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1.
J Toxicol Sci ; 45(9): 539-548, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32879253

RESUMO

We investigated the mechanism underlying intestinal cadmium (Cd) uptake based on the mediators (metal transporters) of essential elements, such as Fe, Zn, Cu, and Ca, under normal conditions in female rats. These elements interact with Cd uptake from the intestinal tract. Cd concentration at each site of the small intestine (duodenum, jejunum, and ileum) increased as Cd exposure increased. However, Cd concentration was the highest in the duodenum. The gene expression of ZIP14, DMT1, and ATP7A increased with increase in Cd concentration. Further, Cu concentration decreased as Cd concentration increased. In contrast, Fe concentration displayed a decreasing tendency with the increase in Cd concentration. The gene expression levels of ZIP14, DMT1, and ATP7A were positively correlated with Cd concentration. Immunohistochemical staining revealed the positive sites of ZIP14 and DMT1 scattered in the area adjacent to the goblet cells, resorbable epithelial cells, and lamina propria in the duodenum tissue, according to the increase in Cd concentration. Cd is induced to synthesize and bind to metallothionein (MT-I and -II) and accumulate in the intestinal tissues, mainly in the duodenum. Such findings suggest that Cd, a contaminant element, is taken up from the intestinal tract by multiple metal transporters such as Cu, Fe, and Zn, thereby involving in the intestinal Cd absorption.


Assuntos
Cádmio/metabolismo , Proteínas de Transporte de Cátions/metabolismo , Absorção Intestinal/genética , Mucosa Intestinal/metabolismo , Intestino Delgado/metabolismo , Animais , Proteínas de Transporte de Cátions/genética , Cobre , ATPases Transportadoras de Cobre/genética , ATPases Transportadoras de Cobre/metabolismo , Duodeno/metabolismo , Feminino , Expressão Gênica , Ferro , Metalotioneína/metabolismo , Ratos , Zinco
2.
Redox Biol ; 36: 101615, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32863223

RESUMO

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has resulted in hundreds of thousands of deaths worldwide. While the majority of people with COVID-19 won't require hospitalization, those who do may experience severe life-threatening complications, including acute respiratory distress syndrome. SARS-CoV-2 infects human cells by binding to the cellular surface protein angiotensin-converting enzyme 2 (ACE2); in addition, the cellular transmembrane serine protease 2 (TMPRSS2) is needed for priming of the spike (S) protein of the virus. Virus entry may also depend on the activity of the endosomal/lysosomal cysteine proteases cathepsin B, L (CTSB, CTSL) although their activity is likely dispensable. Given that the uncertainty of how COVID-19 kills, hampers doctors' ability to choose treatments the need for a deep understanding of COVID-19 biology is urgent. Herein, we performed an expression profiling meta-analysis of ACE2, TMPRSS2 and CTSB/L genes (and proteins) in public repository databases and found that all are widely expressed in human tissues; also, the ACE2 and TMPRSS2 genes tend to be co-regulated. The ACE2 and TMPRSS genes expression is (among others) suppressed by TNF, and is induced by pro-inflammatory conditions including obesity, Barrett's esophagus, stomach infection by helicobacter pylori, diabetes, autoimmune diseases and oxidized LDL; by exercise, as well as by growth factors, viruses' infections, cigarette smoke, interferons and androgens. Regarding currently investigated therapies interferon-beta induced ACE2 gene expression in bronchial epithelial cells, while chloroquine tends to upregulate CTSB/L genes. Finally, we analyzed KEGG pathways modulated by ACE2, TMPRSS2 and CTSB/L and probed DrugBank for drugs that target modules of the affected pathways. Our data indicate possible novel high-risk groups for COVID-19; provide a rich resource for future investigations of its pathogenesis and highlight the therapeutic challenges we face.


Assuntos
Betacoronavirus/fisiologia , Peptidil Dipeptidase A/genética , Serina Endopeptidases/genética , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Catepsinas/genética , Catepsinas/metabolismo , Perfilação da Expressão Gênica , Humanos , Mucosa Intestinal/metabolismo , Rim/metabolismo , Peptidil Dipeptidase A/metabolismo , Mucosa Respiratória/metabolismo , Serina Endopeptidases/metabolismo , Inibidores de Serino Proteinase/farmacologia , Internalização do Vírus/efeitos dos fármacos
3.
Chemosphere ; 254: 126904, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32957297

RESUMO

Estimating bioaccessible content of mercury in soils is essential in evaluating risks that contaminated soils pose. In this study, soil samples spiked with HgCl2 through adsorption were used to test the effects of liming, soil organic matter, soil depth, and Hg concentration on the following bioaccessibility tests: dilute nitric acid at room temperature, dilute nitric acid at body temperature, Simplified Bioaccessibility Extraction Test (SBET) method, and gastric phase of the In vitro Gastrointestinal (IVG) protocol. Soil and sediment samples from Descoberto, Minas Gerais (Brazil), a city with a well-known record of Hg contamination from artisanal mining, were subjected to these bioaccessibility tests for the first time, and the different methods of estimating bioaccessible content were compared. Bioaccessible fractions in spiked samples ranged from 10% to 60%, and this high bioaccessibility was due to the highly soluble species of Hg and the short time under adsorption. In general, clay and organic matter decreased bioaccessible content. Although the soil in Descoberto is undoubtedly polluted, mercury bioaccessibility in that area is low. In general, dilute nitric acid estimated higher bioaccessible content in soil samples, whereas the SBET method estimated higher bioaccessible content in sediment samples. In multivariate analysis, two groups of bioaccessibility tests arise: one with the two nitric acid tests, and the other with SBET and the gastric phase of the IVG protocol. The addition of pepsin and glycine in the last two tests suggests a more reliable test for assessing mercury bioaccessibility.


Assuntos
Argila/química , Substâncias Húmicas/análise , Mercúrio/análise , Mineração , Poluentes do Solo/análise , Solo/química , Adsorção , Disponibilidade Biológica , Brasil , Cidades , Mucosa Gástrica/metabolismo , Humanos , Mucosa Intestinal/metabolismo , Mercúrio/metabolismo , Modelos Biológicos , Ácido Nítrico/química , Poluentes do Solo/metabolismo
4.
Nat Commun ; 11(1): 4766, 2020 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-32958778

RESUMO

Germline telomere maintenance defects are associated with an increased incidence of inflammatory diseases in humans, yet whether and how telomere dysfunction causes inflammation are not known. Here, we show that telomere dysfunction drives pATM/c-ABL-mediated activation of the YAP1 transcription factor, up-regulating the major pro-inflammatory factor, pro-IL-18. The colonic microbiome stimulates cytosolic receptors activating caspase-1 which cleaves pro-IL-18 into mature IL-18, leading to recruitment of interferon (IFN)-γ-secreting T cells and intestinal inflammation. Correspondingly, patients with germline telomere maintenance defects exhibit DNA damage (γH2AX) signaling together with elevated YAP1 and IL-18 expression. In mice with telomere dysfunction, telomerase reactivation in the intestinal epithelium or pharmacological inhibition of ATM, YAP1, or caspase-1 as well as antibiotic treatment, dramatically reduces IL-18 and intestinal inflammation. Thus, telomere dysfunction-induced activation of the ATM-YAP1-pro-IL-18 pathway in epithelium is a key instigator of tissue inflammation.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas de Ciclo Celular/metabolismo , Inflamação/patologia , Telômero/patologia , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Antibacterianos/uso terapêutico , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Caspase 1/metabolismo , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/genética , Criança , Colo/metabolismo , Colo/microbiologia , Colo/patologia , Gastroenteropatias/patologia , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/fisiologia , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/microbiologia , Interleucina-18/genética , Interleucina-18/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Camundongos , Camundongos Mutantes , Fosforilação , Precursores de Proteínas/genética , Precursores de Proteínas/metabolismo , Transdução de Sinais , Telomerase/genética , Telomerase/metabolismo
5.
Emerg Microbes Infect ; 9(1): 2169-2179, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32969768

RESUMO

Studies on patients with the coronavirus disease-2019 (COVID-19) have implicated that the gastrointestinal (GI) tract is a major site of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We established a human GI tract cell line model highly permissive to SARS-CoV-2. These cells, C2BBe1 intestinal cells with a brush border having high levels of transmembrane serine protease 2 (TMPRSS2), showed robust viral propagation, and could be persistently infected with SARS-CoV-2, supporting the clinical observations of persistent GI infection in COVID-19 patients. Ectopic expression of viral receptors revealed that the levels of angiotensin-converting enzyme 2 (ACE2) expression confer permissiveness to SARS-CoV-2 infection, and TMPRSS2 greatly facilitates ACE2-mediated SARS-CoV-2 dissemination. Interestingly, ACE2 but not TMPRSS2 expression was significantly promoted by enterocytic differentiation, suggesting that the state of enterocytic differentiation may serve as a determining factor for viral propagation. Thus, our study sheds light on the pathogenesis of SARS-CoV-2 in the GI tract.


Assuntos
Betacoronavirus/fisiologia , Infecções por Coronavirus/virologia , Mucosa Intestinal/virologia , Pneumonia Viral/virologia , Betacoronavirus/genética , Linhagem Celular , Infecções por Coronavirus/genética , Infecções por Coronavirus/metabolismo , Trato Gastrointestinal/metabolismo , Trato Gastrointestinal/virologia , Humanos , Mucosa Intestinal/metabolismo , Pandemias , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/genética , Pneumonia Viral/metabolismo , Receptores Virais/genética , Receptores Virais/metabolismo , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo
6.
Khirurgiia (Mosk) ; (7): 12-17, 2020.
Artigo em Russo | MEDLINE | ID: mdl-32736458

RESUMO

OBJECTIVE: To determine the value of membrane protective effect in intestine and liver cells for the effectiveness of minimally invasive surgery for acute peritonitis. MATERIAL AND METHODS: Patients with acute peritonitis undergoing laparoscopic (n=60) and open (n=50) surgery are analyzed. Functional characteristics of liver and bowel, disorders of homeostasis were evaluated in early postoperative period. RESULTS: Reduced negative impact of surgical aggression on the state of liver and intestine is essential to improve treatment outcomes in patients with acute peritonitis undergoing minimally invasive surgery. Fast recovery of intestine inevitably results reduced release of endotoxins while restoration of liver function is associated with rapid elimination of these toxins. These processes prevent severe intoxication and facilitate accelerated recovery. Functional restoration of liver and bowel is associated with reduced oxidative stress during laparoscopic operations. It is also important because peritonitis causes activation of free-radical processes per se. Therefore, an additional source of oxidative phenomena is extremely undesirable in these cases. CONCLUSION: Laparoscopic surgery for acute peritonitis minimizes surgical aggression and is associated with more favorable recovery of liver and bowel function. Undoubtedly, these findings should be considered to choose surgical approach in this severe category of patients.


Assuntos
Procedimentos Cirúrgicos Minimamente Invasivos/efeitos adversos , Procedimentos Cirúrgicos Minimamente Invasivos/métodos , Peritonite/cirurgia , Doença Aguda , Membrana Celular/metabolismo , Membrana Celular/patologia , Membrana Celular/fisiologia , Humanos , Mucosa Intestinal/metabolismo , Intestinos/patologia , Intestinos/fisiopatologia , Laparoscopia/efeitos adversos , Laparotomia/efeitos adversos , Fígado/metabolismo , Fígado/patologia , Fígado/fisiopatologia , Estresse Oxidativo/fisiologia , Peritonite/metabolismo , Peritonite/fisiopatologia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/prevenção & controle , Recuperação de Função Fisiológica , Toxinas Biológicas/biossíntese , Toxinas Biológicas/metabolismo
7.
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
8.
Aquat Toxicol ; 226: 105567, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32745893

RESUMO

The increasing contamination of water bodies with mercury (Hg) raises concerns about the possible effects of this metal on native fish species. Our current understanding of its dynamics in fish organs remains limited. In this study, adult individuals of the native species Astyanax eigenmanniorum were exposed to three environmentally relevant HgCl2 concentrations (5, 100, and 170 µg L-1) for 96 h. To evaluate total Hg (THg) elimination, new individuals were exposed to 100 µg L-1 of HgCl2 (96 h), and at the end of the exposure period, half of the fish were placed in tanks with clean water for 168 h. In both assays, the organs were removed, and THg levels were measured using ICP-MS. The uptake of IHg in A. eigenmanniorum showed a differential accumulation in the organs. Gills, intestine, and brain were the tissues with the highest THg levels. Finally, no elimination of THg in the water was observed, but intestine and gills significantly removed the THg accumulated. Probably a Hg redistribution through the tissues could take place.


Assuntos
Characidae/metabolismo , Mercúrio/metabolismo , Poluentes Químicos da Água/metabolismo , Adulto , Animais , Bioacumulação , Encéfalo/metabolismo , Characidae/sangue , Monitoramento Ambiental , Brânquias/metabolismo , Humanos , Mucosa Intestinal/metabolismo , Mercúrio/análise , Mercúrio/toxicidade , Taxa de Depuração Metabólica , Distribuição Tecidual , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/toxicidade
9.
Int J Nanomedicine ; 15: 3869-3875, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764920

RESUMO

Introduction: During routine surgery, rapid hemostasis, especially the rapid hemostasis of internal organs, is very important. The emergence of in-situ electrospinning technology has fundamentally solved this problem. It exhibits a high speed of hemostasis, and no bleeding occurs after surgery. Thus, it is of great significance. The use of sutures in some human organs, such as the intestines and bladder, is inadequate because fluid leakage occurs due to the presence of pinholes. Methods: Three types of large intestine wounds with an opening of about 1 cm were investigated. They were untreated, treated by needle and threaded, and treated by hand-held electrospinning, respectively. Results: The results show that hand-held electrospinning technique effectively prevented the exudation of fluids in the intestinal tract. The average diameter of the nanofibrous membrane was about 0.5 µm with hole of several micrometers. It can be elongated 90% without breakage. The hand-held electrospinning device could be used with nitrile gloves, preventing the risk of infection caused by exposed hands. Discussion: This work can provide a reference for future animal experiments and clinical experiments. However, safety should be investigated before application.


Assuntos
Eletricidade , Hemostasia , Mucosa Intestinal/metabolismo , Procedimentos Cirúrgicos Operatórios/métodos
10.
Nat Commun ; 11(1): 4102, 2020 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-32796823

RESUMO

Emerging evidence suggests that intestinal stromal cells (IntSCs) play essential roles in maintaining intestinal homeostasis. However, the extent of heterogeneity within the villi stromal compartment and how IntSCs regulate the structure and function of specialized intestinal lymphatic capillary called lacteal remain elusive. Here we show that selective hyperactivation or depletion of YAP/TAZ in PDGFRß+ IntSCs leads to lacteal sprouting or regression with junctional disintegration and impaired dietary fat uptake. Indeed, mechanical or osmotic stress regulates IntSC secretion of VEGF-C mediated by YAP/TAZ. Single-cell RNA sequencing delineated novel subtypes of villi fibroblasts that upregulate Vegfc upon YAP/TAZ activation. These populations of fibroblasts were distributed in proximity to lacteal, suggesting that they constitute a peri-lacteal microenvironment. Our findings demonstrate the heterogeneity of IntSCs and reveal that distinct subsets of villi fibroblasts regulate lacteal integrity through YAP/TAZ-induced VEGF-C secretion, providing new insights into the dynamic regulatory mechanisms behind lymphangiogenesis and lymphatic remodeling.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas de Ciclo Celular/metabolismo , Fibroblastos/metabolismo , Mucosa Intestinal/metabolismo , Fatores de Transcrição/metabolismo , Fator C de Crescimento do Endotélio Vascular/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Proteínas de Ciclo Celular/genética , Células Cultivadas , Análise por Conglomerados , Ensaio de Imunoadsorção Enzimática , Fibroblastos/ultraestrutura , Citometria de Fluxo , Imunofluorescência , Hibridização in Situ Fluorescente , Mucosa Intestinal/ultraestrutura , Linfangiogênese/genética , Linfangiogênese/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Eletrônica , Neovascularização Fisiológica/genética , Neovascularização Fisiológica/fisiologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição/genética , Fator C de Crescimento do Endotélio Vascular/genética
11.
PLoS One ; 15(8): e0237086, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764782

RESUMO

Paramylon is a novel ß-glucan that is stored by Euglena gracilis Z, which is a unicellular photosynthesizing green alga with characteristics of both animals and plants. Recent studies have indicated that paramylon functions as an immunomodulator or a dietary fiber. Currently, chronic kidney disease (CKD) is a global health problem, and there is no effective preventive treatment for CKD progression. However, paramylon may suppress the progression of CKD via the elimination of uremic toxins or modulation of gut microbiota, leading to the alleviation of inflammation. The aim of this study was to evaluate the effect of paramylon in CKD rat model. Eight-week-old male Wistar rats with a 5/6 nephrectomy were given either a normal diet or a diet containing 5% paramylon for 8 weeks. Proteinuria was measured intermittently. Serum and kidney tissues were harvested after sacrifice. We performed a renal molecular and histopathological investigation, serum metabolome analysis, and gut microbiome analysis. The results showed that paramylon attenuated renal function, glomerulosclerosis, tubulointerstitial injury, and podocyte injury in the CKD rat model. Renal fibrosis, tubulointerstitial inflammatory cell infiltration, and proinflammatory cytokine gene expression levels tended to be suppressed with paramylon treatment. Further, paramylon inhibited the accumulation of uremic toxins, including tricarboxylic acid (TCA) cycle-related metabolites and modulated a part of CKD-related gut microbiota in the CKD rat model. In conclusion, we suggest that paramylon mainly inhibited the absorption of non-microbiota-derived uremic solutes, leading to protect renal injury via anti-inflammatory and anti-fibrotic effects. Paramylon may be a novel compound that can act against CKD progression.


Assuntos
Glucanos/farmacologia , Rim/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Proteinúria/tratamento farmacológico , Insuficiência Renal Crônica/tratamento farmacológico , Administração Oral , Animais , Ciclo do Ácido Cítrico/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Euglena gracilis/química , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/imunologia , Glucanos/isolamento & purificação , Glucanos/uso terapêutico , Humanos , Mediadores da Inflamação/metabolismo , Absorção Intestinal/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Rim/imunologia , Rim/patologia , Masculino , Substâncias Protetoras/isolamento & purificação , Substâncias Protetoras/uso terapêutico , Proteinúria/sangue , Proteinúria/patologia , Ratos , Ratos Wistar , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/patologia , Insuficiência Renal Crônica/urina , Toxinas Biológicas/sangue , Toxinas Biológicas/metabolismo
12.
Ecotoxicol Environ Saf ; 203: 111032, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32745774

RESUMO

Titanium dioxide nanoparticles (Np-TiO2) have become the common component of sunscreen cosmetic products. Np-TiO2 can affect especially aquatic ecosystems health, including aquatic organisms such as fish. It is therefore necessary to acquire a better understanding of the effect of Np-TiO2 on aquatic organisms. This study evaluated the biological effects of Np-TiO2 on Danio rerio, such as survival rate and weight change and, in particular, the Ti content or retention in the intestine and liver, as well as the activities of catalase and superoxide dismutase enzymes. In addition, the structure of the intestine, kidney, and liver was investigated through histological analysis. Ninety zebrafish were used, randomly divided into three treatment-groups: a control group (fed with food without adding Np-TiO2) and two groups of fish fed with food containing Np-TiO2 exposed for 7 and 14 days. The amount of Ti in the liver and intestine was measured using atomic absorption spectrophotometry coupled to a graphite furnace (GFAAS). Morphological analysis and enzyme catalase and superoxide dismutase assays were likewise performed. Ti was detected in all fish even in control group; probably Ti must have been introduced during production by the fish food industry. Structural changes were detected in fish fed with Np-TiO2 as vacuolization and disruption of the apical cytoplasm of epithelial cells that covered the intestinal villi. Although kidney morphology appeared intact, the lumen of the proximal tubule was enlarged, and the cells of the distal tubule were vacuolated. No morphological changes in the liver were detected; however, superoxide dismutase activity decreased, suggesting that liver changes occurred at the molecular level. Thus, Np-TiO2 causes morphological changes in the intestine, kidney, and liver of zebrafish and biochemical changes in the liver exposed for 7 and 14 days. Although not highly lethal, Np-TiO2 in the food chain can interfere with the morphophysiology of aquatic organisms. Neither mortalities nor body weight losses were recorded among fish in all groups over the duration of the experiment.


Assuntos
Mucosa Intestinal/efeitos dos fármacos , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Nanopartículas/toxicidade , Titânio/toxicidade , Poluentes Químicos da Água/toxicidade , Peixe-Zebra , Animais , Bioacumulação , Catalase , Relação Dose-Resposta a Droga , Ecossistema , Cadeia Alimentar , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Rim/metabolismo , Rim/patologia , Fígado/metabolismo , Fígado/patologia , Nanopartículas/metabolismo , Distribuição Aleatória , Protetores Solares/química , Titânio/metabolismo , Poluentes Químicos da Água/metabolismo
13.
PLoS One ; 15(8): e0236657, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32760089

RESUMO

Crohn's disease is a pathological condition of the gastro-intestinal tract, causing severe transmural inflammation in the ileum and/or colon. Cigarette smoking is one of the best known environmental risk factors for the development of Crohn's disease. Nevertheless, very little is known about the effect of prolonged cigarette smoke exposure on inflammatory modulators in the gut. We examined the effect of cigarette smoke on cytokine profiles in the healthy and inflamed gut of human subjects and in the trinitrobenzene sulphonic acid mouse model, which mimics distal Crohn-like colitis. In addition, the effect of cigarette smoke on epithelial expression of transient receptor potential channels and their concurrent increase with cigarette smoke-augmented cytokine production was investigated. Active smoking was associated with increased IL-8 transcription in ileum of controls (p < 0,001; n = 18-20/group). In the ileum, TRPV1 mRNA levels were decreased in never smoking Crohn's disease patients compared to healthy subjects (p <0,001; n = 20/group). In the colon, TRPV1 mRNA levels were decreased (p = 0,046) in smoking healthy controls (n = 20/group). Likewise, healthy mice chronically exposed to cigarette smoke (n = 10/group) showed elevated ileal Cxcl2 (p = 0,0075) and colonic Kc mRNA levels (p = 0,0186), whereas TRPV1 mRNA and protein levels were elevated in the ileum (p = 0,0315). Although cigarette smoke exposure prior to trinitrobenzene sulphonic acid administration did not alter disease activity, increased pro-inflammatory cytokine production was observed in the distal colon (Kc: p = 0,0273; Cxcl2: p = 0,104; Il1-ß: p = 0,0796), in parallel with the increase of Trpv1 mRNA (p < 0,001). We infer that CS affects pro-inflammatory cytokine expression in healthy and inflamed gut, and that the simultaneous modulation of TRPV1 may point to a potential involvement of TRPV1 in cigarette smoke-induced production of inflammatory mediators.


Assuntos
Colo/metabolismo , Doença de Crohn/metabolismo , Íleo/metabolismo , Canais de Cátion TRPV/metabolismo , Fumar Tabaco/efeitos adversos , Adulto , Idoso , Animais , Células CACO-2 , Colo/patologia , Doença de Crohn/induzido quimicamente , Doença de Crohn/patologia , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Células HT29 , Humanos , Íleo/patologia , Inflamação/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Pesquisa Médica Translacional , Ácido Trinitrobenzenossulfônico
14.
Ecotoxicol Environ Saf ; 204: 111072, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32758694

RESUMO

Zearalenone (ZEN) is a mycotoxin that causes serious health problems in humans and animals. However, few studies have focused on the destruction of the intestinal barrier caused by ZEN. In this study, rats were exposed to different dosages of ZEN (0, 0.2, 1.0 and 5.0 mg/kg bw) by gavage for 4 weeks. The results showed that 1.0 and 5.0 mg/kg ZEN impaired gut morphology, induced the inflammatory response, reduced mucin expression, increased intestinal permeability, decreased the expression of TJ proteins and activated the RhoA/ROCK pathway. However, 0.2 mg/kg ZEN had no significant effect on intestinal barrier except for reducing the expression of some TJ proteins and mucins. Moreover, exposure to ZEN led to slight imbalance in microbiota. In conclusion, ZEN exposure resulted in intestinal barrier dysfunction by inducing intestinal microbiota dysbiosis, decreasing the expression of TJ proteins, activating the RhoA/ROCK pathway, and inducing the inflammatory response.


Assuntos
Microbioma Gastrointestinal/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Jejuno/efeitos dos fármacos , Zearalenona/toxicidade , Animais , Relação Dose-Resposta a Droga , Disbiose/induzido quimicamente , Feminino , Microbioma Gastrointestinal/genética , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Jejuno/microbiologia , Jejuno/patologia , Masculino , Mucinas/metabolismo , Permeabilidade , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Quinases Associadas a rho/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo
15.
Ecotoxicol Environ Saf ; 204: 111069, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32758696

RESUMO

We studied the absorption, cytotoxicity and oxidative stress markers of Paralytic Shellfish Toxins (PST) from three extracts from Alexandrium catenella and A. ostenfeldii, in middle Oncorhynchus mykiss intestine in vitro and ex vivo preparations. We measured glutathione (GSH) content, glutathione-S transferase (GST), glutathione reductase (GR) and catalase (CAT) enzymatic activity, and lipid peroxidation in isolated epithelium exposed to 0.13 and 1.3 µM PST. ROS production and lysosomal membrane stability (as neutral red retention time 50%, NRRT50) were analyzed in isolated enterocytes exposed to PST alone or plus 3 µM of the ABCC transport inhibitor MK571. In addition, the concentration-dependent effects of PST on NRRT50 were assayed in a concentration range from 0 to 1.3 µM PST. We studied the effects of three different PST extracts on the transport rate of the ABCC substrate DNP-SG by isolated epithelium. The extract with highest inhibition capacity was selected for studying polarized DNP-SG transport in everted and non-everted intestinal segments. We registered lower GSH content and GST activity, and higher GR activity, with no significant changes in CAT activity, lipid peroxidation or ROS level. PST exposure decreased NRRT50 in a concentration-depend manner (IC50 = 0.0045 µM), but PST effects were not augmented by addition of MK571. All the three PST extracts inhibited ABCC transport activity, but this inhibition was effective only when the toxins were applied to the apical side of the intestine and DNP-SG transport was measured at the basolateral side. Our results indicate that PST are absorbed by the enterocytes from the intestine lumen. Inside the enterocytes, these toxins decrease GSH content and inhibit the basolateral ABCC transporters affecting the normal functions of the cell. Furthermore, PST produce a strong cytotoxic effect to the enterocytes by damaging the lysosomal membrane, even at low, non-neurotoxic concentrations.


Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Glutationa/análogos & derivados , Mucosa Intestinal/efeitos dos fármacos , Lisossomos/efeitos dos fármacos , Oncorhynchus mykiss/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Saxitoxina/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Catalase/metabolismo , Dinoflagelados/metabolismo , Enterócitos/efeitos dos fármacos , Enterócitos/metabolismo , Glutationa/metabolismo , Glutationa Transferase/metabolismo , Mucosa Intestinal/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Lisossomos/metabolismo , Frutos do Mar
16.
PLoS One ; 15(8): e0235575, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32745084

RESUMO

The sugarcane borer (Diatraea saccharalis, Fabricius, 1794) is a devastating pest that causes millions of dollars of losses each year to sugarcane producers by reducing sugar and ethanol yields. The control of this pest is difficult due to its endophytic behavior and rapid development. Pest management through biotechnological approaches has emerged in recent years as an alternative to currently applied methods. Genetic information about the target pests is often required to perform biotechnology-based management. The genomic and transcriptomic data for D. saccharalis are very limited. Herein, we report a tissue-specific transcriptome of D. saccharalis larvae and a differential expression analysis highlighting the physiological characteristics of this pest in response to two different diets: sugarcane and an artificial diet. Sequencing was performed on the Illumina HiSeq 2000 platform, and a de novo assembly was generated. A total of 27,626 protein-coding unigenes were identified, among which 1,934 sequences were differentially expressed between treatments. Processes such as defence, digestion, detoxification, signaling, and transport were highly represented among the differentially expressed genes (DEGs). Furthermore, seven aminopeptidase genes were identified as candidates to encode receptors of Cry proteins, which are toxins of Bacillus thuringiensis used to control lepidopteran pests. Since plant-insect interactions have produced a considerable number of adaptive responses in hosts and herbivorous insects, the success of phytophagous insects relies on their ability to overcome challenges such as the response to plant defences and the intake of nutrients. In this study, we identified metabolic pathways and specific genes involved in these processes. Thus, our data strongly contribute to the knowledge advancement of insect transcripts, which can be a source of target genes for pest management.


Assuntos
Dieta , Mucosa Intestinal/metabolismo , Lepidópteros/genética , Transcriptoma , Aminopeptidases/genética , Aminopeptidases/metabolismo , Animais , Herbivoria/genética , Proteínas de Insetos/genética , Proteínas de Insetos/metabolismo , Lepidópteros/metabolismo , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo
17.
Life Sci ; 257: 118017, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32603821

RESUMO

AIMS: Mesenchymal stem cell (MSC)-derived exosomes (MSCs-exos) regulate biological functions in different diseases, such as liver fibrosis, diabetes, and ischaemic heart injury. However, the function of MSC-derived exosomes on the intestinal barrier and the underlying mechanisms are poorly characterized. MAIN METHODS: The expression of miR-34a/c-5p, miR-29b-3p and Claudin-3 in human normal intestinal tissues and damaged intestinal tissues was evaluated by RT-qPCR. The effect of MSC-secreted exosomes on Claudins in Caco-2 cells was measured by using confocal microscopy, RT-qPCR and Western blot. Dual luciferase reporter assays and RNA immunoprecipitation (RIP) assays were performed to study the interaction between miR-34a/c-5p, miR-29b-3p and Snail. I/R-induced intestinal damage in rats was used to determine the in vivo effect of MSC-exos on intestinal barrier function. KEY FINDINGS: In this study, we found that miR-34a/c-5p, miR-29b-3p and Claudin-3 were downregulated in damaged human intestinal tissues. MSC-exos increased the expression of Claudin-3, Claudin-2 and ZO-1 in Caco-2 cells. Further studies demonstrated that MSC-exos promoted Claudin-3, Claudin-2 and ZO-1 expression in Caco-2 cells by Snail, which was targeted by miR-34a/c-5p and miR-29b-3p. In vivo experiments showed that MSC-derived exosomes could improve I/R-induced intestinal damage through the Snail/Claudins signaling pathway. SIGNIFICANCE: The findings here suggest a novel molecular basis for the therapy of intestinal barrier dysfunction.


Assuntos
Mucosa Intestinal/metabolismo , MicroRNAs/genética , Animais , Condrócitos/metabolismo , Claudinas/metabolismo , Exossomos/genética , Exossomos/metabolismo , Humanos , Intestinos/fisiologia , Masculino , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/fisiologia , MicroRNAs/fisiologia , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais , Fatores de Transcrição da Família Snail/metabolismo
18.
PLoS Pathog ; 16(7): e1008682, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32730327

RESUMO

Porcine epidemic diarrhea virus (PEDV) mainly infects the intestinal epithelial cells of newborn piglets causing acute, severe atrophic enteritis. The underlying mechanisms of PEDV infection and the reasons why newborn piglets are more susceptible than older pigs remain incompletely understood. Iron deficiency is common in newborn piglets. Here we found that high levels of transferrin receptor 1 (TfR1) distributed in the apical tissue of the intestinal villi of newborns, and intracellular iron levels influence the susceptibility of newborn piglets to PEDV. We show that iron deficiency induced by deferoxamine (DFO, an iron chelating agent) promotes PEDV infection while iron accumulation induced by ferric ammonium citrate (FAC, an iron supplement) impairs PEDV infection in vitro and in vivo. Besides, PEDV infection was inhibited by occluding TfR1 with antibodies or decreasing TfR1 expression. Additionally, PEDV infection was increased in PEDV-resistant Caco-2 and HEK 293T cells over-expressed porcine TfR1. Mechanistically, the PEDV S1 protein interacts with the extracellular region of TfR1 during PEDV entry, promotes TfR1 re-localization and clustering, then activates TfR1 tyrosine phosphorylation mediated by Src kinase, and heightens the internalization of TfR1, thereby promoting PEDV entry. Taken together, these data suggest that the higher expression of TfR1 in the apical tissue of the intestinal villi caused by iron deficiency, accounts for newborn piglets being acutely susceptible to PEDV.


Assuntos
Infecções por Coronavirus/veterinária , Suscetibilidade a Doenças/metabolismo , Mucosa Intestinal/metabolismo , Vírus da Diarreia Epidêmica Suína , Receptores da Transferrina/metabolismo , Doenças dos Suínos/metabolismo , Animais , Animais Recém-Nascidos , Suscetibilidade a Doenças/virologia , Ferro/deficiência , Suínos , Doenças dos Suínos/virologia
19.
Postepy Biochem ; 66(2): 143-150, 2020 06 27.
Artigo em Polonês | MEDLINE | ID: mdl-32700508

RESUMO

Inflammatory bowel diseases are a group of chronic diseases of the digestive tract of unknown origin. The etiology of IBD is multifactorial and involves interaction between genetic, environmental and immunological factors with oxidative stress being an inherent part of any one of them. Therefore, the redox equilibrium is crucial to maintain cell homeostasis in the gastrointestinal (GI) tract, which is constantly exposed to large numbers of commensal and pathological bacteria. Distortion of this homeostasis and increase in oxidative stress leads to the propagation of inflammation, mucosal injury in the GI tract and is associated with the development and exacerbation of IBD.


Assuntos
Doenças Inflamatórias Intestinais/etiologia , Doenças Inflamatórias Intestinais/metabolismo , Estresse Oxidativo , Homeostase , Humanos , Inflamação , Doenças Inflamatórias Intestinais/patologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Oxirredução
20.
Diabetes ; 69(9): 1875-1886, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32669391

RESUMO

Individuals with diabetes suffering from coronavirus disease 2019 (COVID-19) exhibit increased morbidity and mortality compared with individuals without diabetes. In this Perspective, we critically evaluate and argue that this is due to a dysregulated renin-angiotensin system (RAS). Previously, we have shown that loss of angiotensin-I converting enzyme 2 (ACE2) promotes the ACE/angiotensin-II (Ang-II)/angiotensin type 1 receptor (AT1R) axis, a deleterious arm of RAS, unleashing its detrimental effects in diabetes. As suggested by the recent reports regarding the pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), upon entry into the host, this virus binds to the extracellular domain of ACE2 in nasal, lung, and gut epithelial cells through its spike glycoprotein subunit S1. We put forth the hypothesis that during this process, reduced ACE2 could result in clinical deterioration in COVID-19 patients with diabetes via aggravating Ang-II-dependent pathways and partly driving not only lung but also bone marrow and gastrointestinal pathology. In addition to systemic RAS, the pathophysiological response of the local RAS within the intestinal epithelium involves mechanisms distinct from that of RAS in the lung; however, both lung and gut are impacted by diabetes-induced bone marrow dysfunction. Careful targeting of the systemic and tissue RAS may optimize clinical outcomes in subjects with diabetes infected with SARS-CoV-2.


Assuntos
Angiotensina II/metabolismo , Betacoronavirus/metabolismo , Infecções por Coronavirus/metabolismo , Diabetes Mellitus/metabolismo , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/metabolismo , Receptor Tipo 1 de Angiotensina/metabolismo , Sistema Renina-Angiotensina , Medula Óssea/metabolismo , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/fisiopatologia , Humanos , Mucosa Intestinal/metabolismo , Pandemias , Pneumonia Viral/mortalidade , Pneumonia Viral/fisiopatologia , Índice de Gravidade de Doença
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