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1.
Zhonghua Yi Xue Za Zhi ; 100(34): 2689-2695, 2020 Sep 15.
Artigo em Chinês | MEDLINE | ID: mdl-32921018

RESUMO

Objective: To investigate the effects and potential mechanisms of Helicobacter pylori (H.pylori) infection on azoxymethane (AOM)/dextran sulfate sulphate (DSS) induced colitis-associated cancer (CAC) in mice. Methods: A total of 60 specific pathogen free C57BL/6J mice were randomly divided into four groups: normal control group (control group, n=9), H. pylori-infected group (Hp group, n=9), AOM/DSS-treated group (AOM/DSS group,n=21) and AOM/DSS-treated with H.pylori infection group (Hp+AOM/DSS group, n=21). Mice were sacrificed on day19, 45 or 85 after AOM/DSS challenge. Histopathological changes in colonic tissues were determined by hematoxylin and eosin staining. Flow cytometry analysis was performed to determine T helper cells 17 (Th17) and regulatory T cells (Treg) in colonic lamina propria. The expression levels of Th17-and Treg-associated cytokines and transcription factors [interleukin (IL)-10, IL-17A, retinoic acid receptor-related orphan receptor γt (RORγt) and forkhead box P3 (Foxp3)] were determined by quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay. Results: There were no histopathological changes in colonic tissues of mice in control group and Hp group. H.pylori colonization reduced the histopathological scores at the stages of colitis (day 19) and dysplasia (day 45), and also decreased tumor load (day 85) in mice treated with AOM/DSS (all P<0.05). Compared with AOM/DSS group, the percentages of CD3(+)CD4(+)IL-17A(+)Th17 and CD3(+)CD4(+)IL-17A(+)Foxp3(+)Treg cells (1.88±0.17 vs 2.07±0.89, 1.06±0.13 vs 1.89±0.23) and the expression levels of RORγt and IL-17A (1.08±0.59 vs 2.35±1.35, 2.96±0.92 vs 7.78±4.57) were decreased in colonic tissues of Hp+AOM/DSS group (all P<0.05). The percentages of CD3(+)CD4(+)CD25(+)Foxp3(+)Treg and CD3(+)CD4(+)IL-10(+)Foxp3(+)Treg cells (20.60±3.39 vs 15.63±2.71, 2.94±0.52 vs 2.14±0.47) and the expression levels of Foxp3 and IL-10 [17.59(13.77,24.87) vs 6.27(4.41,13.36), 3.52(1.59,5.99) vs 1.17(1.15,2.75)] in colonic tissues were higher (all P<0.05) in mice of Hp+AOM/DSS group compared with AOM/DSS group on day 85. Conclusion: H.pylori infection slows the progress from inflammation to tumor in a AOM/DSS induced CAC modal, accompanied with the downregulation of Th17 response and upregulation of Treg response.


Assuntos
Colite , Infecções por Helicobacter , Helicobacter pylori , Neoplasias , Animais , Azoximetano , Sulfato de Dextrana , Camundongos , Camundongos Endogâmicos C57BL
2.
Ann R Coll Surg Engl ; 102(7): e176-e179, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32803988

RESUMO

Spain has been one of the most affected countries by the COVID-19 outbreak. After the high impact of the pandemic, a wide clinical spectrum of late complications associated with COVID-19 are being observed. We report a case of a severe Clostridium difficile colitis in a post-treatment and recovered COVID-19 patient. A 64-year-woman with a one-month hospital admission for severe bilateral pneumonia associated with COVID-19 and 10 days after discharge presented with diarrhoea and abdominal pain. Severe C. difficile-associated colitis is diagnosed according to clinical features and CT findings. An urgent pancolectomy was performed due to her bad response to conservative treatment. Later evolution slowly improved to recovery. C. difficile-associated colitis is one of the most common hospital-acquired infections. Significant patient-related risk factors for C. difficile infection are antibiotic exposure, older age, and hospitalisation. Initial therapeutic recommendations in our country included administration broad-spectrum antibiotics to all patients with bilateral pneumonia associated with SARS-CoV-2. These antibiotics are strongly associated with C. difficile infection. Our patient developed a serious complication of C. difficile due to the use of broad-spectrum antibiotics. The appearance of late digestive symptoms in patients diagnosed and treated for COVID-19 should alert clinicians to the possibility of C. difficile infection. The updated criteria for severe colitis and severe C. difficile infection should be considered to ensure an early effective treatment for the complication.


Assuntos
Antibacterianos/uso terapêutico , Betacoronavirus , Clostridium difficile/isolamento & purificação , Colite/etiologia , Infecções por Coronavirus/complicações , Infecção Hospitalar/etiologia , Pneumonia Viral/complicações , Colite/tratamento farmacológico , Colite/microbiologia , Infecções por Coronavirus/epidemiologia , Infecção Hospitalar/diagnóstico , Infecção Hospitalar/tratamento farmacológico , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/epidemiologia , Fatores de Risco , Fatores de Tempo , Tomografia Computadorizada por Raios X
4.
Nat Commun ; 11(1): 4076, 2020 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-32796851

RESUMO

Group 3 innate lymphoid cells (ILC3) are an important regulator for immunity, inflammation and tissue homeostasis in the intestine, but how ILC3 activation is regulated remains elusive. Here we identify a new circular RNA (circRNA) circKcnt2 that is induced in ILC3s during intestinal inflammation. Deletion of circKcnt2 causes gut ILC3 activation and severe colitis in mice. Mechanistically, circKcnt2, as a nuclear circRNA, recruits the nucleosome remodeling deacetylase (NuRD) complex onto Batf promoter to inhibit Batf expression; this in turn suppresses Il17 expression and thereby ILC3 inactivation to promote innate colitis resolution. Furthermore, Mbd3-/-Rag1-/- and circKcnt2-/-Rag1-/- mice develop severe innate colitis following dextran sodium sulfate (DSS) treatments, while simultaneous deletion of Batf promotes colitis resolution. In summary, our data support a function of the circRNA circKcnt2 in regulating ILC3 inactivation and resolution of innate colitis.


Assuntos
Colite/imunologia , Colite/metabolismo , Linfócitos/metabolismo , Canais de Potássio Ativados por Sódio/metabolismo , RNA Circular/metabolismo , Animais , Colite/patologia , Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Feminino , Proteínas de Homeodomínio/genética , Homeostase , Humanos , Imunidade Inata , Inflamação/imunologia , Inflamação/patologia , Intestinos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Camundongos Knockout , Canais de Potássio Ativados por Sódio/genética , RNA Circular/genética , RNA não Traduzido/genética , RNA não Traduzido/metabolismo , Fatores de Transcrição/genética
5.
Adv Exp Med Biol ; 1265: 133-151, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32761574

RESUMO

The intestine interacts with a diverse community of antigens and bacteria. To keep its homeostasis, the gut has evolved with a complex defense system, including intestinal microbiota, epithelial layer and lamina propria. Various factors (e.g., nutrients) affect the intestinal defensive system and progression of intestinal diseases. This review highlights the current understanding about the role of amino acids (AAs) in protecting the intestine from harm. Amino acids (e.g., arginine, glutamine and tryptophan) are essential for the function of intestinal microbiota, epithelial cells, tight junction, goblet cells, Paneth cells and immune cells (e.g., macrophages, B cells and T cells). Through the modulation of the intestinal defensive system, AAs maintain the integrity and function of the intestinal mucosa and inhibit the progression of various intestinal diseases (e.g., intestinal infection and intestinal colitis). Thus, adequate intake of functional AAs is crucial for intestinal and whole-body health in humans and other animals.


Assuntos
Aminoácidos/metabolismo , Mucosa Intestinal/citologia , Mucosa Intestinal/metabolismo , Animais , Colite , Microbioma Gastrointestinal , Humanos , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Junções Íntimas
6.
PLoS One ; 15(7): e0235706, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32639988

RESUMO

During type 1 immune responses, CD4 T helper 1 (Th1) cells and CD8 T cells are activated via IL-12 and contribute to the elimination of intracellular pathogens through interferon gamma (IFNγ) production. In this study, we identified Placenta-specific 8 (Plac8) as a gene that is uniquely expressed in Th1 CD4 T cells relative to other CD4 T cell subsets and hypothesized that Plac8 may represent a novel therapeutic target in Th1 CD4 T cells. First, we determined that Plac8 mRNA in CD4 T cells was induced following IL-12 stimulation via an indirect route that required new protein synthesis. Upon evaluating the functional relevance of Plac8 expression in Th1 CD4 T cells, we discovered that Plac8 was important for suppressing IFNγ mRNA and protein production by CD4 T cells 24 hours after IL-12 stimulation, however Plac8 did not contribute to pathogenic CD4 T cell function during two models of intestinal inflammation. We also noted relatively high basal expression of Plac8 in CD8 T cells which could be further induced following IL-12 stimulation in CD8 T cells. Furthermore, Plac8 expression was important for establishing an optimal CD8 T cell response against influenza A virus via a T cell-intrinsic manner. Altogether, these results implicate Plac8 as a potential regulator of Th1 CD4 and CD8 T cell responses during Th1 T cell-driven inflammation.


Assuntos
Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Interferon gama/metabolismo , Proteínas/metabolismo , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Colite/imunologia , Colite/patologia , Modelos Animais de Doenças , Interferon gama/genética , Interleucina-12/farmacologia , Antígenos Comuns de Leucócito/genética , Antígenos Comuns de Leucócito/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/patologia , Proteínas/genética , RNA Mensageiro/metabolismo , Regulação para Cima/efeitos dos fármacos
7.
Sci Total Environ ; 744: 140844, 2020 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-32711312

RESUMO

The potential health risk of environmental pollutant, cadmium, has become a public concern due to its widespread existence and long biological half-life. High-dose cadmium can induce various adverse outcomes, however, the chronic biological influences of cadmium at an environmental dosage and its mechanism remain largely unclear. Here, we investigated the effect of long-term exposure of cadmium at the environmental-relevant concentration on intestinal function. A chronic colitis mouse model was established through multiple cycles of dextran sulfate sodium (DSS) challenge and recovery. 200 nM cadmium in drinking water intensified colonic inflammation induced by DSS (histological score, DSS vs. DSS + Cd: 7.4 ± 1.21 vs. 10.67 ± 0.67, P < 0.05), including fecal occult bleeding and fecal consistency loss. Multiple inflammatory cytokines were significantly up-regulated by cadmium both in colon and plasma (P < 0.05). In addition, intestinal integrity was compromised by cadmium. Goblet cells were markedly reduced (ctrl vs. Cd: 48.33 ± 3.07 vs. 37.5 ± 2.14, P < 0.05) and plasma D-lactate (ctrl vs. Cd: 1.88 ± 0.20 vs. 2.80 ± 0.15, P < 0.01) and diamine oxidase (ctrl vs. Cd: 5.00 ± 0.87 vs. 11.21 ± 2.17, P < 0.05) were increased in cadmium-treated mice, indicating an elevated intestinal permeability. In vitro results showed that long-term exposure of cadmium down-regulated the expression and membrane localization of adherent and tight junction proteins in a time-dependent manner. In conclusion, long-term exposure of environmental dose of cadmium aggravated DSS-induced chronic colitis and disrupted intestinal barrier and impaired the adherent and tight junction proteins. These findings provide a better understanding about the health risk of cadmium in the environment.


Assuntos
Cádmio , Colite , Animais , Sulfato de Dextrana , Mucosa Intestinal , Camundongos , Camundongos Endogâmicos C57BL
10.
Georgian Med News ; (301): 165-170, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32535583

RESUMO

Nowadays, the etiological treatment of infectious diarrhea in both acute intestinal disorders and in chronic inflammatory bowel diseases is based on the use of antibiotics.Given the global formation of antibiotic-resistant strains of many pathogens, their rapid spread and the pronounced negative side effects of antibiotics on the macro-organism, the current trend is the search and creation of new drugs based on natural raw materials. Common Sage (CS) which antimicrobial effect is known, can be used to create drugs for the complex treatment of intestinal diseases. The aim of this study was to investigate the effectiveness of the use of CS extracts for the treatment of dysbiotic disorders that occurred in experimental infectious colitis in rats. To create experimental dysbiosis, animals were administered a suspension of microorganisms S. aureus, C. perfringens, C. albicans. The effect of 50% CS extract, complex of CS phenolic compounds with L-lysine was compared with the action of the antibiotic rifaximin and placebo on different groups of animals. The study found that the use of CS extracts of the drug show in the experiment in vivo antagonistic effect, in the comparison with the antibiotic, on microorganisms, but did not inhibit the representatives of normal gut microbiota. Thus, certain efficacy of CS for the correction of dysbiotic disorders has been revealed, which may be promising for further study of the use of CS extracts in the complex treatment of colitis.


Assuntos
Colite , Microbioma Gastrointestinal , Animais , Disbiose , Intestinos , Ratos , Staphylococcus aureus
11.
Nature ; 583(7816): 447-452, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32499651

RESUMO

Genetic variations underlying susceptibility to complex autoimmune and allergic diseases are concentrated within noncoding regulatory elements termed enhancers1. The functions of a large majority of disease-associated enhancers are unknown, in part owing to their distance from the genes they regulate, a lack of understanding of the cell types in which they operate, and our inability to recapitulate the biology of immune diseases in vitro. Here, using shared synteny to guide loss-of-function analysis of homologues of human enhancers in mice, we show that the prominent autoimmune and allergic disease risk locus at chromosome 11q13.52-7 contains a distal enhancer that is functional in CD4+ regulatory T (Treg) cells and required for Treg-mediated suppression of colitis. The enhancer recruits the transcription factors STAT5 and NF-κB to mediate signal-driven expression of Lrrc32, which encodes the protein glycoprotein A repetitions predominant (GARP). Whereas disruption of the Lrrc32 gene results in early lethality, mice lacking the enhancer are viable but lack GARP expression in Foxp3+ Treg cells, which are unable to control colitis in a cell-transfer model of the disease. In human Treg cells, the enhancer forms conformational interactions with the promoter of LRRC32 and enhancer risk variants are associated with reduced histone acetylation and GARP expression. Finally, functional fine-mapping of 11q13.5 using CRISPR-activation (CRISPRa) identifies a CRISPRa-responsive element in the vicinity of risk variant rs11236797 capable of driving GARP expression. These findings provide a mechanistic basis for association of the 11q13.5 risk locus with immune-mediated diseases and identify GARP as a potential target in their therapy.


Assuntos
Cromossomos Humanos Par 11/genética , Colite/genética , Colite/imunologia , Elementos Facilitadores Genéticos/genética , Predisposição Genética para Doença/genética , Linfócitos T Reguladores/imunologia , Acetilação , Alelos , Animais , Cromossomos de Mamíferos/genética , Feminino , Fatores de Transcrição Forkhead/metabolismo , Histonas/metabolismo , Humanos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Sintenia/genética
12.
J Comput Assist Tomogr ; 44(4): 619-626, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32558769

RESUMO

OBJECTIVE: The aim of the study was to study clinical, imaging findings, response patterns, and immune-related adverse events in classical Hodgkin lymphoma (cHL) and non-Hodgkin lymphoma (NHL) patients treated with immune checkpoint inhibitors (ICIs). METHODS: A retrospective search was performed to identify patients with relapsed/refractory cHL and NHL treated with ICIs from 2015 to 2019. Clinical and laboratory data were collected. Imaging studies were reviewed for treatment response and immune-related adverse events. RESULTS: Ten patients with relapsed/refractory cHL (median age, 41 years) and 14 patients with relapsed/refractory NHL (median age, 61 years) were identified. Overall response rate was 70% for cHL patients. None of the NHL patients demonstrated complete or partial response. One case of hyperprogression and one case with atypical response were radiologically detected in cHL patients. Hypothyroidism requiring treatment occurred in 2 (20%) of 10 cHL patients, one of which had imaging correlate. Of 14 NHL patients, 1 (7%) had radiologic evidence of pneumonitis and 1 (7%) had colitis. CONCLUSIONS: This single-institution observational study demonstrated that overall response rate was higher in patients with cHL undergoing ICI. Immune checkpoint inhibitor therapy has unique response patterns and toxicities in both cHL and NHL patients that radiologists should keep in mind.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Colite/epidemiologia , Doença de Hodgkin/tratamento farmacológico , Hipotireoidismo/epidemiologia , Linfoma não Hodgkin/tratamento farmacológico , Pneumonia/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/efeitos adversos , Colite/induzido quimicamente , Feminino , Doença de Hodgkin/diagnóstico por imagem , Humanos , Hipotireoidismo/induzido quimicamente , Linfoma não Hodgkin/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Nivolumabe/efeitos adversos , Nivolumabe/uso terapêutico , Pneumonia/induzido quimicamente , Interpretação de Imagem Radiográfica Assistida por Computador , Estudos Retrospectivos , Análise de Sobrevida , Centros de Atenção Terciária , Resultado do Tratamento , Adulto Jovem
13.
Acta Cir Bras ; 35(4): e202000404, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32555936

RESUMO

PURPOSE: To analyze the effect of calcitriol treatment on acute colitis in an experimental rat model. METHODS: A total of 24 adult Sprague Dawley albino rats were randomly separated into 3 equal groups: control group (n:8), colitis group (n:8), calcitriol administered group (n:8). A single dose of acetic acid (1 ml of 4% solution) was administered intrarectally to induce colitis. Group 1 was given 1 ml/kg 0.9% NaCl intraperitoneally; rats belonging to Group 2 were administered calcitriol 1 µg/kg for 5 days. RESULTS: Plasma tumor necrosis factor alpha, Pentraxin 3, and malondialdehyde levels were significantly lower in the calcitriol administered colitis group than in the standard colitis group (p<0.01). In the Calcitriol group, there was a significant histological improvement in hyperemia, hemorrhage and necrotic areas in the epithelium compared to the placebo group (p <0.000). CONCLUSION: The findings suggest that calcitriol may be an agent that could be used in acute colitis treatment.


Assuntos
Anti-Inflamatórios/uso terapêutico , Calcitriol/uso terapêutico , Colite/tratamento farmacológico , Doença Aguda , Animais , Proteína C-Reativa/análise , Colite/sangue , Colite/patologia , Modelos Animais de Doenças , Peroxidação de Lipídeos , Masculino , Malondialdeído/sangue , Estresse Oxidativo/genética , Distribuição Aleatória , Ratos Sprague-Dawley , Valores de Referência , Reprodutibilidade dos Testes , Componente Amiloide P Sérico/análise , Resultado do Tratamento , Fator de Necrose Tumoral alfa/análise
15.
Nihon Shokakibyo Gakkai Zasshi ; 117(6): 514-520, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32565509

RESUMO

The patient, a man in his 80s, presented with diarrhea following one year of treatment for non-small cell lung cancer with Nivolumab. CT results showed discontinuous wall thickening of the large bowel and cholangitis. Blood and stool culture tests ruled out immune-related adverse events and identified Edwardsiella tarda;bacterial colitis was diagnosed in the patient. This case confirmed that basic examination should not be neglected, and culture tests should be performed.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas , Colite/microbiologia , Infecções por Enterobacteriaceae/diagnóstico , Neoplasias Pulmonares , Nivolumabe/efeitos adversos , Idoso de 80 Anos ou mais , Edwardsiella tarda , Humanos , Masculino
18.
Nat Commun ; 11(1): 2361, 2020 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-32398640

RESUMO

The development of thymic regulatory T cells (Treg) is mediated by Aire-regulated self-antigen presentation on medullary thymic epithelial cells (mTECs) and dendritic cells (DCs), but the cooperation between these cells is still poorly understood. Here we show that signaling through Toll-like receptors (TLR) expressed on mTECs regulates the production of specific chemokines and other genes associated with post-Aire mTEC development. Using single-cell RNA-sequencing, we identify a new thymic CD14+Sirpα+ population of monocyte-derived dendritic cells (CD14+moDC) that are enriched in the thymic medulla and effectively acquire mTEC-derived antigens in response to the above chemokines. Consistently, the cellularity of CD14+moDC is diminished in mice with MyD88-deficient TECs, in which the frequency and functionality of thymic CD25+Foxp3+ Tregs are decreased, leading to aggravated mouse experimental colitis. Thus, our findings describe a TLR-dependent function of mTECs for the recruitment of CD14+moDC, the generation of Tregs, and thereby the establishment of central tolerance.


Assuntos
Colite/imunologia , Células Dendríticas/imunologia , Células Epiteliais/imunologia , Linfócitos T Reguladores/imunologia , Timo/imunologia , Transferência Adotiva , Animais , Apresentação do Antígeno , Autoantígenos/imunologia , Separação Celular , Quimiocinas/imunologia , Quimiocinas/metabolismo , Modelos Animais de Doenças , Células Epiteliais/metabolismo , Citometria de Fluxo , Receptores de Lipopolissacarídeos/metabolismo , Camundongos , Receptores Imunológicos/metabolismo , Tolerância a Antígenos Próprios , Análise de Sequência de RNA , Transdução de Sinais/imunologia , Análise de Célula Única , Linfócitos T Reguladores/transplante , Timo/citologia , Receptores Toll-Like/metabolismo , Regulação para Cima
20.
PLoS One ; 15(5): e0233044, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32453801

RESUMO

Mice deficient in the transcription factor Runx3 develop a multitude of immune system defects, including early onset colitis. This paper demonstrates that Runx3 is expressed in colonic mononuclear phagocytes (MNP), including resident macrophages (RM) and dendritic cell subsets (cDC2). Runx3 deletion in MNP causes early onset colitis due to their impaired maturation. Mechanistically, the resulting MNP subset imbalance leads to up-regulation of pro-inflammatory genes as occurs in IL10R-deficient RM. In addition, RM and cDC2 display a marked decrease in expression of anti-inflammatory/TGF ß-regulated genes and ß-catenin signaling associated genes, respectively. MNP transcriptome and ChIP-seq data analysis suggest that a significant fraction of genes affected by Runx3 loss are direct Runx3 targets. Collectively, Runx3 imposes intestinal immune tolerance by regulating maturation of colonic anti-inflammatory MNP, befitting the identification of RUNX3 as a genome-wide associated risk gene for various immune-related diseases in humans, including gastrointestinal tract diseases such as Crohn's disease and celiac.


Assuntos
Colite/imunologia , Colo/imunologia , Subunidade alfa 3 de Fator de Ligação ao Core/genética , Sistema Fagocitário Mononuclear/imunologia , Animais , Diferenciação Celular , Colite/genética , Modelos Animais de Doenças , Humanos , Camundongos , Receptores de Interleucina-10/genética , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Regulação para Cima , beta Catenina/metabolismo
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