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1.
FASEB J ; 36(1): e22061, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34861075

RESUMO

Corticosterone, the stress hormone, exacerbates alcohol-associated tissue injury, but the mechanism involved is unknown. We examined the role of the glucocorticoid receptor (GR) in corticosterone-mediated potentiation of alcohol-induced gut barrier dysfunction and systemic response. Hepatocyte-specific GR-deficient (GRΔHC ) and intestinal epithelial-specific GR-deficient (GRΔIEC ) mice were fed ethanol, combined with corticosterone treatment. Intestinal epithelial tight junction integrity, mucosal barrier function, microbiota dysbiosis, endotoxemia, systemic inflammation, liver damage, and neuroinflammation were assessed. Corticosterone potentiated ethanol-induced epithelial tight junction disruption, mucosal permeability, and inflammatory response in GRΔHC mouse colon; these effects of ethanol and corticosterone were absent in GRΔIEC mice. Gut microbiota compositions in ethanol-fed GRΔHC and GRΔIEC mice were similar to each other. However, corticosterone treatment in ethanol-fed mice shifted the microbiota composition to distinctly different directions in GRΔHC and GRΔIEC mice. Ethanol and corticosterone synergistically elevated the abundance of Enterobacteriaceae and Escherichia coli and reduced the abundance of Lactobacillus in GRΔHC mice but not in GRΔIEC mice. In GRΔHC mice, corticosterone potentiated ethanol-induced endotoxemia and systemic inflammation, but these effects were absent in GRΔIEC mice. Interestingly, ethanol-induced liver damage and its potentiation by corticosterone were observed in GRΔHC mice but not in GRΔIEC mice. GRΔIEC mice were also resistant to ethanol- and corticosterone-induced inflammatory response in the hypothalamus. These data indicate that the intestinal epithelial GR plays a central role in alcohol- and corticosterone-induced gut barrier dysfunction, microbiota dysbiosis, endotoxemia, systemic inflammation, liver damage, and neuroinflammation. This study identifies a novel target for potential therapeutic for alcohol-associated tissue injury.


Assuntos
Corticosterona/efeitos adversos , Etanol/efeitos adversos , Mucosa Intestinal/metabolismo , Receptores de Glucocorticoides/metabolismo , Junções Íntimas/metabolismo , Animais , Corticosterona/farmacologia , Escherichia coli/metabolismo , Etanol/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Mucosa Intestinal/microbiologia , Lactobacillus/metabolismo , Camundongos , Camundongos Transgênicos , Permeabilidade/efeitos dos fármacos , Receptores de Glucocorticoides/genética , Junções Íntimas/genética
2.
Environ Toxicol ; 37(1): 28-40, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34558770

RESUMO

Benzophenone-3 (BP-3), one of the most commonly utilized ultraviolet filters in personal care products, has aroused public concern in recent years for its high chances of human exposure. Previous studies have found that BP-3 can impair testes development and spermatogenesis, but the targets of BP-3 are still unknown. In this study, primary Sertoli cells from 20-day-old mice were treated in vitro with 0-100 µM BP-3 for 24 h to identify its toxicity on Sertoli cells and Sertoli cell barrier. Results demonstrated that BP-3 could induce a notable change in cell morphology and impair Sertoli cell viability. The analysis of transepithelial electrical resistance showed that the integrity of the Sertoli cell barrier was destroyed by BP-3 (100 µM). Some structural proteins of the barrier including ZO-1, Occludin, and Connexin43 were lower expressed and the localization of basal ectoplasmic specializations protein ß-catenin was altered because of BP-3 treatment. Further exploration suggested that BP-3 led to Sertoli cell F-actin disorganization by affecting the expression of Rictor, a key component of the mTORC2 complex. Moreover, although increased DNA damage marker γH2A.X was observed in the treatment group, the cell apoptosis rate was changeless which was further confirmed by increased BAX and stable Bcl-2 (two primary apoptosis regulating proteins). In conclusion, this study revealed that BP-3 had the potential to perturb the Sertoli cell barrier through altered junction proteins and disorganized F-actin, but it could hardly evoke Sertoli cell apoptosis.


Assuntos
Actinas , Células de Sertoli , Animais , Apoptose , Benzofenonas , Barreira Hematotesticular , Masculino , Camundongos , Ratos , Ratos Sprague-Dawley , Espermatogênese , Junções Íntimas
3.
J Sci Food Agric ; 102(1): 434-444, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34143895

RESUMO

BACKGROUND: The incidence of inflammatory bowel disease (IBD) continues to increase worldwide. Multiple factors, including diet, loss of the intestinal barrier function, and imbalance of the immune system can cause IBD. A balanced diet is important for maintaining a healthy bowel and preventing IBD from occurring. The effects of probiotic Lactobacillus gasseri-fermented Maillard reaction products (MRPs) prepared by reacting whey protein with galactose on anti-inflammation and intestinal homeostasis were investigated in this study, which compared MPRs and probiotics separately. RESULTS: In an animal colitis model induced by 2% dextran sulfate sodium (DSS), FWG administration alleviated colon length loss and maintained intestinal immune system homeostasis as reflected by down-regulated interleukin (IL)-6, IL-10, tumor necrosis factor (TNF)-α output, and metallopeptidase-9, and epithelial barrier balance as reflected by up-regulated occludin, E-cadherin, and zonula occludens-1 production in the colon. Furthermore, the expression of splenic cytokines such as IL-6, TNF-α, and IL-10 was up-regulated in the FWG-treated mice in a comparable amount to the control group to ensure the balance of immune responses. CONCLUSION: This study showed that the use of FWG protects the intestines from colitis caused by DSS and maintains immune balance. FWG increased antioxidant enzyme activity, increased intestinal permeability, and regulated the balance of pro- and anti-inflammatory cytokines in the intestines and spleen. Continued intake of FWG can alleviate IBD symptoms through the preservation of mucosal immune responses, epithelial junction and homeostasis through the regulated splenic cytokines. © 2021 Society of Chemical Industry.


Assuntos
Colite/tratamento farmacológico , Produtos Finais de Glicação Avançada/administração & dosagem , Lactobacillus gasseri/metabolismo , Probióticos/administração & dosagem , Animais , Anti-Inflamatórios/administração & dosagem , Colite/induzido quimicamente , Colite/imunologia , Colite/fisiopatologia , Colo/efeitos dos fármacos , Colo/imunologia , Sulfato de Dextrana/efeitos adversos , Modelos Animais de Doenças , Galactose/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Homeostase/efeitos dos fármacos , Humanos , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Junções Íntimas/genética , Junções Íntimas/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia , Proteínas do Soro do Leite/metabolismo
4.
Methods Mol Biol ; 2383: 371-384, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34766302

RESUMO

This chapter describes the use of cell-penetrating peptides (CPPs) as carriers for transepithelial delivery of therapeutic peptides. Assessment of transepithelial peptide permeation and the mechanisms of action that permeability enhancing drug carriers exert on the epithelium requires subtle sample preparation and analysis by orthogonal methods. Here, the preparation and use of CPP-insulin physical mixture samples including the quantification of insulin by enzyme-linked immunosorbent assay (ELISA) is described. In addition, effects of CPPs on the epithelium and its barrier properties immediately upon exposure and after a recovery period are evaluated by epithelial cell viability, transepithelial electrical resistance, immunostaining of the tight junction associated zonula occludens (ZO-1) protein, and actin cytoskeleton staining.


Assuntos
Sistemas de Liberação de Medicamentos , Células CACO-2 , Peptídeos Penetradores de Células , Portadores de Fármacos , Humanos , Insulina , Junções Íntimas
5.
Cells ; 10(12)2021 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-34944085

RESUMO

Osmotic stress plays a crucial role in the pathogenesis of many gastrointestinal diseases. Lactobacillus casei and epidermal growth factor (EGF) effects on the osmotic stress-induced epithelial junctional disruption and barrier dysfunction were investigated. Caco-2 cell monolayers were exposed to osmotic stress in the presence or absence of L. casei or EGF, and the barrier function was evaluated by measuring inulin permeability. Tight junction (TJ) and adherens junction integrity were assessed by immunofluorescence confocal microscopy. The role of signaling molecules in the L. casei and EGF effects was determined by using selective inhibitors. Data show that pretreatment of cell monolayers with L. casei or EGF attenuates osmotic stress-induced TJ and adherens junction disruption and barrier dysfunction. EGF also blocked osmotic stress-induced actin cytoskeleton remodeling. U0126 (MEK1/2 inhibitor), the MAP kinase inhibitor, blocked EGF-mediated epithelial protection from osmotic stress. In contrast, the L. casei-mediated epithelial protection from osmotic stress was unaffected by U0126, AG1478 (EGFR tyrosine kinase inhibitor), SP600125 (JNK1/2 inhibitor), or SB202190 (P38 MAP kinase inhibitor). On the other hand, Ro-32-0432 (PKC inhibitor) blocked the L. casei-mediated prevention of osmotic stress-induced TJ disruption and barrier dysfunction. The combination of EGF and L. casei is more potent in protecting the barrier function from osmotic stress. These findings suggest that L. casei and EGF ameliorate osmotic stress-induced disruption of apical junctional complexes and barrier dysfunction in the intestinal epithelium by distinct signaling mechanisms.


Assuntos
Fator de Crescimento Epidérmico/farmacologia , Lactobacillus casei/fisiologia , Pressão Osmótica , Junções Íntimas/patologia , Citoesqueleto de Actina/efeitos dos fármacos , Citoesqueleto de Actina/metabolismo , Junções Aderentes/efeitos dos fármacos , Junções Aderentes/metabolismo , Células CACO-2 , Receptores ErbB/metabolismo , Humanos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Pressão Osmótica/efeitos dos fármacos , Proteína Quinase C/metabolismo , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismo
6.
Sheng Li Xue Bao ; 73(6): 931-939, 2021 Dec 25.
Artigo em Chinês | MEDLINE | ID: mdl-34961868

RESUMO

Endothelial tight junctions (TJs) serve as an important barrier in vascular endothelial structure and maintain vascular function homeostasis. Occludin, the most representative tight junction protein, is involved in sealing cell connections and maintaining the integrity and permeability of vascular endothelium. Recent studies have shown that alterations in the expression, distribution, and structure of endothelial TJs may lead to many related vascular diseases and pathologies (such as stroke, atherosclerosis, and pulmonary hypertension etc.). Here, we reviewed the research advances on the relationship between occludin and vascular endothelial injury, including the biological information of occludin, the signal pathways that occludin exerts the protective effect of vascular endothelium, and the relationship between occludin and vascular endothelial injury-related diseases.


Assuntos
Endotélio Vascular , Junções Íntimas , Ocludina/genética , Transdução de Sinais
7.
Zhonghua Nan Ke Xue ; 27(6): 499-505, 2021 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-34914288

RESUMO

Objective: To investigate the role of occludin in tight junction (TJ) in vitro. METHODS: We constructed RNA interfering lentiviral vectors and transfected them into TM4 cells. Then we detected their inhibitory effect on occuldin by RT-PCR and Western blot and analyzed the role of occuldin in TJ using an in vitro TJ cell model. RESULTS: The pLenti 6.3-EGFP-occludin-miR expression vector was successfully constructed. The results of RT-PCR and Western blot showed that pLenti 6.3-EGFP-occludin-miR-3 significantly inhibited the expression of occludin (P < 0.05), which was remarkably lower than in the blank control and the pLenti 6.3- EGFP transfection group (0.7534 ± 0.089 vs 1.000 and 1.056 ± 0.025, P < 0.05). The expression of occludin was markedly suppressed and the tightness of tight junctions decreased in the TM4 cells transfected with pLenti 6.3-EGFP-occludin-miR-3. CONCLUSIONS: The pLenti 6.3-EGFP-occludin-miR expression vector was successfully constructed, and occludin is one of the functional proteins that maintain tight junctions.


Assuntos
Ocludina , Interferência de RNA , Junções Íntimas , Animais , Linhagem Celular , Lentivirus , Camundongos , Ocludina/genética
8.
Elife ; 102021 12 24.
Artigo em Inglês | MEDLINE | ID: mdl-34951586

RESUMO

Tight junctions (TJs) between blood-brain barrier (BBB) endothelial cells construct a robust physical barrier, whose damage underlies BBB dysfunctions related to several neurodegenerative diseases. What makes these highly specialized BBB-TJs extremely restrictive remains unknown. Here, we use super-resolution microscopy (dSTORM) to uncover new structural and functional properties of BBB TJs. Focusing on three major components, Nano-scale resolution revealed sparse (occludin) vs. clustered (ZO1/claudin-5) molecular architecture. In mouse development, permeable TJs become first restrictive to large molecules, and only later to small molecules, with claudin-5 proteins arrangement compacting during this maturation process. Mechanistically, we reveal that ZO1 clustering is independent of claudin-5 in vivo. In contrast to accepted knowledge, we found that in the developmental context, total levels of claudin-5 inversely correlate with TJ functionality. Our super-resolution studies provide a unique perspective of BBB TJs and open new directions for understanding TJ functionality in biological barriers, ultimately enabling restoration in disease or modulation for drug delivery.


Assuntos
Barreira Hematoencefálica/citologia , Microscopia/métodos , Junções Íntimas/fisiologia , Animais , Camundongos , Camundongos Endogâmicos ICR , Microscopia/classificação
9.
Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi ; 56(11): 1185-1193, 2021 Nov 07.
Artigo em Chinês | MEDLINE | ID: mdl-34749458

RESUMO

Objective: To study the changes in the permeability of the blood labyrinth barrier of the aging cochlea in mice, and to establish a non-contact co-culture model of endothelial cells (EC) and pericytes (PC) to furtherly investigate the cochlear stria vascularis microvascular pericytes impact on the permeability of endothelial cells. Methods: C57BL/6J mice were divided into two groups, three months old as young group, 12 months old as senile group. Cell experiment was divided into four groups, EC group, EC+PC co-culture group, D-gal+EC group and D-gal+EC+PC co-culture group. Auditory brainstem response (auditory brain response, ABR) was used to detect the auditory function of the two groups of mice. Evans blue staining was applied to detect the permeability of the cochlear blood labyrinth barrier of the two groups of mice. Transmission electron microscopy was used to observe the ultrastructure of blood labyrinth barrier endothelial cells, pericytes and tight junctions in the two groups of mice. Immunohistochemistry was used to detect the expression levels of tight junction proteins in the stria vascularis of the cochlea of the two groups of mice. Transwell chamber was used to detect the permeability of endothelial cells. Western blot and immunofluorescence technology were used to detect the expression level of tight junction protein on endothelial cells. SPSS 20.0 software was used to analyze the data. Results: Compared with the young group, the ABR threshold of the aging group was significantly increased, the latency of wave I was prolonged (t=10.25, P<0.01;t=5.61, P<0.05), the permeability of the cochlear blood labyrinth barrier was increased and the expression of tight junction protein on the vascular stria was decreased (P<0.05). The cochlear ultrastructure showed that the cochlear vascular stria microvascular lumen was deformed, the basement membrane thickened and the tight junction gap between endothelium enlarged. The positive rate of ECs and PCs in primary culture was more than 95%. The cells induced by 15 g/L D-gal were determined to be senescent cells. Compared with EC group, the expression of tight junction protein in endothelial cells of D-gal+EC group decreased(t=7.42,P<0.01;t=13.19,P<0.05)and the permeability increased (t=11.17, P<0.01). In the co-culture group, the expression of tight junction protein between endothelial cells in EC+PC co-culture group and D-gal+EC+PC co-culture group increased and the permeability decreased. Conclusions: In aging mice, the permeability of cochlear blood labyrinth barrier will increase and the level of tight junction protein will decrease; in aging state, cochlear vascular stria microvascular pericytes may affect endothelial cell permeability by regulating the expression of tight junction protein.


Assuntos
Pericitos , Estria Vascular , Animais , Cóclea , Células Endoteliais , Camundongos , Camundongos Endogâmicos C57BL , Permeabilidade , Junções Íntimas
10.
J Agric Food Chem ; 69(45): 13500-13509, 2021 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-34729976

RESUMO

The preventive effect and molecular mechanism of lycopene (LP) in dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in mice were evaluated. Compared to the DSS group, the LP prevention groups not only significantly inhibited the DSS-induced weight loss, decreased the disease activity index (DAI) score, increased the colon length, and improved inflammation in the colon but also significantly increased the levels of superoxide dismutase (SOD),catalase (CAT), glutathione peroxidase (GSH-Px), and glutathione (GSH) in the colon and reduced inflammatory cytokine, myeloperoxidase (MPO), and malondialdehyde (MDA) levels. Notably, when compared to the DSS group, the protein expression levels of TLR4, TRIF, and p-NF-κB p65 in the mice colon tissue were downregulated and those of tight junction-related proteins were upregulated in the LP + DSS group, with the most significant effect observed in the 10 mg/kg LP + DSS group. These results confirmed that the upregulation of tight junction-related protein expression after blocking the TLR4/TRIF/NF-κB signaling pathway may be one of the mechanisms through which LP prevents UC.


Assuntos
Colite Ulcerativa , Colite , Proteínas Adaptadoras de Transporte Vesicular , Animais , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/genética , Colo/metabolismo , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Licopeno , Camundongos , NF-kappa B/genética , NF-kappa B/metabolismo , Transdução de Sinais , Junções Íntimas/metabolismo , Receptor 4 Toll-Like/genética
11.
Int J Mol Sci ; 22(21)2021 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-34768787

RESUMO

The intestinal barrier plays an extremely important role in maintaining the immune homeostasis of the gut and the entire body. It is made up of an intricate system of cells, mucus and intestinal microbiota. A complex system of proteins allows the selective permeability of elements that are safe and necessary for the proper nutrition of the body. Disturbances in the tightness of this barrier result in the penetration of toxins and other harmful antigens into the system. Such events lead to various digestive tract dysfunctions, systemic infections, food intolerances and autoimmune diseases. Pathogenic and probiotic bacteria, and the compounds they secrete, undoubtedly affect the properties of the intestinal barrier. The discovery of zonulin, a protein with tight junction regulatory activity in the epithelia, sheds new light on the understanding of the role of the gut barrier in promoting health, as well as the formation of diseases. Coincidentally, there is an increasing number of reports on treatment methods that target gut microbiota, which suggests that the prevention of gut-barrier defects may be a viable approach for improving the condition of COVID-19 patients. Various bacteria-intestinal barrier interactions are the subject of this review, aiming to show the current state of knowledge on this topic and its potential therapeutic applications.


Assuntos
Infecções Bacterianas/terapia , Haptoglobinas/metabolismo , Mucosa Intestinal/metabolismo , Probióticos/uso terapêutico , Precursores de Proteínas/metabolismo , Antibacterianos/uso terapêutico , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/patologia , Fenômenos Fisiológicos Bacterianos , Microbioma Gastrointestinal , Humanos , Mucosa Intestinal/microbiologia , Muco/metabolismo , Junções Íntimas/metabolismo
12.
J Clin Invest ; 131(17)2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34623320

RESUMO

Genome-wide association studies revealed that loss-of-function mutations in protein tyrosine phosphatase non-receptor type 2 (PTPN2) increase the risk of developing chronic immune diseases, such as inflammatory bowel disease (IBD) and celiac disease. These conditions are associated with increased intestinal permeability as an early etiological event. The aim of this study was to examine the consequences of deficient activity of the PTPN2 gene product, T cell protein tyrosine phosphatase (TCPTP), on intestinal barrier function and tight junction organization in vivo and in vitro. Here, we demonstrate that TCPTP protected against intestinal barrier dysfunction induced by the inflammatory cytokine IFN-γ by 2 mechanisms: it maintained localization of zonula occludens 1 and occludin at apical tight junctions and restricted both expression and insertion of the cation pore-forming transmembrane protein, claudin-2, at tight junctions through upregulation of the inhibitory cysteine protease, matriptase. We also confirmed that the loss-of-function PTPN2 rs1893217 SNP was associated with increased intestinal claudin-2 expression in patients with IBD. Moreover, elevated claudin-2 levels and paracellular electrolyte flux in TCPTP-deficient intestinal epithelial cells were normalized by recombinant matriptase. Our findings uncover distinct and critical roles for epithelial TCPTP in preserving intestinal barrier integrity, thereby proposing a mechanism by which PTPN2 mutations contribute to IBD.


Assuntos
Mucosa Intestinal/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 2/metabolismo , Junções Íntimas/metabolismo , Adolescente , Adulto , Idoso , Animais , Claudinas/metabolismo , Modelos Animais de Doenças , Feminino , Estudo de Associação Genômica Ampla , Humanos , Técnicas In Vitro , Doenças Inflamatórias Intestinais/etiologia , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/metabolismo , Mucosa Intestinal/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Permeabilidade , Polimorfismo de Nucleotídeo Único , Proteína Tirosina Fosfatase não Receptora Tipo 2/deficiência , Proteína Tirosina Fosfatase não Receptora Tipo 2/genética , Junções Íntimas/patologia , Adulto Jovem
13.
J Clin Invest ; 131(17)2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34623321

RESUMO

It is clear that excessive mucosal immune activation and intestinal barrier dysfunction both contribute to inflammatory bowel disease (IBD) pathogenesis. T cell protein tyrosine phosphatase (TCPTP), which extinguishes signaling in immune cells, is linked to IBD and other immune-mediated diseases. In this issue of the JCI, Marchelletta and Krishnan et al. demonstrate that, in intestinal epithelial cells, TCPTP regulates tight junction permeability in vivo. Intestinal epithelial TCPTP loss potentiated cytokine-induced barrier loss, and this synergized with effects of TCPTP loss in immune cells. This work implicates a single mutation as the cause of distinct functional aberrations in diverse cell types and demonstrates how one genetic defect can drive multihit disease pathogenesis.


Assuntos
Doenças Inflamatórias Intestinais , Proteína Tirosina Fosfatase não Receptora Tipo 2 , Epitélio , Humanos , Doenças Inflamatórias Intestinais/genética , Mucosa Intestinal , Mutação , Proteína Tirosina Fosfatase não Receptora Tipo 2/genética , Junções Íntimas
14.
FASEB J ; 35(11): e21937, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34606628

RESUMO

Defective permeability barrier is considered to be an incentive of hyperuricemia, however, the link between them has not been proven. Here, we evaluated the potential preventive effects of Lactiplantibacillus plantarum N-1 (LPN1) on gut microbiota and intestinal barrier function in rats with hyperoxaluria-induced kidney stones. Male rats were supplied with 1% ethylene glycol (EG) dissolved in drinking water for 4 weeks to develop hyperoxaluria, and some of them were administered with LPN1 for 4 weeks before EG treatment as a preventive intervention. We found that EG not only resulted hyperoxaluria and kidney stone formation, but also promoted the intestinal inflammation, elevated intestinal permeability, and gut microbiota disorders. Supplementation of LPN1 inhibited the renal crystalline deposits through reducing urinary oxalic acid and renal osteopontin and CD44 expression and improved EG-induced intestinal inflammation and barrier function by decreasing the serum LPS and TLR4/NF-κB signaling and up-regulating tight junction Claudin-2 in the colon, as well as increasing the production of short-chain fatty acid (SCFAs) and the abundance of beneficial SCFAs-producing bacteria, mainly from the families of Lachnospiraceae and Ruminococcaceae. Probiotic LPN1 could prevent EG-induced hyperoxaluria by regulating gut microbiota and enhancing intestinal barrier function.


Assuntos
Etilenoglicol/efeitos adversos , Microbioma Gastrointestinal/genética , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Cálculos Renais/induzido quimicamente , Cálculos Renais/prevenção & controle , Lactobacillaceae , Permeabilidade , Probióticos/administração & dosagem , Animais , Colo/metabolismo , Colo/microbiologia , Ácidos Graxos Voláteis/análise , Ácidos Graxos Voláteis/biossíntese , Fezes/química , Fezes/microbiologia , Hiperoxalúria/induzido quimicamente , Hiperoxalúria/prevenção & controle , Hiperuricemia/induzido quimicamente , Hiperuricemia/prevenção & controle , Inflamação/metabolismo , Masculino , RNA Ribossômico 16S/genética , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Junções Íntimas/metabolismo
15.
Int J Mol Sci ; 22(19)2021 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-34638666

RESUMO

Once weak ultraviolet ray-B (UVB) irradiates the skin cells, the generation of reactive nitrogen species (RNS), but not reactive oxygen species (ROS), is stimulated for the mislocalization of claudin-1 (CLDN1), an essential protein for forming tight junctions (TJs). Since our skin is constantly exposed to sunlight throughout our lives, an effective protection strategy is needed to maintain the skin barrier against weak UVB. In the present study, we investigated whether an ethanol extract of Brazilian green propolis (EBGP) and flavonoids had a protective effect against weak UVB irradiation-induced barrier dysfunction in human keratinocyte-derived HaCaT cells. A pretreatment with EBGP suppressed TJ permeability, RNS production, and the nitration level of CLDN1 in the weak UVB-exposed cells. Among the propolis components, apigenin and apigenin-like flavonoids have potent protective effects against NO production and the mislocalization of CLDN1 induced by UVB. The analyses between structures and biological function revealed that the chemically and structurally characteristic flavonoids with a hydroxyl group at the 4' position on the B-ring might contribute to its protective effect on barrier dysfunction caused by weak UVB irradiation. In conclusion, EBGP and its component apigenin protect HaCaT cells from weak UVB irradiation-induced TJ barrier dysfunction mediated by suppressing NO production.


Assuntos
Apigenina/farmacologia , Claudina-1/metabolismo , Óxido Nítrico/metabolismo , Própole/farmacologia , Substâncias Protetoras/farmacologia , Brasil , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Etanol/química , Células HaCaT , Humanos , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Extratos Vegetais/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismo , Raios Ultravioleta
16.
Int J Mol Sci ; 22(19)2021 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-34638769

RESUMO

The chemical milieu, microbiota composition, and immune activity show prominent differences in distinct healthy skin areas. The objective of the current study was to compare the major permeability barrier components (stratum corneum and tight junction (TJ)), investigate the distribution of (corneo)desmosomes and TJs, and measure barrier function in healthy sebaceous gland-rich (SGR), apocrine gland-rich (AGR), and gland-poor (GP) skin regions. Molecules involved in cornified envelope (CE) formation, desquamation, and (corneo)desmosome and TJ organization were investigated at the mRNA and protein levels using qRT-PCR and immunohistochemistry. The distribution of junction structures was visualized using confocal microscopy. Transepidermal water loss (TEWL) functional measurements were also performed. CE intracellular structural components were similarly expressed in gland-rich (SGR and AGR) and GP areas. In contrast, significantly lower extracellular protein levels of (corneo)desmosomes (DSG1 and CDSN) and TJs (OCLN and CLDN1) were detected in SGR/AGR areas compared to GP areas. In parallel, kallikrein proteases were significantly higher in gland-rich regions. Moreover, gland-rich areas were characterized by prominently disorganized junction structures ((corneo)desmosomes and TJs) and significantly higher TEWL levels compared to GP skin, which exhibited a regular distribution of junction structures. According to our findings, the permeability barrier of our skin is not uniform. Gland-rich areas are characterized by weaker permeability barrier features compared with GP regions. These findings have important clinical relevance and may explain the preferred localization of acantholytic skin diseases on gland-rich skin regions (e.g., Pemphigus foliaceus, Darier's disease, and Hailey-Hailey disease).


Assuntos
Acantólise/metabolismo , Epiderme/metabolismo , Glândulas Sebáceas/metabolismo , Junções Íntimas/metabolismo , Acantólise/patologia , Adulto , Idoso , Epiderme/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Permeabilidade , Glândulas Sebáceas/patologia , Junções Íntimas/patologia
17.
FASEB J ; 35(11): e21854, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34597422

RESUMO

Ammonia is one of the major metabolites produced by intestinal microorganisms; however, its role in intestinal homeostasis is poorly understood. The present study investigated the regulation of intestinal tight junction (TJ) proteins by ammonia and the underlying mechanisms in human intestinal Caco-2 cells. Ammonia (15, 30, and 60 mM) increased the permeability of the cells in a dose-dependent manner, as indicated by reduced transepithelial electrical resistance and increased dextran flux. Immunoblot and immunofluorescence analyses revealed that the ammonia-induced increase in TJ permeability reduced the membrane localization of TJ proteins such as zonula occludens (ZO)1, ZO2, occludin, claudin-1, and claudin-3. DNA microarray analysis identified a biological pathway "response to reactive oxygen species" enriched by ammonia treatment, indicating the induction of oxidative stress in the cells. Ammonia treatment also increased the malondialdehyde content and decreased the ratio of reduced to oxidized glutathione. Meanwhile, ammonia treatment-induced mitochondrial dysfunction, as indicated by the downregulation of genes associated with the electron transport chain, reduction of the cellular ATP, NADH, and tricarboxylic acid cycle intermediate content, and suppression of the mitochondrial membrane potential. In contrast, N-acetyl cysteine reversed the ammonia-induced impairment of TJ permeability and structure without affecting the mitochondrial parameters. Collectively, ammonia impaired the TJ barrier by increasing oxidative stress in Caco-2 cells. A mitochondrial dysfunction is possibly an event preceding ammonia-induced oxidative stress. The findings of this study could potentially improve our understanding of the interplay between intestinal microorganisms and their hosts.


Assuntos
Amônia/farmacologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas de Junções Íntimas/metabolismo , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismo , Trifosfato de Adenosina/metabolismo , Células CACO-2 , Glutationa/metabolismo , Humanos , Interleucina-8/biossíntese , Mucosa Intestinal/metabolismo , Malondialdeído/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , NADP/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Permeabilidade/efeitos dos fármacos , Insuficiência Renal Crônica/metabolismo
19.
Nutrients ; 13(10)2021 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-34684516

RESUMO

The metabolic disorder caused by excessive fructose intake was reported extensively and often accompanied by intestinal barrier dysfunction. And the rising dietary fructose was consumed at an early age of human. However, related researches were almost conducted in rodent models, while in the anatomy and physiology of gastrointestinal tract, pig is more similar to human beings than rodents. Hence, weaned piglets were chosen as the model animals in our study to investigate the fructose's impacts on intestinal tight junction, inflammation response and microbiota structure of piglets. Herein, growth performance, inflammatory response, oxidation resistance and ileal and colonic microbiota of piglet were detected after 35-day fructose supplementation. Our results showed decreased tight junction gene expressions in piglets after fructose addition, with no obvious changes in the growth performance, antioxidant resistance and inflammatory response. Moreover, fructose supplementation differently modified the microbiota structures in ileum and colon. In ileum, the proportions of Streptococcus and Faecalibacterium were higher in Fru group (fructose supplementation). In colon, the proportions of Blautia and Clostridium sensu stricto 1 were higher in Fru group. All the results suggested that tight junction dysfunction might be an earlier fructose-induced event than inflammatory response and oxidant stress and that altered microbes in ileum and colon might be the potential candidates to alleviate fructose-induced intestinal permeability alteration.


Assuntos
Colite/induzido quimicamente , Suplementos Nutricionais/efeitos adversos , Frutose/efeitos adversos , Microbioma Gastrointestinal/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Animais , Colo/efeitos dos fármacos , Íleo/efeitos dos fármacos , Modelos Animais , Estresse Oxidativo/efeitos dos fármacos , Permeabilidade/efeitos dos fármacos , Suínos , Junções Íntimas/efeitos dos fármacos
20.
Nutrients ; 13(10)2021 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-34684313

RESUMO

Peptic ulcer episodes cause damage to the stomach and intestine, with inflammatory cell infiltration and oxidative stress as the main players. In this study, we investigated the potential of anthocyanidin malvidin for preventive and curative peptic ulcer treatment. The anthocyanidin effects were examined in gastric ulcer mouse models induced by ethanol, non-steroidal anti-inflammatory drugs (NSAIDs), ischemia-reperfusion (IR), acetic acid and duodenal ulcer induced by polypharmacy. Expression levels of oxidative and inflammatory genes were measured to investigate the mechanism of anthocyanin activity. At a dose of 5 mg·kg-1, Malvidin prevented gastric ulcer induction by ethanol, NSAID and repaired the tissue after 6 days of IR. Moreover, the anthocyanidin accelerated the healing of acetic acid-induced ulcer, increased the gene expression of EGF and COX-1, and downregulated MMP-9. Anthocyanin treatment mitigated the effect of polypharmacy on inflammation and oxidative stress observed in the intestine. Additionally, the compound downregulated cytokine expression and TLR4 and upregulated HMOX-1 and IL-10, exhibiting protective activity in the mouse gut. Malvidin thus prevented gastric and duodenal ulcers due to prominent anti-inflammatory and antioxidative effects on the gastrointestinal tract that were related to gene expression modulation and an increase in endogenous defense mechanisms.


Assuntos
Antocianinas/uso terapêutico , Inflamação/complicações , Inflamação/tratamento farmacológico , Estresse Oxidativo , Úlcera Péptica/complicações , Úlcera Péptica/tratamento farmacológico , Substâncias Protetoras/uso terapêutico , Ácido Acético , Animais , Antocianinas/farmacologia , Antioxidantes/metabolismo , Biomarcadores/metabolismo , Ciclo-Oxigenase 1/genética , Ciclo-Oxigenase 1/metabolismo , Modelos Animais de Doenças , Duodeno/efeitos dos fármacos , Duodeno/patologia , Fator de Crescimento Epidérmico/genética , Fator de Crescimento Epidérmico/metabolismo , Etanol , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Indometacina , Inflamação/genética , Masculino , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Úlcera Péptica/genética , Úlcera Péptica/imunologia , Polimedicação , Substâncias Protetoras/farmacologia , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/patologia , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/tratamento farmacológico , Úlcera Gástrica/genética , Úlcera Gástrica/imunologia , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismo , Cicatrização/efeitos dos fármacos
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