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Background: Anti-tumor necrosis factor (TNF) monoclonal antibodies, especially infliximab (IFX) and adalimumab (ADA), are considered the first-line treatment for active Crohn's disease (CD). However, the predictive role of therapeutic drug monitoring (TDM) of serum anti-TNF in monitoring the treatment of inflammatory bowel disease (IBD) remains controversial. Objectives: To explore the correlation between serum anti-TNF levels and early endoscopic response in active CD using a TDM-based nomogram. Design: Cross-sectional study. Methods: The simplified endoscopic activity score for CD (SES-CD), Crohn's disease activity index (CDAI), laboratory parameters, and the serum trough levels of IFX and ADA were assessed. Results: The trough levels of IFX or ADA were significantly higher in patients with endoscopic response compared to non-responders in the development cohort (p < 0.001). The IFX and ADA levels showed a weak but significantly negative correlation with SES-CD (p < 0.001), CDAI (p < 0.001), and C-reactive protein (CRP) (p < 0.001) at week 14 post-IFX therapy in the development cohort. Furthermore, the receiver operating characteristic curve revealed that an optimal level of IFX (4.80 µg/mL) and ADA (8.80 µg/mL) exhibited the best performance in predicting endoscopic response. Concomitantly, we developed a novel nomogram prediction model based on the results of multivariate logistic regression analysis, which consisted of CRP, albumin (Alb), and anti-TNF trough levels at week 14. The nomogram showed significant discrimination and calibration for both IFX and ADA in the development cohort and performed well in the external validation cohort. Conclusion: This study demonstrates a robust association between serum concentrations of IFX, ADA, Alb, and CRP and primary endoscopic response in active CD patients. Importantly, the TDM- and laboratory marker-based nomogram may be used to evaluate the primary endoscopic response to anti-TNF therapy, especially for optimizing treatment strategies and switching therapy in CD patients.
Therapeutic drug monitoring-based nomogram predicts primary endoscopic response in Crohn's disease The present study established a therapeutic drug monitoring-based nomogram, which exhibits an exceptional predictive value, remarkable accuracy, and discrimination. This algorithmic nomogram holds the potential to enhance clinicians' comprehension of the underlying mechanisms contributing to individual patients' failure in achieving expected efficacy. Such approach is crucial for optimizing therapy options and facilitating biologic switching in refractory Crohn's disease.
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The study aimed to improve the extraction rate of Platycodon grandiflorum roots polysaccharides (PGPs) using ultrasound-assisted extraction (UAE). A comparative analysis was undertaken to evaluate polysaccharides content, molecular weight distribution, monosaccharide composition, preliminary structure, antioxidant, and hypoglycemic activity of UAE in comparison with heating water extraction (HWE). The optimum extraction conditions included a liquid-to-material ratio of 20 mL/g, ultrasonic power of 150 W, extraction temperature of 70 â, and extraction time of 20 min, resulting in a significantly greater polysaccharides (12.011 ± 0.91 %) compared to HWE (7.62 ± 0.18 %). Through Sephacryl S-100 column elution, two homogenous fraction (PGP-U extracted with UAE and PGP-H extracted with HAE) were obtained. The molecular weight of PGP-U and PGP-H was 3.14 kDa and 3.44 kDa, respectively, mainly composed of different proportions of fourteen monosaccharides. Fourier transform infrared spectroscopy (FT-IR) and Nuclear Magnetic Resonance (NMR) spectra experiment results showed that the two polysaccharides were pyranose ring with α- and ß-glycoside bond. PGP-U and PGP-H exhibited specific antioxidant activities, encompassing total reducing force, scavenging of DPPH radicals, ABTs radicals and hydroxyl radicals in vitro, along with mitigation of H2O2-induced damage in HepG2 cells. Moreover, PGP-U exerted significantly stronger inhibitory activities against α-amylase and α-glucosidase and could significantly enhances the glucose uptake capacity and intracellular glycogen content of insulin-resistant HepG2 (IR-HepG2) cells.
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Antioxidantes , Platycodon , Antioxidantes/farmacología , Antioxidantes/química , Hipoglucemiantes/farmacología , Hipoglucemiantes/química , Espectroscopía Infrarroja por Transformada de Fourier , Peróxido de Hidrógeno , Ultrasonido , Polisacáridos/farmacología , Polisacáridos/químicaRESUMEN
BACKGROUND: Isovitexin-2"-O-D-glucopyranoside (IVG) has been known to exhibit sedative and hypnotic effects. However, there is little understanding of the in vivo pharmacokinetics and tissue distribution of IVG. OBJECTIVE: This study aimed to investigate the pharmacokinetics and tissue distribution of IVG. METHODS: The study employed an HPLC-ESI-MS/MS method to analyze the pharmacokinetics and tissue distribution of IVG. RESULTS: Under mass spectrometry, IVG and internal standard (IS) showed strong negative ionization signals. MRM analysis chose ion transitions m/z 593.3 â 293.0 (IVG) and m/z 579.8 â 271.4 (IS). Method validation indicated high precision, accuracy, and reliability with a quantitation limit under 20 ng/mL. After intravenously administering 5.0 mg/kg of IVG, rapid clearance from rat plasma was observed, with a half-life (t1/2) of 3.49 ± 0.99 h and a clearance rate of 54.53 ± 11.90 mL/kg/h. The area under the curve (AUC0-12h) of 37.79 ± 7.65 µg·h/mL indicated a brisk metabolic rate. Evaluating the tissue distribution, the highest accumulation was seen in the liver (30.32 ± 3.06 µg/g), followed by the kidney (20.58 ± 2.12 µg/g) and intestine (6.69 ± 0.93 µg/g), suggesting a propensity for IVG to concentrate in these tissues. Importantly, the presence of IVG in the brain underlines its potential to traverse the blood-brain barrier. These findings revealed that following intravenous administration, IVG was swiftly and broadly distributed throughout various rat tissues. CONCLUSION: This study provides valuable information on the pharmacokinetics and tissue distribution of IVG, implicating its potential as a novel and effective drug candidate for sedative and anxiolytic treatment.
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Espectrometría de Masas en Tándem , Ratas , Animales , Ratas Sprague-Dawley , Espectrometría de Masas en Tándem/métodos , Distribución Tisular , Reproducibilidad de los ResultadosRESUMEN
Intestinal epithelial cell (IEC) regulation of barrier function and mucosal homeostasis enables the establishment of a harmonious gut microenvironment. However, host-derived regulatory networks that modulate intestinal antimicrobial defenses have not been fully defined. Herein we generated mice with IEC-specific deletion of Gpr65 (Gpr65ΔIEC) and investigated the role of epithelial GPR65 using DSS- and C. rodentium-induced murine colitis models. RNA sequencing analysis was conducted on colonic IECs from Gpr65fl/fl and Gpr65ΔIEC mice, and colonoids and colonic epithelial cell lines were used to evaluate the pH-sensing effect of GPR65. The expression of GPR65 was determined in IECs from patients with inflammatory bowel disease (IBD) and DSS colitis mice by qRT-PCR, Western blot, and immunohistochemistry, respectively. We observed that the absence of GPR65 in IECs abrogated homeostatic antimicrobial programs, including the production of antimicrobial peptides (AMPs) and defense response-associated proteins. Gpr65ΔIEC mice displayed dysbiosis of the gut microbiota and were prone to DSS- and C. rodentium-induced colitis, as characterized by significantly disrupted epithelial antimicrobial responses, pathogen invasion, and increased inflammatory infiltrates in the inflamed colon. RNA sequencing analysis revealed that deletion of GPR65 in IECs provoked dramatic transcriptome changes with respect to the downregulation of immune and defense responses to bacteria. Forced AMP induction assays conducted in vivo or in ex vivo colonoids revealed that IEC-intrinsic GPR65 signaling drove antimicrobial defense. Mechanistically, GPR65 signaling promoted STAT3 phosphorylation to optimize mucosal defense responses. Epithelial cell line and colonoid assays further confirmed that epithelial GPR65 sensing pH synergized with IL-22 to facilitate antimicrobial responses. Finally, the expression of GPR65 was markedly decreased in the inflamed epithelia of IBD patients and DSS colitis mice. Our findings define an important role of epithelial GPR65 in regulating intestinal homeostasis and mucosal inflammation and point toward a potential therapeutic approach by targeting GPR65 in the treatment of IBD.
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Colitis , Microbioma Gastrointestinal , Enfermedades Inflamatorias del Intestino , Receptores Acoplados a Proteínas G , Animales , Humanos , Ratones , Colitis/inducido químicamente , Colitis/genética , Concentración de Iones de Hidrógeno , Inflamación , Enfermedades Inflamatorias del Intestino/genética , Receptores Acoplados a Proteínas G/fisiologíaRESUMEN
INTRODUCTION: We aimed to explore the respiratory tract infection after oral and maxillofacial surgery under general anesthesia and related factors. METHODOLOGY: A total of 494 patients receiving oral and maxillofacial surgery under general anesthesia with tracheal intubation were assigned to a non-infection group (n=469) and an infection group (n=25). Another 494 healthy people undergoing physical examination in the same period were enrolled to establish a classification tree model. The distribution of pathogens, drug resistance of main pathogens, and related influencing factors of postoperative respiratory tract infection were analyzed. The influencing factors of respiratory tract infection were screened by logistic regression analysis. After construction of the classification and regression tree (CART) model based on the influencing factors, the accuracy was evaluated by plotting receiver operating characteristic (ROC) curve. RESULTS: Pseudomonas aeruginosa was highly resistant to cefazolin and more sensitive to cefoperazone, ciprofloxacin, norfloxacin and imipenem. Staphylococcus aureus was highly resistant to gentamicin and more sensitive to vancomycin. Age ≥ 60 years old, history of lung diseases, operation time ≥ 4 h, anesthesia ventilation time ≥ 120 min, and orotracheal intubation were independent influencing factors of respiratory tract infection (p< 0.05). The results of the gain chart, index map, and Risk value indicated a high predictive value of the CART model for the risk of postoperative respiratory tract infection. The area under the ROC curve was 0.869 [95% confidence interval: 0.795-0.947]. CONCLUSIONS: The CART model has a high predictive value and may reduce the risk of postoperative infection.
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Infecciones del Sistema Respiratorio , Cirugía Bucal , Humanos , Persona de Mediana Edad , Anestesia General/efectos adversos , Infecciones del Sistema Respiratorio/epidemiología , Ciprofloxacina , Intubación Intratraqueal/efectos adversos , Estudios RetrospectivosRESUMEN
Chronic stress induces depression- and anxiety-related behaviors, which are common mental disorders accompanied not only by dysfunction of the brain but also of the intestine. Activating transcription factor 4 (ATF4) is a stress-induced gene, and we previously show that it is important for gut functions; however, the contribution of the intestinal ATF4 to stress-related behaviors is not known. Here, we show that chronic stress inhibits the expression of ATF4 in gut epithelial cells. ATF4 overexpression in the colon relieves stress-related behavioral alterations in male mice, as measured by open-field test, elevated plus-maze test, and tail suspension test, whereas intestine-specific ATF4 knockout induces stress-related behavioral alterations in male mice. Furthermore, glutamatergic neurons are inhibited in the paraventricular thalamus (PVT) of two strains of intestinal ATF4-deficient mice, and selective activation of these neurons alleviates stress-related behavioral alterations in intestinal ATF4-deficient mice. The highly expressed gut-secreted peptide trefoil factor 3 (TFF3) is chosen from RNA-Seq data from ATF4 deletion mice and demonstrated decreased in gut epithelial cells, which is directly regulated by ATF4. Injection of TFF3 reverses stress-related behaviors in ATF4 knockout mice, and the beneficial effects of TFF3 are blocked by inhibiting PVT glutamatergic neurons using DREADDs. In summary, this study demonstrates the function of ATF4 in the gut-brain regulation of stress-related behavioral alterations, via TFF3 modulating PVT neural activity. This research provides evidence of gut signals regulating stress-related behavioral alterations and identifies possible drug targets for the treatment of stress-related behavioral disorders.
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Factor de Transcripción Activador 4 , Tálamo , Masculino , Animales , Ratones , Factor de Transcripción Activador 4/metabolismo , Tálamo/metabolismo , Neuronas/metabolismo , Ratones Noqueados , Colon/metabolismoRESUMEN
Colorectal cancer (CRC) is the third most common cancer in the world. Other than adenocarcinomas, exceptional tumors of the colon and rectum represent a neglected clinical issue due to their rarity. Signet ring cell carcinoma (SRCC) is a rare subtype of CRC and has an extremely poor prognosis due to its advanced stage at diagnosis. Here we report a rare case of colorectal SRCC manifested as recurrent intestinal obstruction with a negative colonoscopy. Finally, he was diagnosed with signet ring cell carcinoma of the colon by postoperative pathology. It emphasized the special feature of intramural tumor growth without penetrating the mucosa in SRCC, which requires timely surgical intervention to avoid delay in diagnosis and treatment.
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OBJECTIVES: To investigate the prospective role of intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) in evaluating terminal ileal Crohn's disease (CD) inflammation quantitatively, compared with quantitative dynamic contrastenhanced magnetic resonance imaging (DCE-MRI) and ileocolonoscopic segmental score. METHODS: Fifty CD patients underwent magnetic resonance enterography (MRE) including IVIM-DWI and quantitative DCE-MRI from Jan. 2017 to Nov. 2019. ADC, D, D* and f value of IVIM-DWI and Ktrans, Kep, and Ve value of DCE-MRI in normal (n = 50) and inflamed bowel segments (n = 50), defined during the clinical MRI analysis, were calculated and compared using Wilcoxon signed-rank tests respectively. Receiver operating characteristic (ROC) analysis was performed. Correlations between IVIM-DWI and DCE-MRI parameters in comparison with ileocolonoscopic segmental score were assessed using Spearman's rank correlation analysis. RESULTS: For IVIM-DWI, ADC, D, D* and f value showed significant differences respectively between normal and inflamed bowel segments (p < 0.05). ADC value presented the highest diagnostic accuracy (AUC = 0.813) and sensitivity (92%), and D value presented the highest specificity (84%) for the evaluation of inflamed bowel segments. For DCE-MRI, Ktrans value presented the highest diagnostic accuracy (AUC = 0.835), the highest sensitivity for Kep value (88%) and the highest specificity for Ve value (96%). ADC, f and Ktrans value had high correlations with ileocolonoscopic score respectively (r = -0.739-0.876, p < 0.01). The logarithm of normalized signal intensity/b-values for IVIM-DWI could also indicate directly the evident difference between the normal and inflamed bowel segments of terminal ileal CD. CONCLUSION: IVIM-DWI will be another promising noninvasive tool to provide precise quantitative-indicators in evaluating inflamed bowel segments of terminal ileal CD with little contrast-agent damage worries.
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Enfermedad de Crohn , Humanos , Enfermedad de Crohn/diagnóstico por imagen , Imagen de Difusión por Resonancia Magnética/métodos , Imagen por Resonancia Magnética/métodos , Medios de Contraste , Curva ROCRESUMEN
Background and Aims: Anti-tumor necrosis factor mAb (i.e., adalimumab, ADA) is currently used in the treatment of patients with Crohn's disease (CD). However, its regulation on fecal microbiota is still not fully understood. Methods: A retrospective analysis was conducted on 115 patients with CD who received treatment with ADA for 12 weeks at the Inflammatory Bowel Disease Center in Shanghai Tenth People's Hospital and Department of Gastroenterology in Shanghai General Hospital. The Crohn's disease activity index (CDAI) evaluation was applied to patients before ADA therapy at week 0, 4, 8, and 12. Clinical remission (CR) was defined as the CDAI < 150. All patients underwent ileocolonoscopy or enteroscopy at baseline (week 0) and week 12. Crohn's Disease Endoscopic Index of Severity (CDEIS) scores were calculated by two experienced physicians to assess endoscopic activity. Mucosal healing (MH) was assigned a CDEIS score between 0 and 3. Fecal samples were collected from eight CD patients at baseline and week 12, and the microbiota was analyzed by using 16S RNA sequencing. Results: At week 12, CR was achieved in 70.6% (72/102) of the patients with active CD. A total of 47.1% (48/102) of the patients with active CD attained MH, among which, 56.6% (30/53) of the patients with mildly active CD (3 ≤ CDEIS <9) and 48.0% (12/25) of the moderately active CD patients (9 ≤ CDEIS <12) attained MH, but only 25.0% (6/24) achieved MH in severely active CD patients (CDEIS ≥12). The efficacy of ADA was not associated with lesion locations (χ 2 = 0.409, p = 0.815). Unexpectedly, we found an increase in protective microbiota at the genus level (e.g., Barnesiella, Anaerostipes, Tyzzerella, Lachnoclostridium, and Lachnospiraceae_unclassified) but a decrease in pathogenic bacteria (Escherichia-Shigella) in fecal samples of the ADA-responsive group (ADA-R) when compared with those in the ADA-nonresponsive group (ADA-NR). Notably, the gene bglX coding ß-glucosidase and gph encoding phosphoglycolate phosphatase were enriched in fecal samples of ADA-R. Conversely, the abundance of genes coding ATP-binding cassette (ABC) transporter system proteins was significantly enriched in fecal samples of ADA-NR when compared with that of the ADA-R. Conclusion: This study reveals that ADA markedly improves clinical remission and induces MH in mildly to moderately active CD patients and that distinct changes in the gut microbiota can be used to predict the efficacy of ADA.
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Immune checkpoint inhibitor (ICI)-induced colitis is one of the known complications of therapies targeting cytotoxic programmed cell death protein 1 (PD-1), cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), and programmed cell death ligand 1 (PD-L1). ICI-associated colitis is routinely treated with immunosuppressive therapy, including corticosteroids and/or agents targeting tumor necrosis factor-α (TNF-α). In this report, a 69-year-old male patient developed severe ICI-induced colitis 2 weeks after anti-PD-L1 mAb (i.e., durvalumab) treatment; unexpectedly failed to respond to systemic corticosteroid, anti-TNF, and anti-integrin agents; and unfortunately died in 1 month. This case reminds clinical physicians to be on the alert for early-onset acute ICI-induced colitis and emphasizes that urgent optimized rescue measures are required for patients with severe ICI-induced colitis.
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Background: Exclusive enteral nutrition (EEN) provides an effective strategy for the induction of clinical remission in pediatric Crohn's disease. However, the feasibility of long-term EEN in the management of disease and the underlying mechanism whereby long-term EEN prevents intestinal inflammation are still not fully understood. Methods: Paired male and female adult wild-type (WT) mice were mated to breed littermates, and these pups were then weaned at 3 weeks of age and randomly allocated into regular diet (RT) feeding group and EEN feeding group (Peptisorb; NUTRICIA), respectively. After feeding until adulthood at the age of 8 weeks, mice were sacrificed and phenotypic analysis of immune cells in spleens and mesenteric lymph nodes (MLNs) was performed by flow cytometry. Fecal pellets were also collected to determine the levels of immunoglobulins and gut microbiota by ELISA and 16S rRNA sequencing. The role of long-term EEN in the development of colitis and its underlying mechanisms were evaluated in a TNBS-induced colitis model in mice. Results: Feeding with EEN decreased the percentages of IgA- and IgG-coated bacteria and the levels of soluble IgA and IgG in the feces of EEN-feeding mice compared with the controls, but did not affect the compositions of different immune cells including CD4+, CD8+ T cells and B220+ B cells in the spleens and MLNs. An in-depth analysis of the gut microbiota revealed a decrease of the general diversity of the gut microbiota, but a significant change of the composition of the gut microbiota after EEN feeding, characterized by an increase of the beneficial bacteria including Bacteroides, Parabacteroides, and Alistipes, but a decrease of the detrimental bacteria such as Escherichia-Shigella. Moreover, we found that EEN feeding markedly improved intestinal inflammation in the TNBS-induced colitis model compared to RT feeding, as evidenced by decreased levels of inflammatory cytokines and fecal soluble immunoglobulins and improved microbial community composition. Conclusions: Our data indicate that long-term EEN feeding remodels the composition of gut microbiota and alleviates intestinal mucosal inflammation. It provides new guidance using EEN for the management of gut inflammation.
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Colitis , Nutrición Enteral , Microbioma Gastrointestinal/fisiología , Animales , Colitis/inducido químicamente , Colitis/microbiología , Colitis/patología , Femenino , Microbioma Gastrointestinal/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Factores de Tiempo , Ácido Trinitrobencenosulfónico/efectos adversosRESUMEN
BACKGROUND & AIMS: TOB1 is an anti-proliferative protein of Tob/BTG family and typically involved in the tumorigenesis and T cell activation. Although TOB1 is associated with T helper 17 cell-related autoimmunity, its role in modulating T cell-mediated immune responses in IBD remains poorly understood. Here, we explored its expression and the underlying mechanisms involved in the pathogenesis of inflammatory bowel disease (IBD). METHODS: TOB1 and ID2 expression in IBD patients was examined by quantitative real time polymerase chain reaction and immunohistochemistry. IBD CD4+ T cells were transfected with lentivirus expressing TOB1, ID2, TOB1 short hairpin RNA and ID2 short hairpin RNA, respectively, and Tob1-/-CD4+ T cells were transfected with lentivirus expressing Id2. Experimental colitis was established in Tob1-/- mice by trinitrobenzene sulfonic acid enema and in Rag1-/- mice reconstituted with Tob1-/-CD45RBhighCD4+ T cells to further explore the role of Tob1 in intestinal mucosal inflammation. Splenic CD4+ T cells of Tob1-/- mice were sorted to determine transcriptome differences by RNA sequencing. RESULTS: TOB1 expression was decreased in inflamed mucosa and peripheral blood CD4+ T cells of IBD patients compared with healthy subjects. Overexpression of TOB1 downregulated IBD CD4+ T cells to differentiate into Th1/Th17 cells compared with control subjects. Severe colitis was observed in Tob1-/- mice through trinitrobenzene sulfonic acid enema or in Rag1-/- mice reconstituted with Tob1-/-CD45RBhighCD4+ T cells, compared with control animals. RNA sequencing analysis revealed ID2 as functional target of TOB1 to inhibit IBD CD4+ T cell differentiation into Th1/Th17 cells. Mechanistically, TOB1 was associated with Smad4/5 to induce ID2 expression and restrain Th1/Th17 cell differentiation. CONCLUSIONS: TOB1 restrains intestinal mucosal inflammation through suppressing Th1/Th17 cell-mediated immune responses via the Smad4/5-ID2 pathway. It may serve as a novel therapeutic target for treatment of human IBD.
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Colitis , Enfermedades Inflamatorias del Intestino , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Animales , Proteínas de Homeodominio/metabolismo , Humanos , Inflamación/patología , Enfermedades Inflamatorias del Intestino/patología , Proteína 2 Inhibidora de la Diferenciación/genética , Proteína 2 Inhibidora de la Diferenciación/metabolismo , Mucosa Intestinal/metabolismo , Activación de Linfocitos , Ratones , ARN Interferente Pequeño/metabolismo , Ácidos Sulfónicos/metabolismo , Ácidos Sulfónicos/uso terapéutico , Células TH1 , Células Th17/metabolismo , Células Th17/patología , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismoRESUMEN
BACKGROUND: Inflammatory bowel disease (IBD) is a complex chronic disorder characterized by systemic inflammation, which may cause abnormal state of coagulation, resulting in cardiac events. This study aimed to investigate the incidences and risks of cardiac events in patients with IBD in China. METHODS: A retrospective cohort study was performed comprising 1435 patients with IBD from 12 IBD centers in China. Cases were matched with 1588 eligible participants without IBD from 12 medical centers according to age, sex, and laboratory parameters. RESULTS: Patients with IBD in China exhibited significantly higher incidences of ischemic heart disease (IHD; coronary heart disease included) but lower frequencies of right bundle branch block and premature contraction than those of matched controls. The risk of IHD increased in patients with IBD, peaking at the age of 18-35 years. Female patients with IBD were more likely to experience IHD than male patients. The C-reactive protein (CRP) levels and neutrophil count in the peripheral blood were positively related with the risk of IHD among patients with Crohn's disease, whereas plasma fibrinogen levels were negatively related with the risk of IHD both in patients with Crohn's disease and ulcerative colitis. CONCLUSIONS: The risk of IHD is increased in patients with IBD, especially in young female patients with IBD when compared with matched non-IBD subjects. The CRP and plasma fibrinogen levels and neutrophil count in the peripheral blood may be potential predictors associated with the occurrence of IHD in patients with IBD. The study's findings have significant implications for the management and prevention of cardiac events in patients with IBD.
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Enfermedades Cardiovasculares , Colitis Ulcerosa , Enfermedad de Crohn , Enfermedades Inflamatorias del Intestino , Adolescente , Adulto , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/etiología , Estudios de Cohortes , Colitis Ulcerosa/complicaciones , Enfermedad de Crohn/complicaciones , Enfermedad de Crohn/epidemiología , Femenino , Fibrinógeno , Humanos , Enfermedades Inflamatorias del Intestino/complicaciones , Enfermedades Inflamatorias del Intestino/epidemiología , Masculino , Estudios Retrospectivos , Adulto JovenRESUMEN
At present, the conventional therapies for acute severe ulcerative colitis (ASUC) mainly include corticosteroids, cyclosporin, and biological agents. However, the treatment of patients with severe steroid-refractory ulcerative colitis remains a serious challenge to clinicians. This study reports a case of steroid-refractory ASUC treated with cyclosporin combined with tofacitinib after treatment failure with infliximab.
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Colitis Ulcerosa , Ciclosporina , Piperidinas/uso terapéutico , Pirimidinas/uso terapéutico , Colitis Ulcerosa/tratamiento farmacológico , Ciclosporina/uso terapéutico , Humanos , EsteroidesRESUMEN
AIMS: The endoscopic evaluation is crucial for the management and treatment of ulcerative colitis (UC). Currently, the Mayo Endoscopic Score (MES) and the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) are two major endoscopic score systems to evaluate the status of mucosal inflammation and disease activity. However, in both MES and UCEIS systems, the disease extent is not included. The Degree of Ulcerative Colitis Burden of Luminal Inflammation (DUBLIN) score is a simple clinical score which is calculated as a product of the MES (0-3) and the extent of disease (E1-E3). The objective of this study was to compare the correlation among DUBLIN, UCEIS and MES, and also investigate the clinical characteristics for predicting treatment failure in patients with active UC. METHODS: Between March 2015 and April 2019, 172 patients who were previously diagnosed with UC and had undergone colonoscopy were recruited in this study. We retrospectively reviewed the endoscopic scores and clinical characteristics at the time of the colonoscopy and assessed the prognosis of the patients. Endoscopic response was defined as the decrease in MES ⩾1 grade. RESULTS: DUBLIN showed significant correlation with MES (r = 0.748) and partial Mayo score (pMayo) (r = 0.707), and moderately correlated with CRP (r = 0.590). UCEIS also showed strong correlation with MES (r = 0.712) but moderate correlation with pMayo (r = 0.609) and CRP (r = 0.588). Compared with the UCEIS (cut-off value: 4; sensitivity: 75.73%), DUBLIN score (cut-off value: 4; sensitivity: 86.41%) showed higher diagnostic sensitivity than UCEIS score (McNemar test, p < 0.05). Furthermore, a multivariate analysis also revealed that DUBLIN ⩾4 was the independent factor for predicting treatment failure for UC (p < 0.001, odds ratio: 1.547; 95% confidence interval: 1.32-1.88). CONCLUSION: The DUBLIN score shows superior diagnostic performances in terms of sensitivity value compared with the UCEIS. Moreover, multivariate analysis indicates that DUBLIN ⩾4 is an independent factor for predicting medium- to long-term treatment failure in active UC patients.
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ETHNOPHARMACOLOGICAL RELEVANCE: Sour Jujube seed from Ziziphus jujuba Mill. var. Spinosa (Bunge) Hu ex H. F. Chow is a traditional Chinese herb. It was demonstrated with significant activities in anti-depression and antioxidant by numerous pharmacological studies. Flavonoids is one of the main constituents in sour Jujube seed. AIM OF THE STUDY: The aim of this study was to propose a green ultrasound-assisted extraction (UAE) process of flavonoids from sour Jujube seed. MATERIALS AND METHODS: The extraction parameters were investigated and optimized using single factor experiments, Plackett-Burman design (PBD) and response surface methodology (RSM). Moreover, a comparative analysis between ultrasound-assisted extraction and heat reflux extraction was performed to verify the ameliorating effects of ultrasound-assisted extraction on the flavonoids yield, the composition, antioxidant capacities in vitro and ROS scavenging capacity in PC12â¯cells. Meanwhile, the effects of flavonoids extract (FE) on Aß transgenic Caenorhabditis elegans (GMC101) behavior were investigated. RESULTS: The optimal extracting conditions of total flavonoids were as follows: ethanol concentration 70.60 (v/v%), liquid-solid ratio 15.02:1â¯mL/g, ultrasonic power 404â¯W, extraction time 60.03â¯min. The highest extraction yield was 1.59%. When compared to Heat reflux extraction (HRE) that only has gained a yield of 1.356%. Approximately, the UAE method was able to increase the yield by 17.11%. Moreover, FE extracted by UAE displayed larger capacity of scavenging ABTS, DPPH, superoxide, and hydroxyl radicals and reducing the level of ROS accumulation in PC12â¯cells, suggesting the biological functions of these compounds could be also better protected under UAE conditions. Furthermore, FE could also increase the chemotaxis and heat stress resistance ability, delay the paralysis and extend the lifespan of Caenorhabditis elegans. CONCLUSION: UAE is a green and efficient technique for the preparation of flavonoids from sour Jujube seed. The flavonoids extract can reduce Aß-induced toxicity in Caenorhabditis elegans.
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Péptidos beta-Amiloides/toxicidad , Antioxidantes/farmacología , Flavonoides/farmacología , Extractos Vegetales/farmacología , Semillas/química , Ondas Ultrasónicas , Ziziphus , Péptidos beta-Amiloides/genética , Animales , Animales Modificados Genéticamente , Antioxidantes/química , Conducta Animal/efectos de los fármacos , Caenorhabditis elegans/efectos de los fármacos , Caenorhabditis elegans/fisiología , Flavonoides/química , Radicales Libres/química , Radicales Libres/metabolismo , Células PC12 , Extractos Vegetales/química , Ratas , SonicaciónRESUMEN
BACKGROUND: Immunoglobulin A (IgA) and IgG are major components in human intestinal mucosal surface and sera, and IgA- or IgG-coated bacteria play a vital role in the intestinal homeostasis. However, the correlation of IgA, IgG and their coated bacteria with the clinical characteristics of inflammatory bowel disease (IBD) has not been fully clarified. METHODS: The levels of soluble IgA and IgG in sera and feces were detected by ELISA, and the percentage of IgA- and IgG-coated bacteria in feces was analyzed by flow cytometry. Crohn's disease activity index (CDAI) and Simple Endoscopic Score for Crohn's disease (SES-CD) for Crohn's disease (CD) or Mayo score and ulcerative colitis endoscopic index of severity (UCEIS) for ulcerative colitis (UC), erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were used to evaluate the disease activity. RESULTS: 178 patients with CD, 75 patients with UC and 41 healthy donors were recruited in this study. We found that the concentrations of soluble IgA and IgG in feces of active IBD patients were significantly higher than those in healthy controls and that the levels of soluble IgA and IgG in feces from IBD patients were positively correlated with CRP, ESR, Mayo score, UCEIS, SES-CD, and CDAI, respectively. Moreover, we also observed that the percentage of IgA- and IgG-coated bacteria markedly increased in feces of IBD patients, especially in CD patients at the age of 17 to 40 years old, with terminal ileal lesions and perianal lesions, as well as from E2 UC patients, and was closely associated with disease activities. CONCLUSIONS: The levels of soluble IgA and IgG and the percentage of IgA- and IgG-coated bacteria strikingly increase in feces of IBD patients and correlate with disease activity.
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Bacterias/metabolismo , Heces/microbiología , Inmunoglobulina A/metabolismo , Inmunoglobulina G/metabolismo , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedades Inflamatorias del Intestino/microbiología , Adulto , Sedimentación Sanguínea , Proteína C-Reactiva/metabolismo , Enfermedad de Crohn/sangre , Enfermedad de Crohn/inmunología , Femenino , Humanos , Inmunoglobulina A/sangre , Inmunoglobulina G/sangre , Enfermedades Inflamatorias del Intestino/sangre , Masculino , SolubilidadRESUMEN
Agaricus bisporus is one of the most important edible and medicinal mushrooms in the world. It has been well known that Agaricus bisporus has an immunoregulatory role, but its active ingredients have not been completely identified. In this study, a glucogalactomannan named TJ3 was isolated and purified from Agaricus bisporus. TJ3 (827 kDa) is composed of mannose, galactose, glucose and xylose in the ratio 28.26 : 27.82 : 20.88 : 9.87 mainly joined by ß-linkages. Functional analysis of TJ3 revealed that it effectively induced apoptosis in RAW 264.7 cells, a mouse macrophage cell line. Cell apoptosis was determined by an Annexin V/PI staining assay. After treatment with TJ3 (2 µg mL-1) for 16 h, apoptosis was observed in 34% of the Raw cells (9% in the non-treated control cells). TJ3 treatment remarkably increased the production of cleaved caspase-3, PARP and Bim, and decreased the level of Bcl-2 although no obvious change in the level of Bax was observed. Interestingly, further elucidation of the molecular mechanism underlying the role of TJ3 in the induction of apoptosis showed that TJ3 activated the JNK signaling pathway through TLR4 and subsequently promoted the expression of Bim and activation of caspase-3. Our results demonstrate that TJ3 may be a novel active component in Agaricus bisporus responsible for its immunoregulatory role by the induction of macrophage apoptosis.
Asunto(s)
Agaricus/química , Apoptosis , Proteína 11 Similar a Bcl2/agonistas , Cuerpos Fructíferos de los Hongos/química , Sistema de Señalización de MAP Quinasas , Macrófagos/metabolismo , Mananos/metabolismo , Animales , Antiinflamatorios no Esteroideos/efectos adversos , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/aislamiento & purificación , Antiinflamatorios no Esteroideos/metabolismo , Proteína 11 Similar a Bcl2/metabolismo , Caspasa 3/química , Caspasa 3/metabolismo , Proliferación Celular , Supervivencia Celular , Suplementos Dietéticos/efectos adversos , Suplementos Dietéticos/análisis , Activación Enzimática , Etnofarmacología , Macrófagos/citología , Macrófagos/inmunología , Mananos/efectos adversos , Mananos/química , Mananos/aislamiento & purificación , Medicina Tradicional China , Ratones , Estructura Molecular , Peso Molecular , Poli(ADP-Ribosa) Polimerasas/metabolismo , Proteolisis , Células RAW 264.7RESUMEN
Background: Anti-tumor necrosis factor (TNF) therapy appears to be effective in the treatment of Crohn's disease (CD), a chronic inflammatory disease of the gastrointestinal tract. However, the mechanisms involved are not completely understood. Methods: Fifty-seven active CD patients were enrolled, and cytokine profiles in colonic biopsies of patients with active CD receiving anti-TNF monoclonal antibody (mAb) (infliximab [IFX]) treatment were determined using quantitative real-time polymerase chain reaction (qRT-PCR). Colonic biopsies of active CD patients and healthy donors were cultured with IFX in vitro, and cytokine profiles were measured by qRT-PCR. Peripheral blood (PB)-CD4+ T cells were stimulated with anti-CD3 and anti-CD28 mAbs in the presence of human immunoglobin (HIg), IFX, recombinant human TNF-α converting enzyme (rhTACE), and aryl hydrocarbon receptor (AhR) inhibitor (CH-223191), respectively, to determine interleukin (IL)-22 expression by CD4+ T cells. Caco2 cells were also utilized to study their potential role in modulating epithelial cell barrier repairs in vitro. Results: IFX therapy markedly upregulated IL-22 mRNA expression in the gut mucosa of CD patients. In vitro treatment with IFX greatly promoted CD CD4+ T cells to express IL-22, which was inhibited by rhTACE, indicating that reverse signaling through binding to membrane-bound TNF mediates anti-TNF-induced IL-22 expression of CD CD4+ T cells. However, blockade of AhR markedly inhibited anti-TNF-induced IL-22+CD4+ T (Th22) cell differentiation in CD patients. Moreover, treatment with IL-22 induced intestinal epithelial cell expression of tight junction proteins (eg, claudin1 and ZO-1) and facilitated transepithelial resistance, indicating that IL-22 protects intestinal mucosa from inflammation via maintenance of epithelial barrier integrity. Conclusions: Our results uncover a novel mechanism whereby anti-TNF therapy upregulates IL-22 production in CD patients through promoting Th22 cell differentiation and contributes to intestinal epithelial barrier repairs.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Enfermedad de Crohn/tratamiento farmacológico , Interleucinas/biosíntesis , Células Th17/efectos de los fármacos , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Adolescente , Adulto , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Células CACO-2 , Proliferación Celular/efectos de los fármacos , Enfermedad de Crohn/genética , Enfermedad de Crohn/metabolismo , Enfermedad de Crohn/patología , Femenino , Humanos , Infliximab , Interleucinas/genética , Mucosa Intestinal/patología , Masculino , Células Th17/inmunología , Adulto Joven , Interleucina-22RESUMEN
Ganoderma lucidum is one of the most commonly used mushrooms in traditional Chinese medicine, with significant immunomodulatory and antitumor effects. Triterpenoids are deemed to be the main bioactive components in G. lucidum. In this study, high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (MS) and high-performance liquid chromatography-MS/MS methods were used to identify and quantify, respectively, the main triterpenoids in G. lucidum obtained from different sources. The full MS scan with a daughter ion scan was used to identify a variety of potential derivatives of triterpenoids in the mushroom. Multiple reaction monitoring was performed with transitions of m/z-515.2 â 285.1 (quantifier) and 515.2 â 497.2 (qualifier)-to determine the amount of ganoderic acid A. The developed methods were successfully used to analyze 8 G. lucidum samples from the wild and from cultivated and commercial sources. The results show that the content and composition of triterpenoids differed significantly among these samples. A total of 29 triterpenoids were explicitly or tentatively identified in the wild sample, whereas 23 triterpenoids were found in the cultured sample and 17 in the commercial sample. The results of this study provide a foundation for further research on chemical constituents of, identification of metabolites in, and quality control of the G. lucidum mushroom.