Sensitization of TRPA1 by PAR2 contributes to the sensation of inflammatory pain

Proinflammatory agents trypsin and mast cell tryptase cleave and activate PAR2, which is expressed on sensory nerves to cause neurogenic inflammation. Transient receptor potential A1 (TRPA1) is an excitatory ion channel on primary sensory nerves of pain pathway. Here, we show that a functional interaction of PAR2 and TRPA1 in dorsal root ganglion (DRG) neurons could contribute to the sensation of inflammatory pain. Frequent colocalization of TRPA1 with PAR2 was found in rat DRG neurons. PAR2 activation increased the TRPA1 currents evoked by its agonists in HEK293 cells transfected with TRPA1, as well as DRG neurons. Application of phospholipase C (PLC) inhibitors or phosphatidylinositol-4,5-bisphosphate (PIP(2)) suppressed this potentiation. Decrease of plasma membrane PIP(2) levels through antibody sequestration or PLC-mediated hydrolysis mimicked the potentiating effects of PAR2 activation at the cellular level. Thus, the increased TRPA1 sensitivity may have been due to activation of PLC, which releases the inhibition of TRPA1 from plasma membrane PIP(2). These results identify for the first time to our knowledge a sensitization mechanism of TRPA1 and a novel mechanism through which trypsin or tryptase released in response to tissue inflammation might trigger the sensation of pain by TRPA1 activation.     

Gd‐EOB‐DTPA‐enhanced MR imaging: Prediction of hepatic fibrosis stages using liver contrast enhancement index and liver‐to‐spleen volumetric ratio

Purpose:

To develop and evaluate a quantitative parameter for staging hepatic fibrosis by contrast enhancement signal intensity and morphological measurements from gadoxetic acid (Gd‐EOB‐DTPA)‐enhanced MR imaging.

Materials and Methods:

MR images were obtained in 93 patients; 75 patients had histopathologically proven hepatic fibrosis and 18 patients who had healthy livers were evaluated. The liver‐to‐muscle signal intensity ratio (SI_post = SIliver/SImuscle), contrast enhancement index (CEI = SIpost/SIpre), and liver‐to‐spleen volumetric ratio (VR = Vliver/Vspleen) were evaluated for staging hepatic fibrosis.

Results:

VR was most strongly correlated with fibrosis stage (7.21; r = ?0.83; P < 0.001). Sensitivity, specificity, and area under the ROC curve demonstrated by linear regression formula generated by VR and CEI in predicting fibrous scores were 100%, 73%, and 0.91, respectively, for the detection of hepatic fibrosis F1 or greater (≥ F1),100%, 87%, and 0.96 for ≥ F2, 74%, 98%, and 0.93 for ≥ F3 and 91%, 100%, and 0.97 for F4.

Conclusion:

The liver‐to‐spleen volumetric ratio and contrast enhancement index were reliable biomarkers for the staging of hepatic fibrosis on Gd‐EOB‐DTPA‐enhanced MR imaging. J. Magn. Reson. Imaging 2012;36:1148–1153. © 2012 Wiley Periodicals, Inc.

     

Regulatory science for drug evaluation

The regulatory science is a tool to utilize the fruit of academic science for the public. The regulatory science for drug evaluation is a tool to more effectively evaluate the risk/benefit balance of applied new drugs and enables to ensure faster accessibility to more effective and safer drugs for the public, and also a tool to accelerate the translational research, which leads the shaping of basic scientific discoveries into treatments, the process from scientific breakthrough to the availability of new, innovative medical therapies for patients. Finally, the author suggests that the collaboration of the industry, academia, and regulator is necessary and important to activate the regulatory science, which is the tool of drug evaluation and accelerates the translational research for new drug development.     

An optimal therapeutic expression level is crucial for suicide gene therapy for hepatic metastatic cancer in mice

The most serious problem in current gene therapy is discrepancies between experimental data and actual clinical outcomes, which may be due to insufficient analyses and/or inappropriate animal models. We have explored suicide gene therapy by using various clinically relevant animal models and doubt the clinical use of maximal suicide gene expression, which has been generally recommended. To explore this subject further, we studied what expression level of suicide gene and what promoter led to the maximal clinical benefit in the case of hepatic metastatic cancer in mice. Therapeutic and adverse side effects of 4 adenoviral vectors that express herpes simplex virus thymidine kinase (HSV-tk) under different promoters were scrupulously investigated in 2 mouse models of hepatic metastasis of gastric cancer that possess clinical characteristics. Surprisingly, increases in HSV-tk expression beyond a certain point, achieved by the Rous sarcoma virus long terminal repeat promoter, not only enhanced the adverse side effects of lethal hepatotoxicity and ganciclovir-independent cytotoxicity but also failed to further increase therapeutic potential. Moreover, the carcinoembryonic antigen (CEA) tumor-specific promoter, the therapeutic potential of which had been underestimated, was much more useful-even in the case of low CEA-producing cancer-than had been previously reported. In conclusion, the optimal therapeutic expression level of a suicide gene is a novel concept and a crucial factor for successful cancer gene therapy. The present results, which contradict those of previous studies, alert researchers about possible problems with ongoing and future clinical trials that lack this concept.     

EPZ011989, A Potent,Orally-Available EZH2 Inhibitor with Robust in Vivo Activity

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