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1.
Nat Genet ; 53(10): 1434-1442, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34594041

RESUMO

Mutation accumulation in somatic cells contributes to cancer development and is proposed as a cause of aging. DNA polymerases Pol ε and Pol δ replicate DNA during cell division. However, in some cancers, defective proofreading due to acquired POLE/POLD1 exonuclease domain mutations causes markedly elevated somatic mutation burdens with distinctive mutational signatures. Germline POLE/POLD1 mutations cause familial cancer predisposition. Here, we sequenced normal tissue and tumor DNA from individuals with germline POLE/POLD1 mutations. Increased mutation burdens with characteristic mutational signatures were found in normal adult somatic cell types, during early embryogenesis and in sperm. Thus human physiology can tolerate ubiquitously elevated mutation burdens. Except for increased cancer risk, individuals with germline POLE/POLD1 mutations do not exhibit overt features of premature aging. These results do not support a model in which all features of aging are attributable to widespread cell malfunction directly resulting from somatic mutation burdens accrued during life.


Assuntos
DNA Polimerase III/genética , DNA Polimerase II/genética , Mutação em Linhagem Germinativa/genética , Adolescente , Adulto , Idoso , Desenvolvimento Embrionário/genética , Genoma Humano/genética , Humanos , Neoplasias Intestinais/patologia , Intestinos/patologia , Pessoa de Meia-Idade , Mutagênese/genética , Filogenia , Células-Tronco/patologia , Adulto Jovem
2.
Nutrients ; 13(10)2021 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-34684316

RESUMO

(1) Background: The use of antibiotics affects the composition of gut microbiota. Studies have suggested that the colonization of gut microbiota in early life is related to later food allergies. Still, the relationship between altered intestinal microbiota in adulthood and food allergies is unclear. (2) Methods: We established three mouse models to analyze gut microbiota dysbiosis' impact on the intestinal barrier and determine whether this effect can increase the susceptibility to and severity of food allergy in later life. (3) Results: The antibiotic-induced gut microbiota dysbiosis significantly reduced Lachnospiraceae, Muribaculaceae, and Ruminococcaceae, and increased Enterococcaceae and Clostridiales. At the same time, the metabolic abundance was changed, including decreased short-chain fatty acids and tryptophan, as well as enhanced purine. This change is related to food allergies. After gut microbiota dysbiosis, we sensitized the mice. The content of specific IgE and IgG1 in mice serum was significantly increased, and the inflammatory response was enhanced. The dysbiosis of gut microbiota caused the sensitized mice to have more severe allergic symptoms, ruptured intestinal villi, and a decrease in tight junction proteins (TJs) when re-exposed to the allergen. (4) Conclusions: Antibiotic-induced gut microbiota dysbiosis increases the susceptibility and severity of food allergies. This event may be due to the increased intestinal permeability caused by decreased intestinal tight junction proteins and the increased inflammatory response.


Assuntos
Antibacterianos/efeitos adversos , Disbiose/induzido quimicamente , Disbiose/microbiologia , Hipersensibilidade Alimentar/complicações , Hipersensibilidade Alimentar/microbiologia , Microbioma Gastrointestinal , Intestinos/microbiologia , Intestinos/patologia , Animais , Biodiversidade , Modelos Animais de Doenças , Suscetibilidade a Doenças , Disbiose/complicações , Feminino , Haptoglobinas/metabolismo , Inflamação/patologia , Injeções Intraperitoneais , Metaboloma , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , Ovalbumina/administração & dosagem , Filogenia , Precursores de Proteínas/metabolismo , Receptor PAR-2/metabolismo , Índice de Gravidade de Doença , Proteínas de Junções Íntimas/metabolismo
3.
PLoS One ; 16(9): e0256957, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34478453

RESUMO

BACKGROUND: Intestinal ischemia/reperfusion (I/R)-injury often results in sepsis and organ failure and is of major importance in the clinic. A potential strategy to reduce I/R-injury is the application of ischemic preconditioning (IPC) during which repeated, brief episodes of I/R are applied. The aim of this study was to evaluate physiological and cellular effects of intestinal I/R-injury and to compare the influence of in-vivo IPC (iIPC) with ex-vivo IPC (eIPC), in which blood derived factors and nerval regulations are excluded. METHODS: Using an established perfused rat intestine model, effects of iIPC and eIPC on physiological as well as cellular mechanisms of I/R-injury (60 min hypoxia, 30 min reperfusion) were investigated. iIPC was applied by three reversible occlusions of the mesenteric artery in-vivo for 5 min followed by 5 min of reperfusion before isolating the small intestine, eIPC was induced by stopping the vascular perfusion ex-vivo 3 times for 5 min followed by 5 min of reperfusion after isolation of the intestine. Study groups (each N = 8-9 animals) were: iIPC, eIPC, I/R (iIPC group), I/R (eIPC group), iIPC+I/R, eIPC+I/R, no intervention/control (iIPC group), no intervention/control (eIPC group). Tissue morphology/damage, metabolic functions, fluid shifts and barrier permeability were evaluated. Cellular mechanisms were investigated using signaling arrays. RESULTS: I/R-injury decreased intestinal galactose uptake (iIPC group: p<0.001), increased vascular perfusion pressure (iIPC group: p<0.001; eIPC group: p<0.01) and attenuated venous flow (iIPC group: p<0.05) while lactate-to-pyruvate ratio (iIPC group, eIPC group: p<0.001), luminal flow (iIPC group: p<0.001; eIPC group: p<0.05), goblet cell ratio (iIPC group, eIPC group: p<0.001) and apoptosis (iIPC group, eIPC group: p<0.05) were all increased. Application of iIPC prior to I/R increased vascular galactose uptake (P<0.05) while eIPC had no significant impact on parameters of I/R-injury. On cellular level, I/R-injury resulted in a reduction of the phosphorylation of several MAPK signaling molecules. Application of iIPC prior to I/R increased phosphorylation of JNK2 and p38δ while eIPC enhanced CREB and GSK-3α/ß phosphorylation. CONCLUSION: Intestinal I/R-injury is associated with major physiological and cellular changes. However, the overall influence of the two different IPC strategies on the acute phase of intestinal I/R-injury is rather limited.


Assuntos
Intestinos/irrigação sanguínea , Traumatismo por Reperfusão/metabolismo , Animais , Feminino , Intestinos/patologia , Ratos , Ratos Wistar
4.
Cells ; 10(9)2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34571979

RESUMO

The CCNY gene, which encodes cyclin Y, has been implicated in the pathogenesis of inflammatory bowel disease (IBD). Cyclin Y promotes Wnt/ß-catenin signaling and autophagy, which are critical for intestinal epithelial cell (IEC) homeostasis, and may thereby contribute to wound repair in colitis. However, whether cyclin Y has an essential function in IECs is unknown. We, therefore, investigated the epithelial injury response and mucosal regeneration in mice with conditional knock-out of Ccny in the intestinal epithelium. We observed that Ccny-deficient mice did not exhibit any differences in cell proliferation and disease activity compared to wild-type littermates in the dextran sulfate sodium (DSS) colitis model. Complementary in vitro experiments showed that loss of CCNY in model IECs did not affect Wnt signaling, cell proliferation, or autophagy. Additionally, we observed that expression of the cyclin-Y-associated cyclin-dependent kinase (CDK) 14 is exceedingly low specifically in IEC. Collectively, these results suggest that cyclin Y does not contribute to intestinal epithelial homeostasis, possibly due to low levels of specific CDKs in these cells. Thus, it is unlikely that CCNY mutations are causatively involved in IBD pathogenesis.


Assuntos
Ciclinas/genética , Homeostase/genética , Doenças Inflamatórias Intestinais/genética , Mucosa Intestinal/patologia , Animais , Proliferação de Células/genética , Colite/induzido quimicamente , Colite/genética , Sulfato de Dextrana/farmacologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Células HCT116 , Células HEK293 , Humanos , Doenças Inflamatórias Intestinais/induzido quimicamente , Mucosa Intestinal/efeitos dos fármacos , Intestinos/efeitos dos fármacos , Intestinos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células PC-3 , Via de Sinalização Wnt/genética
5.
Nutrients ; 13(9)2021 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-34579023

RESUMO

The natural history of inflammatory bowel diseases, especially Crohn's disease, is frequently complicated by intestinal fibrosis. Because of the lack of effective treatments for intestinal fibrosis, there is an urgent need to develop new therapies. Factors promoting intestinal fibrosis are currently unclear, but diet is a potential culprit. Diet may influence predisposition to develop intestinal fibrosis or alter its natural history by modification of both the host immune response and intestinal microbial composition. Few studies have documented the effects of dietary factors in modulating IBD-induced intestinal fibrosis. As the mechanisms behind fibrogenesis in the gut are believed to be broadly similar to those from extra-intestinal organs, it may be relevant to investigate which dietary components can inhibit or promote fibrosis factors such as myofibroblasts progenitor activation in other fibrotic diseases.


Assuntos
Dieta/efeitos adversos , Intestinos/patologia , Fibrose , Humanos , Doenças Inflamatórias Intestinais/etiologia , Doenças Inflamatórias Intestinais/patologia , Intestinos/efeitos dos fármacos
6.
Int J Mol Sci ; 22(18)2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34576076

RESUMO

Mesenteric ischemia and reperfusion (I/R) injury can ensue from a variety of vascular diseases and represents a major cause of morbidity and mortality in intensive care units. It causes an inflammatory response associated with local gut dysfunction and remote organ injury. Adenosine monophosphate-activated protein kinase (AMPK) is a crucial regulator of metabolic homeostasis. The catalytic α1 subunit is highly expressed in the intestine and vascular system. In loss-of-function studies, we investigated the biological role of AMPKα1 in affecting the gastrointestinal barrier function. Male knock-out (KO) mice with a systemic deficiency of AMPKα1 and wild-type (WT) mice were subjected to a 30 min occlusion of the superior mesenteric artery. Four hours after reperfusion, AMPKα1 KO mice exhibited exaggerated histological gut injury and impairment of intestinal permeability associated with marked tissue lipid peroxidation and a lower apical expression of the junction proteins occludin and E-cadherin when compared to WT mice. Lung injury with neutrophil sequestration was higher in AMPKα1 KO mice than WT mice and paralleled with higher plasma levels of syndecan-1, a biomarker of endothelial injury. Thus, the data demonstrate that AMPKα1 is an important requisite for epithelial and endothelial integrity and has a protective role in remote organ injury after acute ischemic events.


Assuntos
Proteínas Quinases Ativadas por AMP/deficiência , Lesão Pulmonar Aguda/complicações , Intestinos/enzimologia , Intestinos/lesões , Isquemia Mesentérica/complicações , Traumatismo por Reperfusão/complicações , Proteínas Quinases Ativadas por AMP/genética , Lesão Pulmonar Aguda/enzimologia , Animais , Caderinas/metabolismo , Permeabilidade da Membrana Celular , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Células Epiteliais/metabolismo , Glicocálix/metabolismo , Intestinos/patologia , Isquemia Mesentérica/enzimologia , Camundongos Endogâmicos C57BL , Ocludina/metabolismo , Traumatismo por Reperfusão/enzimologia
7.
Biochem Biophys Res Commun ; 577: 103-109, 2021 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-34509721

RESUMO

As essential phospholipid signaling regulators, phospholipase C (PLC)s are activated by various extracellular ligands and mediate intracellular signal transduction. PLCγ1 is involved in regulating various cancer cell functions. However, the precise in vivo link between PLCγ1 and cancer behavior remains undefined. To investigate the role of PLCγ1 in colorectal carcinogenesis, we generated an intestinal tissue-specific Plcg1 knock out (KO) in adenomatous polyposis coli (Apc) Min/+ mice. Plcg1 deficiency in ApcMin/+ mice showed earlier death, with a higher colorectal tumor incidence in both number and size than in wild-type mice. Mechanistically, inhibition of PLCγ1 increased the levels of its substrate phosphoinositol 4,5-bisphosphate (PIP2) at the plasma membrane and promoted the activation of Wnt receptor low-density lipoprotein receptor-related protein 6 (LRP6) by glycogen synthase kinase 3ß (GSK3ß) to enhance ß-catenin signaling. Enhanced cell proliferation and Wnt/ß-catenin signaling were observed in colon tumors from Plcg1 KO mice. Furthermore, low PLCγ1 expression was associated with a poor prognosis of colon cancer patients. Collectively, we demonstrated the role of PLCγ1 in vivo as a tumor suppressor relationship between the regulation of the PIP2 level and Wnt/ß-catenin-dependent intestinal tumor formation.


Assuntos
Proliferação de Células/genética , Neoplasias Colorretais/genética , Regulação Neoplásica da Expressão Gênica , Fosfolipase C gama/genética , Via de Sinalização Wnt/genética , beta Catenina/genética , Animais , Linhagem Celular Tumoral , Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/patologia , Progressão da Doença , Glicogênio Sintase Quinase 3 beta/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Intestinos/enzimologia , Intestinos/patologia , Estimativa de Kaplan-Meier , Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosfatidilinositol 4,5-Difosfato/metabolismo , Fosfolipase C gama/deficiência , beta Catenina/metabolismo
9.
J Fish Dis ; 44(11): 1819-1829, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34339060

RESUMO

Parasite infections in fish require constant surveillance and strategies for efficient treatments which guarantee the fish health, their sale value and the non-propagation of pathogens in new environments. Fish treatments based on nanotechnology become of increasing interest since nanoparticles have been shown as efficient materials for optimizing administration of bioactives. In this study a chitosan derivative, alginate and praziquantel conjugated nanobioparticle of effective action for oral treatment of digenetic trematodes in highly infected Corydoras schwartzi was evaluated in terms of histological and hematological safety. The inherent absence of alterations in intestinal tissue and the reversible blood cells counting during a period up to 35 days showed the safety of the drug delivery nanobioparticles, which thus represent a promising strategy for effective applications in pathogens treatments by oral administration.


Assuntos
Peixes-Gato/parasitologia , Doenças dos Peixes/tratamento farmacológico , Nanopartículas , Praziquantel/administração & dosagem , Infecções por Trematódeos/veterinária , Administração Oral , Alginatos , Animais , Quitosana , Portadores de Fármacos , Doenças dos Peixes/parasitologia , Intestinos/efeitos dos fármacos , Intestinos/patologia , Trematódeos/efeitos dos fármacos , Infecções por Trematódeos/tratamento farmacológico
10.
Nutrients ; 13(8)2021 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-34444713

RESUMO

Herein, we investigate whether: (1) the administration of glucose or a lipid emulsion is useful in liver transplantation (LT) using steatotic (induced genetically or nutritionally) or non-steatotic livers from donors after brain death (DBDs); and (2) any such benefits are due to reductions in intestinal damage and consequently to gut microbiota preservation. In recipients from DBDs, we show increased hepatic damage and failure in the maintenance of ATP, glycogen, phospholipid and growth factor (HGF, IGF1 and VEGFA) levels, compared to recipients from non-DBDs. In recipients of non-steatotic grafts from DBDs, the administration of glucose or lipids did not protect against hepatic damage. This was associated with unchanged ATP, glycogen, phospholipid and growth factor levels. However, the administration of lipids in steatotic grafts from DBDs protected against damage and ATP and glycogen drop and increased phospholipid levels. This was associated with increases in growth factors. In all recipients from DBDs, intestinal inflammation and damage (evaluated by LPS, vascular permeability, mucosal damage, TLR4, TNF, IL1, IL-10, MPO, MDA and edema formation) was not shown. In such cases, potential changes in gut microbiota would not be relevant since neither inflammation nor damage was evidenced in the intestine following LT in any of the groups evaluated. In conclusion, lipid treatment is the preferable nutritional support to protect against hepatic damage in steatotic LT from DBDs; the benefits were independent of alterations in the recipient intestine.


Assuntos
Morte Encefálica , Fígado Gorduroso , Glucose/administração & dosagem , Transplante de Fígado , Fígado/metabolismo , Fosfolipídeos/administração & dosagem , Óleo de Soja/administração & dosagem , Trifosfato de Adenosina/metabolismo , Animais , Modelos Animais de Doenças , Emulsões/administração & dosagem , Fígado Gorduroso/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Intestinos/patologia , Intestinos/fisiopatologia , Fígado/patologia , Glicogênio Hepático/metabolismo , Masculino , Obesidade , Fosfolipídeos/metabolismo , Ratos , Ratos Zucker , Doadores de Tecidos
11.
Nutrients ; 13(8)2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34444932

RESUMO

Steatohepatitis and hepatobiliary manifestations constitute some of the most common extra-intestinal manifestations of Inflammatory Bowel Disease (IBD). On the other hand, non-alcoholic fatty liver disease (NAFLD) affects around 25% of the world's population and is attracting ever more attention in liver transplant programs. To outline the specific pathways linking these two conditions is a pressing task for 21st-century researchers. We are accustomed to expecting the occurrence of fatty liver disease in obese people, but current evidence suggests that there are several different pathways also occurring in underweight patients. Genetic factors, inflammatory signals and microbiota are key players that could help in understanding the entire pathogenesis of NAFLD, with the aim of defining the multiple expressions of malnutrition. In the current review, we summarize the most recent literature regarding the epidemiology, pathogenesis and future directions for the management of NAFLD in patients affected by IBD.


Assuntos
Doenças Inflamatórias Intestinais/epidemiologia , Desnutrição/epidemiologia , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Colite Ulcerativa/epidemiologia , Transplante de Microbiota Fecal/métodos , Feminino , Microbioma Gastrointestinal , Humanos , Intestinos/patologia , Masculino , Síndrome Metabólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/terapia , Estado Nutricional , Obesidade/epidemiologia , Prevalência , Fatores de Risco
12.
Biomolecules ; 11(8)2021 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-34439760

RESUMO

BACKGROUND: Accumulating evidence indicates that the gut microbiota can synthesize neurotransmitters as well as impact host-derived neurotransmitter levels. In the past, it has been challenging to decipher which microbes influence neurotransmitters due to the complexity of the gut microbiota. METHODS: To address whether a single microbe, Bifidobacterium dentium, could regulate important neurotransmitters, we examined Bifidobacteria genomes and explored neurotransmitter pathways in secreted cell-free supernatant using LC-MS/MS. To determine if B. dentium could impact neurotransmitters in vivo, we mono-associated germ-free mice with B. dentium ATCC 27678 and examined fecal and brain neurotransmitter concentrations. RESULTS: We found that B. dentium possessed the enzymatic machinery to generate γ-aminobutyric acid (GABA) from glutamate, glutamine, and succinate. Consistent with the genome analysis, we found that B. dentium secreted GABA in a fully defined microbial media and elevated fecal GABA in B. dentium mono-associated mice compared to germ-free controls. We also examined the tyrosine/dopamine pathway and found that B. dentium could synthesize tyrosine, but could not generate L-dopa, dopamine, norepinephrine, or epinephrine. In vivo, we found that B. dentium mono-associated mice had elevated levels of tyrosine in the feces and brain. CONCLUSIONS: These data indicate that B. dentium can contribute to in vivo neurotransmitter regulation.


Assuntos
Bifidobacterium/metabolismo , Neurotransmissores/metabolismo , Animais , Infecções por Bifidobacteriales/metabolismo , Encéfalo/metabolismo , Calibragem , Cromatografia Líquida , Microbioma Gastrointestinal , Genoma , Intestinos/patologia , Masculino , Camundongos , Microbiota , Espectrometria de Massas em Tandem , Tirosina/metabolismo
13.
Sci Rep ; 11(1): 16952, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34417512

RESUMO

The aim of the study was to assess the effect of fermented dried soybean (FSBM) and/or fermented rapeseed meal (FRSM) in diets for weaned piglets on production results, nutrient digestibility, gastrointestinal tract histology, and the composition of the gut microbiota. Piglets in the control group received standard diets with soybean meal. Animals in all experimental groups received diets in which a portion of the soybean meal was replaced: in group FR-8% FRSM; in group FR/FS-6% FRSM and 2% FSBM; in group FS/FR-2% FRSM and 6% FSBM and in group FS-8% FSBM. The use of 8% FRSM or 6% FRSM and 2% FSBM in the piglet diets had a positive effect on average daily gains. Piglets from the FR and FR/FS groups had the highest feed conversion rate. Group FS/FR and FS piglets had significantly lower mortality and lower incidence of diarrhoea. Piglets fed a diet with the fermented components, in particular with 8% FRSM or 6% FRSM and 2% FSBM, exhibited a positive effect on the microbiological composition and histology of intestines, which resulted in improved nutrient digestibility coefficients (ATTD and AID).


Assuntos
Brassica napus/química , Dieta , Fermentação , Intestinos/fisiologia , Soja/química , Animais , Peso Corporal , Diarreia/veterinária , Fezes/microbiologia , Íleo/microbiologia , Intestinos/patologia , Suínos
14.
Sci Rep ; 11(1): 15841, 2021 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-34349205

RESUMO

The intestinal epithelium is a unique tissue, serving both as a barrier against pathogens and to conduct the end digestion and adsorption of nutrients. As regards the former, the intestinal epithelium contains a diverse repertoire of immune cells, including a variety of resident lymphocytes, macrophages and dendritic cells. These cells serve a number of roles including mitigation of infection and to stimulate regeneration in response to damage. The transcription factor Cdx2, and to a lesser extent Cdx1, plays essential roles in intestinal homeostasis, and acts as a context-dependent tumour suppressor in colorectal cancer. Deletion of Cdx2 from the murine intestinal epithelium leads to macrophage infiltration resulting in a chronic inflammatory response. However the mechanisms by which Cdx2 loss evokes this response are poorly understood. To better understand this relationship, we used a conditional mouse model lacking all intestinal Cdx function to identify potential target genes which may contribute to this inflammatory phenotype. One such candidate encodes the histocompatability complex protein H2-T3, which functions to regulate intestinal iCD8α lymphocyte activity. We found that Cdx2 occupies the H3-T3 promoter in vivo and directly regulates its expression via a Cdx response element. Loss of Cdx function leads to a rapid and pronounced attenuation of H2-T3, followed by a decrease in iCD8α cell number, an increase in macrophage infiltration and activation of pro-inflammatory cascades. These findings suggest a previously unrecognized role for Cdx in intestinal homeostasis through H2-T3-dependent regulation of iCD8α cells.


Assuntos
Antígenos CD8/imunologia , Fator de Transcrição CDX2/fisiologia , Proteínas de Homeodomínio/fisiologia , Intestinos/imunologia , Linfócitos/imunologia , Macrófagos/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Animais , Diferenciação Celular , Intestinos/patologia , Camundongos , Camundongos Knockout , Regiões Promotoras Genéticas , Elementos de Resposta
15.
Avian Dis ; 65(2): 269-280, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34412458

RESUMO

Hemorrhagic hepatopathy is a syndrome reported in layer pullets resulting in mortality and lesions including hepatic, splenic, and intestinal necrosis; hepatic and splenic enlargement; hemorrhages; amyloidosis of the muscle, spleen, and liver; accumulation of noncoagulated hemorrhagic fluid in the coelom; and frequently, granulomatous myositis at bacterin injection sites. The syndrome is characterized in the literature in table egg layer pullets and is thought to be associated with the administration of bacterin vaccines, namely, frequently Salmonella enterica subsp. enterica bacterins. Hemorrhagic hepatopathy is recognized by industry veterinarians as also occurring infrequently in broiler breeder pullets in the United States. As the condition is likely due to an inflammatory process in response to bacterial lipopolysaccharide inoculation, it is important to characterize both the pathologic changes and predisposing factors for the condition in broiler breeds, which are immunologically different from table egg layer breeds. In this study, we characterize the gross and microscopic lesions observed in a series of diagnostic laboratory cases of hemorrhagic hepatopathy in broiler breeder pullets and suggest a possible pathophysiology for the condition. Additionally, we report results from a case survey of the United States broiler industry that suggest that the condition is due to a reaction to bacterin vaccination and that certain bacterin products may predispose pullet flocks to develop the condition. Although further research is indicated, these findings establish hemorrhagic hepatopathy as a pathologic condition of broiler breeder pullets and may aid in the diagnosis and prevention of the syndrome.


Assuntos
Galinhas , Hepatopatias/veterinária , Doenças das Aves Domésticas/patologia , Amiloidose/veterinária , Animais , Autopsia/veterinária , Feminino , Hemorragia , Incidência , Intestinos/patologia , Fígado/patologia , Hepatopatias/epidemiologia , Hepatopatias/etiologia , Hepatopatias/patologia , Doenças Musculares/epidemiologia , Doenças Musculares/etiologia , Doenças Musculares/patologia , Doenças Musculares/veterinária , Necrose , Doenças das Aves Domésticas/epidemiologia , Doenças das Aves Domésticas/etiologia , Estudos Retrospectivos , Baço/patologia , Inquéritos e Questionários , Síndrome , Vacinação/efeitos adversos , Vacinação/veterinária
16.
Anticancer Res ; 41(7): 3689-3698, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230168

RESUMO

BACKGROUND/AIM: SPARC-related modular calcium-binding protein 2 (SMOC2), a secreted matricellular protein, is reported to be involved in cancer progression such as cell cycle, angiogenesis, and invasion. In this study, we aimed to investigate the expression of SMOC2 in various gastric lesions and assessed its prognostic value in a large cohort of gastric cancer (GC) patients. PATIENTS AND METHODS: SMOC2 mRNA levels were measured by quantitative real-time PCR using 26 matched fresh-frozen GC samples. SMOC2 protein expression was determined by immunohistochemistry on tissue microarrays including 734 GC specimens and its correlations with clinicopathological features and survival were evaluated. RESULTS: The transcription level of SMOC2 was higher in GC samples compared to normal mucosa (p=0.006). Its expression levels were associated with the intestinal stem cell (ISC) marker, LGR5, but there were no correlations with EPHB2 and OLFM4 or the candidate cancer stem cell markers CD133 and CD44. SMOC2 expression was significantly increased in the intestinal metaplasia and was further increased in gastric adenomas and early gastric cancers (EGC). In total, 34% of GCs were positive for SMOC2, and SMOC2 positivity was higher in old (p=0.001) and male (p<0.001) patients, and in well-differentiated GC (p<0.001). SMOC2 expression had a negative association with perineural invasion (p<0.001) and tumor stage (p<0.001). In survival analysis, SMOC2-positive GC patients had much better clinical outcomes in overall survival rates (p<0.001) compared to SMOC2-negative GC patients. The prognostic impact of SMOC2 remained significant both in intestinal (p<0.001) and diffuse-type GC (p<0.001). Remarkably, a multivariate analysis demonstrated SMOC2 as an independent prognostic marker [hazard ratio (HR)=0.732, p=0.045] along with venous invasion (p=0.012), tumor stage (p<0.001) and CDX2 (p=0.028). CONCLUSION: Our results suggest that SMOC2 can be a prognostic marker for better clinical outcomes in GC.


Assuntos
Biomarcadores Tumorais/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Mucosa Intestinal/metabolismo , Intestinos/patologia , Células-Tronco Neoplásicas/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Idoso , Feminino , Humanos , Mucosa Intestinal/patologia , Masculino , Estadiamento de Neoplasias/métodos , Células-Tronco Neoplásicas/patologia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
17.
Fish Shellfish Immunol ; 117: 95-103, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34284110

RESUMO

The toxic effect of dietary histamine on the intestine of aquatic animals has been demonstrated, but reports on the morphological observation of the intestine are limited. Thus, a feeding trial was conducted to determine the effect of dietary histamine on intestinal histology, inflammatory status and gut microbiota of yellow catfish (Pelteobagrus fulvidraco). Here, we showed that histamine-rich diets caused severe abnormality and damage to the intestine, including a decreased villi length and reduced villi number. In addition, the quantitative real-time PCR (qRT-PCR) demonstrates that histamine-rich diets increased the expression of pro-inflammatory genes (Tnfα, Il1ß, and Il8) and decreased the expression of an anti-inflammatory gene (Il10). Furthermore, the alpha-diversity (observed OTUs, Chao1, Shannon and Simpson) and beta-diversity (non-metric multidimensional scaling, with the stress value of 0.17) demonstrated that histamine-rich diets caused alterations in gut microbiota composition and diversity. Co-occurrence networks analysis of the gut microbiota community showed that the histamine influenced the number and the relationship between bacteria species in the phyla of Acidobacteria, Proteobacteria, and Bacteroidetes, which caused the instability of the intestinal microbiota community. Additionally, random forest selected six bacterial species as the biomarkers to separate the three groups, which are Lachnospiraceae Blautia (V520), Bacteroidales S24.7 (V235), Chloroplast Streptophyta (V368), Actinomycetales Streptomycetaceae (V152), Clostridia Clostridiales (V491) and Paraprevotellaceae Prevotella (V245). Finally, Pearson correlation analysis demonstrated that V520, V235, and V491 were negatively correlated with pro-inflammatory factors (Tnfα, Il1ß, and Il8) and positively correlated with an anti-inflammatory factor (Il10), which indicated that V520, V235, and V491 might be anti-inflammatory. These findings improved our understanding of the toxic effect of dietary histamine to intestinal histological damage, the induction of mucosa inflammatory status, and the alteration of gut microbiota.


Assuntos
Peixes-Gato , Microbioma Gastrointestinal/efeitos dos fármacos , Histamina/toxicidade , Intestinos/efeitos dos fármacos , Animais , Peixes-Gato/genética , Peixes-Gato/imunologia , Peixes-Gato/microbiologia , Citocinas/genética , Dieta , Doenças dos Peixes/induzido quimicamente , Doenças dos Peixes/genética , Doenças dos Peixes/microbiologia , Doenças dos Peixes/patologia , Proteínas de Peixes/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/induzido quimicamente , Inflamação/genética , Inflamação/microbiologia , Inflamação/patologia , Intestinos/imunologia , Intestinos/patologia , Masculino
18.
Am J Physiol Gastrointest Liver Physiol ; 321(3): G280-G297, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34288735

RESUMO

Intestinal fibrosis is a common complication of the inflammatory bowel diseases (IBDs), contributing to tissue stiffening and luminal narrowing. Human nuclear receptor 4A 1 (NR4A1) was previously reported to regulate mesenchymal cell function and dampen fibrogenic signaling. NR4A1 gene variants are associated with IBD risk, and it has been shown to regulate intestinal inflammation. Here, we tested the hypothesis that NR4A1 acts as a negative regulator of intestinal fibrosis through regulating myofibroblast function. Using the SAMP1/YitFc mouse, we tested whether two pharmacological agents known to enhance NR4A1 signaling, cytosporone B (Csn-B) or 6-mercaptopurine (6-MP), could reduce fibrosis. We also used the dextran sulfate sodium (DSS) model of colitis and assessed the magnitude of colonic fibrosis in mouse nuclear receptor 4A 1 (Nr4a1-/-) and their wild-type littermates (Nr4a1+/+). Lastly, intestinal myofibroblasts isolated from Nr4a1-/- and Nr4a1+/+ mice or primary human intestinal myofibroblasts were stimulated with transforming growth factor-ß1 (TGF-ß1), in the presence or absence of Csn-B or 6-MP, and proliferation and ECM gene expression assessed. Csn-B or 6-MP treatment significantly reduced ileal thickness, collagen, and overall ECM content in SAMP1/YitFc mice. This was associated with a reduction in proliferative markers within the mesenchymal compartment. Nr4a1-/- mice exposed to DSS exhibited increased colonic thickening and ECM content. Nr4a1-/- myofibroblasts displayed enhanced TGF-ß1-induced proliferation. Furthermore, Csn-B or 6-MP treatment was antiproliferative in Nr4a1+/+ but not Nr4a1-/- cells. Lastly, activating NR4A1 in human myofibroblasts reduced TGF-ß1-induced collagen deposition and fibrosis-related gene expression. Our data suggest that NR4A1 can attenuate fibrotic processes in intestinal myofibroblasts and could provide a valuable clinical target to treat inflammation-associated intestinal fibrosis.NEW & NOTEWORTHY Fibrosis and increased muscle thickening contribute to stricture formation and intestinal obstruction, a complication that occurs in 30%-50% of patients with CD within 10 yr of disease onset. More than 50% of those who undergo surgery to remove the obstructed bowel will experience stricture recurrence. To date, there are no drug-based approaches approved to treat intestinal strictures. In the current submission, we identify NR4A1 as a novel target to treat inflammation-associated intestinal fibrosis.


Assuntos
Fibrose/metabolismo , Inflamação/metabolismo , Miofibroblastos/metabolismo , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Animais , Células Cultivadas , Humanos , Intestinos/patologia , Camundongos , Transdução de Sinais/fisiologia
19.
Dev Cell ; 56(13): 1884-1899.e5, 2021 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-34197724

RESUMO

Tissue homeostasis is achieved by balancing stem cell maintenance, cell proliferation and differentiation, as well as the purging of damaged cells. Elimination of unfit cells maintains tissue health; however, the underlying mechanisms driving competitive growth when homeostasis fails, for example, during tumorigenesis, remain largely unresolved. Here, using a Drosophila intestinal model, we find that tumor cells outcompete nearby enterocytes (ECs) by influencing cell adhesion and contractility. This process relies on activating the immune-responsive Relish/NF-κB pathway to induce EC delamination and requires a JNK-dependent transcriptional upregulation of the peptidoglycan recognition protein PGRP-LA. Consequently, in organisms with impaired PGRP-LA function, tumor growth is delayed and lifespan extended. Our study identifies a non-cell-autonomous role for a JNK/PGRP-LA/Relish signaling axis in mediating death of neighboring normal cells to facilitate tumor growth. We propose that intestinal tumors "hijack" innate immune signaling to eliminate enterocytes in order to support their own growth.


Assuntos
Proteínas de Transporte/genética , Proteínas de Drosophila/genética , Imunidade Inata/genética , MAP Quinase Quinase 4/genética , Neoplasias/genética , Fatores de Transcrição/genética , Animais , Adesão Celular/genética , Proliferação de Células/genética , Modelos Animais de Doenças , Drosophila melanogaster/genética , Drosophila melanogaster/imunologia , Enterócitos/metabolismo , Enterócitos/patologia , Humanos , Intestinos/crescimento & desenvolvimento , Intestinos/patologia , Mecanotransdução Celular/genética , NF-kappa B/genética , Neoplasias/patologia , Transdução de Sinais/genética , Microambiente Tumoral/genética
20.
Folia Parasitol (Praha) ; 682021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34232126

RESUMO

Myxobolus allami sp. n. is described from the intestinal wall of the silvery black porgy, Sparidentex hasta (Valenciennes), off Saudi Arabian coast of Arabian Gulf. Two of 20 examined fish were found to be infected with irregular-shaped plasmodia 3-8 mm long × 2-3 mm wide. Mature myxospores are subspherical to elliptical in the valvular view and oval in the sutural view, and are 11-13 (12) µm long, 7-8 (7.5) µm wide and 10-12 (10.8) µm thick. Spores have relatively thin valves and mostly (~ 72%) end with short caudal appendages of ~3 µm long. The spores also have two polar capsules, which are oval to elliptical and measure 5-7 (5.7) µm in length and 2-3 (2.7) µm in width. Polar filaments are coiled, with three turns. Transmission electron microscopy revealed that caudal appendages originated from the sutural edge at the posterior pole of the myxospore with density similar to that of its valves. The SSU rRNAgene sequence of the present species does not match any available sequences in GenBank. Phylogenetically, this species is sister to Myxobolus khaliji Zhang, Al-Qurausihy et Abdel-Baki, 2014 within a well-supported clade of Myxobolus-Henneguya with species infecting marine fishes. The combination of molecular data and morphological differences between this and other species of Myxobolus Bütschli, 1882 lead us to propose that the present form be established as a new species, M. allami. The present study also provides more evidence for the idea that caudal appendages cannot be reliably used to distinguish the species of the genera Myxobolus and Henneguya Thélohan, 1892.


Assuntos
Doenças dos Peixes/parasitologia , Interações Hospedeiro-Parasita , Intestinos/parasitologia , Myxobolus/classificação , Doenças Parasitárias em Animais/parasitologia , Perciformes , Animais , Intestinos/patologia , Microscopia Eletrônica de Transmissão/veterinária , Myxobolus/anatomia & histologia , Myxobolus/genética , Myxobolus/ultraestrutura , Filogenia , Arábia Saudita
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