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1.
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
2.
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
3.
Medicine (Baltimore) ; 99(36): e21851, 2020 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-32899013

RESUMO

The association between tumor necrosis factor-alpha (TNF-α-308G/A, -238G/A, -863C/A, -1031T/C, and -857C/T) polymorphism and either chronic (CP) or aggressive (AgP) periodontitis susceptibility was conflicting. This meta-analysis aimed to quantitatively estimate the association.A total of 52 studies involving 5519 patients and 7260 controls were identified through a search of multiple electronic databases. Odds ratios (ORs) and their 95% confidence intervals using allele, homozygous, heterozygous, dominant, and recessive genetic models were computed to assess the strength of the association.The TNF-α-308G/A polymorphism was significantly associated with decreased risks of CP (GG vs AA: OR = 0.353, P < .001; GG+GA vs AA: OR = 0.480, P < .001) and AgP (G vs A: OR = 0.651, P < .001; GG vs AA: OR = 0.306, P < .001; GG+GA vs AA: OR = 0.384, P < .001) in Asians. There were no associations between TNF-α-238G/A, -863C/A, -1031T/C, -857C/T polymorphism and susceptibility to AgP. No associations were also found between CP susceptibility and TNF-α-238G/A, -857C/T polymorphism.These findings supported that TNF-α-308G/A polymorphism might be the protective factors of CP and AgP in Asians, and TNF-α-238G/A, -863C/A, -1031T/C, -857C/T polymorphism is not linked to AgP susceptibility.


Assuntos
Predisposição Genética para Doença , Periodontite/genética , Fator de Necrose Tumoral alfa/genética , Grupo com Ancestrais do Continente Asiático , Estudos de Casos e Controles , Humanos , Estudos Observacionais como Assunto , Polimorfismo de Nucleotídeo Único , Fatores de Proteção , Fatores de Risco
4.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 45(7): 752-758, 2020 Jul 28.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-32879077

RESUMO

OBJECTIVES: To investigate whether necrostatin-1 (Nec-1) can protect islet cells from the damage induced by TNF-α. METHODS: After isolation and purification, the neonatal porcine islet cell clusters (NICCs) were divided into 3 groups (islets 10 000 IEQ/group): a Nec-1 group (Nec-1+TNF-α was added to the culture medium), a TNF-α group (TNF-α was added to the culture medium), and a control group (pure medium). The number of cells was observed after 48 h of co-culture. The cell death was evaluated by AO/EB staining. Insulin secretion and DNA of islets were detected by chemiluminescence and nucleic acid quantitative analysis. RT-PCR assay was used to examine the mRNA expressions of insulin gene, glueogan gene and somatostatin gene. Flow cytometry analysis was used to detect the viability of B cells. RESULTS: The number of islets in Nec-1 group, TNF-α group and the control group were (8 425±2 187), (4 325±778), and (7 122±1 558) IEQ, respectively. Compared to the other two groups, the number of dead cells in TNF-α group was greatly increased. The insulin/DNA values in the Nec-1 group, TNF-α group and blank control group were (13.21±3.15), (2.47±0.45), and (7.44±0.97) mIU/mg, respectively. Compared to the TNF-α group and the control group, the mRNA relative expression levels of insulin gene (6.73±1.07), glucagon gene (10.13±1.98), somatostatin gene (8.57±1.11) were significantly increased in the Nec-1 group (all P<0.05), the rate of live cells (97.32±1.87)% and live B cells (90.86±3.68)% were increased significantly in the Nec-1 group (all P<0.05). CONCLUSIONS: TNF-α can induce neonatal porcine islet cells damage, which is attenuated in the presence of Nec-1. Nec-1 can increase the content of endocrine cells in NICCs.


Assuntos
Ilhotas Pancreáticas , Fator de Necrose Tumoral alfa/genética , Animais , Imidazóis , Indóis , Insulina , Suínos
5.
Adv Biol Regul ; 77: 100737, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32773100

RESUMO

Natural killer (NK) cells are pivotal effectors of the innate immunity protecting an individual from microbes. They are the first line of defense against invading viruses, given their substantial ability to directly target infected cells without the need for specific antigen presentation. By establishing cellular networks with a variety of cell types such as dendritic cells, NK cells can also amplify and modulate antiviral adaptive immune responses. In this review, we will examine the role of NK cells in SARS-COV2 infections causing the ongoing COVID19 pandemic, keeping in mind the controversial role of NK cells specifically in viral respiratory infections and in inflammatory-driven lung damage. We discuss lessons learnt from previous coronavirus outbreaks in humans (caused by SARS-CoV-1 and MERS-COV).


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/epidemiologia , Interações Hospedeiro-Patógeno/imunologia , Células Matadoras Naturais/imunologia , Pandemias , Pneumonia Viral/epidemiologia , Insuficiência Respiratória/epidemiologia , Doença Aguda , Infecções por Coronavirus/complicações , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/imunologia , Regulação da Expressão Gênica , Imunidade Inata , Interferon gama/genética , Interferon gama/imunologia , Interleucinas/genética , Interleucinas/imunologia , Células Matadoras Naturais/patologia , Células Matadoras Naturais/virologia , Pulmão/imunologia , Pulmão/patologia , Pulmão/virologia , Ativação Linfocitária , Proteína 1 de Membrana Associada ao Lisossomo/genética , Proteína 1 de Membrana Associada ao Lisossomo/imunologia , Subfamília C de Receptores Semelhantes a Lectina de Células NK/genética , Subfamília C de Receptores Semelhantes a Lectina de Células NK/imunologia , Pneumonia Viral/complicações , Pneumonia Viral/diagnóstico , Pneumonia Viral/imunologia , Insuficiência Respiratória/complicações , Insuficiência Respiratória/diagnóstico , Insuficiência Respiratória/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
6.
PLoS Negl Trop Dis ; 14(8): e0008495, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32764765

RESUMO

Melioidosis is an often-severe tropical infection caused by Burkholderia pseudomallei (Bp) with high associated morbidity and mortality. Burkholderia thailandensis (Bt) is a closely related surrogate that does not require BSL-3 conditions for study. Lactoferrin is an iron-binding glycoprotein that can modulate the innate inflammatory response. Here we investigated the impact of lactoferrin on the host immune response in melioidosis. Lactoferrin concentrations were measured in plasma from patients with melioidosis and following ex vivo stimulation of blood from healthy individuals. Bt growth was quantified in liquid media in the presence of purified and recombinant human lactoferrin. Differentiated THP-1 cells and human blood monocytes were infected with Bt in the presence of purified and recombinant human lactoferrin, and bacterial intracellular replication and cytokine responses (tumor necrosis factor-α (TNF-α), interleukin-1ß and interferon-γ) were measured. In a cohort of 49 melioidosis patients, non-survivors to 28 days had significantly higher plasma lactoferrin concentrations compared to survivors (median (interquartile range (IQR)): 326 ng/ml (230-748) vs 144 ng/ml (99-277), p<0.001). In blood stimulated with heat-killed Bp, plasma lactoferrin concentration significantly increased compared to unstimulated blood (median (IQR): 424 ng/ml (349-479) vs 130 ng/ml (91-214), respectively; p<0.001). Neither purified nor recombinant human lactoferrin impaired growth of Bt in media. Lactoferrin significantly increased TNF-α production by differentiated THP-1 cells and blood monocytes after Bt infection. This phenotype was largely abrogated when Toll-like receptor 4 (TLR4) was blocked with a monoclonal antibody. In sum, lactoferrin is produced by blood cells after exposure to Bp and lactoferrin concentrations are higher in 28-day survivors in melioidosis. Lactoferrin induces proinflammatory cytokine production after Bt infection that may be TLR4 dependent.


Assuntos
Infecções por Burkholderia/metabolismo , Infecções por Burkholderia/microbiologia , Burkholderia , Lactoferrina/metabolismo , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Burkholderia pseudomallei , Células Cultivadas , Humanos , Melioidose/metabolismo , Monócitos , Receptor 4 Toll-Like/genética , Fator de Necrose Tumoral alfa/genética
7.
Gene ; 760: 145021, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32763489

RESUMO

Human B cell activating factor (TNFSF13B, BAFF) is a tumor necrosis factor superfamily member. Binding its unique receptor (TNFRSF13C, BAFF-R) mediates gene expression and cell survival in B cells via activation of NFκB pathway. Furthermore, there is data indicating a role in T cell function. A functionally inhibitory isoform (ΔBAFF) resulting from the deletion of exon 3 in the TNFSF13B pre-RNA has already been reported. However, data on the complexity of post-transcriptional regulation is scarce. Here, we report molecular cloning of nine TNFSF13B transcript variants resulting from alternative splicing of the TNFSF13B pre-mRNA including BAFFX1. This variant is characterized by a partial retention of intron 3 of the TNFSF13B gene causing the appearance of a premature stop codon. We demonstrate the expression of the corresponding BAFFX1 protein in Jurkat T cells, in ex vivo human immune cells and in human tonsillar tissue. Thereby we contribute to the understanding of TNFSF13B gene regulation and reveal that BAFF is regulated through a post-transcriptional mechanism to a greater extent than reported to date.


Assuntos
Fator Ativador de Células B/genética , Fator Ativador de Células B/imunologia , Processamento Alternativo/genética , Fator Ativador de Células B/metabolismo , Linfócitos B/metabolismo , Éxons , Expressão Gênica , Humanos , NF-kappa B/metabolismo , Isoformas de Proteínas/genética , Precursores de RNA/metabolismo , Linfócitos T/metabolismo , Fator de Necrose Tumoral alfa/genética
8.
Nat Rev Immunol ; 20(10): 585-586, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32788708
9.
Life Sci ; 258: 118177, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32738364

RESUMO

AIM: Omapatrilat is an antagonist of angiotensin-converting (ACE) and neprilysin-neuropeptidase (NEP) enzymes. The aim of our study is to show that omapatrilat may have beneficial effects as a treatment for polymicrobial sepsis. MAIN METHODS: A cecal ligation and puncture (CLP) sepsis model was used to evaluate 10 and 20 mg/kg doses of omapatrilat in mice (n = 30) fasted for 12 h. The lungs were removed 12 h after CLP, and lung levels of cytokines (tumor necrosis factor-alpha [TNF-α], interleukin-6 [IL-6], NF-κB), iNOS and eNOS mRNA expression, GSH and MDA levels, and ACE and NEP activities were determined. Histopathological examinations were also performed. KEY FINDINGS: Omapatrilat treatment provided a dose-dependent reduction in oxidative stress and inflammatory parameters in lung tissues. Omapatrilat administration decreased lung iNOS and eNOS mRNA levels at 20 mg/kg dose. Histopathological analysis revealed a decline in the thickening and edema areas in the alveolar septa in the Sepsis+OMA20 group. SIGNIFICANCE: Omapatrilat, a dual ACE and NEP inhibitor, protected lung tissue from sepsis damage by reducing ACE and NEP activities, by decreasing the mRNA expression levels of pro-inflammatory cytokines (TNF-α, IL-6, and NF-κB), by suppressing leukocyte infiltration and edema, by restoring iNOS and eNOS levels, and by restoring SOD activity and GSH and MDA levels, thereby reducing oxidative stress.


Assuntos
Neprilisina/metabolismo , Peptidil Dipeptidase A/metabolismo , Sepse/enzimologia , Transdução de Sinais , Animais , Biomarcadores/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Pulmão/enzimologia , Pulmão/patologia , Masculino , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Estresse Oxidativo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Sepse/patologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
10.
Gene ; 761: 145038, 2020 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-32777532

RESUMO

Neuropathic pain, which results from impairment of the somatosensory system, has affected about 8% population around the world and leads to considerable burdens for patients and world health care system. However, its underlying mechanisms remain poorly understood. In this study, we hypothesized that miR-24-3p was involved in the progression of neuropathic pain in CCI rat models. By measuring miR-24-3p expression in CCI rats, we found that miR-24-3p expression was increased in CCI rats, suggesting miR-24-3p might participate in neuropathic pain progression. Next, by conducting a serial in vitro and vivo experiments, we found that miR-24-3p regulated Wnt5a/ß-Catenin Signaling levels to promote neuropathic pain progression via targeting LPAR3 in CCI rats. Furthermore, we explored the upstream regulator of miR-24-3p by conducting bioinformatics analysis, we found that circular RNA cZRANB1 might sponge to miR-24-3p. Then we applied biotinylated RNA pull-down and luciferase reporter assays to assess the association between cZRANB1 and miR-24-3p. It was found that cZRANB1 mediated LPAR3 expression via sponging miR-24-3p. Collectively, our study suggests that cZRNAB1 regulated Wnt5a/ß-Catenin Signaling expression via miR-24-3p/LPAR3 axis in CCI rat models.


Assuntos
MicroRNAs/genética , Neuralgia/genética , Receptores de Ácidos Lisofosfatídicos/genética , Animais , Constrição Patológica/genética , Progressão da Doença , Regulação da Expressão Gênica/genética , Células HEK293 , Humanos , Inflamação/genética , Masculino , MicroRNAs/metabolismo , RNA Circular/genética , RNA Longo não Codificante/genética , Ratos , Ratos Sprague-Dawley , Receptores de Ácidos Lisofosfatídicos/metabolismo , Transdução de Sinais/genética , Fator de Necrose Tumoral alfa/genética , Ubiquitina Tiolesterase/genética , Via de Sinalização Wnt/genética , Proteína Wnt-5a/genética , Proteína Wnt-5a/metabolismo , beta Catenina/metabolismo
11.
Signal Transduct Target Ther ; 5(1): 121, 2020 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-32641705
12.
Gene ; 759: 144999, 2020 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-32717305

RESUMO

Clostridium perfringens beta2 (CPB2), a key virulence factor, is produced by C. perfringens type C that is the main pathogenic microorganism causing diarrhea in piglets. However, little is known concerning the toxic damage effect of CPB2 on intestinal cells of piglets. In present study, CPB2 toxin obtained by genetic recombination technology was evaluated for its cytotoxicity property using the intestinal porcine epithelial (IPEC-J2) cells, which aims to attempt to understand and explain its mechanism of action in porcine small intestinal epithelial cells. IPEC-J2 cells were treated with different concentrations of CPB2 toxin (5, 10, 20, 30, 40, and 50 µg/mL), and MTT assay results showed that the cell viability of CPB2-treated IPEC-J2 cells decreased in a dose-dependent manner. Lactate dehydrogenase (LDH) assay results revealed that CPB2 significantly increased the LDH release, relative to the control. The expression of tumor necrosis factor α (TNF-α) and interleukin 8 (IL-8) gradually increased, while the expression of interleukin 10 (IL-10) gradually decreased in IPEC-J2 cells with increasing concentration of CPB2 (10-30 µg/mL), as analyzed by quantitative real-time PCR (RT-qPCR). Also, CPB2 increased the content of intracellular reactive oxygen species (ROS) and decreased mitochondrial membrane potential (ΔΨm) of IPEC-J2 cells. Western blot and immunofluorescence results demonstrate that CPB2 decreased the expression of zonula occludens (ZO-1), claudin12 (CLDN12) and occludin (OCLN) in IPEC-J2 cells. In addition, CPB2 increased Bax expression, and inhibited Bcl-2 and Bcl-xL expression, as measured by Western blot. Considering all of these findings, it was concluded that CPB2 toxin shows significant cytotoxicity, cell growth inhibition and increase in cell permeability in IPEC-J2 cells in a concentration-dependent manner, thus leading to abnormal cell apoptosis and functions in porcine small intestinal epithelial cells.


Assuntos
Toxinas Bacterianas/toxicidade , Células Epiteliais/efeitos dos fármacos , Estresse Oxidativo , Animais , Apoptose , Linhagem Celular , Claudinas/genética , Claudinas/metabolismo , Células Epiteliais/metabolismo , Interleucina-10/genética , Interleucina-10/metabolismo , Interleucina-8/genética , Interleucina-8/metabolismo , Potencial da Membrana Mitocondrial , Ocludina/genética , Ocludina/metabolismo , Suínos , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
13.
DNA Cell Biol ; 39(9): 1723-1729, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32700971

RESUMO

Sepsis-related mortality and morbidity are major health care problems worldwide. More effort is required to identify factors associated with adverse outcome. Evaluate the prognostic capacity of tumor necrosis factor (TNF), kidney injury molecule (KIM), and lactate and TNF-α-308 G > A gene polymorphism for prediction of 28 days-intensive care unit (ICU) mortality. TNF-α-308 G > A single nucleotide polymorphisms was detected by real-time-PCR on 112 had septic shock and 88 were septic. Serum TNF-α and urinary KIM were assessed by enzyme-linked immunosorbent assay. This study included 200 critically ill patients, 125 (62.5%) of them died within 28 days in ICU (nonsurvivors). Frequencies of TNF-308 G > A was (70.7) GG, (28) GA and (1.3) AA in survivors versus (85.6) GG, (12) GA and (2.4) AA for nonsurvivors, revealed significant association with ICU mortality but not sepsis severity (p = 0.15) or sepsis-induced acute kidney injury (AKI). In contrast, urinary KIM-1 revealed significant association with sepsis severity (p = 0.036) and AKI (p = 0.0001), but not 28-days ICU mortality. The relative risk of death in patients with GG genotype was 2.5 mainly in ICU younger male patients (odds ratios 24 and 4.9, p = 0.001). The genotype GG and GA were significantly associated with [increased urinary KIM-1 (0.29 ± 0.1) (p = 0.0001), terminal creatinine (1.67 ± 0.8) (p = 0.0001)] and [increased terminal urea (109 ± 0.001) (p = 0.001) and basal serum TNF (60 ± 0.001) (p = 0.0001)], respectively. In linear regression analysis, AKI 0.0001 (0.4-0.67), basal serum TNF 0.04 (0.0001-0.04), and TNF-308 GG 0.007 (0.05-0.33) were associated with 28 days ICU mortality [p value (95% confidence interval)]. The same results were observed for initial urea 0.024 (0.0001-0.003) and lack of diuretic usage 0.0001 (0.35-0.7) mainly in septic patients. Major frequency of TNF-308 G > A polymorphism (mainly in young age male patients), AKI and serum TNF were associated with increased risk for 28 days-ICU mortality. Furthermore, sepsis severity was influenced by TNF and urinary KIM-1, which reflects in AKI.


Assuntos
Lesão Renal Aguda/genética , Polimorfismo de Nucleotídeo Único , Choque Séptico/genética , Fator de Necrose Tumoral alfa/genética , Lesão Renal Aguda/epidemiologia , Lesão Renal Aguda/patologia , Adulto , Fatores Etários , Idoso , Estado Terminal , Feminino , Receptor Celular 1 do Vírus da Hepatite A/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Fatores Sexuais , Choque Séptico/complicações , Choque Séptico/patologia , Fator de Necrose Tumoral alfa/sangue
14.
PLoS One ; 15(6): e0233773, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32559198

RESUMO

In early life and around weaning, pigs are at risk of developing infectious diseases which compromise animal welfare and have major economic consequences for the pig industry. A promising strategy to enhance resistance against infectious diseases is immunomodulation by feed additives. To assess the immune stimulating potential of feed additives in vitro, bone marrow-derived dendritic cells were used. These cells play a central role in the innate and adaptive immune system and are the first cells encountered by antigens that pass the epithelial barrier. Two different feed additives were tested on dendritic cells cultured from fresh and cryopreserved bone marrow cells; a widely used commercial feed additive based on yeast-derived ß-glucans and the gram-negative probiotic strain E. coli Nissle 1917. E. coli Nissle 1917, but not ß-glucans, induced a dose-dependent upregulation of the cell maturation marker CD80/86, whereas both feed additives induced a dose-dependent production of pro- and anti-inflammatory cytokines, including TNFα, IL-1ß, IL-6 and IL-10. Furthermore, E. coli Nissle 1917 consistently induced higher levels of cytokine production than ß-glucans. These immunomodulatory responses could be assessed by fresh as well as cryopreserved in vitro cultured porcine bone marrow-derived dendritic cells. Taken together, these results demonstrate that both ß-glucans and E. coli Nissle 1917 are able to enhance dendritic cell maturation, but in a differential manner. A more mature dendritic cell phenotype could contribute to a more efficient response to infections. Moreover, both fresh and cryopreserved bone marrow-derived dendritic cells can be used as in vitro pre-screening tools which enable an evidence based prediction of the potential immune stimulating effects of different feed additives.


Assuntos
Células da Medula Óssea/imunologia , Células Dendríticas/imunologia , Fatores Imunológicos/farmacologia , Probióticos/farmacologia , Suínos/imunologia , beta-Glucanas/farmacologia , Ração Animal , Animais , Antígeno B7-1/genética , Antígeno B7-1/metabolismo , Antígeno B7-2/genética , Antígeno B7-2/metabolismo , Células da Medula Óssea/citologia , Células da Medula Óssea/efeitos dos fármacos , Diferenciação Celular , Células Cultivadas , Células Dendríticas/citologia , Células Dendríticas/efeitos dos fármacos , Escherichia coli , Fatores Imunológicos/administração & dosagem , Interleucinas/genética , Interleucinas/metabolismo , Probióticos/administração & dosagem , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , beta-Glucanas/administração & dosagem
15.
PLoS One ; 15(6): e0234920, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32559224

RESUMO

Sanguinarine is a bioactive compound as a quaternary benzophenanthridine alkaloid from plant of the Macleaya cordata, Papaveraceae family. The present study was conducted to investigate the effects of dietary sanguinarine supplementation on growth performance, serum biochemistry parameters, intestinal mucosal morphology and gut microbiome in yellow feathered broilers. Two hundred and seventy 1-d-old female broilers were randomly assigned to 3 treatments ① Basal diet (NG); ② Basal diet containing bacitracin methylene disalicylate (50mg/Kg diet) (ANT); ③ Basal diet containing sanguinarine (0.7 mg/ kg of feed) (SAG). The statistical results showed that dietary sanguinarine supplementation enhanced growth performance and decreased glucose, uric acid as well as urea nitrogen levels of broilers at 28d of age (P<0.05). The 16S rRNA gene sequence analysis revealed that sanguinarine significantly decreased the species from the phyla Bacteroidetes, and increased the species from phyla Firmicutes. Moreover, dietary sanguinarine supplementation improved mucosal morphology to achieve higher ratio of intestinal villus height to crypt depth (P < 0.05), and decreased the concentrations of TNF-α and IL-4 in jejunum mucosal. This study demonstrated that sanguinarine supplementation in the diet of yellow feathered broilers improved intestinal morphology and microbiota community structure to promote growth performance on 1-28d.


Assuntos
Anti-Infecciosos/farmacologia , Benzofenantridinas/farmacologia , Galinhas/microbiologia , Microbioma Gastrointestinal , Isoquinolinas/farmacologia , Jejuno/efeitos dos fármacos , Animais , Anti-Infecciosos/administração & dosagem , Proteínas Aviárias/genética , Proteínas Aviárias/metabolismo , Bacteroidetes/efeitos dos fármacos , Bacteroidetes/patogenicidade , Benzofenantridinas/administração & dosagem , Glicemia/metabolismo , Galinhas/crescimento & desenvolvimento , Suplementos Nutricionais , Feminino , Firmicutes/efeitos dos fármacos , Firmicutes/patogenicidade , Interleucina-4/genética , Interleucina-4/metabolismo , Isoquinolinas/administração & dosagem , Jejuno/crescimento & desenvolvimento , Jejuno/metabolismo , Jejuno/microbiologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Ácido Úrico/sangue
16.
Gene ; 755: 144900, 2020 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-32554046

RESUMO

Atherosclerosis (AS) is a serious threat to the cardiovascular system. Circular RNA circ_0003645 was found to be differentially expressed in the process of AS. Our study tried to unravel the effect and underlying mechanism of circ_0003645 in endothelial cells treated with oxidized low-density lipoprotein (oxLDL). Si-RNAs and over-circ0003645 were transfected into human umbilical vein endothelial cells (HUVECs), and the expression levels of circ_0003645 and NF-κB mRNA were measured. The protein level of NF-κB, lactate dehydrogenase leakage (LDH leakage), cell viability, and apoptosis were detected. Further, the expression of interleukin (IL)-6, tumor necrosis factor (TNF)-α, ICAM-1, and VCAM-1 were measured. Circ_0003645 was found up-regulated in AS patients and in HUVECs treated with oxLDL. The LDH leakage, cell apoptosis, and expression levels of IL-6, TNF-α, ICAM-1, VCAM-1, NF-κB mRNA, NF-κB protein were all inhibited by circ_0003645 silencing, while cell viability was promoted, and the opposite effects were observed by the overexpression of circ_0003645. In conclusion, circ_0003645 silencing alleviated inflammation and apoptosis, while promoted the viability in oxLDL-induced endothelial cells by the NF-κB pathway.


Assuntos
Aterosclerose/genética , Lipoproteínas LDL/farmacologia , NF-kappa B/metabolismo , RNA Circular/genética , Apoptose/fisiologia , Aterosclerose/metabolismo , Aterosclerose/patologia , Estudos de Casos e Controles , Linhagem Celular , Células Endoteliais/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Molécula 1 de Adesão Intercelular/genética , Molécula 1 de Adesão Intercelular/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Interferência de RNA/fisiologia , RNA Circular/metabolismo , Transdução de Sinais , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Molécula 1 de Adesão de Célula Vascular/genética , Molécula 1 de Adesão de Célula Vascular/metabolismo
17.
Life Sci ; 256: 117913, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32526287

RESUMO

The growing evidence has been tried to explain and characterize C1q/TNF- related proteins (CTRPs) family as the potential diagnostic or therapeutic targets of obesity-related metabolic disorders such as insulin resistance, type 2 diabetes (T2D), and cardiovascular disorders. However, the underlying mechanism is still obscure. Unraveling the signaling pathways downstream of CTRP family members is of great interest and could certainly be beneficial for finding new insights into therapeutic strategies for improving metabolic abnormalities. This review focused on the role of CTRP members in the initiation and development of obesity-related metabolic disorders with a focus on T2D and cardiovascular diseases. Here we summarize and discuss the role of CTRPs in the regulation of insulin signaling, inflammatory pathways, and energy metabolism, and other signaling pathways pertinent to the pathogenesis of T2D and cardiovascular diseases. We also review available clinical studies to better elucidate the roles of these potential molecules in the initiation and development of the afore-mentioned disorders.


Assuntos
Doenças Cardiovasculares/etiologia , Complemento C1q/metabolismo , Diabetes Mellitus Tipo 2/etiologia , Obesidade/complicações , Fator de Necrose Tumoral alfa/metabolismo , Animais , Doenças Cardiovasculares/metabolismo , Complemento C1q/genética , Diabetes Mellitus Tipo 2/metabolismo , Metabolismo Energético , Regulação da Expressão Gênica , Humanos , Inflamação/metabolismo , Resistência à Insulina , RNA Mensageiro , Transdução de Sinais , Fator de Necrose Tumoral alfa/genética
18.
Proc Natl Acad Sci U S A ; 117(27): 15935-15946, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32571912

RESUMO

Excessive tumor necrosis factor (TNF) is known to cause significant pathology. Paradoxically, deficiency in TNF (TNF-/-) also caused substantial pathology during respiratory ectromelia virus (ECTV) infection, a surrogate model for smallpox. TNF-/- mice succumbed to fulminant disease whereas wild-type mice, and those engineered to express only transmembrane TNF (mTNF), fully recovered. TNF deficiency did not affect viral load or leukocyte recruitment but caused severe lung pathology and excessive production of the cytokines interleukin (IL)-6, IL-10, transforming growth factor beta (TGF-ß), and interferon gamma (IFN-γ). Short-term blockade of these cytokines significantly reduced lung pathology in TNF-/- mice concomitant with induction of protein inhibitor of activated STAT3 (PIAS3) and/or suppressor of cytokine signaling 3 (SOCS3), factors that inhibit STAT3 activation. Consequently, inhibition of STAT3 activation with an inhibitor reduced lung pathology. Long-term neutralization of IL-6 or TGF-ß protected TNF-/- mice from an otherwise lethal infection. Thus, mTNF alone is necessary and sufficient to regulate lung inflammation but it has no direct antiviral activity against ECTV. The data indicate that targeting specific cytokines or cytokine-signaling pathways to reduce or ameliorate lung inflammation during respiratory viral infections is possible but that the timing and duration of the interventive measure are critical.


Assuntos
Citocinas/metabolismo , Infecções por Poxviridae/virologia , Poxviridae/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Animais , Linhagem Celular Tumoral , Feminino , Interferon gama/metabolismo , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Poxviridae/imunologia , Infecções por Poxviridae/imunologia , Infecções por Poxviridae/patologia , Infecções Respiratórias/imunologia , Infecções Respiratórias/virologia , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo , Fator de Crescimento Transformador beta/metabolismo
19.
Proc Natl Acad Sci U S A ; 117(26): 15066-15074, 2020 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-32554492

RESUMO

Cancer incidence increases exponentially with age when human telomeres are shorter. Similarly, telomerase reverse transcriptase (tert) mutant zebrafish have premature short telomeres and anticipate cancer incidence to younger ages. However, because short telomeres constitute a road block to cell proliferation, telomere shortening is currently viewed as a tumor suppressor mechanism and should protect from cancer. This conundrum is not fully understood. In our current study, we report that telomere shortening promotes cancer in a noncell autonomous manner. Using zebrafish chimeras, we show increased incidence of invasive melanoma when wild-type (WT) tumors are generated in tert mutant zebrafish. Tissues adjacent to melanoma lesions (skin) and distant organs (intestine) in tert mutants exhibited higher levels of senescence and inflammation. In addition, we transferred second generation (G2) tert blastula cells into WT to produce embryo chimeras. Cells with very short telomeres induced increased tumor necrosis factor1-α (TNF1-α) expression and senescence in larval tissues in a noncell autonomous manner, creating an inflammatory environment. Considering that inflammation is protumorigenic, we transplanted melanoma-derived cells into G2 tert zebrafish embryos and observed that tissue environment with short telomeres leads to increased tumor development. To test if inflammation was necessary for this effect, we treated melanoma transplants with nonsteroid anti-inflammatory drugs and show that higher melanoma dissemination can be averted. Thus, apart from the cell autonomous role of short telomeres in contributing to genome instability, we propose that telomere shortening with age causes systemic chronic inflammation leading to increased tumor incidence.


Assuntos
Melanoma/metabolismo , Telômero/metabolismo , Peixe-Zebra/metabolismo , Animais , Modelos Animais de Doenças , Humanos , Melanoma/genética , Melanoma/imunologia , Telomerase/genética , Telomerase/metabolismo , Telômero/genética , Encurtamento do Telômero , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia , Peixe-Zebra/genética , Peixe-Zebra/imunologia , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
20.
PLoS One ; 15(6): e0234731, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32544181

RESUMO

Airborne fungi are associated with upper and lower airway inflammatory diseases. Alternaria is commonly found in nasal secretions and induces the production of chemical mediators from sinonasal mucosa. This study aimed to establish an Alternaria-induced chronic rhinosinusitis (CRS) mouse model and determine the influence of host allergic background on the immunopathological characteristics of CRS. BALB/c mice were used for establishing the CRS model. Alternaria was intranasally instilled for 8 or 16 weeks with or without ovalbumin (OVA) presensitization. Total serum IgE and Alternaria-specific IgE levels were measured by enzyme-linked immunosorbent assay (ELISA). Interleukin (IL)-4, IL-10, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α levels in nasal lavage fluid (NLF) and splenocytes were measured by ELISA and their mRNAs and levels of associated transcription factors in sinonasal mucosa were determined with quantitative reverse-transcriptase polymerase chain reaction (RT-PCR). Hematoxylin-eosin staining and periodic acid-Schiff staining were performed to evaluate histological changes. Total serum IgE was increased in both allergic and non-allergic CRS. IL-4 was strongly expressed in NLF in both allergic and non-allergic CRS at 16 weeks and not only eosinophils but also neutrophils were increased in NLF of non-allergic CRS mice. The levels of Th1, Th2, and Treg cytokines and transcription factor mRNAs were significantly increased in sinonasal mucosa of non-allergic CRS mice. Both inflammatory cell infiltration and goblet cell hyperplasia were increased in CRS mice. Repeated intranasal instillation of Alternaria results in sinonasal inflammation with inflammatory cell infiltration. The sinonasal mucosal immune responses against Alternaria were shown to differ depending on the host allergic background.


Assuntos
Alternaria/patogenicidade , Rinite/patologia , Sinusite/patologia , Alternaria/imunologia , Animais , Doença Crônica , Modelos Animais de Doenças , Feminino , Imunoglobulina E/sangue , Interleucina-10/análise , Interleucina-10/genética , Interleucina-10/metabolismo , Interleucina-4/análise , Interleucina-4/genética , Interleucina-4/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Líquido da Lavagem Nasal/química , Mucosa Nasal/metabolismo , Mucosa Nasal/patologia , RNA Mensageiro/metabolismo , Rinite/imunologia , Sinusite/imunologia , Baço/metabolismo , Baço/microbiologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Fator de Necrose Tumoral alfa/análise , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
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