scholarly journals CYP3A5 Genotype as a Potential Pharmacodynamic Biomarker for Tacrolimus Therapy in Ulcerative Colitis in Japanese Patients

2020 ◽  
Vol 21 (12) ◽  
pp. 4347
Author(s):  
Yuki Yamamoto ◽  
Hiroshi Nakase ◽  
Minoru Matsuura ◽  
Shihoko Maruyama ◽  
Satohiro Masuda
Keyword(s):  
Ulcerative Colitis ◽  
Mrna Expression ◽  
Therapeutic Effect ◽  
Blood Concentration ◽  
Colonic Mucosa ◽  
Cyp3a5 Genotype ◽  
Tacrolimus Therapy ◽  
The Relationship ◽  
Mrna Expression Levels ◽  
Cyp3a5 Polymorphism

Tacrolimus has been used to induce remission in patients with steroid-refractory ulcerative colitis. It poses a problem of large individual differences in dosage necessary to attain target blood concentration and, often, this leads to drug inefficacy. We examined the difference in mRNA expression levels of ATP binding cassette transporter B1 (ABCB1) between inflamed and non-inflamed tissues, and the influence of CYP3A5 genotype on tacrolimus therapy. The mRNA expression of CYP3A4 in colonic mucosa and that of cytochrome p450 3A5 (CYP3A5) and ABCB1 in inflamed and non-inflamed areas were examined in 14 subjects. The mRNA expression levels of CYP3A5 were higher than that of CYP3A4. The mRNA expression of ABCB1 was lower in the inflamed than in the non-inflamed mucosa, despite that of CYP3A5 mRNA level being not significantly changed. Hence, the deterioration of the disease is related to the reduction of the barrier in the inflamed mucosa. The relationship between CYP3A5 genotype and blood concentration, dose, and concentration/dose (C/D) ratio of tacrolimus in 15 subjects was studied. The tacrolimus dose to maintain equivalent blood concentrations was lower in CYP3A5*3/*3 than in CYP3A5*1 carriers, and the C/D ratio was significantly higher in the latter. Thus, CYP3A5 polymorphism information played a role in determining the initial dose of tacrolimus. Furthermore, since the effect of tacrolimus appears earlier in CYP3A5*3/*3 than in CYP3A5*1/*1 and *1/*3, it seems necessary to change the evaluation time of therapeutic effect by CYP3A5 genotype. Additionally, the relationship between CYP3A5 genotype and C/D ratio of tacrolimus in colonic mucosa was investigated in 10 subjects. Tacrolimus concentration in the mucosa was two-fold higher in CYP3A5*3/*3 than in CYP3A5*1 carriers, although no significant difference in tacrolimus-blood levels was observed. Therefore, the local concentration of tacrolimus affected by CYP3A5 polymorphism might be related to its therapeutic effect.

Serpin B1 protects colonic epithelial cell via blockage of neutrophil elastase activity and its expression is enhanced in patients with ulcerative colitis

2012 ◽  
Vol 302 (10) ◽  
pp. G1163-G1170 ◽  
Author(s):  
Kazuhiko Uchiyama ◽  
Yuji Naito ◽  
Tomohisa Takagi ◽  
Katsura Mizushima ◽  
Yasuko Hirai ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Mrna Expression ◽  
Real Time ◽  
Neutrophil Elastase ◽  
Colonic Mucosa ◽  
Clinical Samples ◽  
Active Ulcerative Colitis ◽  
Inflammatory Infiltration ◽  
Serpin B1

Serpin B1 is a monocyte neutrophil elastase (NE) inhibitor and is one of the most efficient inhibitors of NE. In the present study, we investigated the role of serpin B1 in the pathogenesis of ulcerative colitis by using clinical samples and an experimental model. The colonic expression of serpin B1 was determined by real-time polymerase chain reaction (PCR), Western blot analysis, and immunohistological studies in both normal and inflamed mucosa from patients with ulcerative colitis. Serpin B1 mRNA expression was determined by real-time PCR in the mouse dextran sodium sulfate (DSS)-induced colitis model. Young adult mouse colonic epithelial (YAMC) cells were used to determine the role of serpin B1. Serpin B1 gene transfected YAMC cells were treated with H2O2 to measure cell viability. The expression of NE was determined in YAMC cells treated with H2O2. NE-silenced YAMC cells were also treated with H2O2 and then measured for viability. Upregulated expression of serpin B1 in colonic mucosa was confirmed from patients with active ulcerative colitis. Immunohistochemical studies showed that serpin B1 expression was localized not only in inflammatory infiltration cells but also in epithelial cells. Serpin B1 mRNA expression was also increased in colonic mucosa of mouse DSS-induced colitis. Serpin B1-transfected YAMC cells were resistant against the treatment of H2O2. H2O2 treatment significantly induced NE in YAMC cells, and NE-silenced YAMC cells were also resistant against the treatment of H2O2. These results suggest that serpin B1 may be a novel marker of active ulcerative colitis and may play an important role in the pathogenesis of inflammatory bowel disease.

Qingdai Granules up-regulate MUC2 mRNA expression but down-regulate iNOS mRNA expression in the colonic mucosa of rats with ulcerative colitis

2010 ◽  
Vol 18 (9) ◽  
pp. 937 ◽  
Author(s):  
Li-Yang Du ◽  
Qing-Fang Liu ◽  
Xiao-Lei Cheng ◽  
Ming-Shi Chen ◽  
Xian-Ming Li ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Mrna Expression ◽  
Colonic Mucosa ◽  
Inos Mrna

Oxytocin-induced phasic and tonic contractions are modulated by the contractile machinery rather than the quantity of oxytocin receptor

2007 ◽  
Vol 292 (4) ◽  
pp. E992-E999 ◽  
Author(s):  
Masaki Kawamata ◽  
Yutaka Tonomura ◽  
Tadashi Kimura ◽  
Yukihiko Sugimoto ◽  
Teruyuki Yanagisawa ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Smooth Muscles ◽  
Cyclopiazonic Acid ◽  
Oxytocin Receptor ◽  
Signal Pathway ◽  
Regulatory Mechanisms ◽  
Uterine Contractions ◽  
Low Concentrations ◽  
The Relationship ◽  
Mrna Expression Levels

To investigate the relationship between the oxytocin (OT) receptor (OTR) quantity and the contractile features systematically, we measured the mRNA expression levels of OTR and L-type Ca2+ channel α1C-subunit ( α 1C) and examined the regulatory mechanisms of OT-induced phasic or tonic contractions of the longitudinal smooth muscles in mouse uteri. The mRNA expression of OTR in 19.0 G (19.0 days of gestation) was greater than those in nonpregnant phases, and that of α 1C in estrus and 19.0 G was higher than in diestrus. OT-induced contractions sparsely occurred in diestrus. The OT-induced all-or-none-type phasic contractions at low concentrations were abolished by verapamil in both estrus and 19.0 G. OT-induced tonic contractions had similar pD2 values in both estrus and 19.0 G. However, the magnitude in 19.0 G was much greater than that in estrus. The large tonic contractions also occurred in PGF2α receptor (FP) knockout mice in 19.0 G despite a small amount of OTR. Verapamil and Y-27632 partially inhibited the tonic contractions in 19.0 G. Cyclopiazonic acid-induced tonic contractions were reciprocally decreased with the increase in the OT-induced ones in 19.0 G. These results indicate that the phasic contractions are dependent on α1C. The tonic contractions in 19.0 G are dependent on both Ca2+ influxes via L-type Ca2+ channels and store-operated Ca2+ channels, and the force is augmented by the Rho signal pathway, which increases the Ca2+ sensitivity. Thus the uterine contractions are mainly controlled by the modification of contractile signal machinery rather than simply by the OTR quantity.

scholarly journals Correlation of Plasma MMP-1 and TIMP-1 Levels and the Colonic Mucosa Expressions in Patients with Ulcerative Colitis

2009 ◽  
Vol 2009 ◽  
pp. 1-5 ◽  
Author(s):  
Ying-De Wang ◽  
Xiao-Yan Tan ◽  
Ke Zhang
Keyword(s):  
Ulcerative Colitis ◽  
Disease Severity ◽  
Plasma Levels ◽  
Colonic Mucosa ◽  
Venous Blood ◽  
Normal Subjects ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Reverse Transcription Pcr ◽  
Matrix Metalloproteinase 1 ◽  
The Relationship

Background. Both plasma and mucosal levels of matrix metalloproteinase-1 (MMP-1) and tissue inhibitor of metalloproteinase-1 (TIMP-1) have been shown to be independently correlated with ulcerative colitis (UC), but their relationship with each other and to disease severity remains unclear. This study aims to evaluate the relationship between colonic mucosal and plasma levels of MMP-1 and TIMP-1 with each other and with the severity of ulcerative colitis (UC).Methods. Colonic mucosal lesions and venous blood samples were collected from 30 patients with UC and 15 normal subjects. Real-time reverse transcription-PCR and immunohistochemistry were used to determine colonic mucosal MMP-1 and TIMP-1 expression; ELISA was used to measure plasma levels of MMP-1 and TIMP-1.Results. Expression of colonic mucosal and plasma MMP-1 and TIMP-1 in patients with UC was significantly higher than that of controls (P<.05), and was positively correlated with disease severity (P<.05). Plasma MMP-1 and TIMP-1 levels were well correlated with their corresponding expression in colonic mucosa (P<.05,r=0.805 and 0.908).Conclusion. Plasma MMP-1 and TIMP-1 levels reflect their colonic mucosal expression to some extent in patients with UC. Plasma MMP-1 and TIMP-1, in particular, demonstrate the potential to become biomarkers to clinically diagnose UC, predict its severity, and guide further therapy.

scholarly journals Colon Mucosa Exhibits Loss of Ectopic MUC5AC Expression in Patients with Ulcerative Colitis Treated with Oral Tacrolimus

2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
Tsutomu Mizoshita ◽  
Satoshi Tanida ◽  
Hironobu Tsukamoto ◽  
Keiji Ozeki ◽  
Takahito Katano ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Activity Index ◽  
Statistical Significance ◽  
Complete Response ◽  
Mayo Score ◽  
Tacrolimus Therapy ◽  
Clinicopathologic Findings ◽  
Endoscopic Activity Index ◽  
The Relationship ◽  
Free Status

Background. Tacrolimus (FK506) is effective for patients with ulcerative colitis (UC). However, there are few reports on tacrolimus therapy (TT) with respect to the relationship with endoscopic and clinicopathologic findings. Methods. Thirty patients with moderate/severe active UC refractory to or dependent on corticosteroid were treated with oral tacrolimus. The expression of ectopic MUC5AC in the colon was pathologically analyzed before and at 12 weeks after TT, evaluating the Mayo score and steroid-sparing effects. Results. Both mean disease and endoscopic activity index scores were reduced at levels of statistical significance in 26 UC patients receiving more than one month of TT (). The dose of prednisolone was reduced by a statistically significant amount (), and 14 of the 26 patients (53.8%) had steroid-free status 12 weeks after TT. The decrease in ectopic MUC5AC expression in the mucous cells of the colon was significantly associated with endoscopic improvement of inflammation in the UC patients with TT (). Loss of ectopic MUC5AC expression was detected in all patients who had complete response. Conclusions. Tacrolimus appears to be effective for the treatment of moderate/severe UC patients. Loss of ectopic MUC5AC expression may be important for pathologic remission in the colon of UC patients.

scholarly journals Relationship between the mRNA expression levels of calpains 1/2 and proteins involved in cytoskeleton remodeling

Acta Naturae ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 110-113
Author(s):  
Gelena V. Kakurina ◽  
Elena S. Kolegova ◽  
Elena E. Shashova ◽  
Olga V. Cheremisina ◽  
Evgeniy L. Choynzonov ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Cancer Progression ◽  
Expression Level ◽  
Actin Binding ◽  
Published Data ◽  
Cytoskeletal Reorganization ◽  
Expression Levels ◽  
Cytoskeleton Remodeling ◽  
The Relationship ◽  
Mrna Expression Levels

Remodeling of the cytoskeleton underlies various cellular processes, including those associated with metastasis. The role of the proteases and proteins involved in cytoskeletal reorganization is being actively studied. However, there are no published data on the relationship between the mRNA expression levels of calpains 1/2 (CAPN 1/2) and the proteins associated with cytoskeleton remodeling. Therefore, the purpose of our study was to establish the relationship between the mRNA expression levels of CAPN 1/2 and the proteins involved in cytoskeletal reorganization, such as cell motility markers (SNAI1, VIM, and RND3) and actin-binding proteins (CFN1, PFN1, EZR, FSCN1, and CAP1) using the model of laryngeal/laryngopharyngeal squamous cell carcinoma (LC). The gene expression level was determined by reverse transcriptase real-time PCR and calculated using the 2-Ct method in paired tissue samples of 44 patients with LC (T1-4N0-2M0). The patients were divided into two groups: those with low and those with high CAPN 1/2 expression levels. It was found that metastasis in LC patients was associated with decreased expression levels of VIM and CAP1, and increased levels of CAPN1. A high level of CAPN2 was accompanied by a high expression level of EZR, indicating the activation of invasion processes. The results obtained need to be confirmed in further studies using a larger sample of patients and target genes. Our study is important in elucidating the mechanisms that underlie cancer progression and metastasis, a development that could subsequently open the way to a search for new prognostic and predictive markers of laryngeal/laryngopharyngeal cancer progression.

scholarly journals Correlation between the Expression of Inflammatory Factors and the Degree of Intervertebral Disc Degeneration

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Tuanmao Guo
Keyword(s):  
Intervertebral Disc ◽  
Mrna Expression ◽  
Disc Degeneration ◽  
Inflammatory Factors ◽  
Cervical Disc ◽  
Expression Levels ◽  
Grade Ii ◽  
Pfirrmann Grade ◽  
The Relationship ◽  
Mrna Expression Levels

Objective: To investigate the relationship between the expression of IL-6, IL-8, IL-15, IFN-a, TNF-a and TRPC6 in the disc tissue of patients with cervical disc degeneration. Methods: The expression levels of inflammatory factors IL-6, IL-8, IL-15, IFN-a, TNF-a and TRPC6 were analyzed by RT-PCR, and the correlation between inflammatory factors and Pfirrmann grade and inflammatory factors was analyzed. Results: The mRNA expression levels of IL-6, IL-8, IL-15, TNF - a and TRPC6 were significantly higher in Pfirrmann grade IV-V than in Pfirrmann grade II-III (P< 0.05), and IFN-a expression level in IV-V intervertebral disc samples was significantly lower than that in II-III discs (P<0.05); The mRNA expression levels of IL-6, IL-8, IL-15, TNF - a and TRPC6 were positively correlated with pfirmann grading (P<0.05), IFN - a was negatively correlated with pfirmann grading (P<0.05), IL-6, IL-8, IL-15, TNF - a and TRPC6 were positively correlated with each other(P<0.05), IFN - a was negatively correlated with IL-6, IL-8, IL-15, TNF-a and TRPC6(P<0.05). Conclusion: IL-6, IL-8, IL-15, IFN-a, TNF- a and TRPC6 are closely related to the degree of cervical disc degeneration.

scholarly journals Effect of Tripterygium wilfordii Polycoride on the NOXs-ROS-NLRP3 Inflammasome Signaling Pathway in Mice with Ulcerative Colitis

2019 ◽  
Vol 2019 ◽  
pp. 1-7 ◽  
Author(s):  
Ma Fangxiao ◽  
Ke Yifan ◽  
Zhong Jihong ◽  
Shen Yan ◽  
Liu Yingchao
Keyword(s):  
Ulcerative Colitis ◽  
Mrna Expression ◽  
Signaling Pathway ◽  
Nlrp3 Inflammasome ◽  
Receptor Protein ◽  
Tripterygium Wilfordii ◽  
Expression Levels ◽  
Caspase 1 ◽  
Model Control ◽  
Mrna Expression Levels

Objective. To explore the effect of Tripterygium wilfordii polycoride (TWP) on the NADPH oxidases (NOXs)-reactive oxygen species (ROS)-NOD-like receptor protein 3 (NLRP3) inflammasome signaling pathway and the possibility of using TWP to treat ulcerative colitis (UC). Methods. BALB/c mice were randomly divided into five groups: model control, low TWP, middle TWP, high TWP, and normal control groups. A UC model was established with dextran sulfate sodium. The determination of ROS was carried out by using the fluorescent probe DCFH-DA, and NOXs activity was detected based on the NADPH consumption rate. The mRNA expression levels of NLRP3, ASC, and caspase-1 in the colon tissues and neutrophils were assessed via real-time PCR. Results. The colon tissues were abnormal with different degrees in TWP groups with disease activity index and histopathological scores lower than those in the model group. In TWP groups, ROS generation, NOXs activity, and the mRNA expression levels of NLRP3, ASC, and caspase-1 in the colon tissues and colon-isolated neutrophils were remarkably lower than those in the model control group (P<0.05) and higher than those in the normal group (P<0.05). The results of pairwise comparison for the efficacy of TWP administration showed that the above indexes were statistically significant with the lowest expression in the high TWP group (P<0.05) and the highest expression in the low TWP group (P<0.05). Conclusion. TWP demonstrated anti-inflammatory effects on UC by decreasing the expression of proinflammatory factors in the NOXs-ROS-NLRP3 signaling pathway.

scholarly journals PTPN2 is Associated with Crohn’s Disease and Its Expression Is Regulated by NKX2-3

2012 ◽  
Vol 32 (2) ◽  
pp. 83-91 ◽  
Author(s):  
Wei Yu ◽  
John P. Hegarty ◽  
Arthur Berg ◽  
Ashley A. Kelly ◽  
Yunhua Wang ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Crohn’S Disease ◽  
B Cells ◽  
Crohn's Disease ◽  
Mrna Expression ◽  
Genetic Variants ◽  
Microvascular Endothelial Cells ◽  
Rt Pcr ◽  
Risk Gene ◽  
Mrna Expression Levels

PTPN2 is a risk gene for Crohn's disease (CD). We investigated whether PTPN2 genetic variants (rs2542151 and rs2542152) were associated with CD in a familial IBD registry. Both rs2542151 and rs2542152 are associated with CD, but not ulcerative colitis (UC). mRNA expression levels of PTPN2 were significantly increased in intestinal tissues (p=0.0493), and nearly significantly increased in B cells (p=0.0889) from CD patients, but not significantly altered in UC. cDNA microarray results found that PTPN2 was down-regulated by NKX2-3 knockdown in human cells. We confirmed this observation by RT-PCR analyses in NKX2-3 knockdown in B cells from IBD patients and human intestinal microvascular endothelial cells (HIMEC). In addition, we found that mRNA expression of another IBD-associated gene, NKX2-3, was increased in intestinal tissues and B cells from CD patients, but not significantly increased in UC patients. A positive correlation was observed between mRNA expression of PTPN2 and NKX2-3 in B cells and in intestinal tissues from both CD and UC patients. These results suggest that PTPN2 may have an important role in CD pathogenesis and may represent a potential diagnostic and therapeutic target for IBD.

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