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1.
Medicine (Baltimore) ; 99(40): e22152, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33019392

RESUMO

BACKGROUND: Gestational diabetes mellitus (GDM) produces numerous problems for maternal and fetal outcomes. However, the precise molecular mechanisms of GDM are not clear. METHODS: In our study, we randomly assigned 22 pregnant women with fasting glucose concentrations, 1 hour oral glucose tolerance test (1H-OGTT) and 2 hour oral glucose tolerance test (2H-OGTT), different than 28 normal pregnant women from a sample of 107 pregnant women at the First Affiliated Hospital of Jinan University in China. Lipopolysaccharide (LPS), interleukin 1 alpha (IL-1α), interleukin-6 (IL-6), interleukin-8 (IL-8) and tumor necrosis factor alpha (TNF-α) were measured from blood plasma of pregnant women and umbilical arteries using ultraviolet spectrophotometry. Hematoxylin & Eosin (H&E), Periodic acid-Schiff (PAS) or Masson staining were performed to examine whether diabetes mellitus altered the morphology of placenta. Quantitative PCR (Q-PCR), western blotting and immunofluorescent staining were performed to examine whether diabetes mellitus and autophagy altered the gene expressions of the placental tissue. RESULTS: We found that women with GDM exhibited increased placental weight and risk of neonatal infection. The concentrations of IL-6 protein and IL-8 protein in GDM were increased in both maternal and umbilical arterial blood. H&E, Masson and PAS staining results showed an increased number of placental villi and glycogen deposition in patients with GDM, but no placental sclerosis was found. Q-PCR results suggested that the expression levels of HIF-1α and the toll like receptor 4 (TLR4)/ myeloid differential protein-88 (MyD88)/ nuclear factor kappa-B (NF-κB) pathway were increased in the GDM placenta. Through Western Blotting, we found that the expression of NF-kappa-B inhibitor alpha (IKBα) and Nuclear factor-κB p65 (NF-κB p65) in GDM placenta was significantly enhanced. We also showed that the key autophagy-related genes, autophagy-related 7 (ATG7) and microtubule-associated protein 1A/1B-light chain 3 (LC3), were increased in GDM compared with normal pregnant women. CONCLUSIONS: Our results suggest that women with GDM exhibit an increased risk of neonatal infection via inflammation and autophagy in the placenta.


Assuntos
Diabetes Gestacional/sangue , Placenta/patologia , Adulto , Diabetes Gestacional/genética , Feminino , Sangue Fetal , Teste de Tolerância a Glucose , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/sangue , Recém-Nascido , Inflamação/sangue , Inflamação/genética , Placenta/microbiologia , Gravidez , Resultado da Gravidez , Receptor 4 Toll-Like/sangue
2.
Adv Exp Med Biol ; 1255: 63-72, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32949390

RESUMO

This chapter overviews roles of DNA methylation in inflammatory cell biology with the focuses on lymphocytes and macrophages/monocytes in lung diseases, although the molecular mechanisms by which target genes are methylated and regulated in lung diseases remain unclear. Most of epigenetic studies on DNA methylation of target genes in lung diseases mainly demonstrated the correlation of DNA methylation of target genes with the levels of other corresponding factors, with the specificity of clinical phenomes, and with the severity of lung diseases. There is an urgent need to identify and validate the specificity and regulatory mechanisms of inflammatory cell epigenetics in depth. The epigenetic heterogeneity among different subsets of T cells and among promoters or non-promoters of target genes should be furthermore clarified in acute or chronic lung diseases and cancers. The hyper/hypo-methylation and modifications of chromosol and extrachromosomal DNA may result in alternations in proteins within inflammatory cells, which can be identified as disease-specific biomarkers and therapeutic targets.


Assuntos
Metilação de DNA , Inflamação/genética , Pneumopatias/genética , Pneumopatias/patologia , Epigênese Genética , Epigenômica , Humanos
3.
Nat Commun ; 11(1): 4678, 2020 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-32938916

RESUMO

Diabetic foot ulcers (DFUs) are a life-threatening disease that often result in lower limb amputations and a shortened lifespan. However, molecular mechanisms contributing to the pathogenesis of DFUs remain poorly understood. We use next-generation sequencing to generate a human dataset of pathogenic DFUs to compare to transcriptional profiles of human skin and oral acute wounds, oral as a model of "ideal" adult tissue repair due to accelerated closure without scarring. Here we identify major transcriptional networks deregulated in DFUs that result in decreased neutrophils and macrophages recruitment and overall poorly controlled inflammatory response. Transcription factors FOXM1 and STAT3, which function to activate and promote survival of immune cells, are inhibited in DFUs. Moreover, inhibition of FOXM1 in diabetic mouse models (STZ-induced and db/db) results in delayed wound healing and decreased neutrophil and macrophage recruitment in diabetic wounds in vivo. Our data underscore the role of a perturbed, ineffective inflammatory response as a major contributor to the pathogenesis of DFUs, which is facilitated by FOXM1-mediated deregulation of recruitment of neutrophils and macrophages, revealing a potential therapeutic strategy.


Assuntos
Pé Diabético/genética , Pé Diabético/imunologia , Proteína Forkhead Box M1/imunologia , Cicatrização/imunologia , Adulto , Idoso , Animais , Proliferação de Células , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/imunologia , Pé Diabético/patologia , Modelos Animais de Doenças , Feminino , Proteína Forkhead Box M1/antagonistas & inibidores , Proteína Forkhead Box M1/metabolismo , Humanos , Inflamação/genética , Inflamação/imunologia , Masculino , Camundongos Endogâmicos , Pessoa de Meia-Idade , Mucosa Bucal/fisiologia , Piridinas/farmacologia , Tiofenos/farmacologia , Transcriptoma/fisiologia , Cicatrização/genética
4.
Environ Health Prev Med ; 25(1): 53, 2020 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-32917140

RESUMO

BACKGROUND: Pilea umbrosa (Urticaceae) is used by local communities (district Abbotabad) for liver disorders, as anticancer, in rheumatism and in skin disorders. METHODS: Methanol extract of P. umbrosa (PUM) was investigated for the presence of polyphenolic constituents by HPLC-DAD analysis. PUM (150 mg/kg and 300 mg/kg) was administered on alternate days for eight weeks in rats exposed with carbon tetrachloride (CCl4). Serum analysis was performed for liver function tests while in liver tissues level of antioxidant enzymes and biochemical markers were also studied. In addition, semi quantitative estimation of antioxidant genes, endoplasmic reticulum (ER) induced stress markers, pro-inflammatory cytokines and fibrosis related genes were carried out on liver tissues by RT-PCR analysis. Liver tissues were also studied for histopathological injuries. RESULTS: Level of antioxidant enzymes such as catalase (CAT), superoxide dismutase (SOD), peroxidase (POD) and glutathione (GSH) decreased (p < 0.05) whereas level of thiobarbituric acid reactive substance (TBARS), H2O2 and nitrite increased in liver tissues of CCl4 treated rat. Likewise increase in the level of serum markers; alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP) and total bilirubin was observed. Moreover, CCl4 caused many fold increase in expression of ER stress markers; glucose regulated protein (GRP-78), x-box binding protein1-total (XBP-1 t), x-box binding protein1-unspliced (XBP-1 u) and x-box binding protein1-spliced (XBP-1 s). The level of inflammatory mediators such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) was aggregated whereas suppressed the level of antioxidant enzymes; γ-glutamylcysteine ligase (GCLC), protein disulfide isomerase (PDI) and nuclear erythroid 2 p45-related factor 2 (Nrf-2). Additionally, level of fibrosis markers; transforming growth factor-ß (TGF-ß), Smad-3 and collagen type 1 (Col1-α) increased with CCl4 induced liver toxicity. Histopathological scrutiny depicted damaged liver cells, neutrophils infiltration and dilated sinusoids in CCl4 intoxicated rats. PUM was enriched with rutin, catechin, caffeic acid and apigenin as evidenced by HPLC analysis. Simultaneous administration of PUM and CCl4 in rats retrieved the normal expression of these markers and prevented hepatic injuries. CONCLUSION: Collectively these results suggest that PUM constituted of strong antioxidant chemicals and could be a potential therapeutic agent for stress related liver disorders.


Assuntos
Tetracloreto de Carbono/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Fibrose/tratamento farmacológico , Inflamação/tratamento farmacológico , Substâncias Protetoras/farmacologia , Urticaceae/química , Animais , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Fibrose/genética , Inflamação/genética , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley
5.
Pestic Biochem Physiol ; 170: 104680, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32980059

RESUMO

The progression of neurodegenerative disease is very complex biological process and the molecular crosstalk of inflammatory cytokines during neurodegeneration is associated with multiple cascade signalling. Few evidences suggest that environmental toxin, Paraquat (PQ) administration activates the microglia and intensify the release of proinflamatory cytokines during progression of Parkinson''s disease (PD) but the proper aetiology remained unknown. However, the fundamental role of anti-inflammatory molecule Decapentaplegic (Dpp), homologue of the secreted mammalian Transforming growth factor-ß (TGF-ß) signalling molecule during neurodegeneration of invertebrate fly model is yet to establish. To elucidate the molecular processes during early stage of Parkinson's disease, we observed neuro-toxin plays a determining role in the increased vulnerability to a particular PQ exposure that is attended by decreased lifespan, severe locomotor deficits, and more loss of dopaminergic (DA) neuron in PQ-treated Dpp deficient fly than wild type (WT). Simultaneously, activated microglia induced the inflammatory response with the release of pro-inflammatory and anti-inflammatory cytokine in Drosophila during neurodegeneration. Moreover, neuro-toxin exposure altered the expression of innate immune genes in both WT and mutant fly compared to the respective PQ-treated flies. Interestingly, PQ exposure reduced the expression of innate immune genes in mutant fly compared to WT. It may indicate that PQ exposure had broken down the immune defence response in mutant fly than WT whereas, without PQ exposure the innate immune tolerance level was higher in fly with reduced Dpp expression than WT. Thus, we observed the conserve anti-inflammatory factor TGF-ß may exhibit a crucial defensive role during inflammation mediated neurodegeneration in invertebrate Drosophila melanogaster.


Assuntos
Proteínas de Drosophila/genética , Doenças Neurodegenerativas/induzido quimicamente , Doenças Neurodegenerativas/genética , Animais , Modelos Animais de Doenças , Drosophila , Drosophila melanogaster/genética , Imunidade Inata/genética , Inflamação/induzido quimicamente , Inflamação/genética , Neuroglia , Paraquat/toxicidade
6.
Nat Commun ; 11(1): 4111, 2020 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-32807776

RESUMO

Mutational inactivation of VHL is the earliest genetic event in the majority of clear cell renal cell carcinomas (ccRCC), leading to accumulation of the HIF-1α and HIF-2α transcription factors. While correlative studies of human ccRCC and functional studies using human ccRCC cell lines have implicated HIF-1α as an inhibitor and HIF-2α as a promoter of aggressive tumour behaviours, their roles in tumour onset have not been functionally addressed. Herein we show using an autochthonous ccRCC model that Hif1a is essential for tumour formation whereas Hif2a deletion has only minor effects on tumour initiation and growth. Both HIF-1α and HIF-2α are required for the clear cell phenotype. Transcriptomic and proteomic analyses reveal that HIF-1α regulates glycolysis while HIF-2α regulates genes associated with lipoprotein metabolism, ribosome biogenesis and E2F and MYC transcriptional activities. HIF-2α-deficient tumours are characterised by increased antigen presentation, interferon signalling and CD8+ T cell infiltration and activation. Single copy loss of HIF1A or high levels of HIF2A mRNA expression correlate with altered immune microenvironments in human ccRCC. These studies reveal an oncogenic role of HIF-1α in ccRCC initiation and suggest that alterations in the balance of HIF-1α and HIF-2α activities can affect different aspects of ccRCC biology and disease aggressiveness.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Células 3T3 , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Western Blotting , Linfócitos T CD8-Positivos/metabolismo , Carcinoma de Células Renais/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Proliferação de Células/fisiologia , Regulação Neoplásica da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/fisiologia , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Imuno-Histoquímica , Inflamação/genética , Inflamação/metabolismo , Neoplasias Renais/genética , Espectrometria de Massas , Camundongos , Proteômica/métodos , Reação em Cadeia da Polimerase em Tempo Real , Análise de Sequência de RNA , Microambiente Tumoral/genética , Microambiente Tumoral/fisiologia
7.
Nat Commun ; 11(1): 3816, 2020 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-32732870

RESUMO

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


Assuntos
Interleucina-1beta/metabolismo , Macrófagos/metabolismo , Fator de Transcrição STAT3/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Linhagem Celular , Células Cultivadas , Expressão Gênica , Glicólise/efeitos dos fármacos , Inflamação/genética , Inflamação/metabolismo , Interleucina-1beta/genética , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Fosforilação , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Fator de Transcrição STAT3/genética , Serina/genética , Serina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Fator 6 Associado a Receptor de TNF/genética , Fator 6 Associado a Receptor de TNF/metabolismo , Receptor 4 Toll-Like/genética
8.
Nature ; 584(7820): 286-290, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32760002

RESUMO

The histone deacetylases (HDACs) are a superfamily of chromatin-modifying enzymes that silence transcription through the modification of histones. Among them, HDAC3 is unique in that interaction with nuclear receptor corepressors 1 and 2 (NCoR1/2) is required to engage its catalytic activity1-3. However, global loss of HDAC3 also results in the repression of transcription, the mechanism of which is currently unclear4-8. Here we report that, during the activation of macrophages by lipopolysaccharides, HDAC3 is recruited to activating transcription factor 2 (ATF2)-bound sites without NCoR1/2 and activates the expression of inflammatory genes through a non-canonical mechanism. By contrast, the deacetylase activity of HDAC3 is selectively engaged at ATF3-bound sites that suppress Toll-like receptor signalling. Loss of HDAC3 in macrophages safeguards mice from lethal exposure to lipopolysaccharides, but this protection is not conferred upon genetic or pharmacological abolition of the catalytic activity of HDAC3. Our findings show that HDAC3 is a dichotomous transcriptional activator and repressor, with a non-canonical deacetylase-independent function that is vital for the innate immune system.


Assuntos
Histona Desacetilases/metabolismo , Inflamação/genética , Inflamação/metabolismo , Fator 2 Ativador da Transcrição/metabolismo , Fator 3 Ativador da Transcrição/metabolismo , Animais , Biocatálise , Regulação da Expressão Gênica/efeitos dos fármacos , Imunidade Inata/efeitos dos fármacos , Imunidade Inata/genética , Lipopolissacarídeos/imunologia , Lipopolissacarídeos/farmacologia , Macrófagos/imunologia , Masculino , Camundongos , Correpressor 1 de Receptor Nuclear , Correpressor 2 de Receptor Nuclear , Proteínas Repressoras/metabolismo , Transcrição Genética/efeitos dos fármacos
9.
Life Sci ; 258: 118176, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32771556

RESUMO

AIMS: We investigated the anti-inflammatory activity of 3ß-hydroxycholest-5-en-7-one from Hippocampus trimaculatus leach and provided a theoretical basis for identifying its therapeutic targets. MAIN METHODS: Small-RNA libraries were constructed for untreated control RAW 264.7 cells and cells treated with lipopolysaccharide (LPS; 1.0 µg/mL) or 10 µM 3ß-hydroxycholest-5-en-7-one +1.0 µg/mL LPS. We constructed and tested a miR-98-5p-interfering lentivirus to evaluate the role of miR-98-5p in the 3ß-hydroxycholest-5-en-7-one-dependent regulation of inflammatory responses in LPS-induced macrophage and murine inflammation models. The small-RNA libraries were analyzed using high-throughput sequencing. KEY FINDINGS: Among the differentially expressed microRNAs, miR-98-5p showed the most significant difference. Bioinformatics tools were used to identify the potential regulatory targets of miR-98-5p, which were tested using dual-luciferase reporter assays. Our results demonstrated that 3ß-hydroxycholest-5-en-7-one exerted an anti-inflammatory effect via miR-98-5p, which negatively regulated the expression of its target gene TNFAIP3. The results indicate that miR-98-5p interference and 3ß-hydroxycholest-5-en-7-one treatment significantly upregulated the low TNFAIP3 expression induced by LPS stimulation, thereby inhibiting TRAF6, RIP, NF-κB, IL-1ß, and TNF-α secretion. SIGNIFICANCE: 3ß-Hydroxycholest-5-en-7-one alleviates inflammation by downregulating miR-98-5p and upregulating TNFAIP3, thereby blocking NF-κB pathway activation. These results reveal the specific anti-inflammatory mechanism of 3ß-hydroxycholest-5-en-7-one, providing a foundation for developing new drugs and identifying drug targets.


Assuntos
Colestenonas/farmacologia , Regulação para Baixo/genética , Inflamação/patologia , MicroRNAs/metabolismo , Smegmamorpha/metabolismo , Regiões 3' não Traduzidas/genética , Animais , Colestenonas/química , Regulação para Baixo/efeitos dos fármacos , Genes Reporter , Inflamação/genética , Lentivirus/metabolismo , Lipopolissacarídeos , Luciferases/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , MicroRNAs/genética , Células RAW 264.7 , Reprodutibilidade dos Testes
10.
J Toxicol Sci ; 45(8): 435-447, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32741896

RESUMO

The imbalance of testosterone to estradiol ratio has been related to the development of prostate diseases. Although rat models of prostate diseases induced by endocrine-disrupting chemicals (EDCs) and/or hormone exposure are commonly used to analyze gene expression profiles in the prostate, most studies utilize a single endpoint. In this study, microarray analysis was used for gene expression profiling in rat prostate tissue after exposure to EDCs and sex hormones over multiple time points (prepubertal through adulthood). We used dorsolateral prostate tissues from Sprague-Dawley rats (male offspring) and postnatally administered estradiol benzoate (EB) on postnatal days (PNDs) 1, 3, and 5, followed by treatment with additional hormones [estradiol (E) and testosterone (T)] on PNDs 90-200, as described by Ho et al. Microarray analysis was performed for gene expression profiling in the dorsolateral prostate, and the results were validated via qRT-PCR. The genes in cytokine-cytokine receptor interaction, cell adhesion molecules, and chemokines were upregulated in the EB+T+E group on PNDs 145 and 200. Moreover, early-stage downregulation of anti-inflammatory gene: bone morphogenetic protein 7 gene was observed. These findings suggest that exposure to EB, T, and E activates multiple pathways and simultaneously downregulates anti-inflammatory genes. Interestingly, these genes are reportedly expressed in prostate cancer tissues/cell lines. Further studies are required to elucidate the mechanism, including analyses using human prostate tissues.


Assuntos
Disruptores Endócrinos/toxicidade , Estradiol/análogos & derivados , Estradiol/toxicidade , Perfilação da Expressão Gênica/métodos , Expressão Gênica , Próstata/metabolismo , Puberdade , Testosterona/toxicidade , Transcriptoma , Fatores Etários , Animais , Proteína Morfogenética Óssea 7/genética , Proteína Morfogenética Óssea 7/metabolismo , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Quimiocinas/genética , Quimiocinas/metabolismo , Disruptores Endócrinos/efeitos adversos , Estradiol/efeitos adversos , Inflamação/genética , Masculino , Análise em Microsséries , Ratos Sprague-Dawley , Receptores de Citocinas/genética , Receptores de Citocinas/metabolismo , Testosterona/efeitos adversos
11.
Nature ; 585(7823): 96-101, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32814898

RESUMO

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders that overlap in their clinical presentation, pathology and genetic origin. Autoimmune disorders are also overrepresented in both ALS and FTD, but this remains an unexplained epidemiologic observation1-3. Expansions of a hexanucleotide repeat (GGGGCC) in the C9orf72 gene are the most common cause of familial ALS and FTD (C9-ALS/FTD), and lead to both repeat-containing RNA and dipeptide accumulation, coupled with decreased C9orf72 protein expression in brain and peripheral blood cells4-6. Here we show in mice that loss of C9orf72 from myeloid cells alone is sufficient to recapitulate the age-dependent lymphoid hypertrophy and autoinflammation seen in animals with a complete knockout of C9orf72. Dendritic cells isolated from C9orf72-/- mice show marked early activation of the type I interferon response, and C9orf72-/- myeloid cells are selectively hyperresponsive to activators of the stimulator of interferon genes (STING) protein-a key regulator of the innate immune response to cytosolic DNA. Degradation of STING through the autolysosomal pathway is diminished in C9orf72-/- myeloid cells, and blocking STING suppresses hyperactive type I interferon responses in C9orf72-/- immune cells as well as splenomegaly and inflammation in C9orf72-/- mice. Moreover, mice lacking one or both copies of C9orf72 are more susceptible to experimental autoimmune encephalitis, mirroring the susceptibility to autoimmune diseases seen in people with C9-ALS/FTD. Finally, blood-derived macrophages, whole blood and brain tissue from patients with C9-ALS/FTD all show an elevated type I interferon signature compared with samples from people with sporadic ALS/FTD; this increased interferon response can be suppressed with a STING inhibitor. Collectively, our results suggest that patients with C9-ALS/FTD have an altered immunophenotype because their reduced levels of C9orf72 cannot suppress the inflammation mediated by the induction of type I interferons by STING.


Assuntos
Proteína C9orf72/genética , Proteína C9orf72/metabolismo , Inflamação/metabolismo , Inflamação/prevenção & controle , Proteínas de Membrana/metabolismo , Células Mieloides/metabolismo , Envelhecimento/imunologia , Esclerose Amiotrófica Lateral/genética , Animais , Proteína C9orf72/deficiência , Células Dendríticas/citologia , Células Dendríticas/imunologia , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/imunologia , Feminino , Humanos , Inflamação/genética , Inflamação/imunologia , Interferon Tipo I/biossíntese , Interferon Tipo I/imunologia , Proteínas de Membrana/antagonistas & inibidores , Camundongos , Células Mieloides/imunologia , Neoplasias/imunologia , Linfócitos T/citologia , Linfócitos T/imunologia
12.
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
13.
Protein Cell ; 11(10): 740-770, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32780218

RESUMO

Age-associated changes in immune cells have been linked to an increased risk for infection. However, a global and detailed characterization of the changes that human circulating immune cells undergo with age is lacking. Here, we combined scRNA-seq, mass cytometry and scATAC-seq to compare immune cell types in peripheral blood collected from young and old subjects and patients with COVID-19. We found that the immune cell landscape was reprogrammed with age and was characterized by T cell polarization from naive and memory cells to effector, cytotoxic, exhausted and regulatory cells, along with increased late natural killer cells, age-associated B cells, inflammatory monocytes and age-associated dendritic cells. In addition, the expression of genes, which were implicated in coronavirus susceptibility, was upregulated in a cell subtype-specific manner with age. Notably, COVID-19 promoted age-induced immune cell polarization and gene expression related to inflammation and cellular senescence. Therefore, these findings suggest that a dysregulated immune system and increased gene expression associated with SARS-CoV-2 susceptibility may at least partially account for COVID-19 vulnerability in the elderly.


Assuntos
Envelhecimento/imunologia , Betacoronavirus , Infecções por Coronavirus/imunologia , Sistema Imunitário/imunologia , Pandemias , Pneumonia Viral/imunologia , Análise de Célula Única , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/genética , Linfócitos T CD4-Positivos/metabolismo , Linhagem da Célula , Montagem e Desmontagem da Cromatina , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/imunologia , Citocinas/biossíntese , Citocinas/genética , Suscetibilidade a Doenças , Citometria de Fluxo/métodos , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Rearranjo Gênico , Humanos , Sistema Imunitário/citologia , Sistema Imunitário/crescimento & desenvolvimento , Imunocompetência/genética , Inflamação/genética , Inflamação/imunologia , Espectrometria de Massas/métodos , Pessoa de Meia-Idade , Análise de Sequência de RNA , Transcriptoma , Adulto Jovem
14.
Am J Hum Genet ; 107(3): 527-538, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32758447

RESUMO

Generalized pustular psoriasis (GPP) is a severe multi-systemic inflammatory disease characterized by neutrophilic pustulosis and triggered by pro-inflammatory IL-36 cytokines in skin. While 19%-41% of affected individuals harbor bi-allelic mutations in IL36RN, the genetic cause is not known in most cases. To identify and characterize new pathways involved in the pathogenesis of GPP, we performed whole-exome sequencing in 31 individuals with GPP and demonstrated effects of mutations in MPO encoding the neutrophilic enzyme myeloperoxidase (MPO). We discovered eight MPO mutations resulting in MPO -deficiency in neutrophils and monocytes. MPO mutations, primarily those resulting in complete MPO deficiency, cumulatively associated with GPP (p = 1.85E-08; OR = 6.47). The number of mutant MPO alleles significantly differed between 82 affected individuals and >4,900 control subjects (p = 1.04E-09); this effect was stronger when including IL36RN mutations (1.48E-13) and correlated with a younger age of onset (p = 0.0018). The activity of four proteases, previously implicated as activating enzymes of IL-36 precursors, correlated with MPO deficiency. Phorbol-myristate-acetate-induced formation of neutrophil extracellular traps (NETs) was reduced in affected cells (p = 0.015), and phagocytosis assays in MPO-deficient mice and human cells revealed altered neutrophil function and impaired clearance of neutrophils by monocytes (efferocytosis) allowing prolonged neutrophil persistence in inflammatory skin. MPO mutations contribute significantly to GPP's pathogenesis. We implicate MPO as an inflammatory modulator in humans that regulates protease activity and NET formation and modifies efferocytosis. Our findings indicate possible implications for the application of MPO inhibitors in cardiovascular diseases. MPO and affected pathways represent attractive targets for inducing resolution of inflammation in neutrophil-mediated skin diseases.


Assuntos
Inflamação/genética , Interleucinas/genética , Peroxidase/genética , Psoríase/genética , Dermatopatias/genética , Adulto , Animais , Citocinas/genética , Armadilhas Extracelulares/genética , Feminino , Humanos , Inflamação/patologia , Interleucina-1/genética , Interleucinas/metabolismo , Masculino , Camundongos , Mutação/genética , Neutrófilos/metabolismo , Psoríase/patologia , Doenças Raras/enzimologia , Doenças Raras/genética , Doenças Raras/patologia , Pele/enzimologia , Pele/patologia , Dermatopatias/patologia
15.
Clin Exp Hypertens ; 42(8): 743-747, 2020 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-32631160

RESUMO

AIMS: Circulating miR-29b and inflammatory process play a vital role in hypertension and hypertensive nephropathy. The aim of the present study was to investigate the association of circulating miR-29b and inflammatory markers with albuminuria and assess the predictive value of circulating miR-29b for albuminuria in essential hypertension. METHODS: This cross-sectional study was continuously enrolled 150 subjects and were divided into three groups based on random urinary albumin/creatinine ratio (UACR, mg/g), the patients with ACR<30 mg/g were classified as normal albuminuria, the values of 30< ACR<300 was defined as micro-albuminuria while the group with ACR over 300 mg/g are macro-albuminuria. Circulating miR-29b was assessed by quantitative real-time polymerase chain reaction (qRT-PCR). Multivariate logistic regression and area under the ROC curve (AUC) were used. RESULTS: We found miR-29b, C-reactive protein, and transforming growth factor-ß1 (TGF-ß1) in macro-albuminuria group were significantly higher than those in the micro-albuminuria and normal albuminuria group. The level of miR-29b was positively associated with TGF-ß1, C-reactive protein, and UACR, while negatively related to glomerular filtration rate. Circulating miR-29b was a significant independent determinant factor for albuminuria. CONCLUSION: Our results provided a clinical evidence of a positive association between circulating miR-29b, inflammatory markers, and UACR, and implied miR-29b was a significant independent determinant factor for albuminuria.


Assuntos
Albuminúria/complicações , Hipertensão Essencial/complicações , Inflamação/genética , MicroRNAs/genética , Idoso , Área Sob a Curva , Biomarcadores/sangue , Proteína C-Reativa/análise , Estudos Transversais , Feminino , Humanos , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo Real , Fator de Crescimento Transformador beta1/sangue
16.
PLoS One ; 15(6): e0234566, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32603365

RESUMO

Hashimoto's thyroiditis (HT) is present in the background of around 30% of papillary thyroid carcinomas (PTCs). The genetic predisposition effect of this autoimmune condition is not thoroughly understood. We analyzed the microarray expression profiles of 13 HT, eight PTCs with (w/) coexisting HT, six PTCs without (w/o) coexisting HT, six micro PTCs (mPTCs), and three normal thyroid (TN) samples. Based on a false discovery rate (FDR)-adjusted p-value ≤ 0.05 and a fold change (FC) > 2, four comparison groups were defined, which were HT vs. TN; PTC w/ HT vs. TN; PTC w/o HT vs. TN; and mPTC vs. TN. A Venn diagram displayed 15 different intersecting and non-intersecting differentially expressed gene (DEG) sets, of which a set of 71 DEGs, shared between the two comparison groups HT vs. TN ∩ PTC w/ HT vs. TN, harbored the relatively largest number of genes related to immune and inflammatory functions; oxidative stress and reactive oxygen species (ROS); DNA damage and DNA repair; cell cycle; and apoptosis. The majority of the 71 DEGs were upregulated and the most upregulated DEGs included a number of immunoglobulin kappa variable genes, and other immune-related genes, e.g., CD86 molecule (CD86), interleukin 2 receptor gamma (IL2RG), and interferon, alpha-inducible protein 6 (IFI6). Upregulated genes preferentially associated with other gene ontologies (GO) were, e.g., STAT1, MMP9, TOP2A, and BRCA2. Biofunctional analysis revealed pathways related to immunogenic functions. Further data analysis focused on the set of non-intersecting 358 DEGs derived from the comparison group of HT vs. TN, and on the set of 950 DEGs from the intersection of all four comparison groups. In conclusion, this study indicates that, besides immune/inflammation-related genes, also genes associated with oxidative stress, ROS, DNA damage, DNA repair, cell cycle, and apoptosis are comparably more deregulated in a data set shared between HT and PTC w/ HT. These findings are compatible with the conception of a genetic sequence where chronic inflammatory response is accompanied by deregulation of genes and biofunctions associated with oncogenic transformation. The generated data set may serve as a source for identifying candidate genes and biomarkers that are practical for clinical application.


Assuntos
Perfilação da Expressão Gênica , Doença de Hashimoto/genética , Câncer Papilífero da Tireoide/genética , Neoplasias da Glândula Tireoide/genética , Adolescente , Adulto , Idoso , Transformação Celular Neoplásica/genética , Feminino , Predisposição Genética para Doença , Doença de Hashimoto/complicações , Humanos , Inflamação/genética , Masculino , Pessoa de Meia-Idade , Câncer Papilífero da Tireoide/complicações , Neoplasias da Glândula Tireoide/complicações , Regulação para Cima
17.
Vet Clin North Am Equine Pract ; 36(2): 273-288, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32654783

RESUMO

Host defenses against infection by viruses, bacteria, fungi, and parasites are critical to survival. It has been estimated that upwards of 7% of the coding genes of mammals function in immunity and inflammation. This high level of genomic investment in defense has resulted in an immune system characterized by extraordinary complexity and many levels of redundancy. Because so many genes are involved with immunity, there are many opportunities for mutations to arise that have negative effects. However, redundancy in the mammalian defense system and the adaptive nature of key immune mechanisms buffer the untoward outcomes of many such deleterious mutations.


Assuntos
Doenças dos Cavalos/genética , Doenças dos Cavalos/imunologia , Doenças do Sistema Imunitário/veterinária , Animais , Cavalos , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/imunologia , Inflamação/genética , Inflamação/imunologia , Inflamação/veterinária
18.
Vet Clin North Am Equine Pract ; 36(2): 379-394, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32654786

RESUMO

Laminitis is a devastating disease with diverse etiologies and few, if any, effective treatments. Gene expression and hypothesis-generating genomic studies have provided a fresh look at the key molecular players at crucial timepoints in diverse experimental and naturally affected tissues. We summarize findings to date, and propose a unifying model of the laminitis disease process that includes several pathogenesis concepts shared with other diseases of epidermal and epithelial tissues. The value of these new pathways as potential therapeutic targets is exciting but will require careful future work to validate new methods and launch systematic clinical trials.


Assuntos
Doenças do Pé/veterinária , Doenças dos Cavalos/genética , Doenças dos Cavalos/metabolismo , Animais , Doenças do Pé/genética , Doenças do Pé/metabolismo , Doenças do Pé/patologia , Casco e Garras/metabolismo , Casco e Garras/patologia , Doenças dos Cavalos/patologia , Cavalos , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Inflamação/veterinária , Transdução de Sinais
19.
PLoS One ; 15(7): e0236044, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32649683

RESUMO

In the experiment the influence of inflammation on neuropeptide Y (NPY) receptor subtype 1 (Y1Rs) and 2 (Y2Rs) expression pattern in the gilt myometrium and NPY effect alone or with Y1Rs and Y2Rs antagonists on contractility of an inflamed uterus were recognized. On Day 3 of the estrous cycle, either E.coli suspension (E.coli group) or saline (SAL group) were administered into uterine horns. In the control gilts (CON group), only laparotomy was carried out. Eight days later, E.coli treatment evoked severe acute endometritis, significantly reduced Y1Rs mRNA and protein expression and increased Y2Rs protein expression in myometrium in relation to the CON and SAL groups. Compared to period before NPY application, NPY (10-7 M) significantly reduced amplitude in myometrium and endometrium/myometrium and frequency in myometrium of the CON and SAL groups and amplitude in endometrium/myometrium and frequency in strips of the E.coli group. In this group, after using NPY (10-7 M), the amplitude rose significantly in both kinds of strips, while frequency fell in endometrium/myometrium in relation to the SAL group. In the CON and SAL groups, NPY (10-7 M) with Y1Rs antagonist significantly increased the amplitude in endometrium/myometrium, while with Y2Rs antagonist caused a rise in myometrium. In the E.coli group after using Y1Rs or Y2Rs antagonist and NPY (10-7 M) amplitude did not significantly change in endometrium/myometrium, and this parameter was significantly lower after using the NPY and Y1Rs antagonist than in other groups. Y1Rs antagonist and NPY (10-8, 10-7 M) significantly increased frequency in endometrium/myometrium of the CON and SAL groups. In the E.coli group, Y1Rs or Y2Rs antagonists and NPY (10-7 M) significantly increased frequency in myometrium and it was significantly higher than in the CON group. Inflammation changes Y1Rs and Y2Rs expression in myometrium of the inflamed pig uterus and NPY reduces this organ contractility by Y1Rs and Y2Rs.


Assuntos
Miométrio/metabolismo , Receptores de Neuropeptídeo Y/metabolismo , Contração Uterina , Animais , Feminino , Inflamação/genética , Inflamação/metabolismo , Miométrio/fisiologia , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Receptores de Neuropeptídeo Y/genética , Suínos
20.
Nat Commun ; 11(1): 3730, 2020 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-32709840

RESUMO

Long-term follow up studies from Ebola virus disease (EVD) survivors (EBOV_S) are lacking. Here, we evaluate immune and gene expression profiles in 35 Guinean EBOV_S from the last West African outbreak, a median of 23 months (IQR [18-25]) after discharge from treatment center. Compared with healthy donors, EBOV_S exhibit increases of blood markers of inflammation, intestinal tissue damage, T cell and B cell activation and a depletion of circulating dendritic cells. All survivors have EBOV-specific IgG antibodies and robust and polyfunctional EBOV-specific memory T-cell responses. Deep sequencing of the genes expressed in blood reveals an enrichment in 'inflammation' and 'antiviral' pathways. Integrated analyses identify specific immune markers associated with the persistence of clinical symptoms. This study identifies a set of biological and genetic markers that could be used to define a signature of "chronic Ebola virus disease (CEVD)".


Assuntos
Ebolavirus/imunologia , Doença pelo Vírus Ebola/complicações , Doença pelo Vírus Ebola/imunologia , Doenças do Sistema Imunitário/complicações , Doenças do Sistema Imunitário/imunologia , Adulto , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Antivirais/farmacologia , Linfócitos B/imunologia , Citocinas/sangue , Ebolavirus/efeitos dos fármacos , Ebolavirus/genética , Feminino , Marcadores Genéticos , Doença pelo Vírus Ebola/tratamento farmacológico , Doença pelo Vírus Ebola/virologia , Humanos , Doenças do Sistema Imunitário/genética , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Inflamação/genética , Ativação Linfocitária , Masculino , Sobreviventes , Linfócitos T/imunologia , Transcriptoma , Adulto Jovem
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