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1.
Front Immunol ; 12: 681516, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34489933

RESUMO

Coronavirus disease 2019 (COVID-19) broke out and then became a global epidemic at the end of 2019. With the increasing number of deaths, early identification of disease severity and interpretation of pathogenesis are very important. Aiming to identify biomarkers for disease severity and progression of COVID-19, 75 COVID-19 patients, 34 healthy controls and 23 patients with pandemic influenza A(H1N1) were recruited in this study. Using liquid chip technology, 48 cytokines and chemokines were examined, among which 33 were significantly elevated in COVID-19 patients compared with healthy controls. HGF and IL-1ß were strongly associated with APACHE II score in the first week after disease onset. IP-10, HGF and IL-10 were correlated positively with virus titers. Cytokines were significantly correlated with creatinine, troponin I, international normalized ratio and procalcitonin within two weeks after disease onset. Univariate analyses were carried out, and 6 cytokines including G-CSF, HGF, IL-10, IL-18, M-CSF and SCGF-ß were found to be associated with the severity of COVID-19. 11 kinds of cytokines could predict the severity of COVID-19, among which IP-10 and M-CSF were excellent predictors for disease severity. In conclusion, the levels of cytokines in COVID-19 were significantly correlated with the severity of the disease in the early stage, and serum cytokines could be used as warning indicators of the severity and progression of COVID-19. Early stratification of disease and intervention to reduce hypercytokinaemia may improve the prognosis of COVID-19 patients.


Assuntos
COVID-19/imunologia , Citocinas/genética , Citocinas/imunologia , SARS-CoV-2/imunologia , Índice de Gravidade de Doença , Transcriptoma/imunologia , Adulto , Idoso , Biomarcadores/sangue , Quimiocinas/sangue , Quimiocinas/genética , Quimiocinas/imunologia , Citocinas/sangue , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Influenza Humana/sangue , Influenza Humana/imunologia , Masculino , Pessoa de Meia-Idade
2.
J Agric Food Chem ; 69(36): 10506-10514, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34478286

RESUMO

The present study investigated the effect of eugenol (EUG) on dextran sulfate sodium (DSS)-induced colitis and explored the underlying mechanisms. C57BL/6 mice were intragastrically administered normal saline or EUG (20 mg/kg body weight) for 17 days, and colitis was induced by using 3% DSS from day 7. The results showed that EUG increased the body weight and reduced the disease activity index score and colon pathological scores in DSS-treated mice (P < 0.05). Further, EUG preserved the proinflammatory cytokines (interleukin (IL)-6, -12, -21, and -23), lowered (P < 0.05) colonic malondialdehyde (MDA), uncoupling protein 2 (UCP2) expression and p65 phosphorylation, and activated (P < 0.05) colonic kelch-like ECH-associated protein 1 and nuclear factor (erythroid-derived 2)-like 2 expressions but did not affect the intestinal microbiota in DSS-treated mice. Furthermore, EUG ameliorated colitis in antibiotic-treated mice, while fecal microbiota transplantation from EUG preadministered mice failed to ameliorate colitis. In conclusion, EUG could alleviate colitis by attenuating colonic inflammation and oxidative stress independent of intestinal microbiota.


Assuntos
Colite , Microbioma Gastrointestinal , Animais , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/genética , Colo , Citocinas/genética , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Eugenol , Camundongos , Camundongos Endogâmicos C57BL
3.
Zhongguo Dang Dai Er Ke Za Zhi ; 23(8): 828-834, 2021 Aug 15.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-34511173

RESUMO

OBJECTIVES: To study the expression of adipokines in children with primary nephrotic syndrome (PNS) before and after treatment and its correlation with blood lipids, as well as the role of adipokines in PNS children with hyperlipidemia. METHODS: A total of 90 children who were diagnosed with incipient PNS or recurrence of PNS after corticosteroid withdrawal for more than 6 months were enrolled as subjects. Thirty children who underwent physical examination were enrolled as the control group. Venous blood samples were collected from the children in the control group and the children with PNS before corticosteroid therapy (active stage) and after urinary protein clearance following 4 weeks of corticosteroid therapy (remission stage). ELISA was used to measure the levels of adipokines. An automatic biochemical analyzer was used to measure blood lipid levels. RESULTS: Compared with the control group, the children with PNS had a significantly lower level of omentin-1 in both active and remission stages, and their level of omentin-1 in the active stage was significantly lower than that in the remission stage (P<0.001). For the children with PNS, the level of chemerin in the active stage was significantly higher than that in the remission stage, and the children with PNS in the active stage had a significantly higher level of chemerin than the control group (P<0.001). For the children with PNS, atherogenic index of plasma, atherogenic coefficient (AC), castelli risk index-1 (CRI-1), castelli risk index-2 (CRI-2), and non-high-density lipoprotein in the active stage were significantly higher than those in the remission stage (P<0.001), and these indices in the children with PNS in the active stage were significantly higher than those in the control group (P<0.001). The children with PNS in the remission stage had significantly higher atherogenic index of plasma, AC, CRI-1, and non-high-density lipoprotein than the control group (P<0.001). Compared with the control group, the children with PNS in the remission stage had significantly higher serum levels of total cholesterol, triglyceride, high-density lipoprotein, low-density lipoprotein, apolipoprotein B, and apolipoprotein A (P<0.01). In the children with PNS, the ratio of omentin-1 before and after corticosteroid therapy was positively correlated with that of high-density lipoprotein, 24-hour urinary protein excretion, and high-density lipoprotein/apolipoprotein A before and after treatment, and it was negatively correlated with the ratio of AC and CRI-1 before and after treatment (P<0.05). The PNS children with low omentin-1 levels in the active stage had significantly higher levels of CRI-1, CRI-2, AC, and apolipoprotein B/apolipoprotein A ratio than those with high omentin-1 levels (P<0.05). CONCLUSIONS: Omentin-1 may be associated with disease activity, dyslipidemia, and proteinuria in children with PNS. Blood lipid ratios may be more effective than traditional blood lipid parameters in monitoring early cardiovascular risk in children with PNS.


Assuntos
Citocinas/metabolismo , Hiperlipidemias , Lectinas/metabolismo , Síndrome Nefrótica , Adipocinas , Quimiocinas , Criança , Citocinas/genética , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Humanos , Lectinas/genética , Lipídeos , Síndrome Nefrótica/tratamento farmacológico , Proteinúria
4.
Nat Commun ; 12(1): 4869, 2021 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-34381043

RESUMO

In COVID-19, immune responses are key in determining disease severity. However, cellular mechanisms at the onset of inflammatory lung injury in SARS-CoV-2 infection, particularly involving endothelial cells, remain ill-defined. Using Syrian hamsters as a model for moderate COVID-19, we conduct a detailed longitudinal analysis of systemic and pulmonary cellular responses, and corroborate it with datasets from COVID-19 patients. Monocyte-derived macrophages in lungs exert the earliest and strongest transcriptional response to infection, including induction of pro-inflammatory genes, while epithelial cells show weak alterations. Without evidence for productive infection, endothelial cells react, depending on cell subtypes, by strong and early expression of anti-viral, pro-inflammatory, and T cell recruiting genes. Recruitment of cytotoxic T cells as well as emergence of IgM antibodies precede viral clearance at day 5 post infection. Investigating SARS-CoV-2 infected Syrian hamsters thus identifies cell type-specific effector functions, providing detailed insights into pathomechanisms of COVID-19 and informing therapeutic strategies.


Assuntos
COVID-19/imunologia , Modelos Animais de Doenças , Células Epiteliais Alveolares/imunologia , Animais , Cricetinae , Citocinas/genética , Citocinas/imunologia , Células Endoteliais/imunologia , Humanos , Imunoglobulina M/imunologia , Inflamação , Pulmão/imunologia , Macrófagos/imunologia , Mesocricetus , Monócitos/imunologia , SARS-CoV-2/imunologia , Transdução de Sinais , Linfócitos T Citotóxicos/imunologia , Receptores Toll-Like/imunologia
5.
J Microbiol ; 59(9): 861-870, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34382146

RESUMO

Salmonella Typhimurium (ST313) has caused an epidemic of invasive disease in sub-Saharan Africa and has been recently identified in Brazil. As the virulence of this ST is poorly understood, the present study aimed to (i) perform the RNA-seq in vitro of S. Typhimurium STm30 (ST313) grown in Luria-Bertani medium at 37°C; (ii) compare it with the RNA-seq of the S. Typhimurium SL1344 (ST19) and S. Typhimurium STm11 (ST19) strains under the same growing conditions; and (iii) examine the colonization capacity and expression of virulence genes and cytokines in murine colon. The STm30 (ST313) strain exhibited stronger virulence and was associated with a more inflammatory profile than the strains SL1344 (ST19) and STm11 (ST19), as demonstrated by transcriptome and in vivo assay. The expression levels of the hilA, sopD2, pipB, and ssaS virulence genes, other Salmonella pathogenicity islands SPI-1 and SPI-2 genes or effectors, and genes of the cytokines IL-1ß, IFN-γ, TNF-α, IL-6, IL-17, IL-22, and IL-12 were increased during ST313 infection in C57BL/6J mice. In conclusion, S. Typhimurium STm30 (ST313) isolated from human feces in Brazil express higher levels of pathogenesis-related genes at 37°C and has stronger colonization and invasion capacity in murine colon due to its high expression levels of virulence genes, when compared with the S. Typhimurium SL1344 (ST19) and STm11 (ST19) strains. STm30 (ST313) also induces stronger expression of pro-inflammatory cytokines in this organ, suggesting that it causes more extensive tissue damage.


Assuntos
Colo/microbiologia , Infecções por Salmonella/imunologia , Infecções por Salmonella/microbiologia , Salmonella typhimurium/patogenicidade , Animais , Brasil , Colo/imunologia , Citocinas/genética , Citocinas/imunologia , Fezes/microbiologia , Ilhas Genômicas , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Infecções por Salmonella/genética , Salmonella typhimurium/genética , Salmonella typhimurium/isolamento & purificação , Salmonella typhimurium/fisiologia , Virulência
6.
Int J Mol Sci ; 22(16)2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34445430

RESUMO

Age-related macular degeneration (AMD), the leading cause of vision loss in the elderly, is a degenerative disease of the macula, where retinal pigment epithelium (RPE) cells are damaged in the early stages of the disease, and chronic inflammatory processes may be involved. Besides aging and lifestyle factors as drivers of AMD, a strong genetic association to AMD is found in genes of the complement system, with a single polymorphism in the complement factor H gene (CFH), accounting for the majority of AMD risk. However, the exact mechanism of CFH dysregulation confers such a great risk for AMD and its role in RPE cell homeostasis is unclear. To explore the role of endogenous CFH locally in RPE cells, we silenced CFH in human hTERT-RPE1 cells. We demonstrate that endogenously expressed CFH in RPE cells modulates inflammatory cytokine production and complement regulation, independent of external complement sources, or stressors. We show that loss of the factor H protein (FH) results in increased levels of inflammatory mediators (e.g., IL-6, IL-8, GM-CSF) and altered levels of complement proteins (e.g., C3, CFB upregulation, and C5 downregulation) that are known to play a role in AMD. Moreover, our results identify the NF-κB pathway as the major pathway involved in regulating these inflammatory and complement factors. Our findings suggest that in RPE cells, FH and the NF-κB pathway work in synergy to maintain inflammatory and complement balance, and in case either one of them is dysregulated, the RPE microenvironment changes towards a proinflammatory AMD-like phenotype.


Assuntos
Citocinas/metabolismo , Inativação Gênica , Degeneração Macular/genética , Epitélio Pigmentado da Retina/imunologia , Linhagem Celular , Fator H do Complemento/genética , Proteínas do Sistema Complemento/metabolismo , Citocinas/genética , Regulação da Expressão Gênica , Humanos , Degeneração Macular/imunologia , Modelos Biológicos , NF-kappa B/genética , NF-kappa B/metabolismo , Epitélio Pigmentado da Retina/metabolismo , Transdução de Sinais
7.
Nutrients ; 13(7)2021 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-34371956

RESUMO

We examined the immunomodulatory and anti-inflammatory effects of asiatic acid (AA) in atopic dermatitis (AD). AA treatment (5-20 µg/mL) dose-dependently suppressed the tumor necrosis factor (TNF)-α level and interleukin (IL)-6 protein expression in interferon (IFN)-γ + TNF-α-treated HaCaT cells. The 2,4-dinitrocholrlbenzene (DNCB)-induced AD animal model was developed by administering two AA concentrations (30 and 75 mg/kg/d: AD + AA-L and AD + AA-H groups, respectively) for 18 days. Interestingly, AA treatment decreased AD skin lesions formation and affected other AD characteristics, such as increased ear thickness, lymph node and spleen size, dermal and epidermal thickness, collagen deposition, and mast cell infiltration in dorsal skin. In addition, in the DNCB-induced AD animal model, AA treatment downregulated the mRNA expression level of AD-related cytokines, such as Th1- (TNF-α and IL-1ß and -12) and Th2 (IL-4, -5, -6, -13, and -31)-related cytokines as well as that of cyclooxygenase-2 and CXCL9. Moreover, in the AA treatment group, the protein level of inflammatory cytokines, including COX-2, IL-6, TNF-α, and IL-8, as well as the NF-κB and MAPK signaling pathways, were decreased. Overall, our study confirmed that AA administration inhibited AD skin lesion formation via enhancing immunomodulation and inhibiting inflammation. Thus, AA can be used as palliative medication for regulating AD symptoms.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Citocinas/metabolismo , Dermatite Atópica/tratamento farmacológico , Fatores Imunológicos/farmacologia , Triterpenos Pentacíclicos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/uso terapêutico , Linhagem Celular , Sobrevivência Celular , Colágeno/análise , Citocinas/genética , Dermatite Atópica/imunologia , Dermatite Atópica/patologia , Derme/patologia , Dinitroclorobenzeno , Modelos Animais de Doenças , Epiderme/patologia , Feminino , Regulação da Expressão Gênica , Humanos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/uso terapêutico , Imunomodulação , Tecido Linfoide/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Mastócitos , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , Tamanho do Órgão/efeitos dos fármacos , Triterpenos Pentacíclicos/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos
8.
Free Radic Biol Med ; 174: 135-143, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34363947

RESUMO

Aquaporin-8 (AQP8) is a peroxiporin, a transmembrane water and hydrogen peroxide (H2O2) transport protein expressed in the mitochondrial and plasma membranes of pancreatic ß-cells. AQP8 protein expression is low under physiological conditions, but it increases after cytokine exposure both, in vitro and in vivo, possibly related to a NF-κB consensus sequence in the promoter. AQP8 knockdown (KD) insulin-producing RINm5F cells are particularly susceptible to cytokine-mediated oxidative stress. Cytokine (a mixture of IL-1ß, TNF-α, and IFN-γ) treated AQP8 KD cells exhibited pronounced sensitivity to reactive oxygen and nitrogen species (ROS and RNS), resulting in a significant loss of ß-cell viability due to enhanced toxicity of the increased concentrations of H2O2 and hydroxyl radicals (●OH) in mitochondria of AQP8 KD cells. This viability loss went along with increased caspase activities, reduced nitrite concentration (representative of nitric oxide (NO●) accumulation) and increased lipid peroxidation. The explanation for the increased toxicity of the proinflammatory cytokines in AQP8 KD cells resides in the fact that efflux of the H2O2 generated during oxidative stress in the ß-cell mitochondria is hampered through the loss of the peroxiporin channels in the mitochondrial membranes of the AQP8 KD cells. The increased proinflammatory cytokine toxicity due to loss of AQP8 expression in the KD ß-cell mitochondria is thus the result of increased rates of apoptosis. This decreased cell viability is caused by increased levels of oxidative stress along with a ferroptosis-mediated cell death component due to decreased NO● generation.


Assuntos
Aquaporinas , Células Secretoras de Insulina , Animais , Citocinas/genética , Peróxido de Hidrogênio/metabolismo , Peróxido de Hidrogênio/toxicidade , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Ratos
9.
Int J Mol Sci ; 22(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34360840

RESUMO

Obesity is characterized as a chronic, low-grade inflammation state accompanied by the infiltration of immune cells into adipose tissue and higher levels of inflammatory cytokines and chemokines. This study aimed to investigate the mechanisms and effects of Coptidis Rhizoma (CR) on obesity and its associated inflammation. First, we applied a network pharmacology strategy to search the target genes and pathways regulated by CR in obesity. Next, we performed in vivo experiments to confirm the antiobesity and anti-inflammatory effects of CR. Mice were assigned to five groups: normal chow (NC), control (high-fat diet (HFD)), HFD + CR 200 mg/kg, HFD + CR 400 mg/kg, and HFD + metformin 200 mg/kg. After 16 weeks of the experimental period, CR administration significantly reduced the weight of the body, epididymal fat, and liver; it also decreased insulin resistance, as well as the area under the curve of glucose in the oral glucose tolerance test and triglyceride in the oral fat tolerance test. We observed a decrease in adipose tissue macrophages (ATMs) and inflammatory M1 ATMs, as well as an increase in anti-inflammatory M2 ATMs. Gene expression levels of inflammatory cytokines and chemokines, including tumor necrosis factor-α, F4/80, and C-C motif chemokine (CCL)-2, CCL4, and CCL5, were suppressed in adipose tissue in the CR groups than levels in the control group. Additionally, histological analyses suggested decreased fat accumulation in the epididymal fat pad and liver in the CR groups than that in the control group. Taken together, these results suggest that CR has a therapeutic effect on obesity-induced inflammation, and it functions through the inhibition of macrophage-mediated inflammation in adipose tissue.


Assuntos
Citocinas/genética , Medicamentos de Ervas Chinesas/farmacologia , Inflamação/tratamento farmacológico , Macrófagos/metabolismo , Obesidade/complicações , Tecido Adiposo/citologia , Tecido Adiposo/efeitos dos fármacos , Animais , Anti-Inflamatórios/farmacologia , Simulação por Computador , Dieta Hiperlipídica , Regulação da Expressão Gênica , Inflamação/etiologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
10.
Int J Mol Sci ; 22(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34360974

RESUMO

Erythropoietin (EPO) downregulates hepcidin expression to increase the availability of iron; the downregulation of hepcidin is mediated by erythroferrone (ERFE) secreted by erythroblasts. Erythroblasts also express transferrin receptor 2 (TFR2); however, the possible role of TFR2 in hepcidin downregulation is unclear. The purpose of the study was to correlate liver expression of hepcidin with the expression of ERFE and TFR2 in murine bone marrow and spleen at 4, 16, 24, 48, 72 and 96 h following administration of a single dose of EPO. Splenic Fam132b expression increased 4 h after EPO injection; liver hepcidin mRNA was decreased at 16 h. In the spleen, expression of TFR2 and transferrin receptor (TFR1) proteins increased by an order of magnitude at 48 and 72 h after EPO treatment. The EPO-induced increase in splenic TFR2 and TFR1 was associated with an increase in the number of Tfr2- and Tfr1-expressing erythroblasts. Plasma exosomes prepared from EPO-treated mice displayed increased amount of TFR1 protein; however, no exosomal TFR2 was detected. Overall, the results confirm the importance of ERFE in stress erythropoiesis, support the role of TFR2 in erythroid cell development, and highlight possible differences in the removal of TFR2 and TFR1 from erythroid cell membranes.


Assuntos
Eritropoetina/farmacologia , Receptores da Transferrina/genética , Animais , Células Cultivadas , Citocinas/genética , Citocinas/metabolismo , Eritroblastos/efeitos dos fármacos , Eritroblastos/metabolismo , Exossomos/metabolismo , Hepcidinas/genética , Hepcidinas/metabolismo , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Receptores da Transferrina/metabolismo , Baço/metabolismo
11.
Int J Mol Sci ; 22(16)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34445305

RESUMO

Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling. Recent evidence supports that inflammation plays a key role in triggering and maintaining pulmonary vascular remodeling. Recent studies have shown that garlic extract has protective effects in PAH, but the precise role of allicin, a compound derived from garlic, is unknown. Thus, we used allicin to evaluate its effects on inflammation and fibrosis in PAH. Male Wistar rats were divided into three groups: control (CON), monocrotaline (60 mg/kg) (MCT), and MCT plus allicin (16 mg/kg/oral gavage) (MCT + A). Right ventricle (RV) hypertrophy and pulmonary arterial medial wall thickness were determined. IL-1ß, IL-6, TNF-α, NFκB p65, Iκß, TGF-ß, and α-SMA were determined by Western blot analysis. In addition, TNF-α and TGF-ß were determined by immunohistochemistry, and miR-21-5p and mRNA expressions of Cd68, Bmpr2, and Smad5 were determined by RT-qPCR. Results: Allicin prevented increases in vessel wall thickness due to TNF-α, IL-6, IL-1ß, and Cd68 in the lung. In addition, TGF-ß, α-SMA, and fibrosis were lower in the MCT + A group compared with the MCT group. In the RV, allicin prevented increases in TNF-α, IL-6, and TGF-ß. These observations suggest that, through the modulation of proinflammatory and profibrotic markers in the lung and heart, allicin delays the progression of PAH.


Assuntos
Anti-Inflamatórios/uso terapêutico , Dissulfetos/uso terapêutico , Hipertensão Pulmonar/tratamento farmacológico , Ácidos Sulfínicos/uso terapêutico , Animais , Antígenos CD/genética , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/genética , Antígenos de Diferenciação Mielomonocítica/metabolismo , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/genética , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/metabolismo , Citocinas/genética , Citocinas/metabolismo , Fibrose , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/metabolismo , Ventrículos do Coração/patologia , Masculino , NF-kappa B/genética , NF-kappa B/metabolismo , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/metabolismo , Artéria Pulmonar/patologia , Ratos , Ratos Wistar , Proteína Smad5/genética , Proteína Smad5/metabolismo
12.
Front Immunol ; 12: 700184, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34408749

RESUMO

Coronavirus disease 2019 (COVID-19), which has high incidence rates with rapid rate of transmission, is a pandemic that spread across the world, resulting in more than 3,000,000 deaths globally. Currently, several drugs have been used for the clinical treatment of COVID-19, such as antivirals (radecivir, baritinib), monoclonal antibodies (tocilizumab), and glucocorticoids (dexamethasone). Accumulating evidence indicates that long noncoding RNAs (lncRNAs) are essential regulators of virus infections and antiviral immune responses including biological processes that are involved in the regulation of COVID-19 and subsequent disease states. Upon viral infections, cellular lncRNAs directly regulate viral genes and influence viral replication and pathology through virus-mediated changes in the host transcriptome. Additionally, several host lncRNAs could help the occurrence of viral immune escape by inhibiting type I interferons (IFN-1), while others could up-regulate IFN-1 production to play an antiviral role. Consequently, understanding the expression and function of lncRNAs during severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection will provide insights into the development of lncRNA-based methods. In this review, we summarized the current findings of lncRNAs in the regulation of the strong inflammatory response, immune dysfunction and thrombosis induced by SARS-CoV-2 infection, discussed the underlying mechanisms, and highlighted the therapeutic challenges of COVID-19 treatment and its future research directions.


Assuntos
COVID-19/imunologia , Interações entre Hospedeiro e Microrganismos/genética , Imunidade Inata/genética , RNA Longo não Codificante/metabolismo , Trombose/imunologia , Antivirais/farmacologia , Antivirais/uso terapêutico , Biomarcadores/análise , COVID-19/complicações , COVID-19/tratamento farmacológico , COVID-19/genética , Teste para COVID-19/métodos , Citocinas/genética , Citocinas/metabolismo , Regulação Viral da Expressão Gênica/efeitos dos fármacos , Regulação Viral da Expressão Gênica/imunologia , Interações entre Hospedeiro e Microrganismos/efeitos dos fármacos , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Evasão da Resposta Imune/genética , Pandemias/prevenção & controle , RNA Longo não Codificante/análise , RNA Longo não Codificante/antagonistas & inibidores , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/genética , SARS-CoV-2/imunologia , SARS-CoV-2/patogenicidade , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Trombose/genética , Trombose/virologia , Replicação Viral/efeitos dos fármacos , Replicação Viral/genética , Replicação Viral/imunologia
13.
Nat Commun ; 12(1): 5152, 2021 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-34446707

RESUMO

The immunological features that distinguish COVID-19-associated acute respiratory distress syndrome (ARDS) from other causes of ARDS are incompletely understood. Here, we report the results of comparative lower respiratory tract transcriptional profiling of tracheal aspirate from 52 critically ill patients with ARDS from COVID-19 or from other etiologies, as well as controls without ARDS. In contrast to a "cytokine storm," we observe reduced proinflammatory gene expression in COVID-19 ARDS when compared to ARDS due to other causes. COVID-19 ARDS is characterized by a dysregulated host response with increased PTEN signaling and elevated expression of genes with non-canonical roles in inflammation and immunity. In silico analysis of gene expression identifies several candidate drugs that may modulate gene expression in COVID-19 ARDS, including dexamethasone and granulocyte colony stimulating factor. Compared to ARDS due to other types of viral pneumonia, COVID-19 is characterized by impaired interferon-stimulated gene (ISG) expression. The relationship between SARS-CoV-2 viral load and expression of ISGs is decoupled in patients with COVID-19 ARDS when compared to patients with mild COVID-19. In summary, assessment of host gene expression in the lower airways of patients reveals distinct immunological features of COVID-19 ARDS.


Assuntos
COVID-19/genética , RNA/genética , Síndrome do Desconforto Respiratório/genética , Traqueia/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , COVID-19/imunologia , COVID-19/virologia , Estudos de Casos e Controles , Estudos de Coortes , Estado Terminal , Citocinas/genética , Citocinas/imunologia , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , RNA/metabolismo , Síndrome do Desconforto Respiratório/imunologia , Síndrome do Desconforto Respiratório/virologia , SARS-CoV-2/fisiologia , Análise de Sequência de RNA
14.
Viruses ; 13(8)2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34452468

RESUMO

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19), a global pandemic characterized by an exaggerated immune response and respiratory illness. Age (>60 years) is a significant risk factor for developing severe COVID-19. To better understand the host response of the aged airway epithelium to SARS-CoV-2 infection, we performed an in vitro study using primary human bronchial epithelial cells from donors >67 years of age differentiated on an air-liquid interface culture. We demonstrate that SARS-CoV-2 infection leads to early induction of a proinflammatory response and a delayed interferon response. In addition, we observed changes in the genes and pathways associated with cell death and senescence throughout infection. In summary, our study provides new and important insights into the temporal kinetics of the airway epithelial innate immune response to SARS-CoV-2 in older individuals.


Assuntos
Brônquios/imunologia , Brônquios/virologia , Imunidade Inata , Mucosa Respiratória/imunologia , Mucosa Respiratória/virologia , SARS-CoV-2/imunologia , Idoso , Envelhecimento/imunologia , Brônquios/citologia , Brônquios/metabolismo , COVID-19/imunologia , Morte Celular/genética , Células Cultivadas , Senescência Celular/genética , Citocinas/biossíntese , Citocinas/genética , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Células Epiteliais/virologia , Feminino , Humanos , Inflamação , Interferons/biossíntese , Interferons/genética , Masculino , RNA-Seq , Mucosa Respiratória/citologia , Mucosa Respiratória/metabolismo , SARS-CoV-2/fisiologia , Transdução de Sinais/genética
15.
Microbiol Spectr ; 9(1): e0077421, 2021 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-34378952

RESUMO

The primary target organ of coronavirus disease 2019 (COVID-19) infection is the respiratory tract. Currently, there is limited information on the ability of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to infect and regulate innate immunity in human immune cells and lung epithelial cells. Here, we compared the ability of four Finnish isolates of SARS-CoV-2 from COVID-19 patients to replicate and induce interferons (IFNs) and other cytokines in different human cells. All isolates failed to replicate in dendritic cells, macrophages, monocytes, and lymphocytes, and no induction of cytokine gene expression was seen. However, most of the isolates replicated in Calu-3 cells, and they readily induced type I and type III IFN gene expression. The hCoV-19/Finland/FIN-25/2020 isolate, originating from a traveler from Milan in March 2020, showed better ability to replicate and induce IFN and inflammatory responses in Calu-3 cells than other isolates of SARS-CoV-2. Our data increase the knowledge on the pathogenesis and antiviral mechanisms of SARS-CoV-2 infection in human cell systems. IMPORTANCE With the rapid spread of the coronavirus disease 2019 (COVID-19) pandemic, information on the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and regulation of innate immunity in human immune cells and lung epithelial cells is needed. In the present study, we show that SARS-CoV-2 failed to productively infect human immune cells, but different isolates of SARS-CoV-2 showed differential ability to replicate and regulate innate interferon responses in human lung epithelial Calu-3 cells. These findings will open up the way for further studies on the mechanisms of pathogenesis of SARS-CoV-2 in human cells.


Assuntos
COVID-19/imunologia , Células Epiteliais/imunologia , Imunidade Inata , Pulmão/imunologia , SARS-CoV-2/isolamento & purificação , Replicação Viral/fisiologia , Enzima de Conversão de Angiotensina 2 , Antivirais/farmacologia , Citocinas/genética , Células Epiteliais/virologia , Expressão Gênica , Humanos , Interferon Tipo I/genética , Interferons/genética , Cinética , Pulmão/virologia , Filogenia , RNA Viral , SARS-CoV-2/classificação , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus , Tripsina
16.
Am J Hum Genet ; 108(9): 1590-1610, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34390653

RESUMO

Our study investigated the underlying mechanism for the 14q24 renal cell carcinoma (RCC) susceptibility risk locus identified by a genome-wide association study (GWAS). The sentinel single-nucleotide polymorphism (SNP), rs4903064, at 14q24 confers an allele-specific effect on expression of the double PHD fingers 3 (DPF3) of the BAF SWI/SNF complex as assessed by massively parallel reporter assay, confirmatory luciferase assays, and eQTL analyses. Overexpression of DPF3 in renal cell lines increases growth rates and alters chromatin accessibility and gene expression, leading to inhibition of apoptosis and activation of oncogenic pathways. siRNA interference of multiple DPF3-deregulated genes reduces growth. Our results indicate that germline variation in DPF3, a component of the BAF complex, part of the SWI/SNF complexes, can lead to reduced apoptosis and activation of the STAT3 pathway, both critical in RCC carcinogenesis. In addition, we show that altered DPF3 expression in the 14q24 RCC locus could influence the effectiveness of immunotherapy treatment for RCC by regulating tumor cytokine secretion and immune cell activation.


Assuntos
Carcinoma de Células Renais/genética , Cromossomos Humanos Par 14 , Proteínas de Ligação a DNA/genética , Loci Gênicos , Neoplasias Renais/genética , Fator de Transcrição STAT3/genética , Fatores de Transcrição/genética , Carcinogênese/genética , Carcinogênese/imunologia , Carcinogênese/patologia , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/terapia , Linhagem Celular Tumoral , Cromatina/química , Cromatina/imunologia , Montagem e Desmontagem da Cromatina/imunologia , Citocinas/genética , Citocinas/imunologia , Proteínas de Ligação a DNA/imunologia , Regulação da Expressão Gênica , Predisposição Genética para Doença , Genoma Humano , Estudo de Associação Genômica Ampla , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imunoterapia/métodos , Neoplasias Renais/imunologia , Neoplasias Renais/patologia , Neoplasias Renais/terapia , Polimorfismo de Nucleotídeo Único , Fator de Transcrição STAT3/imunologia , Linfócitos T Citotóxicos , Fatores de Transcrição/imunologia
17.
Molecules ; 26(16)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34443423

RESUMO

Chronic liver inflammation has become a major global health concern. In the absence of clinical surrogate markers to diagnose inflammatory liver disease, the intervention with effective drugs in modern medicine tends to be late. In Sri Lanka, traditional medical practitioners prescribe herbal preparations from Osbeckia octandra for the prevention and treatment of liver disorders. To test the efficacy of such treatments, we have administered thioacetamide (TAA) to male Wistar rats to induce chronic liver damage (disease control; DC) and examined how various leaf extracts: crude leaf suspension (CLS), boiled leaf extract (BLE), sonicated leaf extract (SLE), methanol leaf extract (MLE) and hexane leaf extract (HLE) of O. octandra ameliorate TAA-induced liver disease. The CLS, BLE and SLE treatments in cirrhotic rats significantly attenuated disease-related changes, such as liver weight and hepato-enzymes. The mRNA levels of Tnf-α were significantly decreased by 3.6, 10 and 3.9 times in CLS, BLE and SLE compared to DC. The same treatments resulted in significantly lower (19.5, 4.2 and 2.4 times) α-Sma levels compared to DC. In addition, Tgf-ß1 and Vegf-R2 mRNA expressions were significantly lower with the treatments. Moreover, BLE expressed a strong anti-angiogenic effect. We conclude that CLS, BLE and SLE from O. octandra have potent hepatic anti-fibrotic effects in TAA-induced liver cirrhosis.


Assuntos
Cirrose Hepática Experimental/tratamento farmacológico , Melastomataceae/química , Neovascularização Patológica/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Folhas de Planta/química , Citocinas/genética , Citocinas/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Fígado/enzimologia , Fígado/patologia , Cirrose Hepática Experimental/sangue , Neovascularização Patológica/sangue , Tamanho do Órgão/efeitos dos fármacos , Extratos Vegetais/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Tioacetamida , Regulação para Cima/efeitos dos fármacos , Água , Perda de Peso/efeitos dos fármacos
18.
FASEB J ; 35(9): e21667, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34405442

RESUMO

Long noncoding RNAs (lncRNAs) are central regulators of the inflammatory response and play an important role in inflammatory diseases. PINT has been reported to be involved in embryonic development and tumorigenesis. However, the potential functions of PINT in the innate immune system are largely unknown. Here, we revealed the transcriptional regulation of inflammatory genes by PINT, whose expression is primarily dependent on the NF-κB signaling pathway in human and mouse macrophage and intestinal epithelial cell lines. Functionally, PINT selectively regulates the expression of TNF-α in basal and LPS-stimulated cells. Mechanistically, PINT acts as a modular scaffold of p65 and EZH2 to coordinate their localization and specify their binding to the target genes. Further, a high expression level of PINT was detected in intestinal mucosal tissues from patients with ulcerative colitis (UC). Together, these findings demonstrate that PINT acts as an activator of inflammatory responses, highlighting the importance of this lncRNA as a potential therapeutic target in infectious diseases and inflammatory diseases.


Assuntos
Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Regulação da Expressão Gênica , RNA Longo não Codificante/genética , Fator de Transcrição RelA/metabolismo , Transcrição Genética , Fator de Necrose Tumoral alfa/genética , Animais , Linhagem Celular , Colite Ulcerativa/genética , Colite Ulcerativa/patologia , Citocinas/genética , Humanos , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/patologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Regiões Promotoras Genéticas/genética , Ligação Proteica , Transcrição Genética/genética
19.
Molecules ; 26(15)2021 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-34361576

RESUMO

Prunus mahaleb L. fruit has long been used in the production of traditional liqueurs. The fruit also displayed scavenging and reducing activity, in vitro. The present study focused on unravelling peripheral and central protective effects, antimicrobial but also anti-COVID-19 properties exerted by the water extract of P. mahaleb. Anti-inflammatory effects were studied in isolated mouse colons exposed to lipopolysaccharide. Neuroprotection, measured as a blunting effect on hydrogen-peroxide-induced dopamine turnover, was investigated in hypothalamic HypoE22 cells. Antimicrobial effects were tested against different Gram+ and Gram- bacterial strains. Whereas anti-COVID-19 activity was studied in lung adenocarcinoma H1299 cells, where the gene expression of ACE2 and TMPRSS2 was measured after extract treatment. The bacteriostatic effects induced on Gram+ and Gram- strains, together with the inhibition of COX-2, TNFα, HIF1α, and VEGFA in the colon, suggest the potential of P. mahaleb water extract in contrasting the clinical symptoms related to ulcerative colitis. The inhibition of the hydrogen peroxide-induced DOPAC/DA ratio indicates promising neuroprotective effects. Finally, the downregulation of the gene expression of ACE2 and TMPRSS2 in H1299 cells, suggests the potential to inhibit SARS-CoV-2 virus entry in the human host. Overall, the results support the valorization of the local cultivation of P. mahaleb.


Assuntos
Bactérias/efeitos dos fármacos , Colo/efeitos dos fármacos , Neuroproteção , Extratos Vegetais/farmacologia , SARS-CoV-2/efeitos dos fármacos , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antivirais/química , Antivirais/farmacologia , COVID-19 , Linhagem Celular , Colite Ulcerativa/tratamento farmacológico , Citocinas/genética , Citocinas/metabolismo , Dopamina/metabolismo , Frutas/química , Regulação da Expressão Gênica/efeitos dos fármacos , Células HCT116 , Humanos , Inflamação/tratamento farmacológico , Masculino , Camundongos , Extratos Vegetais/química , Prunus/química , Serina Endopeptidases/metabolismo
20.
Nutrients ; 13(7)2021 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-34371878

RESUMO

Alzheimer's disease (AD) is characterized by the aberrant processing of amyloid precursor protein (APP) and the accumulation of hyperphosphorylated tau, both of which are accompanied by neuroinflammation. Dietary supplementation with spray-dried porcine plasma (SDP) has anti-inflammatory effects in inflammation models. We investigated whether dietary supplementation with SDP prevents the neuropathological features of AD. The experiments were performed in 2- and 6-month-old SAMP8 mice fed a control diet, or a diet supplemented with 8% SDP, for 4 months. AD brain molecular markers were determined by Western blot and real-time PCR. Senescent mice showed reduced levels of p-GSK3ß (Ser9) and an increase in p-CDK5, p-tau (Ser396), sAPPß, and the concentration of Aß40, (all p < 0.05). SDP prevented these effects of aging and reduced Bace1 levels (all p < 0.05). Senescence increased the expression of Mme1 and Ide1 and pro-inflammatory cytokines (Il-17 and Il-18; all p < 0.05); these changes were prevented by SDP supplementation. Moreover, SDP increased Tgf-ß expression (p < 0.05). Furthermore, in aged mice, the gene expression levels of the microglial activation markers Trem2, Ym1, and Arg1 were increased, and SDP prevented these increases (all p < 0.05). Thus, dietary SDP might delay AD onset by reducing its hallmarks in senescent mice.


Assuntos
Doença de Alzheimer/prevenção & controle , Encéfalo/efeitos dos fármacos , Suplementos Nutricionais , Plasma , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Ração Animal , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Quinase 5 Dependente de Ciclina/metabolismo , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica , Glicogênio Sintase Quinase 3 beta/metabolismo , Mediadores da Inflamação/metabolismo , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Emaranhados Neurofibrilares/efeitos dos fármacos , Emaranhados Neurofibrilares/metabolismo , Emaranhados Neurofibrilares/patologia , Fragmentos de Peptídeos/metabolismo , Fosforilação , Transdução de Sinais , Secagem por Atomização , Sus scrofa , Proteínas tau/metabolismo
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