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1.
Front Immunol ; 12: 777665, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34899735

RESUMO

Lactic acid, a metabolic by-product of host and intestinal microbiota, has been recovered as an active signal molecule in the immune system. In this study, a lactic acid biosynthesis pathway that directly produces lactic acid from glucose rather than ethanol with high production was reconstructed in Saccharomyces cerevisiae. The engineered S. cerevisiae showed anti-inflammatory activity in dextran sulfate sodium (DSS)-induced mice with improved histological damage, increased mucosal barrier, and decreased intestinal immune response. Lactic acid regulated the macrophage polarization state and inhibited the expression of pro-inflammatory cytokines in vivo and in vitro. Increasing the macrophage monocarboxylic acid transporter-mediated active lactic acid uptake suppressed the excessive activation of the NLRP3 inflammasome and the downstream caspase-1 pathway in macrophages. Moreover, lactic acid promoted histone H3K9 acetylation and histone H3K18 lactylation. Meanwhile, the engineered S. cerevisiae altered the diversity and composition of the intestinal microbiota and changed the abundance of metabolic products in mice with colitis. In conclusion, this study shows that the application of engineered S. cerevisiae attenuated DSS-induced colitis in mice via suppressing macrophage pyroptosis and modulating the intestinal microbiota, which is an effective and safe treatment strategy for ulcerative colitis.

2.
Front Immunol ; 12: 700995, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34804005

RESUMO

The prevalence of inflammatory bowel disease (IBD) is increasing worldwide and correlates with dysregulated immune response because of gut microbiota dysbiosis. Some adverse early life events influence the establishment of the gut microbiota and act as risk factors for IBD. Prenatal maternal stress (PNMS) induces gut dysbiosis and perturbs the neuroimmune network of offspring. In this study, we aimed to investigate whether PNMS increases the susceptibility of offspring to colitis in adulthood. The related index was assessed during the weaning period and adulthood. We found that PNMS impaired the intestinal epithelial cell proliferation, goblet cell and Paneth cell differentiation, and mucosal barrier function in 3-week-old offspring. PNMS induced low-grade intestinal inflammation, but no signs of microscopic inflammatory changes were observed. Although there was no pronounced difference between the PNMS and control offspring in terms of their overall measures of alpha diversity for the gut microbiota, distinct microbial community changes characterized by increases in Desulfovibrio, Streptococcus, and Enterococcus and decreases in Bifidobacterium and Blautia were induced in the 3-week-old PNMS offspring. Notably, the overgrowth of Desulfovibrio persisted from the weaning period to adulthood, consistent with the results observed using fluorescence in situ hybridization in the colon mucosa. Mechanistically, the fecal microbiota transplantation experiment showed that the gut microbiota from the PNMS group impaired the intestinal barrier function and induced low-grade inflammation. The fecal bacterial solution from the PNMS group was more potent than that from the control group in inducing inflammation and gut barrier disruption in CaCo-2 cells. After treatment with a TNF-α inhibitor (adalimumab), no statistical difference in the indicators of inflammation and intestinal barrier function was observed between the two groups. Finally, exposure to PNMS remarkably increased the values of the histopathological parameters and the inflammatory cytokine production in a mouse model of experimental colitis in adulthood. These findings suggest that PNMS can inhibit intestinal development, impair the barrier function, and cause gut dysbiosis characterized by the persistent overgrowth of Desulfovibrio in the offspring, resulting in exacerbated experimental colitis in adulthood.

3.
Gastroenterol Rep (Oxf) ; 9(4): 329-338, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34567565

RESUMO

Background: Infliximab (IFX) is effective at inducing and maintaining clinical remission and mucosal healing in patients with Crohn's disease (CD); however, 9%-40% of patients do not respond to primary IFX treatment. This study aimed to construct and validate nomograms to predict IFX response in CD patients. Methods: A total of 343 patients diagnosed with CD who had received IFX induction from four tertiary centers between September 2008 and September 2019 were enrolled in this study and randomly classified into a training cohort (n = 240) and a validation cohort (n = 103). The primary outcome was primary non-response (PNR) and the secondary outcome was mucosal healing (MH). Nomograms were constructed from the training cohort using multivariate logistic regression. Performance of nomograms was evaluated by area under the receiver-operating characteristic curve (AUC) and calibration curve. The clinical usefulness of nomograms was evaluated by decision-curve analysis. Results: The nomogram for PNR was developed based on four independent predictors: age, C-reactive protein (CRP) at week 2, body mass index, and non-stricturing, non-penetrating behavior (B1). AUC was 0.77 in the training cohort and 0.76 in the validation cohort. The nomogram for MH included four independent factors: baseline Crohn's Disease Endoscopic Index of Severity, CRP at week 2, B1, and disease duration. AUC was 0.79 and 0.72 in the training and validation cohorts, respectively. The two nomograms showed good calibration in both cohorts and were superior to single factors and an existing matrix model. The decision curve indicated the clinical usefulness of the PNR nomogram. Conclusions: We established and validated nomograms for the prediction of PNR to IFX and MH in CD patients. This graphical tool is easy to use and will assist physicians in therapeutic decision-making.

4.
Nutrients ; 13(9)2021 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-34579027

RESUMO

Inflammatory bowel disease (IBD) is a chronic, relapsing inflammatory disorder of the gastrointestinal tract, with increasing prevalence, and its pathogenesis remains unclear. Accumulating evidence suggested that gut microbiota and bile acids play pivotal roles in intestinal homeostasis and inflammation. Patients with IBD exhibit decreased microbial diversity and abnormal microbial composition marked by the depletion of phylum Firmicutes (including bacteria involved in bile acid metabolism) and the enrichment of phylum Proteobacteria. Dysbiosis leads to blocked bile acid transformation. Thus, the concentration of primary and conjugated bile acids is elevated at the expense of secondary bile acids in IBD. In turn, bile acids could modulate the microbial community. Gut dysbiosis and disturbed bile acids impair the gut barrier and immunity. Several therapies, such as diets, probiotics, prebiotics, engineered bacteria, fecal microbiota transplantation and ursodeoxycholic acid, may alleviate IBD by restoring gut microbiota and bile acids. Thus, the bile acid-gut microbiota axis is closely connected with IBD pathogenesis. Regulation of this axis may be a novel option for treating IBD.


Assuntos
Ácidos e Sais Biliares/fisiologia , Microbioma Gastrointestinal/fisiologia , Doenças Inflamatórias Intestinais/etiologia , Animais , Ácidos e Sais Biliares/metabolismo , Humanos
5.
Int Immunopharmacol ; 91: 107308, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33383448

RESUMO

Bicyclol, an innovative chemical drug with proprietary intellectual property rights in China, is based on derivative of traditional Chinese medicine (TCM) Schisandra chinensis (Wuweizi) of North. Mounting data has proved that bicyclol has therapeutic potential in various pathological conditions in liver. In this narrative review, we provide the first summary of pharmacological activities, pharmacokinetic characteristics and toxicity of bicyclol, and discuss future research perspectives. Our results imply that bicyclol has a wide spectrum of pharmacological properties, including anti-viral, anti-inflammatory, immuno-regulatory, anti-oxidative, antisteatotic, anti-fibrotic, antitumor, cell death regulatory effects and modulation of heat shock proteins. Pharmacokinetic studies have indicated that bicyclol is the main substrate of CYP3A/2E1. Additionally, no obvious drug interactions have been found when bicyclol is administered simultaneously with other prescriptions. Furthermore, the results of chronic toxicity have strongly addressed that bicyclol has no noticeable toxic effects on all biochemical indices and pathological examinations of the main organs. In view of good pharmacological actions and safety, bicyclol is anticipated to be a potential candidate for various liver diseases, including acute liver injury, fulminant hepatitis, non-alcoholic fatty liver disease, fibrosis and hepatocellular carcinoma. Further studies are therefore required to delineate its molecular mechanisms and targets to confer this well-designed drug a far greater potency. We hope that bicyclol-based therapeutics for liver diseases might be broadly used in clinical practice worldwide.


Assuntos
Compostos de Bifenilo/uso terapêutico , Medicamentos de Ervas Chinesas/uso terapêutico , Hepatopatias/tratamento farmacológico , Fígado/efeitos dos fármacos , Medicina Tradicional Chinesa , Animais , Compostos de Bifenilo/efeitos adversos , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/farmacocinética , Medicamentos de Ervas Chinesas/efeitos adversos , Medicamentos de Ervas Chinesas/farmacocinética , Humanos , Fígado/imunologia , Fígado/metabolismo , Fígado/patologia , Hepatopatias/diagnóstico , Hepatopatias/imunologia , Hepatopatias/metabolismo , Resultado do Tratamento
6.
Ann Palliat Med ; 9(6): 4146-4155, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33302675

RESUMO

BACKGROUND: Inflammatory bowel disease (IBD) has the characteristics of chronic relapse and remission, which makes early diagnosis and effective evaluation of disease activity especially crucial. With the development of ultrasound technology, its role in the diagnosis and treatment of IBD is increasing. This study aimed to explore the value of multimodal ultrasound in the assessment of disease activity and complications in IBD. METHODS: Patients with clinically confirmed IBD were selected and examined with two-dimensional ultrasound, Doppler ultrasound, contrast-enhanced ultrasound (CEUS), elastography, endoscopy with biopsies, and whole-abdominal enhanced computed tomography (CT). Collect relevant laboratory data, including C-reactive protein, erythrocyte sedimentation rate, etc. Endoscopy is used as the gold standard for disease activity assessment, and the diagnostic value of each ultrasound parameter is compared separately, and correlation analysis is made. RESULTS: Intestinal maximum wall thickness in patients in the disease activity group (active group) was significantly thicker than that in patients in remission group (7.93±2.65 vs. 4.16±1.08 mm, P<0.001). The mean values of Peak Enhancement (PE) and the area under the receiver operating characteristic (ROC) curve (AUC) were higher in the active stage than in remission, with a significant difference (-40.66±4.81 vs. -50.47±5.03 db, 356.44±170.67 vs. 194.42±92.09 dBsec, both P<0.05). Time To Peak (TTP) showed no significant difference between the active stage and remission (20.04±8.74 vs. 20.09±11.13 s, P>0.05). Twenty cases of intestinal stricture were detected by ultrasound, and no fistula or abscesses were detected. CEUS and elastography could distinguish inflammatory bowel stenosis and fibrous bowel stenosis in patients with IBD. In the fibrosis group and inflammation group, the mean shear wave velocity, Young's modulus, TTP, PE, and AUC were statistically significantly different (P<0.05). The mean maximum wall thickness and disease extent assessed by ultrasound and CT were strongly correlated (r=0.799, 0.831). Wall thickness showed a moderate positive correlation with CRP and ESR and a strong positive correlation with Mayo score (P<0.05), but no significant correlation with CDAI (P>0.05). CONCLUSIONS: Multimodal ultrasound provides more detailed clinical reference values for the comprehensive evaluation of IBD.


Assuntos
Técnicas de Imagem por Elasticidade , Doenças Inflamatórias Intestinais , Humanos , Doenças Inflamatórias Intestinais/diagnóstico por imagem , Intestinos/diagnóstico por imagem , Estudos Prospectivos , Ultrassonografia
7.
Stem Cell Rev Rep ; 16(6): 1292-1304, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33011925

RESUMO

Crohn's disease (CD) with externally fistulizing openings indicates the aggressive and relapsing manifestation and results in undesirable long-term outcomes of patients. MSC-based approach combined with multidisciplinary strategy has mandated a redefinition of the administration and management of numerous recurrent and refractory diseases whereas the spatio-temporal evaluation of the metabolokinetics and efficacy of MSCs on intractable CD with enterocutaneous fistula (EF) are largely inaccessible and dauntingly complex. Herein, we primitively established dual-fluorescence expressing placenta-derived MSCs (DF-MSCs) and explored their multidimensional attributes, including cytomorphology, immunophenotying, multilineage differentiation and long-term proliferation, together with the recognition of bifluorescence intensity (BLI). Then, with the aid of in vivo living imaging, clinicopathological or inflammatory cytokine examinations and in vitro analyses, we systematically and meticulously dissected the metabolokinetics and curative effect of MSCs on mice with refractory Crohn's-like EF (EF mice), together with revealing the underlying mechanism including reactive oxygen species (ROS) and neovascularization. Strikingly, the DF-MSCs exhibited stabilized BLI and biological properties. The spatio-temporal distribution and therapeutic process of MSCs in EF mice were intuitively delineated. Meanwhile, our data indicated the curative mechanisms of DF-MSCs by simultaneously downregulating ROS and accelerating neovascularization. Collectively, we systematically illuminated the spatio-temporal biofunction and mechanism of DF-MSCs on EF mice. Our findings have supplied new references for safety and effectiveness assessments as well as the establishment of guidelines for optimal administrations of MSC-based cytotherapy in preclinical studies, which collectively indicates the prospect of P-MSC administration in clinical trials during a wide spectrum of disease remodeling including the fistulizing CD. Graphical abstract.


Assuntos
Doença de Crohn/terapia , Fístula Intestinal/terapia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Placenta/citologia , Animais , Diferenciação Celular , Linhagem da Célula , Movimento Celular , Feminino , Fluorescência , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Imunofenotipagem , Inflamação/patologia , Camundongos , Neovascularização Fisiológica , Gravidez , Espécies Reativas de Oxigênio/metabolismo , Análise de Sobrevida , Fatores de Tempo
8.
Int J Mol Med ; 46(4): 1551-1561, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32945344

RESUMO

Mesenchymal stem cells (MSCs) are pluripotent cells that can be applied to the treatment of immune disorders, including inflammatory bowel disease (IBD). The therapeutic effects of MSCs have been mostly attributed to the secretion of soluble factors with paracrine actions, such as extracellular vesicles (EVs), which may play a relevant role in the repair of damaged tissues. In the present study, a mouse model of colitis was induced with the use of trinitrobenzene sulfonic acid (TNBS). EVs derived from human placental mesenchymal stem cells (hP­MSCs) were used for the treatment of colitis by in situ injection. Clinical scores were applied to verify the therapeutic effects of EVs on mice with colitis. Inflammation in the colon was evaluated by measuring the levels of various inflammatory cytokines. The content of reactive oxygen species (ROS) was detected by the use of molecular imaging methods for real­time tracking and the therapeutic effects of EVs on mucosal healing in mice with colitis were evaluated. The results revealed that the injection of EVs regulated the balance of pro­inflammatory and anti­inflammatory cytokines in colon tissue. Treatment with EVs also suppressed oxidative stress by decreasing the activity of myeloperoxidase (MPO) and ROS. Histological analysis further confirmed that the EVs significantly promoted mucosal healing, as reflected by the promotion of the proliferation of colonic epithelial cells and the maintenance of tight junctions. Taken together, the findings of the present study demonstrated that EVs derived from hP­MSCs alleviated TNBS­induced colitis by inhibiting inflammation and oxidative stress. These findings may provide a novel theoretical basis for the EV­based treatment of IBD.


Assuntos
Colite/patologia , Vesículas Extracelulares/patologia , Inflamação/patologia , Células-Tronco Mesenquimais/patologia , Estresse Oxidativo/fisiologia , Placenta/fisiologia , Animais , Células Cultivadas , Colite/induzido quimicamente , Colite/metabolismo , Colo/efeitos dos fármacos , Colo/metabolismo , Colo/patologia , Citocinas/metabolismo , Modelos Animais de Doenças , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Vesículas Extracelulares/metabolismo , Feminino , Humanos , Fatores Imunológicos/metabolismo , Inflamação/induzido quimicamente , Inflamação/metabolismo , Masculino , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Placenta/metabolismo , Gravidez , Ácido Trinitrobenzenossulfônico/farmacologia
9.
Theranostics ; 10(17): 7697-7709, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32685014

RESUMO

Background: Mesenchymal stem cell (MSC)-based therapies hold great promise for the treatment of inflammatory bowel disease (IBD). In order to optimize and maximize the therapeutic benefits of MSCs, we investigated whether cotransplantation of a chitosan (CS)-based injectable hydrogel with immobilized IGF-1 C domain peptide (CS-IGF-1C) and human placenta-derived MSCs (hP-MSCs) could ameliorate colitis in mice. Methods: IGF-1C hydrogel was generated by immobilizing IGF-1C to CS hydrogel. Colitis was induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS) in mice. We initially applied hP-MSCs and CS-IGF-1C hydrogel for the treatment of colitis by in situ injection, and molecular imaging methods were used for real-time imaging of reactive oxygen species (ROS) and tracking of transplanted hP-MSCs by bioluminescence imaging (BLI). Furthermore, the effects of CS-IGF-1C hydrogel on prostaglandin E2 (PGE2) secretion of hP-MSCs and polarization of M2 macrophages were investigated as well. Results: The CS-IGF-1C hydrogel significantly increased hP-MSC proliferation and promoted the production of PGE2 from hP-MSCs in vitro. Moreover, in vivo studies indicated that the CS-IGF-1C hydrogel promoted hP-MSC survival as visualized by BLI and markedly alleviated mouse colitis, which was possibly mediated by hP-MSC production of PGE2 and interleukin-10 (IL-10) production by polarized M2 macrophages. Conclusions: The CS-IGF-1C hydrogel improved the engraftment of transplanted hP-MSCs, ameliorated inflammatory responses, and further promoted the functional and structural recovery of colitis through PGE2-mediated M2 macrophage polarization. Molecular imaging approaches and therapeutic strategies for hydrogel application provide a versatile platform for exploring the promising therapeutic potential of MSCs in the treatment of IBD.


Assuntos
Colite Ulcerativa/terapia , Dinoprostona/metabolismo , Portadores de Fármacos/química , Fator de Crescimento Insulin-Like I/administração & dosagem , Transplante de Células-Tronco Mesenquimais/métodos , Animais , Células Cultivadas , Quitosana/química , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/imunologia , Colo/efeitos dos fármacos , Colo/imunologia , Modelos Animais de Doenças , Feminino , Humanos , Hidrogéis/química , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Ativação de Macrófagos/imunologia , Macrófagos Peritoneais/imunologia , Masculino , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Camundongos , Placenta/citologia , Gravidez , Cultura Primária de Células , Ácido Trinitrobenzenossulfônico/administração & dosagem , Ácido Trinitrobenzenossulfônico/toxicidade
10.
Pharmacol Res ; 159: 104945, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32454225

RESUMO

Genipin is an aglycone derived from the geniposide, the most abundant iridoid glucoside constituent of Gardenia jasminoides Ellis. For decades, genipin is the focus of studies as a versatile compound in the treatment of various pathogenic conditions. In particularly, Gardenia jasminoides Ellis has long been used in traditional Chinese medicine for the prevention and treatment of liver disease. Mounting experimental data has proved genipin possesses therapeutic potential for cholestatic, septic, ischemia/reperfusion-triggered acute liver injury, fulminant hepatitis and NAFLD. This critical review is a reflection on the valuable lessons from decades of research regarding pharmacological activities of genipin. Of note, genipin represents choleretic effect by potentiating bilirubin disposal and enhancement of genes in charge of the efflux of a number of organic anions. The anti-inflammatory capability of genipin is mediated by suppression of the production and function of pro-inflammatory cytokines and inflammasome. Moreover, genipin modulates various transcription factor and signal transduction pathway. Genipin appears to trigger the upregulation of several key genes encoding antioxidant and xenobiotic-metabolizing enzymes. Furthermore, the medicinal impact of genipin extends to modulation of regulated cell death, including autophagic cell death, apoptosis, necroptosis and pyroptosis, and modulation of quality of cellular organelle. Another crucial effect of genipin appears to be linked to dual role in targeting uncoupling protein 2 (UCP2). As a typical UCP2-inhibiting compound, genipin could inhibit AMP-activated protein kinase or NF-κB in circumstance. On the contrary, reactive oxygen species production and cellular lipid deposits mediated by genipin through the upregulation of UCP2 is observed in liver steatosis, suggesting the precise role of genipin is disease-specific. Collectively, we comprehensively summarize the mechanisms and pathways associated with the hepatoprotective activity of genipin and discuss potential toxic impact. Notably, our focus is the direct medicinal effect of genipin itself, whereas its utility as a crosslinking agent in tissue engineering is out of scope for the current review. Further studies are therefore required to disentangle these complicated pharmacological properties to confer this natural agent a far greater potency.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Colagogos e Coleréticos/farmacologia , Iridoides/farmacologia , Fígado/efeitos dos fármacos , Necrose Hepática Massiva/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Animais , Anti-Inflamatórios/toxicidade , Antioxidantes/toxicidade , Morte Celular/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Colagogos e Coleréticos/toxicidade , Humanos , Iridoides/toxicidade , Fígado/metabolismo , Fígado/patologia , Necrose Hepática Massiva/metabolismo , Necrose Hepática Massiva/patologia , Mitocôndrias Hepáticas/efeitos dos fármacos , Mitocôndrias Hepáticas/metabolismo , Mitocôndrias Hepáticas/patologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Proteína Desacopladora 2/metabolismo
11.
Front Pharmacol ; 11: 463, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32362825

RESUMO

Bicyclol, a novel synthetic antihepatitis drug, has been shown to protect against liver injury via various pharmacological activities. The purpose of the current study was to further investigate the protective effect of bicyclol against carbon tetrachloride (CCl4)-induced acute liver injury (ALI) and its underlying molecular mechanism, particularly autophagic machinery, anti-oxidative, and anti-inflammatory potentials. Our results found that treatment with bicyclol significantly reduced CCl4-induced hepatotoxicity by alleviating histopathological liver changes, decreasing the alanine transaminase levels, promoting autophagic flux, attenuating the expression of inflammatory cytokines, and modulating oxidative markers. Furthermore, bicyclol efficiently induced the conversion of LC3 and enhanced the liver expressions of ATG7 and Beclin-1. Meanwhile, bicyclol induced the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) and p62. These protective effects may be mediated by activation of AMP-activated protein kinase and inhibition of mTOR or MAPK signaling pathways. Taken together, our study firstly suggests that bicyclol has protective potential against CCl4-induced hepatotoxicity, which might be closely associated with induction of autophagy, concomitant anti-oxidative stress, and anti-inflammatory response.

12.
J Agric Food Chem ; 68(16): 4641-4649, 2020 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-32249565

RESUMO

The intestinal epithelium barrier functions to protect human bodies from damages such as harmful microorganisms, antigens, and toxins. In this study, we evaluated the protective effect and molecular mechanism of a dominant polymethoxyflavone nobiletin (NOB) from tangerine peels on intestinal epithelial integrity. The results from transepithelial electrical resistance (TEER) suggested that NOB pretreatment counteracts epithelial injury induced by inflammatory cytokines (TEER value in 48 h: vehicle, 135.6 ± 3.9 Ω/cm2; TNF-α + IL-1ß, 90.7 ± 0.5 Ω/cm2; 10 µM NOB + TNF-α + IL-1ß, 126.1 ± 0.8 Ω/cm2; 100 µM NOB + TNF-α + IL-1ß, 125.3 ± 0.5 Ω/cm2. P < 0.001). Clinical and pathological test results suggested that administration of NOB effectively alleviates intestinal barrier injury induced by dextran sulfate sodium (DSS) as evidenced by the length of colon villi on day 7 (control, 253.7 ± 4.8 µm, DSS 131.6 ± 4.6 µm, NOB + DSS, 234.5 ± 5.1 µm. P < 0.001). Interestingly, when screening tight junction molecules for intestinal barrier integrity, we observed that independent treatment with NOB sharply increased claudin-7 levels (ratio of claudin-7 over GAPDH: control, 1.0 ± 0.06; DSS, 0.02 ± 0.001; NOB + DSS, 0.3 ± 0.07. P < 0.001), which was previously suppressed upon DSS stimulation. Furthermore, hepatocyte nuclear factor 4α (HNF-4α) transcriptional regulation of claudin-7 contributed to intestinal barrier homeostasis. Therefore, our study suggests potential intestinal protective strategies based on polymethoxyflavones of aged tangerine peels.


Assuntos
Claudinas/metabolismo , Colite/tratamento farmacológico , Medicamentos de Ervas Chinesas/administração & dosagem , Flavonas/administração & dosagem , Fator 4 Nuclear de Hepatócito/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Animais , Células CACO-2 , Claudinas/genética , Colite/induzido quimicamente , Colite/genética , Colite/metabolismo , Citocinas/genética , Citocinas/metabolismo , Sulfato de Dextrana/efeitos adversos , Modelos Animais de Doenças , Fator 4 Nuclear de Hepatócito/genética , Humanos , Mucosa Intestinal/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
13.
Microb Cell Fact ; 19(1): 94, 2020 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-32334588

RESUMO

BACKGROUND: Obesity is a major problem worldwide and severely affects public safety. As a metabolite of gut microbiota, endogenous butyric acid participates in energy and material metabolism. Considering the serious side effects and weight regain associated with existing weight loss interventions, novel strategies are urgently needed for prevention and treatment of obesity. RESULTS: In the present study, we engineered Bacillus subtilis SCK6 to exhibited enhanced butyric acid production. Compared to the original Bacillus subtilis SCK6 strain, the genetically modified BsS-RS06550 strain had higher butyric acid production. The mice were randomly divided into four groups: a normal diet (C) group, a high-fat diet (HFD) group, an HFD + Bacillus subtilis SCK6 (HS) group and an HFD + BsS-RS06550 (HE) group. The results showed BsS-RS06550 decreased the body weight, body weight gain, and food intake of HFD mice. BsS-RS06550 had beneficial effects on blood glucose, insulin resistance and hepatic biochemistry. After the 14-week of experiment, fecal samples were collected for nontargeted liquid chromatography-mass spectrometry analysis to identify and quantify significant changes in metabolites. Sixteen potentially significant metabolites were screened, and BsS-RS06550 was shown to potentially regulate disorders in glutathione, methionine, tyrosine, phenylalanine, and purine metabolism and secondary bile acid biosynthesis. CONCLUSIONS: In this study, we successfully engineered Bacillus subtilis SCK6 to have enhanced butyric acid production. The results of this work revealed that the genetically modified live bacterium BsS-RS06550 showed potential anti-obesity effects, which may have been related to regulating the levels of metabolites associated with obesity. These results indicate that the use of BsS-RS06550 may be a promising strategy to attenuate obesity.


Assuntos
Bacillus subtilis/genética , Bacillus subtilis/metabolismo , Butiratos/metabolismo , Dieta Hiperlipídica , Engenharia Genética , Obesidade/prevenção & controle , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/metabolismo
14.
Therap Adv Gastroenterol ; 13: 1756284820979442, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33425010

RESUMO

Background: Recent evidence has shown that the complete blood count (CBC) is abnormal in patients with Crohn's disease (CD). We aimed to investigate an effective CBC parameter and explore its impact on disease activity in a large CD cohort. Methods: We performed a retrospective analysis of patients with established CD who underwent clinically indicated endoscopy at four tertiary centres in China between 2016 and 2020. Individual variables of the Simple Endoscopic Score for CD, CBC parameters, C-reactive protein (CRP) levels, erythrocyte sedimentation rate, and faecal calprotectin (FC) were independently reviewed by different investigators. The hold-out method was used to verify the predictive power of the established model. Results: Data from a total of 1388 endoscopic procedures performed for 882 eligible CD patients were available with routine blood parameters and related indicators. The model using platelet-to-lymphocyte percentage ratio (PLpR) had high accuracy for identifying patients in endoscopic remission (ER), with an area under the curve (AUC) of 0.785 [95% confidence interval (CI): 0.784-0.787], which was comparable with that for CRP (AUC: 0.775, 95% CI: 0.774-0.777). Notably, the AUC of PLpR was significantly higher than that of CRP in patients with colonic disease and with a history of surgery. Moreover, after combining the FC with PLpR, the AUC value of FC + PLpR increased up to 0.892 (95% CI: 0.890-0.894) for identifying ER. Conclusions: We explored an index (PLpR) to identify CD patients in ER based on platelet and lymphocyte percentage from the CBC. PLpR helped evaluate the degree of disease activity and monitor the therapeutic response.

15.
Theranostics ; 8(19): 5348-5361, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30555551

RESUMO

Wound healing is regulated by a complex series of events and overlapping phases. A delicate balance of cytokines and mediators in tissue repair is required for optimal therapy in clinical applications. Molecular imaging technologies, with their versatility in monitoring cellular and molecular events in living organisms, offer tangible options to better guide tissue repair by regulating the balance of cytokines and mediators at injured sites. Methods: A murine cutaneous wound healing model was developed to investigate if incorporation of prostaglandin E2 (PGE2) into chitosan (CS) hydrogel (CS+PGE2 hydrogel) could enhance its therapeutic effects. Bioluminescence imaging (BLI) was used to noninvasively monitor the inflammation and angiogenesis processes at injured sites during wound healing. We also investigated the M1 and M2 paradigm of macrophage activation during wound healing. Results: CS hydrogel could prolong the release of PGE2, thereby improving its tissue repair and regeneration capabilities. Molecular imaging results showed that the prolonged release of PGE2 could ameliorate inflammation by promoting the M2 phenotypic transformation of macrophages. Also, CS+PGE2 hydrogel could augment angiogenesis at the injured sites during the early phase of tissue repair, as revealed by BLI. Furthermore, our results demonstrated that CS+PGE2 hydrogel could regulate the balance among the three overlapping phases-inflammation, regeneration (angiogenesis), and remodeling (fibrosis)-during cutaneous wound healing. Conclusion: Our findings highlight the potential of the CS+PGE2 hydrogel as a novel therapeutic strategy for promoting tissue regeneration via M2 macrophage polarization. Moreover, molecular imaging provides a platform for monitoring cellular and molecular events in real-time during tissue repair and facilitates the discovery of optimal therapeutics for injury repair by regulating the balance of cytokines and mediators at injured sites.


Assuntos
Dinoprostona/administração & dosagem , Portadores de Fármacos/administração & dosagem , Hidrogel de Polietilenoglicol-Dimetacrilato/administração & dosagem , Fatores Imunológicos/administração & dosagem , Macrófagos Peritoneais/efeitos dos fármacos , Cicatrização/efeitos dos fármacos , Ferimentos e Lesões/terapia , Animais , Células Cultivadas , Quitosana/administração & dosagem , Modelos Animais de Doenças , Inflamação/patologia , Medições Luminescentes , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos Peritoneais/imunologia , Camundongos , Imagem Molecular , Neovascularização Fisiológica/efeitos dos fármacos , Resultado do Tratamento
16.
Front Immunol ; 9: 2608, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30483266

RESUMO

Background: Accumulating evidence shows that high fat diet is closely associated with inflammatory bowel disease. However, the effects and underlying mechanisms of maternal high fat diet (MHFD) on the susceptibility of offspring to colitis in adulthood lacks confirmation. Methods: C57BL/6 pregnant mice were given either a high fat (60 E% fat, MHFD group) or control diet [10 E% fat, maternal control diet (MCD) group] during gestation and lactation. The intestinal development, mucosal barrier function, microbiota, and mucosal inflammation of 3-week old offspring were assessed. After weaning all mice were fed a control diet until 8 weeks of age when the microbiota was analyzed. Offspring were also treated with 2% DSS solution for 5 days and the severity of colitis was assessed. Results: The offspring in MHFD group were significantly heavier than those in MCD group only at 2-4 weeks of age, while no differences were found in the body weight between two groups at other measured time points. Compared with MCD group, MHFD significantly inhibited intestinal development and disrupted barrier function in 3-week old offspring. Although H&E staining showed no obvious microscopic inflammation in both groups of 3-week old offspring, increased production of inflammatory cytokines indicated low-grade inflammation was induced in MHFD group. Moreover, fecal analysis of the 3-week old offspring indicated that the microbiota compositions and diversity were significantly changed in MHFD group. Interestingly after 5 weeks consumption of control diet in both groups, the microbiota composition of offspring in MHFD group was still different from that in MCD group, although the bacterial diversity was partly recovered at 8 weeks of age. Finally, after DSS treatment in 8-week old offspring, MHFD significantly exacerbated the severity of colitis and increased the production of proinflammatory cytokine. Conclusions: Our data reveal that MHFD in early life can inhibit intestinal development, induce dysbiosis and low-grade inflammation and lead to the disruption of intestinal mucosal barrier in offspring, and enhance DSS-induced colitis in adulthood.


Assuntos
Colite/induzido quimicamente , Colite/microbiologia , Sulfato de Dextrana/farmacologia , Dieta Hiperlipídica/efeitos adversos , Microbioma Gastrointestinal/fisiologia , Animais , Peso Corporal/fisiologia , Colite/fisiopatologia , Citocinas/metabolismo , Feminino , Inflamação/metabolismo , Inflamação/microbiologia , Inflamação/fisiopatologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Mucosa Intestinal/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Gravidez
18.
Biomaterials ; 158: 34-43, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29275121

RESUMO

With the abilities of self-renewal and differentiation, embryonic stem (ES) cells provide an unlimited source for stem cell-based therapeutics. However, the maintenance of ES cells with mouse embryonic fibroblasts (MEFs) can limit the clinical translation of ES cells. In the present study, we synthesized a fusion protein of the immunoglobulin G (IgG) fragment crystallizable region and vascular endothelial cadherin (VE-cadherin) extracellular domain (VE-cad-Fc) as a substrate for mouse ES cell culture, and we hypothesized that VE-cadherin could enhance the pluripotency and self-renewal of ES cells. Furthermore, we introduced a Stat3 reporter imaging system into ES cells and investigated the mechanism of the pluripotency enhancement mediated by VE-cadherin through cultured ES cells on VE-cad-Fc-coated plates using molecular imaging techniques. The resulting data revealed that VE-cad-Fc could activate the Stat3 signaling pathway, leading to the upregulation of stemness-related markers SSEA-1 and alkaline phosphatase (ALP). Moreover, VE-cad-Fc recovered the expression of Oct4, c-Myc, Nanog, Sox2, Tbx3 and Klf4 in differentiated ES cells, as well as enhanced the pluripotency of ES cells. In conclusion, VE-cadherin fusion protein coating methods provide an alternative towards feeder free culture of ES cells, and the strategy developed in the present study may benefit the clinical translation of ES cell-based therapeutics.


Assuntos
Antígenos CD/metabolismo , Caderinas/metabolismo , Diferenciação Celular , Células-Tronco Embrionárias , Animais , Antígenos CD/genética , Caderinas/genética , Técnicas de Cultura de Células , Diferenciação Celular/fisiologia , Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/metabolismo , Fragmentos Fc das Imunoglobulinas/genética , Fragmentos Fc das Imunoglobulinas/metabolismo , Antígenos CD15/metabolismo , Camundongos , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais
19.
Int J Clin Pharmacol Ther ; 55(7): 571-580, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28513424

RESUMO

Anti-TNF-α therapy, such as infliximab (IFX), has profoundly changed treatment to induce and maintain remission for inflammatory bowel diseases patients who do not respond to conventional therapies. Unfortunately, IFX, as a chimeric protein, is potentially immunogenic, and antibodies to infliximab (ATI) may interfere with the pharmacodynamics and pharmacokinetics of the drug, thus resulting in a loss of response for a substantial proportion of patients. The clinical efficacy of IFX is correlated with the levels of IFX and ATI. Therefore, monitoring patients for the trough levels of IFX and the presence of ATI is very important. The procedures and characteristics of six assays for monitoring IFX and ATI are described in this review, and the comparisons between them are also discussed. To date, there has been no optimal assay for monitoring IFX and ATI. Therefore, many technical problems need to be solved to make therapeutic drug and immunogenicity monitoring a part of routine clinical management.
.


Assuntos
Anticorpos/sangue , Produtos Biológicos/sangue , Cromatografia em Gel , Monitoramento de Medicamentos/métodos , Técnicas Imunoenzimáticas , Infliximab/sangue , Radioimunoensaio , Produtos Biológicos/efeitos adversos , Produtos Biológicos/imunologia , Ensaio de Imunoadsorção Enzimática , Genes Reporter , Humanos , Infliximab/efeitos adversos , Infliximab/imunologia , Valor Preditivo dos Testes , Reprodutibilidade dos Testes
20.
Artigo em Inglês | MEDLINE | ID: mdl-28286741

RESUMO

Identifying intestinal microbiota is arguably an important task that is performed to determine the pathogenesis of inflammatory bowel diseases (IBD); thus, it is crucial to collect and analyze intestinally-associated microbiota. Analyzing a single niche to categorize individuals does not enable researchers to comprehensively study the spatial variations of the microbiota. Therefore, characterizing the spatial community structures of the inflammatory bowel disease microbiome is critical for advancing our understanding of the inflammatory landscape of IBD. However, at present there is no universally accepted consensus regarding the use of specific sampling strategies in different biogeographic locations. In this review, we discuss the spatial distribution when screening sample collections in IBD microbiota research. Here, we propose a novel model, a three-dimensional spatial community structure, which encompasses the x-, y-, and z-axis distributions; it can be used in some sampling sites, such as feces, colonoscopic biopsy, the mucus gel layer, and oral cavity. On the basis of this spatial model, this article also summarizes various sampling and processing strategies prior to and after DNA extraction and recommends guidelines for practical application in future research.


Assuntos
Disbiose/diagnóstico , Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais/microbiologia , Mucosa Intestinal/microbiologia , Microbiota , Manejo de Espécimes/métodos , Humanos , Doenças Inflamatórias Intestinais/patologia , Mucosa Intestinal/patologia
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