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1.
Tissue Eng Regen Med ; 22(2): 181-194, 2025 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-39820960

RESUMO

BACKGROUND: The main challenge in new drug development is accurately predicting the human response in preclinical models. METHODS: In this study, we developed three different intestinal barrier models using advanced biofabrication techniques: (i) a manual model containing Caco-2 and HT-29 cells on a collagen bed, (ii) a manual model with a Caco-2/HT-29 layer on a HDFn-laden collagen layer, and (iii) a 3D bioprinted model incorporating both cellular layers. Each model was rigorously tested for its ability to simulate a functional intestinal membrane. RESULTS: All models successfully replicated the structural and functional aspects of the intestinal barrier. The 3D bioprinted intestinal model, however, demonstrated superior epithelial barrier integrity enhanced tight junction formation, microvilli development, and increased mucus production. When subjected to Ibuprofen, the 3D bioprinted model provided a more predictive response, underscoring its potential as a reliable in vitro tool for drug toxicity testing. CONCLUSION: Our 3D bioprinted intestinal model presents a robust and predictive platform for drug toxicity assessments, significantly reducing the need for animal testing. This model not only aligns with ethical testing protocols but also offers enhanced accuracy in predicting human responses, thereby advancing the field of drug development.


Assuntos
Mucosa Intestinal , Humanos , Células CACO-2 , Células HT29 , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Ibuprofeno/farmacologia , Animais , Impressão Tridimensional , Testes de Toxicidade/métodos , Bioimpressão/métodos , Engenharia Tecidual/métodos , Modelos Biológicos , Alternativas aos Testes com Animais , Intestinos/efeitos dos fármacos
2.
PLoS Biol ; 23(1): e3002997, 2025 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-39874242

RESUMO

The DAF-2/insulin/insulin-like growth factor signaling (IIS) pathway plays an evolutionarily conserved role in regulating reproductive development, life span, and stress resistance. In Caenorhabditis elegans, DAF-2/IIS signaling is modulated by an extensive array of insulin-like peptides (ILPs) with diverse spatial and temporal expression patterns. However, the release dynamics and specific functions of these ILPs in adapting to different environmental conditions remain poorly understood. Here, we show that the ILP, insulin-3 (INS-3), plays a crucial role in modulating the response to various environmental stressors in C. elegans. ins-3 mutants display increased resistance to heat, oxidative stress, and starvation; however, this advantage is countered by slower reproductive development under favorable conditions. We find that ins-3 expression is downregulated in response to environmental stressors, whereas, the neurohormone tyramine, which is released during the acute flight response, increases ins-3 expression. We show that tyramine induces intestinal calcium (Ca2+) transients through the activation of the TYRA-3 receptor. Our data support a model in which tyramine negatively impacts environmental stress resistance by stimulating the release of INS-3 from the intestine via the activation of a TYRA-3-Gαq-IP3 pathway. The release of INS-3 systemically activates the DAF-2 pathway, resulting in the inhibition of cytoprotective mechanisms mediated by DAF-16/FOXO. These studies offer mechanistic insights into a brain-gut communication pathway that weighs adaptive strategies to respond to acute and long-term stressors.


Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Insulina , Estresse Fisiológico , Tiramina , Animais , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/genética , Tiramina/metabolismo , Tiramina/farmacologia , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Insulina/metabolismo , Estresse Fisiológico/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Intestinos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Cálcio/metabolismo , Receptor de Insulina/metabolismo , Receptor de Insulina/genética , Fatores de Transcrição Forkhead
3.
Immunol Res ; 73(1): 33, 2025 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-39808251

RESUMO

The ABCC subfamily contains thirteen members. Nine of these transporters are called multidrug resistance proteins (MRPs). The MRPs have been associated with developing ulcerative colitis (UC). This study aimed to evaluate the ABCC expression in UC patients and its role in a dextran sulfate sodium (DSS)-induced colitis mice model under 5-aminosalicylates or methylprednisolone treatment and compared with control without inflammation. DSS-induced colitis mice were treated with 5-aminosalicylates (50 mg/kg 24 h) or methylprednisolone (2 mg/kg 24 h). Human rectal biopsies were obtained from UC patients. The abcc-relative mRNA levels and protein expression were determined by RT-PCR and immunohistochemistry. abcc4, abcc5, and abcc6 mRNA levels were significantly increased in DSS-induced colitis compared to the other groups. The 5-aminosalicylate treatment dramatically increased the abcc2 and abcc3 mRNA levels vs. control. Methylprednisolone treatment increased abcc1 vs. DSS-induced colitis and colitis treated with 5-aminosalicylate. Immunohistochemical analysis revealed down-regulation of ABCC1/ABCC2/ABCC5/ABCC7 in mice colitis vs. control. Treatment with 5-aminosalicylate restored ABCC5 levels, while methylprednisolone restored ABCC2/ABCC5/ABCC7 in colitis mice at similar control levels. Relative mRNA levels of mrp1-5 were increased in active UC patients vs. control. ABCC2/ABCC4/ABCC7 were conspicuously expressed in the mucosa of 5-aminosalicylate and/or methylprednisolone-treated UC patients, while ABCC2/ABCC4/ABCC5/ABCC7 in submucosa, ABCC1/ABCC5/ABCC7 in muscular, and ABCC1/ABCC4/ABCC5/ABCC7 in serosa were expressed vs. controls. This is the first report about the differential up-regulation of the ABCC subfamily gene and protein expression in DSS-induced colitis under aminosalicylates or methylprednisolone treatment.


Assuntos
Colite Ulcerativa , Sulfato de Dextrana , Metilprednisolona , Proteínas Associadas à Resistência a Múltiplos Medicamentos , Animais , Humanos , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Camundongos , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/genética , Colite Ulcerativa/imunologia , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/metabolismo , Metilprednisolona/uso terapêutico , Metilprednisolona/farmacologia , Masculino , Modelos Animais de Doenças , Proteína 2 Associada à Farmacorresistência Múltipla , Feminino , Mesalamina/uso terapêutico , Mesalamina/farmacologia , Colite/induzido quimicamente , Colite/metabolismo , Colite/tratamento farmacológico , Colite/genética , Adulto , Pessoa de Meia-Idade , RNA Mensageiro/metabolismo , RNA Mensageiro/genética , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Mucosa Intestinal/efeitos dos fármacos
4.
J Biol Inorg Chem ; 29(7-8): 773-784, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-39617837

RESUMO

The rise of atmospheric oxygen as a result of photosynthesis in cyanobacteria and chloroplasts has transformed most environmental iron into the ferric state. In contrast, cells within organisms maintain a reducing internal milieu and utilize predominantly ferrous iron. Ferric reductases are enzymes that transfer electrons to ferric ions, either extracellularly or within endocytic vesicles, enabling cellular ferrous iron uptake through Divalent Metal Transporter 1. In mammals, duodenal cytochrome b is a ferric reductase of the intestinal epithelium, but how insects reduce and absorb dietary iron remains unknown. Here we provide indirect evidence of extracellular ferric reductase activity in a small subset of Drosophila melanogaster intestinal epithelial cells, positioned at the neck of the midgut's anterior region. Dietary-supplemented bathophenanthroline sulphate (BPS) captures locally generated ferrous iron and precipitates into pink granules, whose chemical identity was probed combining in situ X-ray absorption near edge structure and electron paramagnetic resonance spectroscopies. An increased presence of manganese ions upon BPS feeding was also found. Control animals were fed with ferric ammonium citrate, which is accumulated into ferritin iron in distinct intestinal subregions suggesting iron trafficking between different cells inside the animal. Spectroscopic signals from the biological samples were compared to purified Drosophila and horse spleen ferritin and to chemically synthesized BPS-iron and BPS-manganese complexes. The results corroborated the presence of BPS-iron in a newly identified ferric iron reductase region of the intestine, which we propose constitutes the major site of iron absorption in this organism.


Assuntos
Drosophila melanogaster , Animais , Drosophila melanogaster/enzimologia , FMN Redutase/metabolismo , Ferro/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/enzimologia , Compostos Férricos/metabolismo
5.
Front Cell Infect Microbiol ; 14: 1393369, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39703371

RESUMO

Enteropathogenic Escherichia coli (EPEC) strains are subdivided into typical (tEPEC) and atypical (aEPEC) according to the presence or absence of a virulence-associated plasmid called pEAF. Our research group has previously demonstrated that two aEPEC strains, 0421-1 and 3991-1, induce an increase in mucus production in a rabbit ileal loop model in vivo. This phenomenon was not observed with a tEPEC prototype strain. Few studies on aEPEC strains evaluating their capacity to induce intestinal mucus hypersecretion were done. This study aimed to investigate aEPEC strains regarding their genotypic and phenotypic characteristics, their ability to alter mucus production in an in vivo intestinal infection model, and their potential mucinolytic activity. To investigate the relationship between strains 0421-1 and 3991-1 and 11 other aEPEC strains, their serotypes, sequence types (ST), and virulence factors (VF), several sequencing and genomic analyses were carried out. The study also involved researching the reproduction of mucus hypersecretion in rabbits in vivo. We found that the two mucus-inducing strains and two other strains (1582-4 and 2531-13) shared the same phylogroup (A), ST (378), serotype (O101/O162:H33), and intimin subtype (ι2), were phylogenetically related, and induced mucus hypersecretion in vivo. A wide diversity of VFs was found among the strains, confirming their genomic heterogeneity. However, among the genes studied, no unique virulence factor or gene set was identified exclusively in the mucus-inducing strains, suggesting the multifactorial nature of this phenomenon. The two strains (1582-4 and 2531-13) closely related to the two aEPEC strains that induced mucus production in vivo also induced the phenomenon. The investigation of the mucinolytic activity revealed that all aEPEC strains used mucins as their carbon sources. Ten of the 13 aEPEC strains could cross a mucin layer, and only four adhered better to agar containing mucin than to agar without mucin. The present study paves the way for subsequent investigations into the molecular mechanisms regarding cellular interactions and responses, as well as the correlation between virulence factors and the induction of mucus production/expression during aEPEC infections.


Assuntos
Escherichia coli Enteropatogênica , Infecções por Escherichia coli , Muco , Fatores de Virulência , Animais , Escherichia coli Enteropatogênica/genética , Escherichia coli Enteropatogênica/metabolismo , Escherichia coli Enteropatogênica/patogenicidade , Coelhos , Fatores de Virulência/genética , Fatores de Virulência/metabolismo , Muco/metabolismo , Muco/microbiologia , Infecções por Escherichia coli/microbiologia , Modelos Animais de Doenças , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Família Multigênica , Filogenia , Mucinas/metabolismo , Genótipo , Virulência/genética , Genoma Bacteriano , Mucosa Intestinal/microbiologia , Mucosa Intestinal/metabolismo , Plasmídeos/genética , Sorogrupo
6.
Front Cell Infect Microbiol ; 14: 1440514, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39529636

RESUMO

Introduction: Yersinia enterocolitica (Ye) is a Gram-negative bacterium that causes gastrointestinal infections. The myeloid-derived suppressor cells (MDSCs) constitute a cellular population with the capacity of inducing the specific suppression of T cells. Although there is evidence supporting the role of MDSCs in controlling the immune responses in several bacterial infections, its role during Ye infection has not yet been reported. Therefore, the purpose of the present work was to analyze MDSCs after oral Ye infection. Methods: C57BL/6 wild-type mice were infected with Ye WAP-314 serotype O:8. The proliferation of splenocytes and mesenteric lymph nodes (MLN) cells was measured as well as the levels of cytokines and nitric oxide (NO) in culture supernatants. The frequency and subsets of MDSCs were analyzed in the intestinal mucosa and spleen by flow cytometry. Furthermore, monocytic-MDSCs (Mo-MDSCs) and polymorphonuclear-MDSCs (PMN-MDSCs) were purified from the spleen of infected mice and their suppressor activity was evaluated in co-cultures with purified T cells. Results: we observed a marked expansion of CD11b+Gr-1+ cells, a phenotype consistent with MDSCs, in the spleen and intestinal mucosa of Ye-infected mice. Interestingly, a robust proliferation of splenocytes and MLN cells was observed only when the MDSCs were depleted or the NO production was blocked. In addition, we determined that only Mo-MDSCs had the ability to suppress T-cell proliferation. Conclusion: Our results highlight a mechanism by which Ye may induce suppression of the immune responses. We suggest that NO-producing Mo-MDSCs expand and accumulate in MLN and spleen of Ye-infected mice. These cells can then suppress the T-cell function without interfering with the anti-bacterial effector response. Instead, these immature myeloid cells may perform an important function in regulating the inflammatory response and protecting affected tissues.


Assuntos
Citocinas , Linfonodos , Camundongos Endogâmicos C57BL , Células Supressoras Mieloides , Óxido Nítrico , Baço , Yersiniose , Yersinia enterocolitica , Animais , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/metabolismo , Linfonodos/microbiologia , Linfonodos/imunologia , Baço/imunologia , Baço/microbiologia , Baço/metabolismo , Óxido Nítrico/metabolismo , Yersiniose/imunologia , Yersiniose/microbiologia , Camundongos , Citocinas/metabolismo , Proliferação de Células , Modelos Animais de Doenças , Antígeno CD11b/metabolismo , Monócitos/imunologia , Monócitos/metabolismo , Feminino , Linfócitos T/imunologia , Linfócitos T/metabolismo , Mesentério , Mucosa Intestinal/microbiologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo
7.
Sci Rep ; 14(1): 28698, 2024 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-39562789

RESUMO

Inflammatory bowel diseases (IBD) are idiopathic disorders characterized by chronic gastrointestinal inflammation. Given conventional therapies' adverse effects and clinical failures, novel approaches are being investigated. Recent studies have highlighted the role of specialized pro-resolving lipid mediators (SPMs) in the active resolution of chronic inflammation. In this regard, omega-3 fatty acid-derived Resolvin D2 (RvD2) appears to play a protective role in the pathophysiology of IBD. Therefore, we characterized the RvD2 pathway and its receptor expression in the intestinal mucosa of experimental colitis induced by dextran sulfate sodium. We also evaluated the preventive impact of an omega-3-enriched diet and the therapeutic efficacy of RvD2 compared with anti-TNF-α treatment. We found an increase in TNFα and IL22 expression and decreased levels of enzymes involved in RvD2 biosynthesis, such as PLA2, 15-LOX, 5-LOX, and its receptor GPR18 in experimental colitis. Omega-3 supplementation reduced the Disease Activity Index (DAI), weight loss, colonic shortening, and inflammation. These results and the increased IL-10 transcriptional levels after RvD2 treatment suggest that this mediator attenuated experimental colitis. These results enhance our understanding of the molecular mechanisms involved in the exacerbated inflammatory response present in experimental colitis and suggest that RvD2 and its omega-3 precursor offer a promising therapeutic approach for IBD.


Assuntos
Ácidos Docosa-Hexaenoicos , Ácidos Graxos Ômega-3 , Doenças Inflamatórias Intestinais , Ácidos Docosa-Hexaenoicos/farmacologia , Ácidos Graxos Ômega-3/farmacologia , Ácidos Graxos Ômega-3/metabolismo , Animais , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/metabolismo , Camundongos , Colite/tratamento farmacológico , Colite/metabolismo , Colite/induzido quimicamente , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Masculino , Modelos Animais de Doenças , Sulfato de Dextrana , Fator de Necrose Tumoral alfa/metabolismo , Camundongos Endogâmicos C57BL
8.
Lett Appl Microbiol ; 77(11)2024 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-39496521

RESUMO

Postbiotic lactate modulates the immune system in inflammatory bowel diseases. However, its role in experimental intestinal mucositis (IM) has not been elucidated. This study aimed to evaluate the effects of lactate supplementation (1 and 2 × 10-1 mol/l) in a 5-fluorouracil (5-FU)-induced IM model. Male BALB/c mice (6-8 weeks old) were randomly divided into four groups: control (CTL), mucositis (MUC), mucositis with 1 × 10-1 mol/l lactate solution (MUC10), and mucositis with 2 × 10-1 mol/l lactate solution (MUC200). Lactate was administered via oral gavage for 10 days. Following the treatment period, the animals were subjected to an intraperitoneal injection of 300 mg/kg 5-FU to induce IM and were euthanized 72 h later for analysis. The MUC group presented intestinal damage with a poor histological score and decreased morphometric parameters as well as decreased mucus production and increased inflammatory infiltration and intestinal permeability compared to those of the CTL group (P < .05). However, the MUC200 group exhibited better results for the evaluated parameters than the MUC group (P < .05). Notably, the results in the MUC10 group were similar to those in the MUC group (P > .05). In conclusion, lactate supplementation attenuates mucositis-induced damage in a dose-dependent manner.


Assuntos
Fluoruracila , Ácido Láctico , Camundongos Endogâmicos BALB C , Mucosite , Animais , Mucosite/induzido quimicamente , Mucosite/tratamento farmacológico , Mucosite/patologia , Mucosite/prevenção & controle , Camundongos , Masculino , Ácido Láctico/metabolismo , Fluoruracila/efeitos adversos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Modelos Animais de Doenças
9.
Int J Mol Sci ; 25(22)2024 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-39596507

RESUMO

Semaphorins are an immunoregulatory protein family. Plexins bind semaphorins (SEMAs) and can form receptor complexes that give them chemotactic capacity. The role and expression profile of semaphorins and plexins in inflammatory bowel disease (IBD) is currently unknown. AIM: Characterize the semaphorins and plexins gene and protein expression in intestinal tissue from IBD patients and correlate them with the clinical phenotype. MATERIAL AND METHODS: This comparative and cross-sectional study enrolled 54 diagnosed IBD patients and 20 controls. Gene and protein expression of semaphorins and plexins were determined by RT-PCR and IHQ for the co-localization with neutrophils (myeloperoxidase, MPO) or CD123 plasmacytoid dendritic cells in intestinal tissue from IBD patients. RESULTS: Colonic mucosa from active and remission ulcerative colitis (UC) had a significantly lower SEMA4D and PLXNA1, but higher PLXNB1 gene expression than the control group. The only significant difference between active UC and remission was observed in the higher gene expression of SEMA6D in remission. It was associated with histological remission (p = 0.01, OR = 15, 95% CI: 1.39-16.1). The low expression of PLXNA1 was associated with mild intermittent activity with two relapses per year (p = 0.003, OR = 0.05, CI = 0.006-0.51). Higher SEMA4D+ positive cells were detected in the submucosa, while PLXNC1+/MPO+ in the mucosal and submucosa of active UC patients compared with controls. CONCLUSIONS: The increased expression of the semaphorin and plexin family in IBD patients suggests their immunoregulatory function and is associated with remission and clinical phenotype in patients with UC.


Assuntos
Doenças Inflamatórias Intestinais , Proteínas do Tecido Nervoso , Receptores de Superfície Celular , Semaforinas , Humanos , Semaforinas/metabolismo , Semaforinas/genética , Feminino , Masculino , Adulto , Pessoa de Meia-Idade , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/patologia , Receptores de Superfície Celular/metabolismo , Receptores de Superfície Celular/genética , Proteínas do Tecido Nervoso/metabolismo , Proteínas do Tecido Nervoso/genética , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Colite Ulcerativa/metabolismo , Colite Ulcerativa/genética , Colite Ulcerativa/patologia , Estudos Transversais , Estudos de Casos e Controles , Antígenos CD/metabolismo , Antígenos CD/genética , Moléculas de Adesão Celular
10.
PLoS One ; 19(10): e0312775, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39466773

RESUMO

Intestinal parasites are part of the intestinal ecosystem and have been shown to establish close interactions with the intestinal microbiota. However, little is known about the influence of intestinal protozoa on the regulation of the immune response. In this study, we analyzed the regulation of the immune response of germ-free mice transplanted with fecal microbiota (FMT) from individuals with multiple parasitic protozoans (P) and non-parasitized individuals (NP). We determined the production of intestinal cytokines, the lymphocyte populations in both the colon and the spleen, and the genetic expression of markers of intestinal epithelial integrity. We observed a general downregulation of the intestinal immune response in mice receiving FMT-P. We found significantly lower intestinal production of the cytokines IL-6, TNF, IFN-γ, MCP-1, IL-10, and IL-12 in the FMT-P. Furthermore, a significant decrease in the proportion of CD3+, CD4+, and Foxp3+ T regulatory cells (Treg) was observed in both, the colon and spleen with FMT-P in contrast to FMT-NP. We also found that in FMT-P mice there was a significant decrease in tjp1 expression in all three regions of the small intestine; ocln in the ileum; reg3γ in the duodenum and relmß in both the duodenum and ileum. We also found an increase in colonic mucus layer thickness in mice colonized with FMT-P in contrast with FMT-NP. Finally, our results suggest that gut protozoa, such as Blastocystis hominis, Entamoeba coli, Endolimax nana, Entamoeba histolytica/E. dispar, Iodamoeba bütschlii, and Chilomastix mesnili consortia affect the immunoinflammatory state and induce functional changes in the intestine via the gut microbiota. Likewise, it allows us to establish an FMT model in germ-free mice as a viable alternative to explore the effects that exposure to intestinal parasites could have on the immune response in humans.


Assuntos
Transplante de Microbiota Fecal , Vida Livre de Germes , Animais , Camundongos , Microbioma Gastrointestinal/imunologia , Citocinas/metabolismo , Linfócitos T Reguladores/imunologia , Intestinos/imunologia , Intestinos/parasitologia , Intestinos/microbiologia , Camundongos Endogâmicos C57BL , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Regulação para Baixo , Feminino , Baço/imunologia , Baço/metabolismo
11.
Int J Mol Sci ; 25(20)2024 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-39456655

RESUMO

Aberrant signaling through damage-associated molecular patterns (DAMPs) has been linked to several health disorders, attracting considerable research interest over the last decade. Adenosine triphosphate (ATP), a key extracellular DAMP, activates the purinergic receptor P2X7, which acts as a danger sensor in immune cells and is implicated in distinct biological functions, including cell death, production of pro-inflammatory cytokines, and defense against microorganisms. In addition to driving inflammation mediated by immune and non-immune cells, the persistent release of endogenous DAMPs, including ATP, has been shown to result in epigenetic modifications. In intestinal diseases such as inflammatory bowel disease (IBD) and colorectal cancer (CRC), consequent amplification of the inflammatory response and the resulting epigenetic reprogramming may impact the development of pathological changes associated with specific disease phenotypes. P2X7 is overexpressed in the gut mucosa of patients with IBD, whereas the P2X7 blockade prevents the development of chemically induced experimental colitis. Recent data suggest a role for P2X7 in determining gut microbiota composition. Regulatory mechanisms downstream of the P2X7 receptor, combined with signals from dysbiotic microbiota, trigger intracellular signaling pathways and inflammasomes, intensify inflammation, and foster colitis-associated CRC development. Preliminary studies targeting the ATP-P2X7 pathway have shown favorable therapeutic effects in human IBD and experimental colitis.


Assuntos
Receptores Purinérgicos P2X7 , Receptores Purinérgicos P2X7/metabolismo , Receptores Purinérgicos P2X7/genética , Humanos , Animais , Inflamação/metabolismo , Inflamação/patologia , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/patologia , Trifosfato de Adenosina/metabolismo , Microbioma Gastrointestinal , Transdução de Sinais , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Neoplasias Colorretais/etiologia , Intestinos/patologia , Intestinos/microbiologia
12.
Toxicol Appl Pharmacol ; 492: 117130, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-39426530

RESUMO

Metronomic chemotherapy (MCT) is a cancer therapeutic approach characterized by low dose drug chronic administration and limited or null toxicity. Obesity-induced metabolic alterations worsen cancer prognosis and influence the intestinal biochemical barrier, altering the Multidrug resistance-associated protein 2 (Mrp2) and Multidrug resistance protein-1 (Mdr-1), efflux pumps that transport chemotherapeutic drugs. Obesity and cancer are frequent co-morbidities; thus, our aim was to evaluate the effectiveness and toxicity of MCT with cyclophosphamide (Cy) in obese mice with metabolic alterations bearing a mammary adenocarcinoma. Simultaneously, the expression and activities of intestinal Mrp2 and Mdr-1 were assessed. CBi male mice, were fed with chow diet (C) or diet with 40 % of fat (HFD). After 16 weeks, metabolic alterations were confirmed by biochemical and morphological parameters. At that time-point, HFD group showed decreased expressions of Mrp2 mRNA (53 %) as well as Mdr-1a and Mdr-1b (42 % and 59 %, respectively), compared to C (P < 0.05). This result correlated with decreased intestinal Mrp2 and Mdr-1 efflux activities (64 % and 45 %, respectively), compared to C (P < 0.05). Ultimately, mice were challenged with M-406 mammary adenocarcinoma; when the tumor was palpable, mice were distributed into 4 groups. The % inhibition of tumor growth with Cy (30 mg/kg/day) in C + Cy was higher than that of HFD + Cy (P = 0.052). Besides, it was observed a 21 % diminution in body weight and leukopenia in the HFD + Cy group. Conclusion: Obesity-induced metabolic alterations impair intestinal Mrp2 and Mdr-1 functions, bringing about increments in Cy absorption, leading to toxicity; in addition, the antitumor effectiveness of MCT decreased in obese animals.


Assuntos
Administração Metronômica , Ciclofosfamida , Obesidade , Animais , Ciclofosfamida/toxicidade , Camundongos , Obesidade/metabolismo , Masculino , Feminino , Proteína 2 Associada à Farmacorresistência Múltipla , Antineoplásicos Alquilantes/toxicidade , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/patologia , Neoplasias Mamárias Experimentais/induzido quimicamente , Camundongos Obesos , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Adenocarcinoma/patologia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Transportadores de Cassetes de Ligação de ATP/genética , Dieta Hiperlipídica
13.
Int J Biol Macromol ; 281(Pt 3): 136399, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-39395521

RESUMO

In recent years, natural polysaccharides (PSs) have attracted increasing interest because of their remarkable biological properties and potential in various areas, such as medicine, and food. This study aimed to present a detailed review of the evidence on the therapeutic potential of PSs for the treatment of gastrointestinal diseases. The main evidence was correlated with their chemical composition, mechanism of action and therapeutic effect. The main results showed that the action can be attributed to their ability to suppress excessive inflammatory responses, regulating the expression of cytokines and interleukins, reducing intestinal inflammation and promoting wound healing. Furthermore, we discussed how PSs help in the repair of the intestinal mucosa and related these effects with the composition of monosaccharides. A detailed analysis was performed on the ability of PSs to modulate the intestinal microbiota, promoting the growth of beneficial bacteria and suppressing inflammatory bacteria, in addition to its probiotic action with production of short-chain fatty acids. All this evidence was also taken into a broader context, in which the main challenges in processing PSs were considered and strategies to circumvent them were pointed out. Therefore, this review sought to demonstrate the great potential and viability of PSs as innovative and effective therapeutic agents.


Assuntos
Microbioma Gastrointestinal , Polissacarídeos , Humanos , Polissacarídeos/farmacologia , Polissacarídeos/química , Polissacarídeos/uso terapêutico , Microbioma Gastrointestinal/efeitos dos fármacos , Animais , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/metabolismo , Gastroenteropatias/tratamento farmacológico , Cicatrização/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo
14.
Int J Mol Sci ; 25(18)2024 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-39337509

RESUMO

Inflammatory bowel diseases (IBDs) involve chronic inflammation of the gastrointestinal tract, where effector CD4+ T-cells play a central role. Thereby, the recruitment of T-cells into the colonic mucosa represents a key process in IBD. We recently found that CCR9 and DRD5 might form a heteromeric complex on the T-cell surface. The increase in CCL25 production and the reduction in dopamine levels associated with colonic inflammation represent a dual signal stimulating the CCR9:DRD5 heteromer, which promotes the recruitment of CD4+ T-cells into the colonic lamina propria. Here, we aimed to analyse the molecular requirements involved in the heteromer assembly as well as to determine the underlying cellular mechanisms involved in the colonic tropism given by the stimulation of the CCR9:DRD5 complex. The results show that dual stimulation of the CCR9:DRD5 heteromer potentiates the phosphorylation of the myosin light chain 2 (MLC2) and the migration speed in confined microchannels. Accordingly, disrupting the CCR9:DRD5 assembly induced a sharp reduction in the pMLC2 in vitro, decreased the migratory speed in confined microchannels, and dampened the recruitment of CD4+ T-cells into the inflamed colonic mucosa. Furthermore, in silico analysis confirmed that the interface of interaction of CCR9:DRD5 is formed by the transmembrane segments 5 and 6 from each protomer. Our findings demonstrated that the CCR9:DRD5 heteromeric complex plays a fundamental role in the migration of CD4+ T-cells into the colonic mucosa upon inflammation. Thereby, the present study encourages the design of strategies for disassembling the formation of the CCR9:DRD5 as a therapeutic opportunity to treat IBD.


Assuntos
Linfócitos T CD4-Positivos , Mucosa Intestinal , Receptores CCR , Receptores de Dopamina D5 , Transdução de Sinais , Receptores CCR/metabolismo , Receptores CCR/genética , Humanos , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/imunologia , Receptores de Dopamina D5/metabolismo , Receptores de Dopamina D5/genética , Mucosa Intestinal/metabolismo , Colo/metabolismo , Movimento Celular , Dopamina/metabolismo , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/patologia , Doenças Inflamatórias Intestinais/imunologia
15.
Acta Cir Bras ; 39: e395524, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39230095

RESUMO

PURPOSE: To investigate the impact of the Chinese medicine compound Ento-PB on oxazolone (OXZ)-induced ulcerative colitis (UC) in rats. METHODS: UC rats induced by OXZ were treated with Ento-PB. The damage to the colon was assessed using several measures, including the disease activity index (DAI), colon length, colon weight/length ratio, colonic mucosal damage index, and histological score. The levels of interleukin-4 (IL-4), interleukin-10 (IL-10), interleukin-13 (IL-13), epidermal growth factor (EGF), inducible nitric oxide synthase, and total nitric oxide synthase (tNOS) in rat serum, as well as the levels of tumor necrosis factor-α (TNF-α) and myeloperoxidase (MPO) in rat colon tissue, were determined using enzyme-linked immunosorbent assay and conventional kits. RESULTS: After being treated with Ento-PB, the DAI score and macroscopic lesion score of OXZ-induced UC rats were significantly reduced. Ento-PB prevented the shortening of rat colons, reduced the ratio of colon weight to length, and improved colon tissue lesions. Meanwhile, Ento-PB could significantly inhibit the activities of proinflammatory cytokines TNF-α, IL-13, and MPO, as well as tNOS and iNOS, while upregulating the expression of anti-inflammatory cytokines IL-4 and IL-10. Moreover, a significant increase in the expression level of EGF was observed in UC rats treated with Ento-PB, indicating that Ento-PB could enhance the repair of damaged intestinal epithelial tissue. CONCLUSIONS: Ento-PB demonstrates significant anti-UC activities in OXZ-induced UC rats by regulating the expression levels of inflammatory factors and promoting the repair of colon tissue. This study provides scientific evidence to support the further development of Ento-PB.


Assuntos
Colite Ulcerativa , Colo , Oxazolona , Peroxidase , Animais , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/patologia , Masculino , Colo/efeitos dos fármacos , Colo/patologia , Colo/metabolismo , Peroxidase/análise , Peroxidase/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Modelos Animais de Doenças , Fator de Necrose Tumoral alfa/análise , Fator de Necrose Tumoral alfa/metabolismo , Ratos Sprague-Dawley , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Mucosa Intestinal/metabolismo , Ratos , Ensaio de Imunoadsorção Enzimática , Fator de Crescimento Epidérmico/análise , Citocinas/metabolismo , Interleucina-13/análise , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico Sintase Tipo II/análise , Reprodutibilidade dos Testes , Resultado do Tratamento
16.
J Pharm Sci ; 113(11): 3323-3331, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-39216537

RESUMO

Novel thiomer/nanoclay nanocomposites based on a thiomer and montmorillonite (MMT) were prepared in order to obtain a mucoadhesive material with controlled release properties for its potential use as drug carrier. The thiomer was synthesized by immobilization of L-cysteine in alginate mediated by carbodiimide reaction and further characterized by FT-IR and Ellman's reaction. Nanocomposites with growing concentrations of thiomer and MMT were prepared and analyzed by XRD, TGA and TEM. Rheological behavior of nanocomposite in contact with mucin and intestinal mucus were studied as in vitro and in situ mucoadhesion approach, showing until ∼10-fold increasing in the complex viscosity and ∼27-fold in elastic modulus when the amount of thiomer is increased. Higuchi and Korsmeyer-Peppas kinetic models were evaluated in order to study the release of deltamethrin from nanocomposite films. Release profiles showed a retard in the migration of the drug influenced by the amount of MMT (P < 0.05). Diffusion coefficient (D) showed a significant decrease (P < 0.0001) when concentration of MMT is increased reaching D = 4.18 × 10-7 m2 h-1, which resulted ∼7-fold lower in comparison with formulation without MMT. This hybrid nanocomposite can be projected as a potential mucoadhesive drug carrier with controlled release properties.


Assuntos
Bentonita , Preparações de Ação Retardada , Portadores de Fármacos , Liberação Controlada de Fármacos , Nanocompostos , Nanocompostos/química , Portadores de Fármacos/química , Bentonita/química , Mucinas/química , Adesividade , Argila/química , Alginatos/química , Cisteína/química , Animais , Reologia , Viscosidade , Mucosa Intestinal/metabolismo
17.
Int J Mol Sci ; 25(15)2024 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-39125769

RESUMO

A T-cell-independent (TI) pathway activated by microbiota results in the generation of low-affinity homeostatic IgA with a critical role in intestinal homeostasis. Moderate aerobic exercise (MAE) provides a beneficial impact on intestinal immunity, but the action of MAE on TI-IgA generation under senescence conditions is unknown. This study aimed to determine the effects of long-term MAE on TI-IgA production in young (3 month old) BALB/c mice exercised until adulthood (6 months) or aging (24 months). Lamina propria (LP) from the small intestine was obtained to determine B cell and plasma cell sub-populations by flow cytometry and molecular factors related to class switch recombination [Thymic Stromal Lymphopoietin (TSLP), A Proliferation-Inducing Ligand (APRIL), B Cell Activating Factor (BAFF), inducible nitric oxide synthase (iNOS), and retinal dehydrogenase (RDH)] and the synthesis of IgA [α-chain, interleukin (IL)-6, IL-21, and Growth Factor-ß (TGF-ß)]; and epithelial cells evaluated IgA transitosis [polymeric immunoglobulin receptor (pIgR), tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), IL-4] by the RT-qPCR technique. The results were compared with data obtained from sedentary age-matched mice. Statistical analysis was computed with ANOVA, and p < 0.05 was considered to be a statistically significant difference. Under senescence conditions, MAE promoted the B cell and IgA+ B cells and APRIL, which may improve the intestinal response and ameliorate the inflammatory environment associated presumably with the downmodulation of pro-inflammatory mediators involved in the upmodulation of pIgR expression. Data suggested that MAE improved IgA and downmodulate the cytokine pro-inflammatory expression favoring homeostatic conditions in aging.


Assuntos
Envelhecimento , Homeostase , Imunoglobulina A , Camundongos Endogâmicos BALB C , Condicionamento Físico Animal , Animais , Imunoglobulina A/metabolismo , Imunoglobulina A/imunologia , Camundongos , Envelhecimento/imunologia , Citocinas/metabolismo , Linfócitos B/imunologia , Linfócitos B/metabolismo , Fator Ativador de Células B/metabolismo , Fator Ativador de Células B/genética , Mucosa Intestinal/metabolismo , Mucosa Intestinal/imunologia , Intestino Delgado/imunologia , Intestino Delgado/metabolismo , Masculino , Plasmócitos/imunologia , Plasmócitos/metabolismo , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética
18.
Braz J Med Biol Res ; 57: e13452, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38958368

RESUMO

The misuse of anabolic androgenic steroid associated or not with physical workouts disrupts gastrointestinal (GI) function homeostasis. Our goal was to investigate the effects of nandrolone decanoate (ND) and moderate swimming on the GI transit of solid meals, GI motor contractility, and intestinal histology in rats. Male Wistar rats were allocated to four groups that received intramuscular injections of ND (5.0 mg/kg) or vehicle (60.0 µL) and were submitted or not to swimming sessions (60 min, 5% body weight overload) for 4 weeks. Gastric emptying, intestinal transit, in vitro GI contractility, intestinal morphometry, and duodenal mucosal mast cells were evaluated in all experimental groups. ND treatment accelerated gastric emptying, slowed small intestine transit time, enhanced gastric carbachol-mediated reactivity, decreased crypt depth and villus height, reduced mucosal thickness, and increased the circular and longitudinal muscle layer thickness of the duodenum in sedentary rats. Moderate exercise accelerated intestinal transit time and reduced submucosa thickness. In vehicle-treated animals, a strong negative correlation was found between intestinal transit and mucosal mast cells, which was reversed by ND treatment. Combining ND treatment and swimming accelerated gastric emptying, increased duodenal cholinergic reactivity, inhibited the sodium nitroprusside relaxing response, increased the number of duodenal mast cells, decreased villus height, and increased the thickness of all muscle layers. ND changed the morphological and functional properties of the GI tract over time, with intense dysmotility, especially in sedentary animals, but moderate exercise seemed to have played a compensatory role in these harmful effects in the gut.


Assuntos
Anabolizantes , Duodeno , Motilidade Gastrointestinal , Decanoato de Nandrolona , Nandrolona , Condicionamento Físico Animal , Ratos Wistar , Animais , Masculino , Decanoato de Nandrolona/farmacologia , Duodeno/efeitos dos fármacos , Motilidade Gastrointestinal/efeitos dos fármacos , Anabolizantes/farmacologia , Nandrolona/farmacologia , Nandrolona/análogos & derivados , Mastócitos/efeitos dos fármacos , Ratos , Natação , Esvaziamento Gástrico/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Trânsito Gastrointestinal/efeitos dos fármacos
19.
Int J Biol Macromol ; 277(Pt 2): 134216, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39069058

RESUMO

Lactobacillus delbrueckii CIDCA 133 is a promising health-promoting bacterium shown to alleviate intestinal inflammation. However, the specific bacterial components responsible for these effects remain largely unknown. Here, we demonstrated that consuming extractable proteins from the CIDCA 133 strain effectively relieved acute ulcerative colitis in mice. This postbiotic protein fraction reduced the disease activity index and prevented colon shortening in mice. Furthermore, histological analysis revealed colitis prevention with reduced inflammatory cell infiltration into the colon mucosa. Postbiotic consumption also induced an immunomodulatory profile in colitic mice, as evidenced by both mRNA transcript levels (Tlr2, Nfkb1, Nlpr3, Tnf, and Il6) and cytokines concentration (IL1ß, TGFß, and IL10). Additionally, it enhanced the levels of secretory IgA, upregulated the transcript levels of tight junction proteins (Hp and F11r), and improved paracellular intestinal permeability. More interestingly, the consumption of postbiotic proteins modulated the gut microbiota (Bacteroides, Arkkemansia, Dorea, and Oscillospira). Pearson correlation analysis indicated that IL10 and IL1ß levels were positively associated with Bacteroides and Arkkemansia_Lactobacillus abundance. Our study reveals that CIDCA 133-derived proteins possess anti-inflammatory properties in colonic inflammation.


Assuntos
Anti-Inflamatórios , Modelos Animais de Doenças , Microbioma Gastrointestinal , Lactobacillus delbrueckii , Animais , Camundongos , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Microbioma Gastrointestinal/efeitos dos fármacos , Citocinas/metabolismo , Proteínas de Bactérias/farmacologia , Doenças Inflamatórias Intestinais/microbiologia , Doenças Inflamatórias Intestinais/patologia , Probióticos/farmacologia , Mucosa Intestinal/microbiologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Colite Ulcerativa/microbiologia , Colite Ulcerativa/patologia , Colo/patologia , Colo/microbiologia , Colo/metabolismo , Masculino
20.
World J Gastroenterol ; 30(24): 3022-3035, 2024 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-38983953

RESUMO

Managing inflammatory bowel disease (IBD) is becoming increasingly complex and personalized, considering the advent of new advanced therapies with distinct mechanisms of action. Achieving mucosal healing (MH) is a pivotal therapeutic goal in IBD management and can prevent IBD progression and reduce flares, hospitalization, surgery, intestinal damage, and colorectal cancer. Employing proactive disease and therapy assessment is essential to achieve better control of intestinal inflammation, even if subclinical, to alter the natural course of IBD. Periodic monitoring of fecal calprotectin (FC) levels and interval endoscopic evaluations are cornerstones for evaluating response/remission to advanced therapies targeting IBD, assessing MH, and detecting subclinical recurrence. Here, we comment on the article by Ishida et al Moreover, this editorial aimed to review the role of FC and endoscopic scores in predicting MH in patients with IBD. Furthermore, we intend to present some evidence on the role of these markers in future targets, such as histological and transmural healing. Additional prospective multicenter studies with a stricter MH criterion, standardized endoscopic and histopathological analyses, and virtual chromoscopy, potentially including artificial intelligence and other biomarkers, are desired.


Assuntos
Biomarcadores , Fezes , Doenças Inflamatórias Intestinais , Mucosa Intestinal , Complexo Antígeno L1 Leucocitário , Humanos , Complexo Antígeno L1 Leucocitário/análise , Fezes/química , Mucosa Intestinal/patologia , Mucosa Intestinal/metabolismo , Biomarcadores/análise , Biomarcadores/metabolismo , Doenças Inflamatórias Intestinais/patologia , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/terapia , Índice de Gravidade de Doença , Cicatrização , Colonoscopia , Progressão da Doença , Recidiva , Endoscopia Gastrointestinal/métodos
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