001), and the strength of the predictive ability increased when susceptibility haplotypes AGC and GGGGCT were involved (AUC: 0.90, 95%CI: 0.87-0.95, p< 0.001).This study offers a predictive marker for KOA based on the risk scores of some pertinent genes and their genetic variants along with some pro-inflammatory markers and traditional risk variables.


Assuntos
Osteoartrite do Joelho , Biomarcadores , Haplótipos , Humanos , Interleucina-6/genética , Osteoartrite do Joelho/genética , Polimorfismo de Nucleotídeo Único
4.
Biomolecules ; 11(5)2021 05 18.
Artigo em Inglês | MEDLINE | ID: covidwho-1234666

RESUMO

Several RNA viruses, including SARS-CoV-2, can infect or use the eye as an entry portal to cause ocular or systemic diseases. Povidone-Iodine (PVP-I) is routinely used during ocular surgeries and eye banking as a cost-effective disinfectant due to its broad-spectrum antimicrobial activity, including against viruses. However, whether PVP-I can exert antiviral activities in virus-infected cells remains elusive. In this study, using Zika (ZIKV) and Chikungunya (CHIKV) virus infection of human corneal and retinal pigment epithelial cells, we report antiviral mechanisms of PVP-I. Our data showed that PVP-I, even at the lowest concentration (0.01%), drastically reduced viral replication in corneal and retinal cells without causing cellular toxicity. Antiviral effects of PVP-I against ZIKV and CHIKV were mediated by direct viral inactivation, thus attenuating the ability of the virus to infect host cells. Moreover, one-minute PVP-I exposure of infected ocular cells drastically reduced viral replication and the production of infectious progeny virions. Furthermore, viral-induced (CHIKV) expression of inflammatory genes (TNF-α, IL-6, IL-8, and IL1ß) were markedly reduced in PVP-I treated corneal epithelial cells. Together, our results demonstrate potent antiviral effects of PVP-I against ZIKV and CHIKV infection of ocular cells. Thus, a low dose of PVP-I can be used during tissue harvesting for corneal transplants to prevent potential transmission of RNA viruses via infected cells.


Assuntos
Antivirais/farmacologia , Povidona-Iodo/farmacologia , Vírus de RNA/fisiologia , Replicação Viral/efeitos dos fármacos , Animais , Linhagem Celular , Vírus Chikungunya/fisiologia , Chlorocebus aethiops , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Epitélio Pigmentado da Retina/citologia , Epitélio Pigmentado da Retina/metabolismo , Epitélio Pigmentado da Retina/virologia , SARS-CoV-2/fisiologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Células Vero , Zika virus/fisiologia
5.
Nat Commun ; 12(1): 3878, 2021 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-34188032

RESUMO

Different levels of regulatory mechanisms, including posttranscriptional regulation, are needed to elaborately regulate inflammatory responses to prevent harmful effects. Terminal uridyltransferase 7 (TUT7) controls RNA stability by adding uridines to its 3' ends, but its function in innate immune response remains obscure. Here we reveal that TLR4 activation induces TUT7, which in turn selectively regulates the production of a subset of cytokines, including Interleukin 6 (IL-6). TUT7 regulates IL-6 expression by controlling ribonuclease Regnase-1 mRNA (encoded by Zc3h12a gene) stability. Mechanistically, TLR4 activation causes TUT7 to bind directly to the stem-loop structure on Zc3h12a 3'-UTR, thereby promotes Zc3h12a uridylation and degradation. Zc3h12a from LPS-treated TUT7-sufficient macrophages possesses increased oligo-uridylated ends with shorter poly(A) tails, whereas oligo-uridylated Zc3h12a is significantly reduced in Tut7-/- cells after TLR4 activation. Together, our findings reveal the functional role of TUT7 in sculpting TLR4-driven responses by modulating mRNA stability of a selected set of inflammatory mediators.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Nucleotidiltransferases/metabolismo , RNA Mensageiro/metabolismo , Ribonucleases/genética , Receptor 4 Toll-Like/metabolismo , Regiões 3' não Traduzidas , Animais , Citocinas/genética , Citocinas/metabolismo , Regulação da Expressão Gênica , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Estabilidade de RNA , RNA Mensageiro/genética , Ribonucleases/metabolismo , Uridina Monofosfato/metabolismo
6.
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 Anterior/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 Anterior/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
7.
Zhen Ci Yan Jiu ; 46(5): 353-61, 2021 May 25.
Artigo em Chinês | MEDLINE | ID: mdl-34085456

RESUMO

OBJECTIVE: To explore the effect of electroacupuncture (EA) on the ability of spatial learning-memory and the expression of IL-1ß, IL-6 and TNF-α in the hippocampus and spleen tissues and the number of hippocampal neurons and spleen lymphocytes in Alzheimer's disease (AD) mice, so as to study its mechanisms underlying improvement of AD. METHODS: Twenty-four SAMP8 mice were randomly and equally divided into AD model, EA and medication groups, and 8 SAMR1 mice were used as the control group. EA (2 Hz, 0.1 mA) was applied to "Baihui"(GV20) and "Yintang"(EX-HN3) for 20 min in the EA group, and intragastric administration of donepezil hydrochloride (0.92 mg/kg) was applied in the medication group, once daily for 15 d. The learning-memory ability was determined by Morris water maze task, and the histopathological changes of hippocampus were observed after H.E. staining, followed by determining neurons and the number of splenic lymphocytes. The expression levels of IL-1ß, IL-6 and TNF-α in the hippocampus and spleen were detected by immunohistochemistry and Western blot, respectively. RESULTS: After mode-ling, the escape latency of place navigation test in the Morris water maze, the spleen index, immunoactivity and expression levels of IL-1ß, IL-6 and TNF-α proteins in the hippocampus and spleen tissues were significantly increased (P<0.05, P<0.01). Compared with the model group, the escape latency, spleen index, immunoactivity and expression levels of IL-1ß, IL-6 and TNF-α proteins in both hippocampus and spleen were significantly down-regulated in the medication (except the escape latency) and EA groups (P<0.01, P<0.05). The effect of EA was evidently superior to that of medication in shortening the escape latency, lowering the spleen index, and immunoactivity of hippocampal IL-6 and splenic TNF-α immunoactivity (P<0.01, P<0.05). Outcomes of H.E. staining showed disordered arrangement of neurons with nuclear pyknosis or apoptosis in partial neurons in the hippocampus, and thickened and swollen spleen capsule tissue with loose structure and an increased number of lymphocytes in the model group, which was relatively milder in the EA and medication groups. CONCLUSION: EA can improve the learning-memory ability of AD mice, which may be associated with its effect in relieving the inflammation reaction in the hippocampus and spleen tissues.


Assuntos
Doença de Alzheimer , Eletroacupuntura , Doença de Alzheimer/genética , Doença de Alzheimer/terapia , Animais , Hipocampo , Interleucina-6/genética , Camundongos , Baço , Fator de Necrose Tumoral alfa/genética
8.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 37(6): 532-537, 2021 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-34060448

RESUMO

Objective To find out indicators for rapid identification of Gram-positive (G+) and Gram-negative (G-) bacteria through transcriptome sequencing of peripheral blood mononuclear cells (PBMCs) and serum liquid-phase chip technology in early sepsis. Methods 35 eligible cases out of 182 sepsis patients in the emergency intensive care unit (EICU) were selected for retrospective analysis. They were divided into G+ group (12 cases) and G- group (23 cases) based on their blood culture results. General characteristics like patients' age, gender, sequential organ failure assessment (SOFA) scores, etc. and other laboratory indexes such as blood routine, IL-6, CRP, procalcitonin(PCT)of these two groups were analyzed. PBMCs were isolated through single density gradient centrifugation. Total RNA was extracted for transcriptome sequencing to find out differential genes. Serum liquid-phase chip technology was performed to detect serum granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), IFN-γ, IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17, monocytes chemotactic protein 1 (MCP-1), tumor necrosis factor alpha (TNF-α) in two groups. Receiver operating characteristic (ROC) curve was drawn using bacteria types as a dependent variable and selected cytokines as test variables, to analyze the correlation between selected biomarkers and bacteria type. Results No significant difference in general characteristics, CRP, and PCT were found between the G+ and G- group. The serum level of IL-6 in G+ group was lower than that in the G- group. Transcriptome sequencing results revealed 30 immune-related genes that were differentially expressed in the PBMCs of two groups. Compared to the G+ group, the serum levels of IL-6 and IL-1ß in G- group significantly increased, while serum IL-10 was reduced. ROC curve analysis indicated that serum IL-6, IL-1ß, and IL-10 levels could identify the G- and G+ bacteria types. The combined diagnosis using these three indicators is highly applicable in distinguishing G- and G+ bacteria. Conclusion IL-6, IL-1ß and IL-10 levels can be used as indicators for early identification of sepsis induced by G+ or G- bacteria.


Assuntos
Interleucina-10 , Sepse , Humanos , Interleucina-6/genética , Leucócitos Mononucleares , Estudos Retrospectivos , Sepse/diagnóstico
9.
Int J Mol Sci ; 22(11)2021 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-34067421

RESUMO

Base Excision Repair (BER) addresses base lesions and abasic sites induced by exogenous and endogenous stressors. X-ray cross complementing group 1 (XRCC1) functions as a scaffold protein in BER and single-strand break repair (SSBR), facilitating and coordinating repair through its interaction with a host of critical repair proteins. Alterations of XRCC1 protein and gene expression levels are observed in many cancers, including colorectal, ovarian, and breast cancer. While increases in the expression level of XRCC1 are reported, the transcription factors responsible for this up-regulation are not known. In this study, we identify the signal transducer and activator of transcription 3 (STAT3) as a novel regulator of XRCC1 through chromatin immunoprecipitation. Activation of STAT3 through phosphorylation at Y705 by cytokine (IL-6) signaling increases the expression of XRCC1 and the occupancy of STAT3 within the XRCC1 promoter. In triple negative breast cancer, the constitutive activation of STAT3 upregulates XRCC1 gene and protein expression levels. Increased expression of XRCC1 is associated with aggressiveness and resistance to DNA damaging chemotherapeutics. Thus, we propose that activated STAT3 regulates XRCC1 under stress and growth conditions, but constitutive activation in cancers results in dysregulation of XRCC1 and subsequently BER and SSBR.


Assuntos
Regiões Promotoras Genéticas/genética , Fator de Transcrição STAT3/genética , Neoplasias de Mama Triplo Negativas/genética , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/genética , Linhagem Celular , Linhagem Celular Tumoral , Quebras de DNA de Cadeia Simples , Dano ao DNA/genética , Reparo do DNA/genética , Proteínas de Ligação a DNA/genética , Células HEK293 , Humanos , Interleucina-6/genética , Fosforilação/genética , Regulação para Cima/genética
10.
Biomolecules ; 11(5)2021 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-34069869

RESUMO

Several RNA viruses, including SARS-CoV-2, can infect or use the eye as an entry portal to cause ocular or systemic diseases. Povidone-Iodine (PVP-I) is routinely used during ocular surgeries and eye banking as a cost-effective disinfectant due to its broad-spectrum antimicrobial activity, including against viruses. However, whether PVP-I can exert antiviral activities in virus-infected cells remains elusive. In this study, using Zika (ZIKV) and Chikungunya (CHIKV) virus infection of human corneal and retinal pigment epithelial cells, we report antiviral mechanisms of PVP-I. Our data showed that PVP-I, even at the lowest concentration (0.01%), drastically reduced viral replication in corneal and retinal cells without causing cellular toxicity. Antiviral effects of PVP-I against ZIKV and CHIKV were mediated by direct viral inactivation, thus attenuating the ability of the virus to infect host cells. Moreover, one-minute PVP-I exposure of infected ocular cells drastically reduced viral replication and the production of infectious progeny virions. Furthermore, viral-induced (CHIKV) expression of inflammatory genes (TNF-α, IL-6, IL-8, and IL1ß) were markedly reduced in PVP-I treated corneal epithelial cells. Together, our results demonstrate potent antiviral effects of PVP-I against ZIKV and CHIKV infection of ocular cells. Thus, a low dose of PVP-I can be used during tissue harvesting for corneal transplants to prevent potential transmission of RNA viruses via infected cells.


Assuntos
Antivirais/farmacologia , Povidona-Iodo/farmacologia , Vírus de RNA/fisiologia , Replicação Viral/efeitos dos fármacos , Animais , Linhagem Celular , Vírus Chikungunya/fisiologia , Chlorocebus aethiops , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Epitélio Pigmentado da Retina/citologia , Epitélio Pigmentado da Retina/metabolismo , Epitélio Pigmentado da Retina/virologia , SARS-CoV-2/fisiologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Células Vero , Zika virus/fisiologia
11.
Int J Mol Sci ; 22(11)2021 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-34070915

RESUMO

Systemic inflammation induced by periodontitis is suggested to be the link between periodontitis and cardiovascular disease. The aim of this work was to explore the oral microbiome in periodontitis in relation to disease severity and systemic inflammation. The saliva and subgingival microbiome from periodontal pocket samples of patients with severe (n = 12) and mild periodontitis (n = 13) were analyzed using metagenomic shotgun sequencing. The taxa and pathways abundances were quantified. The diversity was assessed and the abundances to phenotype associations were performed using ANCOM and linear regression. A panel of inflammatory markers was measured in blood and was associated with taxa abundance. The microbial diversity and species richness did not differ between severe and mild periodontitis in either saliva or periodontal pockets. However, there were significant differences in the microbial composition between severe and mild periodontitis in the subgingival microbiome (i.e., pocket samples) and, in a lower grade, in saliva, and this is positively associated with systemic inflammatory markers. The "red complex" and "cluster B" abundances in periodontal pockets were strongly associated with inflammatory markers interleukin-6 and the white blood cell count. Our data suggest that systemic inflammation in severe periodontitis may be driven by the oral microbiome and may support the indirect (inflammatory) mechanism for the association between periodontitis and cardiovascular disease.


Assuntos
Metagenoma , Microbiota/genética , Periodontite/microbiologia , Periodonto/microbiologia , Idoso , Biomarcadores/metabolismo , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/imunologia , Doenças Cardiovasculares/microbiologia , Doenças Cardiovasculares/patologia , Feminino , Expressão Gênica , Variação Genética , Humanos , Inflamação , Proteína Antagonista do Receptor de Interleucina 1/genética , Proteína Antagonista do Receptor de Interleucina 1/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Leucócitos/imunologia , Leucócitos/microbiologia , Masculino , Pessoa de Meia-Idade , Periodontite/complicações , Periodontite/imunologia , Periodontite/patologia , Periodonto/imunologia , Periodonto/patologia , Fenótipo , Filogenia , Índice de Gravidade de Doença
12.
Int J Mol Sci ; 22(11)2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34072918

RESUMO

We previously showed that Lactiplantibacillus plantarum K8 and its cell wall components have immunoregulatory effects. In this study, we demonstrate that pre-treatment of L. plantarum K8 lysates reduced LPS-induced TNF-α production in THP-1 cells by down-regulating the early signals of mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB). The down-regulation of signals may be caused by the induction of negative regulators involved in toll-like receptor (TLR)-mediated signaling. However, co-treatment with high concentrations of L. plantarum K8 lysates and lipopolysaccharide (LPS) activated the late signaling of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and NF-κB pathways and resulted in the induction of absent in melanoma 2 (AIM2) inflammasome-mediated interleukin (IL)-1ß secretion. Intraperitoneal injection of L. plantarum K8 lysates in LPS-induced endotoxin shock mice alleviated mortality and reduced serum tumor-necrosis factor (TNF)-α, IL-1ß, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. In addition, the mRNA levels of TNF-α, IL-1ß, and IL-6 decreased in livers from mice injected with L. plantarum K8 followed by LPS. Hematoxylin and eosin (H&E) staining of the liver showed that the cell size was enlarged by LPS injection and slightly reduced by L. plantarum K8 lysate pre-injection followed by LPS injection. Macrophage infiltration of the liver also decreased in response to the combination injection compared with mice injected with only LPS. Taken together, our results show that although L. plantarum K8 lysates differentially regulated the production of LPS-induced inflammatory cytokines in THP-1 cells, the lysates inhibited overall inflammation in mice. Thus, this study suggests that L. plantarum K8 lysates could be developed as a substance that modulates immune homeostasis by regulating inflammation.


Assuntos
Inflamação/genética , Lactobacillaceae/química , Fígado/efeitos dos fármacos , Choque Séptico/genética , Animais , Proteínas de Ligação a DNA/genética , Endotoxinas/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamação/induzido quimicamente , Inflamação/patologia , Interleucina-1beta/genética , Interleucina-6/genética , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Lipopolissacarídeos/farmacologia , Lipopolissacarídeos/toxicidade , Fígado/metabolismo , Fígado/patologia , Camundongos , NF-kappa B/genética , Choque Séptico/induzido quimicamente , Choque Séptico/patologia , Fator de Necrose Tumoral alfa/genética
13.
J Med Chem ; 64(11): 7667-7690, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34044539

RESUMO

The activation of cyclic GMP-AMP synthase (cGAS) by double-stranded DNA is implicated in the pathogenesis of many hyperinflammatory and autoimmune diseases, and the cGAS-targeting small molecule has emerged as a novel therapeutic strategy for treating these diseases. However, the currently reported cGAS inhibitors are far beyond maturity, barely demonstrating in vivo efficacy. Inspired by the structural novelty of compound 5 (G140), we conducted a structural optimization on both its side chain and the central tricyclic core, leading to several subseries of compounds, including those unexpectedly cyclized complex ones. Compound 25 bearing an N-glycylglycinoyl side chain was identified as the most potent one with cellular IC50 values of 1.38 and 11.4 µM for h- and m-cGAS, respectively. Mechanistic studies confirmed its direct targeting of cGAS. Further, compound 25 showed superior in vivo anti-inflammatory effects in the lipopolysaccharide-induced mouse model. The encouraging result of compound 25 provides solid evidence for further pursuit of cGAS-targeting inhibitors as a new anti-inflammatory treatment.


Assuntos
Anti-Inflamatórios/síntese química , Carbolinas/química , Nucleotidiltransferases/antagonistas & inibidores , Animais , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/etiologia , Sítios de Ligação , Carbolinas/metabolismo , Carbolinas/farmacologia , Carbolinas/uso terapêutico , Sobrevivência Celular/efeitos dos fármacos , DNA/química , DNA/metabolismo , Modelos Animais de Doenças , Desenho de Fármacos , Feminino , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Lipopolissacarídeos/toxicidade , Camundongos , Camundongos Endogâmicos BALB C , Conformação Molecular , Simulação de Acoplamento Molecular , Nucleotidiltransferases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade
14.
Phytomedicine ; 87: 153552, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33994251

RESUMO

BACKGROUND: The naturally occurring flavonol fisetin (3,3',4',7-tetrahydroxyflavone), widely dispersed in fruits, vegetables and nuts, has been reported to exert anti-inflammatory, antioxidant and anti-angiogenic effects. Our previous study indicated fisetin ameliorated inflammation and apoptosis in septic kidneys. However, the potential nephroprotective effect of fisetin in hyperuricemic mice remains unknown. PURPOSE: The current study was designed to investigate the effect of fisetin on hyperuricemic nephropathy (HN) and explore the underlying mechanisms. METHODS: The HN was induced in mice by mixing of potassium oxonate (2400 mg/kg) and adenine (160 mg/kg) in male C57BL/6J mice. Fisetin (50 or 100 mg/kg) was orally administrated either simultaneously with the establishment of HN or after HN was induced. As a positive control, allopurinol of 10 mg/kg was included. Uric acid levels in the serum and urine as well as renal function parameters were measured. Renal histological changes were measured by periodic acid-Schiff (PAS) and Masson's trichrome stainings. The expression of gene/protein in relation to inflammation, fibrosis, and uric acid excretion in the kidneys of HN mice or uric acid-treated mouse tubular epithelial (TCMK-1) cells were measured by RNA-seq, RT-PCR, western blot and immunohistochemical analysis. RESULTS: Treatment with fisetin, regardless of administration regimen, dose-dependently attenuated hyperuricemia-induced kidney injury as indicated by the improved renal function, preserved tissue architecture, and decreased urinary albumin-to-creatinine ratio. Additionally, fisetin lowered uricemia by modulating the expression of kidney urate transporters including urate transporter 1(URAT1), organic anion transporter 1 (OAT1), organic anion transporter 3 (OAT3) and ATP binding cassette subfamily G member 2 (ABCG2). Moreover, hyperuricemia-induced secretions of proinflammatory factors including tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6) and monocyte chemoattractant protein-1(MCP-1) in HN mice and uric acid-stimulated TCMK-1 cells were mitigated by fisetin treatment. Meanwhile, fisetin attenuated kidney fibrosis in HN mice with restored expressions of alpha-smooth muscle actin (α-SMA), collagen I and fibronectin. Mechanistically, fisetin regulated the aberrant activation of signal transducer and activator of transcription-3 (STAT3) signaling and transforming growth factor-ß (TGF-ß) signaling in the HN kidneys and uric acid-stimulated TCMK-1 cells. CONCLUSION: Fisetin lowered uricemia, suppressed renal inflammatory response, and improved kidney fibrosis to protect against hyperuricemic nephropathy via modulation of STAT3 and TGF-ß signaling pathways. The results highlighted that fisetin might represent a potential therapeutic strategy against hyperuricemic nephropathy.


Assuntos
Flavonóis/farmacologia , Hiperuricemia/tratamento farmacológico , Interleucina-6/metabolismo , Nefropatias/tratamento farmacológico , Fator de Crescimento Transformador beta/metabolismo , Administração Oral , Animais , Fibrose , Flavonóis/administração & dosagem , Flavonóis/uso terapêutico , Regulação da Expressão Gênica/efeitos dos fármacos , Hiperuricemia/patologia , Interleucina-6/antagonistas & inibidores , Interleucina-6/genética , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Rim/efeitos dos fármacos , Rim/patologia , Nefropatias/sangue , Nefropatias/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Proteína Smad3/genética , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta/genética , Ácido Úrico/sangue , Ácido Úrico/urina
15.
Phytomedicine ; 87: 153583, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: covidwho-1213465

RESUMO

BACKGROUND: A key clinical feature of COVID-19 is a deep inflammatory state known as "cytokine storm" and characterized by high expression of several cytokines, chemokines and growth factors, including IL-6 and IL-8. A direct consequence of this inflammatory state in the lungs is the Acute Respiratory Distress Syndrome (ARDS), frequently observed in severe COVID-19 patients. The "cytokine storm" is associated with severe forms of COVID-19 and poor prognosis for COVID-19 patients. Sulforaphane (SFN), one of the main components of Brassica oleraceae L. (Brassicaceae or Cruciferae), is known to possess anti-inflammatory effects in tissues from several organs, among which joints, kidneys and lungs. PURPOSE: The objective of the present study was to determine whether SFN is able to inhibit IL-6 and IL-8, two key molecules involved in the COVID-19 "cytokine storm". METHODS: The effects of SFN were studied in vitro on bronchial epithelial IB3-1 cells exposed to the SARS-CoV-2 Spike protein (S-protein). The anti-inflammatory activity of SFN on IL-6 and IL-8 expression has been evaluated by RT-qPCR and Bio-Plex analysis. RESULTS: In our study SFN inhibits, in cultured IB3-1 bronchial cells, the gene expression of IL-6 and IL-8 induced by the S-protein of SARS-CoV-2. This represents the proof-of-principle that SFN may modulate the release of some key proteins of the COVID-19 "cytokine storm". CONCLUSION: The control of the cytokine storm is one of the major issues in the management of COVID-19 patients. Our study suggests that SFN can be employed in protocols useful to control hyperinflammatory state associated with SARS-CoV-2 infection.


Assuntos
Brônquios/virologia , Interleucina-6/genética , Interleucina-8/genética , Isotiocianatos/farmacologia , Glicoproteína da Espícula de Coronavírus/toxicidade , Sulfóxidos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Apoptose/efeitos dos fármacos , Brônquios/citologia , Brônquios/efeitos dos fármacos , COVID-19/fisiopatologia , Linhagem Celular , Quimiocinas/genética , Quimiocinas/metabolismo , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , SARS-CoV-2/patogenicidade , Regulação para Cima/efeitos dos fármacos
16.
Arch Virol ; 166(8): 2141-2149, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34009439

RESUMO

Porcine circovirus type 3 (PCV3) has been widely detected throughout the world since it was first discovered on pig farms in 2015. PCV3 is closely associated with cardiac and multisystem inflammation, respiratory disease, congenital tremors, myocarditis, diarrhea, encephalitis and neurologic disease, and periarteritis. However, there have been few reports on the relationship between PCV3 and inflammatory pathways. The NF-κB signaling pathway plays an important role in the defense against viral infection. Here, we demonstrate that the capsid protein (Cap) of PCV3 plays a key role in the activation of NF-κB signaling in HEK-293T cells. Furthermore, PCV3 Cap promotes the mRNA expression of the pro-inflammatory cytokines IL6 and TNFα. In addition, PCV3 Cap promotes RIG-I and MDA5 mRNA expression in RIG-like receptor (RLR) signaling and MyD88 mRNA expression in Toll-like receptor (TLR) signaling but does not influence TRIF mRNA expression in TLR signaling. These results show that PCV3 Cap activates NF-κB signaling, possibly through the RLR and the TLR signaling pathways. This work illustrates that PCV3 Cap activates NF-κB signaling and thus may provide a basis for the pathogenesis of PCV3 and the innate immunity of the host.


Assuntos
Proteínas do Capsídeo/imunologia , Circovirus/metabolismo , Citocinas/genética , Transdução de Sinais , Circovirus/imunologia , Proteína DEAD-box 58/genética , Células HEK293 , Humanos , Helicase IFIH1 Induzida por Interferon/genética , Interleucina-6/genética , Fator 88 de Diferenciação Mieloide/genética , NF-kappa B/metabolismo , Fator de Necrose Tumoral alfa/genética
17.
Int Heart J ; 62(3): 616-626, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34054002

RESUMO

Atrial fibrillation (AF) is a relatively common complication of hypertension. Chronic hypertension induces cardiac HDAC6 catalytic activity. However, whether HDAC6 activation contributes to hypertension-induced AF is still uncertain. We examined whether chronic cardiac HDAC6 activation-induced atrial remodeling, leading to AF induction.The HDAC6 constitutively active transgenic (TG) (HDAC6 active TG) mouse overexpressing the active HDAC6 protein, specifically in cardiomyocytes, was created to examine the effects of chronic HDAC6 activation on atrial electrical and structural remodeling and AF induction in HDAC6 active TG and non-transgenic (NTG) mice. Left atrial burst pacing (S1S1 = 30 msec) for 15-30 sec significantly increased the frequency of sustained AF in HDAC6 active-TG mice compared with NTG mice. Left steady-state atrial pacing (S1S1 = 80 msec) decreased the atrial conduction velocity in isolated HDAC6 active TG compared with NTG mouse atria. The atrial size was similar between HDAC6 active TG and NTG mice. In contrast, atrial interstitial fibrosis increased in HDAC6 active TG compared with that of NTG mouse atria. While protein expression levels of both CX40 and CX43 were similar between HDAC6 active TG and NTG mouse atria, a heterogeneous distribution of CX40 and CX43 occurred in HDAC6 active-TG mouse atria but not in NTG mouse atria. Gene expression of interleukin 6 increased in HDAC6 active TG compared with NTG mouse atria.Chronic cardiac HDAC6 activation induced atrial electrical and structural remodeling, and sustained AF. Hypertension-induced cardiac HDAC6 catalytic activity may play important roles in the development of AF.


Assuntos
Fibrilação Atrial/fisiopatologia , Conexinas/metabolismo , Átrios do Coração/fisiopatologia , Desacetilase 6 de Histona/farmacologia , Interleucina-6/metabolismo , Animais , Fibrilação Atrial/etiologia , Fibrilação Atrial/metabolismo , Remodelamento Atrial , Estimulação Cardíaca Artificial/métodos , Estudos de Casos e Controles , Feminino , Fibrose , Átrios do Coração/patologia , Desacetilase 6 de Histona/metabolismo , Hipertensão/complicações , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Interleucina-6/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Modelos Animais , Miócitos Cardíacos/metabolismo
18.
Wei Sheng Yan Jiu ; 50(2): 261-273, 2021 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-33985634

RESUMO

OBJECTIVE: To investigate the associations between the polymorphisms and interaction of the interleukin 6(IL-6) genes at-634 C/G, -174 G/C, -1363 G/T loci, as well as the interactions between the three loci and tumor necrosis factor(TNF-α), and peripheral blood leukocytes(white blood cell, WBC) with metabolic syndrome(MS). METHODS: Using the case-control research method, according to the inclusion and exclusion criteria, from March 2015 to March 2016 from the General Hospital of Ningxia Medical University and Wuzhong City People's Hospital, 376 unrelated cases and 408 control groups were selected. We conducted questionnaire surveys(including general conditions, disease and medication history, family history, etc. ), physical examinations(including height, weight and calculation of body mass index(BMI), waist circumference, hip circumference and calculation of waist-to-hip ratio(WHR), SBP, DBP, etc. ), blood collection and testing(including WBC count, serum TNF-α level and biochemical indicators TG, TC, HDL-C, LDL-C, FPG, UA, AST, ALT, etc. ), and the polymorphism detection of IL-6 gene at-634 C/G, -174 G/C, -1363 G/T sites. The SNPstats online software was used to analyze the relationship between the polymorphisms of IL-6 gene and MS. The SHEsis online software was used to analyze the linkage disequilibrium(LD) of the IL-6 three-site and the relationship between haplotype and MS. GMDR 0. 7 software was used to analyze the interactions among the three sites of IL-6 gene, and one between the three sites and TNF-α and WBC, respectively. RESULTS: Before and after adjustment of sex, age and nationality, the polymorphism at the 3 position of IL-6 gene was not related to the onset of MS in different genetic models(both P> 0. 05). There was a linkage disequilibrium between the three loci of IL-6 gene, but the haploids formed by these three loci were not associated with MS susceptibility(all P> 0. 05). There was no interaction among the three sites, but the two-factor, three-factor, and four-factor interaction models consisting of the three sites and TNF-α were all statistically significant(all P<0. 001) and the replacement tests were all P<0. 001, and were all associated with MS occurrence. The two-factor, three-factor, and four-factor interaction models consisting of the three sites and WBC were all P<0. 01, and the replacement tests were all P<0. 05. The differences were statistically significant, which was related to the onset of MS. CONCLUSION: The IL-6 gene-634 C/G, -174 G/C, and-1363 G/T loci polymorphism may not be significantly associated with the prevalence of MS. Interactions between the three sites and TNF-α and WBC levels can significantly increase the risk of MS.


Assuntos
Síndrome Metabólica , Humanos , Interleucina-6/genética , Leucócitos , Síndrome Metabólica/genética , Fator de Necrose Tumoral alfa/genética , Circunferência da Cintura
19.
Braz J Med Biol Res ; 54(7): e10687, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34008757

RESUMO

Helicobacter pylori (H. pylori) induces an intense inflammatory response, mediated by proinflammatory cytokines, including interleukin (IL)-6 and its membrane receptor (IL-6R), which activates important signaling pathways in the development of gastric disease and cancer. We investigated the gene and protein expression of IL-6 and IL-6R and the influence of polymorphisms rs1800795, rs1800796, and rs1800797 on its gene expression together with H. pylori infection. Furthermore, an in-silico analysis was performed to support our results. Gastric biopsies were obtained from patients with gastric symptoms and patients with gastric cancer (GC) and were divided into groups (Control, Gastritis, and Cancer). H. pylori was detected by PCR. Real-time-qPCR was employed to determine gene expression, and western blot assay was used to analyze protein expression levels. PCR-RFLP was used to characterize IL-6 polymorphisms. Bioinformatics analyses were performed using the Gene Expression Omnibus (GEO) database and GEO2R to screen out differentially expressed genes (DEGs). H. pylori was detected in 43.3% of the samples. Statistically significant differences were found for IL-6 (P=0.0001) and IL-6R (P=0.0005) genes among the three groups, regardless of the presence of H. pylori. Among patients with H. pylori infection, the IL-6 and IL-6R gene and protein expressions were significantly increased, highlighting IL-6 gene overexpression in patients with GC. No statistically significant differences were found for the rs1800795, rs1800796, and rs1800797 polymorphisms compared to IL-6 gene expression. The results indicated that the IL-6 polymorphisms do not influence its expression, but IL-6 and IL-6R expression seems to be altered by the presence of H. pylori.


Assuntos
Gastrite , Infecções por Helicobacter , Helicobacter pylori , Interleucina-6/genética , Neoplasias Gástricas , Mucosa Gástrica , Gastrite/genética , Infecções por Helicobacter/genética , Humanos , Interleucina-8 , Neoplasias Gástricas/genética
20.
Phytomedicine ; 87: 153583, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34033999

RESUMO

BACKGROUND: A key clinical feature of COVID-19 is a deep inflammatory state known as "cytokine storm" and characterized by high expression of several cytokines, chemokines and growth factors, including IL-6 and IL-8. A direct consequence of this inflammatory state in the lungs is the Acute Respiratory Distress Syndrome (ARDS), frequently observed in severe COVID-19 patients. The "cytokine storm" is associated with severe forms of COVID-19 and poor prognosis for COVID-19 patients. Sulforaphane (SFN), one of the main components of Brassica oleraceae L. (Brassicaceae or Cruciferae), is known to possess anti-inflammatory effects in tissues from several organs, among which joints, kidneys and lungs. PURPOSE: The objective of the present study was to determine whether SFN is able to inhibit IL-6 and IL-8, two key molecules involved in the COVID-19 "cytokine storm". METHODS: The effects of SFN were studied in vitro on bronchial epithelial IB3-1 cells exposed to the SARS-CoV-2 Spike protein (S-protein). The anti-inflammatory activity of SFN on IL-6 and IL-8 expression has been evaluated by RT-qPCR and Bio-Plex analysis. RESULTS: In our study SFN inhibits, in cultured IB3-1 bronchial cells, the gene expression of IL-6 and IL-8 induced by the S-protein of SARS-CoV-2. This represents the proof-of-principle that SFN may modulate the release of some key proteins of the COVID-19 "cytokine storm". CONCLUSION: The control of the cytokine storm is one of the major issues in the management of COVID-19 patients. Our study suggests that SFN can be employed in protocols useful to control hyperinflammatory state associated with SARS-CoV-2 infection.


Assuntos
Brônquios/virologia , Interleucina-6/genética , Interleucina-8/genética , Isotiocianatos/farmacologia , Glicoproteína da Espícula de Coronavírus/toxicidade , Sulfóxidos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Apoptose/efeitos dos fármacos , Brônquios/citologia , Brônquios/efeitos dos fármacos , COVID-19/fisiopatologia , Linhagem Celular , Quimiocinas/genética , Quimiocinas/metabolismo , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , SARS-CoV-2/patogenicidade , Regulação para Cima/efeitos dos fármacos
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