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1.
Gut ; 71(1): 43-54, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-33452178

RESUMO

OBJECTIVE: Nucleotides are danger signals that activate inflammatory responses via binding P2 receptors. The nucleoside triphosphate diphosphohydrolase-8 (NTPDase8) is an ectonucleotidase that hydrolyses P2 receptor ligands. We investigated the role of NTPDase8 in intestinal inflammation. DESIGN: We generated NTPDase8-deficient (Entpd8 -/-) mice to define the role of NTPDase8 in the dextran sodium sulfate (DSS) colitis model. To assess inflammation, colons were collected and analysed by histopathology, reverse transcriptase-quantitative real-time PCR (RT-qPCR) and immunohistochemistry. P2 receptor expression was analysed by RT-qPCR on primary intestinal epithelium and NTPDase8 activity by histochemistry. The role of intestinal P2Y6 receptors was assessed by bone marrow transplantation experiments and with a P2Y6 receptor antagonist. RESULTS: NTPDase8 is the dominant enzyme responsible for the hydrolysis of nucleotides in the lumen of the colon. Compared with wild-type (WT) control mice, the colon of Entpd8 -/- mice treated with DSS displayed significantly more histological damage, immune cell infiltration, apoptosis and increased expression of several proinflammatory cytokines. P2Y6 was the dominant P2Y receptor expressed at the mRNA level by the colonic epithelia. Irradiated P2ry6 -/- mice transplanted with WT bone marrow were fully protected from DSS-induced intestinal inflammation. In agreement, the daily intrarectal injection of a P2Y6 antagonist protected mice from DSS-induced intestinal inflammation in a dose-dependent manner. Finally, human intestinal epithelial cells express NTPDase8 and P2Y6 similarly as in mice. CONCLUSION: NTPDase8 protects the intestine from inflammation most probably by limiting the activation of P2Y6 receptors in colonic epithelial cells. This may provide a novel therapeutic strategy for the treatment of inflammatory bowel disease.


Assuntos
Adenosina Trifosfatases/metabolismo , Colite/metabolismo , Isotiocianatos/farmacologia , Receptores Purinérgicos P2/genética , Receptores Purinérgicos P2/metabolismo , Tioureia/análogos & derivados , Adenosina Trifosfatases/genética , Animais , Apoptose , Transplante de Medula Óssea , Colo/metabolismo , Citocinas/metabolismo , Sulfato de Dextrana/farmacologia , Modelos Animais de Doenças , Células Epiteliais/metabolismo , Humanos , Imuno-Histoquímica , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Tioureia/farmacologia
2.
J Exp Med ; 219(1)2022 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-34854884

RESUMO

We previously demonstrated that lifelong antibiotic (ABX) perturbations of the gut microbiome in male APPPS1-21 mice lead to reductions in amyloid ß (Aß) plaque pathology and altered phenotypes of plaque-associated microglia. Here, we show that a short, 7-d treatment of preweaned male mice with high-dose ABX is associated with reductions of Aß amyloidosis, plaque-localized microglia morphologies, and Aß-associated degenerative changes at 9 wk of age in male mice only. More importantly, fecal microbiota transplantation (FMT) from transgenic (Tg) or WT male donors into ABX-treated male mice completely restored Aß amyloidosis, plaque-localized microglia morphologies, and Aß-associated degenerative changes. Transcriptomic studies revealed significant differences between vehicle versus ABX-treated male mice and FMT from Tg mice into ABX-treated mice largely restored the transcriptome profiles to that of the Tg donor animals. Finally, colony-stimulating factor 1 receptor (CSF1R) inhibitor-mediated depletion of microglia in ABX-treated male mice failed to reduce cerebral Aß amyloidosis. Thus, microglia play a critical role in driving gut microbiome-mediated alterations of cerebral Aß deposition.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Amiloidose/metabolismo , Encéfalo/metabolismo , Microbioma Gastrointestinal/fisiologia , Microglia/metabolismo , Amiloidose/genética , Animais , Anticorpos/administração & dosagem , Encéfalo/efeitos dos fármacos , Quimiocinas/sangue , Quimiocinas/genética , Quimiocinas/metabolismo , Citocinas/sangue , Citocinas/genética , Citocinas/metabolismo , Transplante de Microbiota Fecal , Fezes/microbiologia , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/genética , Perfilação da Expressão Gênica/métodos , Ontologia Genética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , RNA-Seq/métodos , Fatores Sexuais
3.
Endocrinology ; 163(1)2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34791151

RESUMO

Cancer immunology is the most rapidly expanding field in cancer research, with the importance of immunity in cancer pathogenesis now well accepted including in the endocrine-related cancers. The immune system plays an essential role in the development of ductal and luminal epithelial differentiation in the mammary gland. Originally identified as evolutionarily conserved antipathogen cytokines, interferons (IFNs) have shown important immune-modulatory and antineoplastic properties when administered to patients with various types of cancer, including breast cancer. Recent studies have drawn attention to the role of tumor- and stromal-infiltrating lymphocytes in dictating therapy response and outcome of breast cancer patients, which, however, is highly dependent on the breast cancer subtype. The emerging role of tumor cell-inherent IFN signaling in the subtype-defined tumor microenvironment could influence therapy response with protumor activities in breast cancer. Here we review evidence with new insights into tumor cell-intrinsic and tumor microenvironment-derived IFN signaling, and the crosstalk of IFN signaling with key signaling pathways in estrogen receptor-positive (ER+) breast cancer. We also discuss clinical implications and opportunities exploiting IFN signaling to treat advanced ER+ breast cancer.


Assuntos
Neoplasias da Mama/metabolismo , Receptor alfa de Estrogênio/biossíntese , Interferons/metabolismo , Animais , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Diferenciação Celular , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/metabolismo , Citocinas/metabolismo , Células Dendríticas/citologia , Feminino , Fibroblastos/metabolismo , Fator 3-alfa Nuclear de Hepatócito/metabolismo , Humanos , Linfócitos do Interstício Tumoral/citologia , Camundongos , NF-kappa B/metabolismo , Transdução de Sinais , Fator de Transcrição AP-1/metabolismo , Microambiente Tumoral , Macrófagos Associados a Tumor/metabolismo
4.
Am J Surg Pathol ; 46(1): 89-96, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34081038

RESUMO

Approximately 20% of patients with symptomatic syndrome-associated coronavirus-2 (SARS-CoV-2) infection have gastrointestinal bleeding and/or diarrhea. Most are managed without endoscopic evaluation because the risk of practitioner infection outweighs the value of biopsy analysis unless symptoms are life-threatening. As a result, much of what is known about the gastrointestinal manifestations of coronavirus disease-2019 (COVID-19) has been gleaned from surgical and autopsy cases that suffer from extensive ischemic injury and/or poor preservation. There are no detailed reports describing any other gastrointestinal effects of SARS-CoV-2 even though >3,000,000 people have died from COVID-19 worldwide. The purpose of this study is to report the intestinal findings related to SARS-CoV-2 infection by way of a small case series including one with evidence of direct viral cytopathic effect and 2 with secondary injury attributed to viral infection. Infection can be confirmed by immunohistochemical stains directed against SARS-CoV-2 spike protein, in situ hybridization for spike protein-encoding RNA, and ultrastructural visualization of viruses within the epithelium. It induces cytoplasmic blebs and tufted epithelial cells without inflammation and may not cause symptoms. In contrast, SARS-CoV-2 infection can cause gastrointestinal symptoms after the virus is no longer detected, reflecting systemic activation of cytokine and complement cascades rather than direct viral injury. Reversible mucosal ischemia features microvascular injury with hemorrhage, small vessel thrombosis, and platelet-rich thrombi. Systemic cytokine elaboration and dysbiosis likely explain epithelial cell injury that accompanies diarrheal symptoms. These observations are consistent with clinical and in vitro data and contribute to our understanding of the protean manifestations of COVID-19.


Assuntos
COVID-19/patologia , Enteropatias/patologia , Enteropatias/virologia , Intestinos/patologia , Intestinos/virologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/metabolismo , Biópsia , COVID-19/diagnóstico , COVID-19/imunologia , Citocinas/metabolismo , Hemorragia Gastrointestinal/diagnóstico , Hemorragia Gastrointestinal/imunologia , Hemorragia Gastrointestinal/patologia , Hemorragia Gastrointestinal/virologia , Humanos , Enteropatias/diagnóstico , Enteropatias/imunologia , Intestinos/imunologia , Isquemia/diagnóstico , Isquemia/imunologia , Isquemia/patologia , Isquemia/virologia , Masculino , Trombose/diagnóstico , Trombose/imunologia , Trombose/patologia , Trombose/virologia
5.
J Ethnopharmacol ; 282: 114574, 2022 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-34461187

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Gekko gecko is used as a traditional medicine for various diseases including respiratory disorders in northeast Asian countries, mainly Korea, Japan, and China. AIM OF THE STUDY: Allergic asthma is a chronic respiratory disease caused by an inappropriate immune response. Due to the recent spread of coronavirus disease 2019, interest in the treatment of pulmonary disorders has rapidly increased. In this study, we investigated the anti-asthmatic effects of G. gecko extract (GGE) using an established mouse model of ovalbumin-induced asthma. MATERIALS AND METHODS: To evaluate the anti-asthmatic effects of GGE, we evaluated histological changes and the responses of inflammatory mediators related to allergic airway inflammation. Furthermore, we investigated the regulatory effects of GGE on type 2 helper T (Th2) cell activation. RESULTS: Administration of GGE attenuated asthmatic phenotypes, including inflammatory cell infiltration, mucus production, and expression of Th2 cytokines. Furthermore, GGE treatment reduced Th2 cell activation and differentiation. CONCLUSIONS: These results indicate that GGE alleviates allergic airway inflammation by regulating Th2 cell activation and differentiation.


Assuntos
Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Medicina Tradicional do Leste Asiático , Muco/metabolismo , Ovalbumina , Extratos Vegetais/uso terapêutico , Animais , Asma/induzido quimicamente , Asma/patologia , Líquido da Lavagem Broncoalveolar , COVID-19 , Citocinas/metabolismo , Feminino , Citometria de Fluxo , Imunoglobulina E/imunologia , Mediadores da Inflamação/metabolismo , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Pandemias , Células Th2/efeitos dos fármacos , Células Th2/imunologia , Triptaminas/farmacologia
6.
Biochim Biophys Acta Mol Basis Dis ; 1868(1): 166295, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34718118

RESUMO

Several organs, such as the heart, breasts, intestine, testes, and ovaries, have been reported to be target tissues of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. To date, no studies have demonstrated SARS-CoV-2 infection in the female reproductive system. In the present study, we investigated the effects of SARS-CoV-2 infection on ovarian function by comparing follicular fluid (FF) from control and recovered coronavirus disease 2019 (COVID-19) patients and by evaluating the influence of these FF on human endothelial and non-luteinized granulosa cell cultures. Our results showed that most FFs (91.3%) from screened post COVID-19 patients were positive for IgG antibodies against SARS-CoV-2. Additionally, patients with higher levels of IgG against SARS-CoV-2 had lower numbers of retrieved oocytes. While VEGF and IL-1ß were significantly lower in post COVID-19 FF, IL-10 did not differ from that in control FF. Moreover, in COV434 cells stimulated with FF from post COVID-19 patients, steroidogenic acute regulatory protein (StAR), estrogen-receptor ß (Erß), and vascular endothelial growth factor (VEGF) expression were significantly decreased, whereas estrogen-receptor α (ERα) and 3ß-hydroxysteroid dehydrogenase (3ß-HSD) did not change. In endothelial cells stimulated with post COVID-19 FF, we observed a decrease in cell migration without changes in protein expression of certain angiogenic factors. Both cell types showed a significantly higher γH2AX expression when exposed to post COVID-19 FF. In conclusion, our results describe for the first time that the SARS-CoV-2 infection adversely affects the follicular microenvironment, thus dysregulating ovarian function.


Assuntos
COVID-19/metabolismo , COVID-19/virologia , Interações Hospedeiro-Patógeno , Ovário/metabolismo , Técnicas de Reprodução Assistida , SARS-CoV-2 , Adulto , Anticorpos Antivirais/imunologia , Biomarcadores , COVID-19/imunologia , Células Cultivadas , Citocinas/metabolismo , Ensaio de Imunoadsorção Enzimática , Feminino , Fertilidade , Líquido Folicular/metabolismo , Células da Granulosa/metabolismo , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunoglobulina G/imunologia , Oócitos/metabolismo , Adulto Jovem
7.
Cytokine ; 149: 155757, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34763156

RESUMO

BACKGROUND: To determine and compare nasopharyngeal microbiota (NM) composition, in vitro basal (Nil tube), provoked (Mitogen tube) production of cytokines at the early stage of COVID-19. METHODS: This cross-sectional study included 4 age and sex-matched study groups; group 1 (recovered COVID-19) (n = 26), group 2 (mild COVID-19) (n = 24), group 3 (severe COVID-19) (n = 25), and group 4 (healthy controls) (n = 25). The study parameters obtained from the COVID-19 (group 2, and 3) at the early phase of hospital admission. RESULTS: The results from the reaserch deoicted that the Mean ± SD age was 53.09 ± 14.51 years. Some of the in vitro cytokines production was significantly different between the study groups. Some of the findinggs on cytokines depicted a significant differences between study groups were interleukin (IL)-1ß Nil, IL-1ß Mitogen, and their subtraction (i.e Mitogen-Nil). Regarding IL-10, and IL-17a levels, Mitogen, and Mitogen-Nil tube production levels were significantly different between the groups. Surprisingly, most of these measures were lowest in the severe COVID-19 patients' group. Using discriminant analysis effect size (LEfSe), Taxa of NM with significant abundance was determined. About 20 taxa with an LDA score > 4 were identified as candidate biomarkers. Some of these taxa showed a significant correlation with IL-1ß and IL-10 Mitogen and Mitogen- Nil levels (R > 0.3 or < -0.3, p < 0.05). CONCLUSIONS: The findings of this perticular study regarting the early stage of COVID-19 showed that in vitro cytokines production, studies might be more useful than the ordinary cytokines' blood level measurement. Besides, the study identified some NM species that could be candidate biomarkers in managing this infection. However, further detailed studies are needed in these fields.


Assuntos
COVID-19/metabolismo , COVID-19/microbiologia , Citocinas/metabolismo , Microbiota/fisiologia , Nasofaringe/microbiologia , Nasofaringe/virologia , COVID-19/virologia , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
8.
Parasit Vectors ; 14(1): 611, 2021 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-34930417

RESUMO

BACKGROUND: Trehalose-6-phosphate phosphatase (TPP6) is a key enzyme in the trehalose biosynthesis pathway. The accumulation of TPP6 inside the body is harmful to the pathogen, but almost nothing is currently known about the function of TPP6 from Haemonchus contortus (CRE-GOB-1). METHODS: The H. contortus CRE-GOB-1 (HcGOB) gene was cloned and recombinant protein of GOB (rHcGOB) was expressed; transcription of the HcGOB gene at different developmental stages of H. contortus was then studied. The spatial expression pattern of the HcGOB gene in adult female and male worms was determined by both quantitative real-time PCR (qPCR) and immunofluorescence. The binding of the rHcGOB protein to goat PBMCs was assessed by immunofluorescence assay. The immunomodulatory impacts of rHcGOB on cell proliferation, nitric oxide generation and cytokine secretion were assessed by co-culture of rHcGOB protein with goat PBMCs. RESULTS: The HcGOB protein was transcribed in eggs, infective third-stage larvae (iL3s) and adults of H. contortus, with the highest transcript levels found in the egg stage. The transcript levels were significantly elevated in iL3s after manual desheathing. HcGOB was widely distributed in adult worms where it was mainly localized in the gut and gonads. rHcGOB was observed to bind to PBMCs and also to be recognized by sera collected from a goat infected with H. contortus. rHcGOB significantly activated the interleukin-10/transforming growth factor ß/signal transducer and activator of transcription 3 (IL-10/TGF-ß/STAT3) pathway in PBMCs while suppressing the transcription and expression of IL-4 and IL-17. CONCLUSIONS: These results suggest that the HcGOB gene plays an important role in the development, parasitism and reproduction of H. contortus. The rHcGOB protein affected the immunomodulatory function of PBMCs in the in vitro study, suggesting that this protein would be a promising vaccine target.


Assuntos
Haemonchus/enzimologia , Leucócitos Mononucleares/fisiologia , Monoéster Fosfórico Hidrolases/metabolismo , Animais , Proliferação de Células , Clonagem Molecular , Citocinas/genética , Citocinas/metabolismo , Feminino , Regulação da Expressão Gênica/imunologia , Regulação Enzimológica da Expressão Gênica , Cabras , Haemonchus/classificação , Haemonchus/genética , Masculino , Monoéster Fosfórico Hidrolases/genética , Filogenia , Conformação Proteica , Ratos , Reprodutibilidade dos Testes
9.
Cells ; 10(12)2021 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-34944017

RESUMO

Fibrosis is responsible for approximately 45% of deaths in the industrialized world and has been a major global healthcare burden. Excessive fibrosis is the primary cause of organ failure. However, there are currently no approved drugs available for the prevention or treatment of fibrosis-related diseases. It has become evident that fibrosis is characterized by inflammation. In a large number of studies of various organs in mice and humans, pyroptosis has been found to play a significant role in fibrosis. Pyroptosis is a form of programmed cell death mediated by the N-terminal fragment of cysteinyl aspartate-specific proteinase (caspase)-1-cleaved gasdermin D (GSDMD, producing GSDMD-N) that gives rise to inflammation via the release of some proinflammatory cytokines, including IL-1ß, IL-18 and HMGB1. These cytokines can initiate the activation of fibroblasts. Inflammasomes, an important factor upstream of GSDMD, can activate caspase-1 to trigger the maturation of IL-1ß and IL-18. Moreover, the inhibition of inflammasomes, proinflammatory cytokines and GSDMD can prevent the progression of fibrosis. This review summarizes the growing evidence indicating that pyroptosis triggers fibrosis, and highlights potential novel targets for antifibrotic therapies.


Assuntos
Piroptose , Animais , Biomarcadores/metabolismo , Citocinas/metabolismo , Fibrose , Humanos , Inflamassomos/metabolismo , Terapia de Alvo Molecular
10.
Viruses ; 13(12)2021 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-34960708

RESUMO

The persistent circulation of SARS-CoV-2 represents an ongoing global threat due to the emergence of new viral variants that can sometimes evade the immune system of previously exposed or vaccinated individuals. We conducted a follow-up study of adult individuals that had received an inactivated SARS-CoV-2 vaccine, evaluating antibody production and neutralizing activity over a period of 6 months. In addition, we performed mice immunization with inactivated SARS-CoV-2, and evaluated the immune response and pathological outcomes against Gamma and Zeta variant infection. Vaccinated individuals produced high levels of antibodies with robust neutralizing activity, which was significantly reduced against Gamma and Zeta variants. Production of IgG anti-S antibodies and neutralizing activity robustly reduced after 6 months of vaccination. Immunized mice demonstrated cellular response against Gamma and Zeta variants, and after viral infection, reduced viral loads, IL-6 expression, and histopathological outcome in the lungs. TNF levels were unchanged in immunized or not immunized mice after infection with the Gamma variant. Furthermore, serum neutralization activity rapidly increases after infection with the Gamma and Zeta variants. Our data suggest that immunization with inactivated WT SARS-CoV-2 induces a promptly responsive cross-reactive immunity response against the Gamma and Zeta variants, reducing COVID-19 pathological outcomes.


Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , SARS-CoV-2/imunologia , Vacinas de Produtos Inativados/imunologia , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , COVID-19/imunologia , COVID-19/patologia , COVID-19/virologia , Vacinas contra COVID-19/administração & dosagem , Proteção Cruzada , Citocinas/metabolismo , Seguimentos , Humanos , Imunização , Pulmão/metabolismo , Pulmão/patologia , Camundongos , Vacinas de Produtos Inativados/administração & dosagem , Carga Viral
11.
Viruses ; 13(12)2021 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-34960806

RESUMO

BACKGROUND: The SARS-CoV-2 spike protein mediates attachment of the virus to the host cell receptor and fusion between the virus and the cell membrane. The S1 subunit of the spike glycoprotein (S1 protein) contains the angiotensin converting enzyme 2 (ACE2) receptor binding domain. The SARS-CoV-2 variants of concern contain mutations in the S1 subunit. The spike protein is the primary target of neutralizing antibodies generated following infection, and constitutes the viral component of mRNA-based COVID-19 vaccines. METHODS: Therefore, in this work we assessed the effect of exposure (24 h) to 10 nM SARS-CoV-2 recombinant S1 protein on physiologically relevant human bronchial (bro) and alveolar (alv) lung mucosa models cultured at air-liquid interface (ALI) (n = 6 per exposure condition). Corresponding sham exposed samples served as a control. The bro-ALI model was developed using primary bronchial epithelial cells and the alv-ALI model using representative type II pneumocytes (NCI-H441). RESULTS: Exposure to S1 protein induced the surface expression of ACE2, toll like receptor (TLR) 2, and TLR4 in both bro-ALI and alv-ALI models. Transcript expression analysis identified 117 (bro-ALI) and 97 (alv-ALI) differentially regulated genes (p ≤ 0.01). Pathway analysis revealed enrichment of canonical pathways such as interferon (IFN) signaling, influenza, coronavirus, and anti-viral response in the bro-ALI. Secreted levels of interleukin (IL) 4 and IL12 were significantly (p < 0.05) increased, whereas IL6 decreased in the bro-ALI. In the case of alv-ALI, enriched terms involving p53, APRIL (a proliferation-inducing ligand) tight junction, integrin kinase, and IL1 signaling were identified. These terms are associated with lung fibrosis. Further, significantly (p < 0.05) increased levels of secreted pro-inflammatory cytokines IFNγ, IL1ꞵ, IL2, IL4, IL6, IL8, IL10, IL13, and tumor necrosis factor alpha were detected in alv-ALI, whereas IL12 was decreased. Altered levels of these cytokines are also associated with lung fibrotic response. CONCLUSIONS: In conclusion, we observed a typical anti-viral response in the bronchial model and a pro-fibrotic response in the alveolar model. The bro-ALI and alv-ALI models may serve as an easy and robust platform for assessing the pathogenicity of SARS-CoV-2 variants of concern at different lung regions.


Assuntos
Pulmão/metabolismo , Mucosa Respiratória/metabolismo , SARS-CoV-2/patogenicidade , Glicoproteína da Espícula de Coronavírus/metabolismo , Enzima de Conversão de Angiotensina 2/metabolismo , Brônquios/metabolismo , Citocinas/metabolismo , Perfilação da Expressão Gênica , Humanos , Modelos Biológicos , Domínios e Motivos de Interação entre Proteínas , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , SARS-CoV-2/metabolismo , Glicoproteína da Espícula de Coronavírus/química , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/metabolismo
12.
Invest Ophthalmol Vis Sci ; 62(15): 14, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34919120

RESUMO

Purpose: Previously, we demonstrated that miR-183/96/182 cluster (miR-183C) knockout mice exhibit decreased severity of Pseudomonas aeruginosa (PA)-induced keratitis. This study tests the hypothesis that prophylactic knockdown of miR-183C ameliorates PA keratitis indicative of a therapeutic potential. Methods: Eight-week-old miR-183C wild-type and C57BL/6J inbred mice were used. Locked nucleic acid-modified anti-miR-183C or negative control oligoribonucleotides with scrambled sequences (NC ORNs) were injected subconjunctivally 1 day before and then topically applied once daily for 5 days post-infection (dpi) (strain 19660). Corneal disease was graded at 1, 3, and 5 dpi. Corneas were harvested for RT-PCR, ELISA, immunofluorescence (IF), myeloperoxidase and plate count assays, and flow cytometry. Corneal nerve density was evaluated in flatmounted corneas by IF staining with anti-ß-III tubulin antibody. Results: Anti-miR-183C downregulated miR-183C in the cornea. It resulted in an increase in IL-1ß at 1 dpi, which was decreased at 5 dpi; fewer polymorphonuclear leukocytes (PMNs) at 5 dpi; lower viable bacterial plate count at both 1 and 5 dpi; increased percentages of MHCII+ macrophages (Mϕ) and dendritic cells (DCs), consistent with enhanced activation/maturation; and decreased severity of PA keratitis. Anti-miR-183C treatment in the cornea of naïve mice resulted in a transient reduction of corneal nerve density, which was fully recovered one week after the last anti-miR application. miR-183C targets repulsive axon-guidance receptor molecule Neuropilin 1, which may mediate the effect of anti-miR-183C on corneal nerve regression. Conclusions: Prophylactic miR-183C knockdown is protective against PA keratitis through its regulation of innate immunity, corneal innervation, and neuroimmune interactions.


Assuntos
Úlcera da Córnea/prevenção & controle , Infecções Oculares Bacterianas/prevenção & controle , Regulação da Expressão Gênica/fisiologia , MicroRNAs/genética , Infecções por Pseudomonas/prevenção & controle , Animais , Úlcera da Córnea/genética , Úlcera da Córnea/metabolismo , Citocinas/metabolismo , Ensaio de Imunoadsorção Enzimática , Infecções Oculares Bacterianas/genética , Infecções Oculares Bacterianas/metabolismo , Feminino , Citometria de Fluxo , Técnicas de Silenciamento de Genes , Imunidade Inata , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia de Fluorescência , Neutrófilos/fisiologia , Infecções por Pseudomonas/genética , Infecções por Pseudomonas/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Transfecção
13.
Cells ; 10(12)2021 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-34944097

RESUMO

Background: The single nucleotide polymorphism (SNP) rs1042058 within the gene locus encoding tumor progression locus 2 (TPL2) has been recently identified as a risk gene for inflammatory bowel disease (IBD). TPL2 has been shown to regulate pro-inflammatory signaling and cytokine secretion, while inhibition of TPL2 decreases intestinal inflammation in vivo. However, the clinical and molecular implications of this disease-associated TPL2 variation in IBD patients have not yet been studied. Methods: We analyzed the impact of the IBD-associated TPL2 variation using clinical data of 2145 genotyped patients from the Swiss IBD Cohort Study (SIBDCS). Furthermore, we assessed the molecular consequences of the TPL2 variation in ulcerative colitis (UC) and Crohn's disease (CD) patients by real-time PCR and multiplex ELISA of colon biopsies or serum, respectively. Results: We found that presence of the SNP rs1042058 within the TPL2 gene locus results in significantly higher numbers of CD patients suffering from peripheral arthritis. In contrast, UC patients carrying this variant feature a lower risk for intestinal surgery. On a molecular level, the presence of the rs1042058 (GG) IBD-risk polymorphism in TPL2 was associated with decreased mRNA levels of IL-10 in CD patients and decreased levels of IL-18 in the intestine of UC patients. Conclusions: Our data suggest that the presence of the IBD-associated TPL2 variation might indicate a more severe disease course in CD patients. These results reveal a potential therapeutic target and demonstrate the relevance of the IBD-associated TPL2 SNP as a predictive biomarker in IBD.


Assuntos
Progressão da Doença , Loci Gênicos , Predisposição Genética para Doença , Doenças Inflamatórias Intestinais/genética , MAP Quinase Quinase Quinases/genética , Polimorfismo de Nucleotídeo Único/genética , Proteínas Proto-Oncogênicas/genética , Adolescente , Adulto , Alelos , Artrite/sangue , Artrite/genética , Colite Ulcerativa/sangue , Colite Ulcerativa/genética , Colite Ulcerativa/cirurgia , Doença de Crohn/sangue , Doença de Crohn/genética , Citocinas/sangue , Citocinas/genética , Citocinas/metabolismo , Análise Fatorial , Feminino , Humanos , Doenças Inflamatórias Intestinais/patologia , Masculino , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fatores de Risco , Adulto Jovem
14.
Front Immunol ; 12: 778913, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34912345

RESUMO

The current global pandemic of the Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) causing COVID-19, has infected millions of people and continues to pose a threat to many more. Angiotensin-Converting Enzyme 2 (ACE2) is an important player of the Renin-Angiotensin System (RAS) expressed on the surface of the lung, heart, kidney, neurons, and endothelial cells, which mediates SARS-CoV-2 entry into the host cells. The cytokine storms of COVID-19 arise from the large recruitment of immune cells because of the dis-synchronized hyperactive immune system, lead to many abnormalities including hyper-inflammation, endotheliopathy, and hypercoagulability that produce multi-organ dysfunction and increased the risk of arterial and venous thrombosis resulting in more severe illness and mortality. We discuss the aberrated interconnectedness and forthcoming crosstalks between immunity, the endothelium, and coagulation, as well as how sex disparities affect the severity and outcome of COVID-19 and harm men especially. Further, our conceptual framework may help to explain why persistent symptoms, such as reduced physical fitness and fatigue during long COVID, may be rooted in the clotting system.


Assuntos
COVID-19/epidemiologia , COVID-19/virologia , SARS-CoV-2 , Biomarcadores , Coagulação Sanguínea , Transtornos da Coagulação Sanguínea/diagnóstico , Transtornos da Coagulação Sanguínea/etiologia , COVID-19/complicações , COVID-19/diagnóstico , Citocinas/metabolismo , Suscetibilidade a Doenças , Endotélio/metabolismo , Feminino , Interações Hospedeiro-Patógeno/imunologia , Humanos , Mediadores da Inflamação , Masculino , Sistema Renina-Angiotensina , Índice de Gravidade de Doença , Fatores Sexuais
15.
Front Immunol ; 12: 789735, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34925369

RESUMO

Background: The host immune response has a prominent role in the progression and outcome of SARS-CoV-2 infection. Lymphopenia has been described as an important feature of SARS-CoV-2 infection and has been associated with severe disease manifestation. Lymphocyte dysregulation and hyper-inflammation have been shown to be associated with a more severe clinical course; however, a T cell subpopulation whose dysfunction correlate with disease progression has yet to be identify. Methods: We performed an immuno-phenotypic analysis of T cell sub-populations in peripheral blood from patients affected by different severity of COVID-19 (n=60) and undergoing a different clinical evolution. Clinical severity was established based on a modified WHO score considering both ventilation support and respiratory capacity (PaO2/FiO2 ratio). The ability of circulating cells at baseline to predict the probability of clinical aggravation was explored through multivariate regression analyses. Results: The immuno-phenotypic analysis performed by multi-colour flow cytometry confirmed that patients suffering from severe COVID-19 harboured significantly reduced circulating T cell subsets, especially for CD4+ T, Th1, and regulatory T cells. Peripheral T cells also correlated with parameters associated with disease severity, i.e., PaO2/FiO2 ratio and inflammation markers. CD4+ T cell subsets showed an important significant association with clinical evolution, with patients presenting markedly decreased regulatory T cells at baseline having a significantly higher risk of aggravation. Importantly, the combination of gender and regulatory T cells allowed distinguishing between improved and worsened patients with an area under the ROC curve (AUC) of 82%. Conclusions: The present study demonstrates the association between CD4+ T cell dysregulation and COVID-19 severity and progression. Our results support the importance of analysing baseline regulatory T cell levels, since they were revealed able to predict the clinical worsening during hospitalization. Regulatory T cells assessment soon after hospital admission could thus allow a better clinical stratification and patient management.


Assuntos
COVID-19/epidemiologia , COVID-19/imunologia , Hospitalização , Contagem de Linfócitos , SARS-CoV-2/imunologia , Linfócitos T Reguladores/imunologia , Biomarcadores , COVID-19/diagnóstico , COVID-19/virologia , Teste Sorológico para COVID-19 , Citocinas/sangue , Citocinas/metabolismo , Progressão da Doença , Humanos , Imunofenotipagem , Mediadores da Inflamação/sangue , Mediadores da Inflamação/metabolismo , Prognóstico , Vigilância em Saúde Pública , Curva ROC , Índice de Gravidade de Doença , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/metabolismo
16.
Front Immunol ; 12: 733539, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34899693

RESUMO

The response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is largely impacted by the level of virus exposure and status of the host immunity. The nature of protection shown by direct asymptomatic contacts of coronavirus disease 2019 (COVID-19)-positive patients is quite intriguing. In this study, we have characterized the antibody titer, SARS-CoV-2 surrogate virus neutralization, cytokine levels, single-cell T-cell receptor (TCR), and B-cell receptor (BCR) profiling in asymptomatic direct contacts, infected cases, and controls. We observed significant increase in antibodies with neutralizing amplitude in asymptomatic contacts along with cytokines such as Eotaxin, granulocyte-colony stimulating factor (G-CSF), interleukin 7 (IL-7), migration inhibitory factor (MIF), and macrophage inflammatory protein-1α (MIP-1α). Upon single-cell RNA (scRNA) sequencing, we explored the dynamics of the adaptive immune response in few representative asymptomatic close contacts and COVID-19-infected patients. We reported direct asymptomatic contacts to have decreased CD4+ naive T cells with concomitant increase in CD4+ memory and CD8+ Temra cells along with expanded clonotypes compared to infected patients. Noticeable proportions of class switched memory B cells were also observed in them. Overall, these findings gave an insight into the nature of protection in asymptomatic contacts.


Assuntos
Imunidade Adaptativa/imunologia , COVID-19/imunologia , Genômica/métodos , SARS-CoV-2/imunologia , Análise de Célula Única/métodos , Imunidade Adaptativa/genética , Adulto , Anticorpos Antivirais/imunologia , COVID-19/genética , COVID-19/virologia , Citocinas/imunologia , Citocinas/metabolismo , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Masculino , /metabolismo , Pessoa de Meia-Idade , SARS-CoV-2/fisiologia , Análise de Sequência de RNA/métodos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/virologia , Adulto Jovem
17.
Medicina (Kaunas) ; 57(12)2021 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-34946332

RESUMO

Background and objectives: The purpose of this study was to confirm the effect of Galgeunhwanggeumhwangryeon-tang (GGRT) on the skin barrier integrity and inflammation in an atopic dermatitis-like animal model. Materials and Methods: The model was established using lipid barrier elimination (LBE) in BALB/c mice. Ceramide 3B, a control drug, and GGRT were applied to the skin of LBE mice. Gross observation and histological examination were combined with measurement of skin score, trans-epidermal water loss, and pH. The expression of filaggrin, kallikrein-related peptidase 7 (KLK7), protease-activated receptor-2 (PAR-2), thymic stromal lymphopoietin (TSLP), and interleukin 4 (IL-4) was examined. Results: The effect of GGRT on atopic dermatitis was estimated in silico using two individual gene sets of human atopic dermatitis. In animal experiments, GGRT treatment reduced atopic dermatitis-like symptoms, as confirmed via gross and histological observations, skin score, pH change, and trans-epidermal water loss. The expression level of filaggrin increased in the skin of GGRT-treated mice compared to that in the LBE group. The expression levels of KLK7, PAR2, TSLP, and IL-4 were decreased in GGRT-treated mice skin compared to those in LBE mice. Conclusions: We demonstrated that GGRT restored the skin barrier and reduced inflammatory reactions in a murine model of atopic dermatitis.


Assuntos
Citocinas , Medicamentos de Ervas Chinesas/administração & dosagem , Interleucina-4 , Lipídeos , Pele/efeitos dos fármacos , Administração Cutânea , Animais , Citocinas/genética , Citocinas/metabolismo , /metabolismo , Inflamação/tratamento farmacológico , Interleucina-4/genética , Interleucina-4/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Fenômenos Fisiológicos da Pele
18.
PLoS One ; 16(12): e0260130, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34965258

RESUMO

The objective of the current study is to investigate the effect of rice bran oil (RBO) on hepatic fibrosis as a characteristic response to persistent liver injuries. Rats were randomly allocated into five groups: the negative control group, thioacetamide (TAA) group (thioacetamide 100 mg/kg thrice weekly for two successive weeks, ip), RBO 0.2 and 0.4 groups (RBO 0.2mL and 0.4 mL/rat/day, po) and standard group (silymarin 100 mg/kg/day, po) for two weeks after TAA injection. Blood and liver tissue samples were collected for biochemical, molecular, and histological analyses. Liver functions, oxidative stress, inflammation, liver fibrosis markers were assessed. The obtained results showed that RBO reduced TAA-induced liver fibrosis and suppressed the extracellular matrix formation. Compared to the positive control group, RBO dramatically reduced total bilirubin, AST, and ALT blood levels. Furthermore, RBO reduced MDA and increased GSH contents in the liver. Simultaneously RBO downregulated the NF-κß signaling pathway, which in turn inhibited the expression of some inflammatory mediators, including Cox-2, IL-1ß, and TNF-α. RBO attenuated liver fibrosis by suppressing the biological effects of TGF-ß1, α-SMA, collagen I, hydroxyproline, CTGF, and focal adhesion kinase (FAK). RBO reduced liver fibrosis by inhibiting hepatic stellate cell activation and modulating the interplay among the TGF-ß1 and FAK signal transduction. The greater dosage of 0.4 mL/kg has a more substantial impact. Hence, this investigation presents RBO as a promising antifibrotic agent in the TAA model through inhibition of TGF-ß1 /FAK/α-SMA.


Assuntos
Actinas/metabolismo , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/metabolismo , Óleo de Farelo de Arroz/uso terapêutico , Fator de Crescimento Transformador beta1/metabolismo , Albuminas/metabolismo , Animais , Becaplermina/metabolismo , Biomarcadores/metabolismo , Colágeno Tipo I/metabolismo , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Cromatografia Gasosa-Espectrometria de Massas , Globulinas/metabolismo , Glutationa/metabolismo , Hidroxiprolina/metabolismo , Mediadores da Inflamação/metabolismo , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/patologia , Cirrose Hepática/sangue , Cirrose Hepática/induzido quimicamente , Masculino , Malondialdeído/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Wistar , Óleo de Farelo de Arroz/farmacologia , Transdução de Sinais/efeitos dos fármacos , Tioacetamida , Transaminases/sangue , Transaminases/metabolismo
19.
Cell Mol Life Sci ; 79(1): 17, 2021 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-34971407

RESUMO

Innate-like T (iT) cells comprise a population of immunoregulatory T cells whose effector function is imposed during their development in the thymus to provide protective immunity prior to antigen encounter. The molecular mechanism that drives the generation of iT cells remains unclear. Here, we report that the cytokine receptor γc plays a previously unappreciated role for thymic iT cells by controlling their cellular abundance, lineage commitment, and subset differentiation. As such, γc overexpression on thymocytes dramatically altered iT cell generation in the thymus, as it skewed the subset composition of invariant NKT (iNKT) cells and promoted the generation of IFNγ-producing innate CD8 T cells. Mechanistically, we found that the γc-STAT6 axis drives the differentiation of IL-4-producing iNKT cells, which in turn induced the generation of innate CD8 T cells. Collectively, these results reveal a cytokine-driven circuity of thymic iT cell differentiation that is controlled by the abundance of γc proteins.


Assuntos
Imunidade Inata , Subunidade gama Comum de Receptores de Interleucina/metabolismo , Linfócitos T/metabolismo , Timo/citologia , Animais , Linfócitos T CD8-Positivos , Diferenciação Celular , Citocinas/metabolismo , Camundongos Transgênicos , Células T Matadoras Naturais/metabolismo , Proteína com Dedos de Zinco da Leucemia Promielocítica , Fator de Transcrição STAT6/metabolismo , Transdução de Sinais , Timócitos/metabolismo
20.
PLoS One ; 16(12): e0260963, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34914797

RESUMO

This study measured the intraoperative anterior aqueous humor concentrations of various cytokines during corneal endothelial transplantation and searched for relationships between these concentrations and postoperative corneal endothelial cell (CEC) depletion. We recruited 30 consecutive patients who underwent corneal endothelial transplantation with Descemet's stripping automated endothelial keratoplasty (DSAEK) at Tohoku University Hospital between February 2014 and July 2017. During surgery, we obtained aqueous humor samples and later measured the concentrations of 27 cytokines with a Multiplex Bead Assay (Bio-Plex Pro). We counted CECs 1, 6 and 12 months after surgery, and used Spearman's rank correlation coefficient to identify relationships between CEC depletion and the concentrations of detected cytokines. The loss of CECs 1-6 months after surgery was significantly correlated with IL-7, IP-10, MIP-1a and MIP-1b concentrations (-0.67, -0.48, -0.39, and -0.45, respectively, all P <0.01). CEC loss 1-12 months after surgery was significantly correlated with IL-1b, IL-7, IP-10 and RANTES concentrations (-0.46, -0.52, -0.48, and -0.43, respectively). Multiple regression analysis showed that IL-7 concentration was significantly associated with CEC loss 1-6 months after surgery (b = -0.65, P < 0.01) and IP-10 concentration was associated with CEC loss 1-12 months after surgery (ß = -0.38, P < 0.05). These results suggest that not only inflammatory cytokines but also IL-7, a cytokine related to lymphocytes, may be involved in the depletion of CECs after DSAEK, particularly depletion that occurs relatively early.


Assuntos
Humor Aquoso/metabolismo , Doenças da Córnea/cirurgia , Perda de Células Endoteliais da Córnea/patologia , Citocinas/metabolismo , Ceratoplastia Endotelial com Remoção da Lâmina Limitante Posterior/efeitos adversos , Endotélio Corneano/transplante , Complicações Pós-Operatórias/patologia , Idoso , Perda de Células Endoteliais da Córnea/etiologia , Perda de Células Endoteliais da Córnea/metabolismo , Endotélio Corneano/citologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/metabolismo , Prognóstico , Estudos Retrospectivos
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