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1.
Life Sci ; 273: 119295, 2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-33667522

RESUMO

AIMS: Dipeptidyl peptidase-4 (DPP-4) has been involved in the pathogenesis of inflammatory bowel diseases (IBD), yet the underlying mechanisms remain inconclusive. The present study aimed to investigate the potential of linagliptin, a potent/selective DPP-4 inhibitor with marked anti-inflammatory actions, to attenuate trinitrobenzene sulfonic acid (TNBS)-evoked colitis in rats; an experimental model of IBD, and the implicated molecular mechanisms. This may add to the clinical utility of linagliptin for the management of patients with coexisting IBD and diabetes mellitus. Notably, no former studies have linked JAK2/STAT3, HMGB1/NF-κB, and Nrf2/HO-1 signaling in TNBS-evoked colitis. MATERIALS AND METHODS: Western blotting and ELISA were used to determine the levels of target signals. KEY FINDINGS: Administration of linagliptin (1.5 mg/kg; p.o.) mitigated the colitis severity via diminishing the disease activity index, colon weight/length ratio, and macroscopic scores. Linagliptin also lowered the colonic histologic scores and leukocyte invasion. Notably, linagliptin inhibited the colonic DPP-4 activity and upregulated the expression of intestinotrophic GLP-2 without incurring hypoglycemia in animals. Linagliptin curbed inflammation through the suppression of colonic IL-6, TNF-α, and myeloperoxidase and upregulation of IL-10. It also inhibited the IL-6/JAK2/STAT3 pathway via downregulating p-JAK2/JAK2 and p-STAT3/STAT3 protein expression and HMGB1/RAGE/NF-κB cascade through lowering HMGB1, RAGE, and p-NF-κB p65/NF-κB p65 protein expression. In the context of mucosal oxidative stress, linagliptin diminished lipid peroxides and augmented GSH, GPx, and total antioxidant capacity. It also activated Nrf2/HO-1 pathway via upregulating Nrf2 and HO-1 protein expression. SIGNIFICANCE: Linagliptin shows a promise for the management of IBD via targeting IL-6/JAK2/STAT3, HMGB1/RAGE/NF-κB, and Nrf2/HO-1 pathways.


Assuntos
Colite/tratamento farmacológico , Hipoglicemiantes/farmacologia , Inflamação/tratamento farmacológico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Linagliptina/farmacologia , Ácido Trinitrobenzenossulfônico/toxicidade , Animais , Colite/induzido quimicamente , Colite/metabolismo , Colite/patologia , Citocinas/genética , Citocinas/metabolismo , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Doenças Inflamatórias Intestinais/induzido quimicamente , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/patologia , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Masculino , NF-kappa B/genética , NF-kappa B/metabolismo , Oxirredução , Ratos , Ratos Wistar , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais
2.
Int J Mol Sci ; 22(2)2021 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-33466734

RESUMO

Cannabis sativa L. turned out to be a valuable source of chemical compounds of various structures, showing pharmacological activity. The most important groups of compounds include phytocannabinoids and terpenes. The pharmacological activity of Cannabis (in epilepsy, sclerosis multiplex (SM), vomiting and nausea, pain, appetite loss, inflammatory bowel diseases (IBDs), Parkinson's disease, Tourette's syndrome, schizophrenia, glaucoma, and coronavirus disease 2019 (COVID-19)), which has been proven so far, results from the affinity of these compounds predominantly for the receptors of the endocannabinoid system (the cannabinoid receptor type 1 (CB1), type two (CB2), and the G protein-coupled receptor 55 (GPR55)) but, also, for peroxisome proliferator-activated receptor (PPAR), glycine receptors, serotonin receptors (5-HT), transient receptor potential channels (TRP), and GPR, opioid receptors. The synergism of action of phytochemicals present in Cannabis sp. raw material is also expressed in their increased bioavailability and penetration through the blood-brain barrier. This review provides an overview of phytochemistry and pharmacology of compounds present in Cannabis extracts in the context of the current knowledge about their synergistic actions and the implications of clinical use in the treatment of selected diseases.


Assuntos
Canabinoides/farmacologia , Cannabis/química , Descoberta de Drogas , Compostos Fitoquímicos/farmacologia , Terpenos/farmacologia , Animais , Canabinoides/química , Canabinoides/uso terapêutico , Sinergismo Farmacológico , Endocanabinoides/metabolismo , Epilepsia/tratamento farmacológico , Epilepsia/metabolismo , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/metabolismo , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Compostos Fitoquímicos/química , Compostos Fitoquímicos/uso terapêutico , Receptores de Canabinoides/metabolismo , Esquizofrenia/tratamento farmacológico , Esquizofrenia/metabolismo , Terpenos/química , Terpenos/uso terapêutico , Síndrome de Tourette/tratamento farmacológico , Síndrome de Tourette/metabolismo
3.
Int J Mol Sci ; 22(3)2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-33498177

RESUMO

The pathophysiological processes of inflammatory bowel diseases (IBDs), i.e., Crohn's disease (CD) and ulcerative colitis (UC), are still not completely understood. The exact etiology remains unknown, but it is well established that the pathogenesis of the inflammatory lesions is due to a dysregulation of the gut immune system resulting in over-production of pro-inflammatory cytokines. Increasing evidence underlines the involvement of both environmental and genetic factors. Regarding the environment, the microbiota seems to play a crucial role. Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that exert pleiotropic effects on glucose homeostasis, lipid metabolism, inflammatory/immune processes, cell proliferation, and fibrosis. Furthermore, PPARs modulate interactions with several environmental factors, including microbiota. A significantly impaired PPARγ expression was observed in UC patients' colonic epithelial cells, suggesting that the disruption of PPARγ signaling may represent a critical step of the IBD pathogenesis. This paper will focus on the role of PPARγ in the interaction between environmental factors and IBD, and it will analyze the most suitable in vitro and in vivo models available to better study these relationships.


Assuntos
Meio Ambiente , Doenças Inflamatórias Intestinais/metabolismo , PPAR gama/metabolismo , Animais , Microbioma Gastrointestinal , Homeostase , Humanos , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/microbiologia , PPAR gama/genética
5.
Postepy Biochem ; 66(1): 42-48, 2020 03 31.
Artigo em Polonês | MEDLINE | ID: mdl-33320478

RESUMO

Sphingosine-1-phosphate (S1P) belongs to the group of biologically active sphingolipids. Because of its ability to regulate the migration of lymphocytes, S1P constitutes an important element of pathophysiology of several diseases, such as: lupus erythematosus, multiple sclerosis or inflammatory bowel diseases. Inflammatory bowel diseases (IBD) are the group of chronic and recurrent diseases of the gastrointestinal tract. The most common among IBD are: Crohn's disease and ulcerative colitis. Drugs that are currently used in the therapy of IBD alleviate symptoms, improve patients' quality of life and induce remission but their efficacy is not satisfactory. Modulators of S1P receptors constitu­te an emerging option in the therapy of IBD. In this review we will discuss the role of S1P, its receptor and enzymes that participate in the metabolism of S1P under physiological conditions and in the course of IBD. Moreover, we will sum up the results of preclinical and clinical studies on S1P receptors modulators in IBD.


Assuntos
Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/metabolismo , Lisofosfolipídeos/metabolismo , Esfingosina/análogos & derivados , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/metabolismo , Doença de Crohn/tratamento farmacológico , Doença de Crohn/metabolismo , Humanos , Qualidade de Vida , Esfingosina/metabolismo
6.
Int J Mol Sci ; 21(24)2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33334069

RESUMO

Inflammatory colon diseases, which are a global health concern, include a variety of gastrointestinal tract disorders, such as inflammatory bowel disease and colon cancer. The pathogenesis of these colon disorders involves immune alterations with the pronounced infiltration of innate and adaptive immune cells into the intestines and the augmented expression of mucosal pro-inflammatory cytokines stimulated by commensal microbiota. Epidemiological studies during the past half century have shown that the proportion of obese people in a population is associated with the incidence and pathogenesis of gastrointestinal tract disorders. The advancement of understanding of the immunological basis of colon disease has shown that adipocyte-derived biologically active substances (adipokines) modulate the role of innate and adaptive immune cells in the progress of intestinal inflammation. The biomedical significance in immunological homeostasis of adipokines, including adiponectin, leptin, apelin and resistin, is clear. In this review, we highlight the existing literature on the effect and contribution of adipokines to the regulation of immunological homeostasis in inflammatory colon diseases and discuss their crucial roles in disease etiology and pathogenesis, as well as the implications of these results for new therapies in these disorders.


Assuntos
Adipocinas/metabolismo , Suscetibilidade a Doenças , Homeostase , Imunomodulação , Doenças Inflamatórias Intestinais/etiologia , Doenças Inflamatórias Intestinais/metabolismo , Adipocinas/farmacologia , Tecido Adiposo/imunologia , Tecido Adiposo/metabolismo , Animais , Biomarcadores , Homeostase/efeitos dos fármacos , Humanos , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Sistema Imunitário/patologia , Imunomodulação/efeitos dos fármacos , Doenças Inflamatórias Intestinais/patologia
7.
Clin Sci (Lond) ; 134(21): 2823-2833, 2020 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-33140827

RESUMO

ACE2 is a type I membrane protein with extracellular carboxypeptidase activity displaying a broad tissue distribution with highest expression levels at the brush border membrane (BBM) of small intestine enterocytes and a lower expression in stomach and colon. In small intestinal mucosa, ACE2 mRNA expression appears to increase with age and to display higher levels in patients taking ACE-inhibitors (ACE-I). There, ACE2 protein heterodimerizes with the neutral amino acid transporter Broad neutral Amino acid Transporter 1 (B0AT1) (SLC6A19) or the imino acid transporter Sodium-dependent Imino Transporter 1 (SIT1) (SLC6A20), associations that are required for the surface expression of these transport proteins. These heterodimers can form quaternary structures able to function as binding sites for SARS-CoV-2 spike glycoproteins. The heterodimerization of the carboxypeptidase ACE2 with B0AT1 is suggested to favor the direct supply of substrate amino acids to the transporter, but whether this association impacts the ability of ACE2 to mediate viral infection is not known. B0AT1 mutations cause Hartnup disorder, a condition characterized by neutral aminoaciduria and, in some cases, pellagra-like symptoms, such as photosensitive rash, diarrhea, and cerebellar ataxia. Correspondingly, the lack of ACE2 and the concurrent absence of B0AT1 expression in small intestine causes a decrease in l-tryptophan absorption, niacin deficiency, decreased intestinal antimicrobial peptide production, and increased susceptibility to inflammatory bowel disease (IBD) in mice. Thus, the abundant expression of ACE2 in small intestine and its association with amino acid transporters appears to play a crucial role for the digestion of peptides and the absorption of amino acids and, thereby, for the maintenance of structural and functional gut integrity.


Assuntos
Sistemas de Transporte de Aminoácidos Neutros/metabolismo , Betacoronavirus/patogenicidade , Infecções por Coronavirus/enzimologia , Absorção Intestinal , Mucosa Intestinal/enzimologia , Proteínas de Membrana Transportadoras/metabolismo , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/enzimologia , Internalização do Vírus , Animais , Infecções por Coronavirus/virologia , Interações Hospedeiro-Patógeno , Humanos , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/metabolismo , Pandemias , Peptidil Dipeptidase A/genética , Pneumonia Viral/virologia , Multimerização Proteica
8.
J Exp Med ; 217(3): e20192195, 2020 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-32997932

RESUMO

The cytokine interleukin-22 (IL-22) is a critical regulator of epithelial homeostasis. It has been implicated in multiple aspects of epithelial barrier function, including regulation of epithelial cell growth and permeability, production of mucus and antimicrobial proteins (AMPs), and complement production. In this review, we focus specifically on the role of IL-22 in the intestinal epithelium. We summarize recent advances in our understanding of how IL-22 regulates homeostasis and host defense, and we discuss the IL-22 pathway as a therapeutic target in diseases of the intestine, including inflammatory bowel disease (IBD), graft-versus-host disease (GVHD), and cancer.


Assuntos
Interleucinas/metabolismo , Mucosa Intestinal/metabolismo , Intestinos/patologia , Animais , Células Epiteliais/metabolismo , Doença Enxerto-Hospedeiro/metabolismo , Humanos , Doenças Inflamatórias Intestinais/metabolismo
9.
Nat Commun ; 11(1): 4018, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32782301

RESUMO

The gut microbiome is an ecosystem that involves complex interactions. Currently, our knowledge about the role of the gut microbiome in health and disease relies mainly on differential microbial abundance, and little is known about the role of microbial interactions in the context of human disease. Here, we construct and compare microbial co-abundance networks using 2,379 metagenomes from four human cohorts: an inflammatory bowel disease (IBD) cohort, an obese cohort and two population-based cohorts. We find that the strengths of 38.6% of species co-abundances and 64.3% of pathway co-abundances vary significantly between cohorts, with 113 species and 1,050 pathway co-abundances showing IBD-specific effects and 281 pathway co-abundances showing obesity-specific effects. We can also replicate these IBD microbial co-abundances in longitudinal data from the IBD cohort of the integrative human microbiome (iHMP-IBD) project. Our study identifies several key species and pathways in IBD and obesity and provides evidence that altered microbial abundances in disease can influence their co-abundance relationship, which expands our current knowledge regarding microbial dysbiosis in disease.


Assuntos
Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais/microbiologia , Consórcios Microbianos , Obesidade/microbiologia , Adulto , Bactérias/crescimento & desenvolvimento , Bactérias/isolamento & purificação , Bactérias/metabolismo , Estudos de Coortes , Disbiose/metabolismo , Disbiose/microbiologia , Feminino , Microbioma Gastrointestinal/genética , Especificidade de Hospedeiro , Humanos , Doenças Inflamatórias Intestinais/metabolismo , Masculino , Redes e Vias Metabólicas , Pessoa de Meia-Idade , Obesidade/metabolismo
10.
Am J Physiol Gastrointest Liver Physiol ; 319(2): G170-G174, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32658620

RESUMO

Defective intestinal tight-junction (TJ) barrier has been implicated in the pathogenesis of inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), and other inflammatory conditions of the gut. The role of microRNAs (miRNA's or miR's) has also been demonstrated in the last two decades in the pathogenesis of IBD and in the regulation of intestinal TJ barrier function. MiRNAs are noncoding regulators of gene expression at the posttranscription level that have an essential role in targeting transcripts encoding proteins of intestinal TJs and their regulators. Many miRNAs have been reported to regulate or deregulate the TJ proteins responsible for the intestinal barrier integrity and intestinal permeability. Many of those miRNAs have been reported to have essential roles in the pathogenesis of IBD. In this mini-review, we summarize the results of studies in the last three years that implicate miRNAs in the defective TJ barrier in relation to IBD. The therapeutic potential of using specific miRNAs to target the intestinal TJ barrier might be of great insight for IBD therapy.


Assuntos
Mucosa Intestinal/metabolismo , MicroRNAs/metabolismo , Animais , Humanos , Doenças Inflamatórias Intestinais/metabolismo , MicroRNAs/genética
11.
J Oleo Sci ; 69(7): 751-757, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32612025

RESUMO

The rising incidence of inflammatory bowel disease (IBD) in East Asian countries has necessitated the implementation of preventive methods in the form of dietary supplementation and changes in dietary habits. We have previously reported that dietary golden oyster mushroom (Pleurotus citrinopileatus) ethanol extract (GOMEE) suppresses intestinal inflammation in mouse models of IBD induced by dextran sulfate sodium salt (DSS). Here, we investigated the components of GOMEE that exert suppressive effects on colon inflammation in vivo and in vitro. The total lipid fraction was extracted from GOMEE, and the polar and neutral lipid fractions were subsequently separated via solvent fractionation. Mice were assigned to dietary groups-control, 1% total lipid, 1% polar lipid, or 1% neutral lipid diet-and fed the respective diets for one week; mice were administered 1.5% DSS in drinking water ad libitum for 20 days. Dietary supplementation with the total or polar lipid fraction alleviated DSS-induced chorionic crypt injury as determined by morphological observation, while dietary supplementation with the neutral lipid fraction did not produce such effects. In the in vitro study, using differentiated Caco-2 cells as the colon model, treatment with the total or polar lipid fraction suppressed cell decrease by lipopolysaccharide (LPS)-induced apoptosis whereas treatment with the neutral lipid fraction did not. Moreover, accumulation of glucosylceramide (GlcCer), a fungal sphingolipid, was observed in the intestinal cells after treatment with polar lipid fraction. These results suggest that the active components of GOMEE that suppress colon inflammation are polar lipids, especially GlcCer. The structure of mushroom GlcCer differs from that of the plant counterpart and is therefore expected to exert different food functions.


Assuntos
Apoptose/efeitos dos fármacos , Colo/metabolismo , Colo/patologia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Fitoterapia , Pleurotus/química , Esfingolipídeos/farmacologia , Esfingolipídeos/uso terapêutico , Animais , Células CACO-2 , Fracionamento Químico , Suplementos Nutricionais , Modelos Animais de Doenças , Glucosilceramidas , Humanos , Doenças Inflamatórias Intestinais/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Esfingolipídeos/isolamento & purificação
12.
Postepy Biochem ; 66(2): 143-150, 2020 06 27.
Artigo em Polonês | MEDLINE | ID: mdl-32700508

RESUMO

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


Assuntos
Doenças Inflamatórias Intestinais/etiologia , Doenças Inflamatórias Intestinais/metabolismo , Estresse Oxidativo , Homeostase , Humanos , Inflamação , Doenças Inflamatórias Intestinais/patologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Oxirredução
13.
Biomed Khim ; 66(3): 233-240, 2020 May.
Artigo em Russo | MEDLINE | ID: mdl-32588829

RESUMO

Inflammatory bowel diseases (IBD), which include ulcerative colitis (UC) and Crohn's disease (CD), are chronic intestinal inflammatory disorders with an unknown etiology. They are characterized by chronic recurrent inflammation of the intestinal mucosa and lead to a significant decrease in the quality of life and death of patients. IBD are associated with suppression of normal intestinal microflora, including a decrease in bacteria, producers of short chain fatty acids (SCFAs), exhibiting anti-inflammatory and protective properties. Among the various methods of intestinal microflora correction, fecal microbiota transplantation (FMT), which engrafts the fecal microbiota from a healthy donor into a patient recipient, is of a particular interest. As a result, a positive therapeutic effect is observed, accompanied by the restoration of the normal intestinal microflora of the patient. A significant drawback of the method is the lack of standardization. Metabolites produced by intestinal microflora, namely SCFAs, allow objective assessment of the functional state of the intestinal microbiota and, consequently, the success of the FMT procedure. Using gas chromatography and nuclear magnetic resonance spectroscopy techniques, we have analyzed concentrations and molar ratios of SCFAs in fecal samples of 60 healthy donors. Results were in good accord when comparing two methods as well as with published data. Analysis of SCFAs in feces of patients with UC (19 patients) and CD (17 patients) revealed a general decrease in the concentration of fatty acids in the experimental groups with significant fluctuations in the values in experimental groups compared to control group of healthy donors. On the limited group of IBD patients (6 patients with UC and 5 patients with CD) concentration of SCFAs before and within 30 days of observation after FMT was determined. It was shown that FMT had a significant impact on the SCFAs levels within 1 month term; tendency to reach characteristics of healthy donors is unambiguously traced for both diseases.


Assuntos
Fezes , Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais , Transplante de Microbiota Fecal , Fezes/química , Humanos , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/terapia , Qualidade de Vida
14.
J Pharmacol Exp Ther ; 374(3): 420-427, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32546529

RESUMO

Inflammatory bowel diseases are caused by inflammation of the gastrointestinal tract, which may or may not have a specific cause or pathogen. They affect millions of people around the world and there are still few effective treatments. The aim of this work is to investigate the anti-inflammatory effect of the IKK-ß inhibitor LASSBio-1524 and its three analogs, LASSBio-1760, LASSBio-1763, and LASSBio-1764, on mediator production and expression of inflammatory enzymes using experimental animal models of intestinal inflammatory diseases. Colitis was performed using two different models, which mimic Crohn disease (induced by dinitrobenzene acid) and ulcerative colitis (induced by sodium dextran sulfate) in mice. In both models, a therapeutic protocol with a daily dose of 1, 3, or 30 µmol/kg was performed. LASSBio-1524 and its three analogs reduced the secretion of tumor necrosis factor-α, IL-1ß, IL-6, IL-12, and IFN-γ and increased secretion of IL-10, protecting gastrointestinal homeostasis. All compounds reduced macro- and microscopic colonic damage caused by experimental colitis and p38 mitogen-activated protein kinase expression in the colon, as well as leukocytosis and anemia resulting from the disease. Our data may suggest LASSBio-1524 and its analogs (LASSBio-1760, LASSBio-1763, and LASSBio-1764) as promising candidates for new prototypes designed to treat inflammatory bowel diseases. SIGNIFICANCE STATEMENT: Three new N-acylhydrazones were synthetized as analogs of LASSBio-1524. All new substances were evaluated in dextran sulfate- and dinitrobenzene acid-induced colitis, with LASSBio-1760, LASSBio-1762, and LASSBio-1763 presenting a significant effect in both models of colitis without toxic effects. The new substances could be considered as a new prototype for the development of new anti-inflammatory treatments of colitis.


Assuntos
Anti-Inflamatórios/farmacologia , Colite Ulcerativa/tratamento farmacológico , Inflamação/tratamento farmacológico , Animais , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/metabolismo , Colo/efeitos dos fármacos , Colo/metabolismo , Citocinas/metabolismo , Sulfato de Dextrana/farmacologia , Modelos Animais de Doenças , Feminino , Inflamação/induzido quimicamente , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Doenças Inflamatórias Intestinais/induzido quimicamente , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Camundongos , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
16.
Pediatr Surg Int ; 36(7): 799-807, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32448932

RESUMO

PURPOSE: Our previous studies demonstrated that mature adipocyte-derived dedifferentiated fat (DFAT) cells possess similar multipotency as mesenchymal stem cells. Here, we examined the immunoregulatory potential of DFAT cells in vitro and the therapeutic effect of DFAT cell transplantation in a mouse inflammatory bowel disease (IBD) model. METHODS: The effect of DFAT cell co-culture on T cell proliferation and expression of immunosuppression-related genes in DFAT cells were evaluated. To create IBD, CD4+CD45RBhigh T cells were intraperitoneally injected into SCID mice. One week later, DFAT cells (1 × 105, DFAT group) or saline (Control group) were intraperitoneally injected. Subsequently bodyweight was measured every week and IBD clinical and histological scores were evaluated at 5 weeks after T cell administration. RESULTS: The T cell proliferation was inhibited by co-cultured DFAT cells in a cell density-dependent manner. Gene expression of TRAIL, IDO1, and NOS2 in DFAT cells was upregulated by TNFα stimulation. DFAT group improved IBD-associated weight loss, IBD clinical and histological scores compared to Control group. CONCLUSION: DFAT cells possess immunoregulatory potential and the cell transplantation promoted recovery from colon damage and improved clinical symptoms in the IBD model. DFAT cells could play an important role in the treatment of IBD.


Assuntos
Adipócitos/metabolismo , Adipócitos/transplante , Desdiferenciação Celular/fisiologia , Transplante de Células/métodos , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/terapia , Animais , Técnicas de Cultura de Células , Proliferação de Células , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Endogâmicos BALB C
17.
Adv Clin Exp Med ; 29(5): 547-556, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32424999

RESUMO

BACKGROUND: The effect of bowel inflammation and cancer on the expression of the most prevalent internal controls: ACTB, GAPDH and B2M in whole blood is unknown, although at least GAPDH occurred to be tightly regulated and suspected of supporting cancer growth, challenging its suitability as a reference. OBJECTIVES: To evaluate the effect of colorectal cancer (CRC) and active inflammatory bowel disease (IBD) on the stability of ACTB, B2M, GAPDH, HPRT1, SDHA, and TBP leukocyte expression. MATERIAL AND METHODS: Gene expression in controls and CRC and IBD patients (n = 21/18/25) was evaluated in real-time quantitative polymerase chain reaction (RT-qPCR) using NormFinder, geNorm, BestKeeper, and comparative ΔCt method, and validated by comparison with absolute quantification of interleukin 1ß (IL-1ß) and CCL4. RESULTS: HPRT1, SDHA and TBP were superior normalizers in CRC and IBD. The highest expression variability was noted in active IBD. B2M was significantly lower in CRC but higher in IBD. GAPDH was higher in CRC and IBD. ACTB and GAPDH corresponded with CRC advancement (ρ = 0.52 and ρ = 0.53) and with clinical activity in Crohn's disease (ρ = 0.44 and ρ = 0.57) and ulcerative colitis (GAPDH: ρ = 0.72). ACTB, B2M and GAPDH correlated with circulating inflammatory/angiogenic indices, differently in IBD and CRC. CONCLUSIONS: Leukocyte GAPDH, ACTB, and B2M expression is affected by bowel inflammation and cancer, rendering them unsuitable as a reference in CRC and IBD.


Assuntos
Actinas/sangue , Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Perfilação da Expressão Gênica/métodos , Gliceraldeído-3-Fosfato Desidrogenase (Fosforiladora)/sangue , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/patologia , Reação em Cadeia da Polimerase em Tempo Real/métodos , Microglobulina beta-2/sangue , Actinas/metabolismo , Indutores da Angiogênese/sangue , Quimiocina CCL4 , Neoplasias Colorretais/metabolismo , Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Gliceraldeído-3-Fosfato Desidrogenase (Fosforiladora)/metabolismo , Humanos , Doenças Inflamatórias Intestinais/metabolismo , Interleucina-1beta , Fragmentos de Peptídeos , Padrões de Referência , Microglobulina beta-2/metabolismo
18.
Scand J Immunol ; 92(3): e12897, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32443180

RESUMO

Inflammatory bowel diseases (IBD) are a group of chronic recurrent gastrointestinal inflammatory diseases, including ulcerative colitis (UC), Crohn's disease (CD) and IBD unclassified. The pathogenesis may be related to the mucosal immune dysfunction in genetically susceptible hosts affected by environmental factors. Current therapeutic agents mainly include aminosalicylates, corticosteroids, immunosuppressive drugs and novel biological agents. The purpose of treatment is to suppress inflammation and prevent irreversible structural damage. However, long-term application of these drugs may lead to multiple adverse effects and is not always effective. Mesenchymal stem cells (MSCs) are multipotent progenitors with low immunogenicity, which can be obtained and expanded easily. They play an important role in regulating immune responses and repairing damaged tissues in vivo. Therefore, MSCs are considered to be a promising option for the treatment of IBD. Nonetheless, there are many factors that can reduce the efficacy of MSCs, such as gradual deterioration of functional stem cells with age, low recruitment and persistence in vivo and different routes of administration. In recent years, researchers have been able to improve the efficacy of MSCs by pretreatment, genetic modification or co-application with other substances, as well as using different tissue-derived cells, administration methods or doses. This article reviews these methods to provide references for more effective application of MSCs in the treatment of IBD in the future.


Assuntos
Doenças Inflamatórias Intestinais/terapia , Transplante de Células-Tronco Mesenquimais , Animais , Biomarcadores , Terapia Combinada , Engenharia Genética , Humanos , Doenças Inflamatórias Intestinais/etiologia , Doenças Inflamatórias Intestinais/metabolismo , Transplante de Células-Tronco Mesenquimais/efeitos adversos , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Especificidade de Órgãos , Fenótipo , Condicionamento Pré-Transplante/métodos , Resultado do Tratamento
19.
Aliment Pharmacol Ther ; 52(1): 155-167, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32412673

RESUMO

BACKGROUND: Small intestinal bacterial overgrowth may play a role in gastrointestinal and non-gastrointestinal diseases. AIMS: To use quantitative polymerase chain reaction (qPCR) to determine and compare bacterial loads of duodenal biopsies in asymptomatic controls, and patients with functional gastrointestinal disorders (FGIDs) and inflammatory bowel disease (IBD) including ulcerative colitis (UC) and Crohn's disease (CD). To define effects of gastric acid inhibition on bacterial load, explore links of bacterial load and gastrointestinal symptoms in response to a standardised nutrient challenge and compare bacterial load with glucose breath test results. METHODS: In 237 patients (63 controls, 84 FGID and 90 IBD), we collected mucosal samples under aseptic conditions during endoscopy extracted and total DNA. Bacterial load metric was calculated utilising qPCR measurements of the bacterial 16S rRNA gene, normalised to human beta-actin expression. Standard glucose breath test and nutrient challenge test were performed. RESULTS: The duodenal microbial load was higher in patients with FGID (0.22 ± 0.03) than controls (0.07 ± 0.05; P = 0.007) and patients with UC (0.01 ± 0.05) or CD (0.02 ± 0.09), (P = 0.0001). While patients treated with proton pump inhibitors (PPI) had significantly higher bacterial loads than non-users (P < 0.05), this did not explain differences between patient groups and controls. Bacterial load was significantly (r = 0.21, P < 0.016) associated with the symptom response to standardised nutrient challenge test. Methane, but not hydrogen values on glucose breath test were associated with bacterial load measured utilising qPCR. CONCLUSIONS: Utilising qPCR, a diagnosis of FGID and treatment with PPI were independently associated with increased bacterial loads. Increased bacterial loads are associated with an augmented symptom response to a standardised nutrient challenge.


Assuntos
Duodeno/microbiologia , Gastroenteropatias/microbiologia , Doenças Inflamatórias Intestinais/microbiologia , Adulto , Idoso , Bactérias/genética , Bactérias/isolamento & purificação , Carga Bacteriana , Biópsia , Testes Respiratórios/métodos , Feminino , Gastroenteropatias/metabolismo , Glucose/metabolismo , Humanos , Doenças Inflamatórias Intestinais/metabolismo , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase/métodos , RNA Ribossômico 16S/genética
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