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Articles by J Mimura
Total Records ( 2 ) for J Mimura
  K Kosaka , J Mimura , K Itoh , T Satoh , Y Shimojo , C Kitajima , A Maruyama , M Yamamoto and T. Shirasawa
 

Neurotrophins such as NGF promote neuronal survival and differentiation via the cell surface TrkA neurotrophin receptor. Compounds with neurotrophic actions that are low in molecular weight and can permeate the blood–brain barrier are promising therapeutic agents against neurodegenerative diseases such as Alzheimer’s disease. Carnosic acid (CA), an electrophilic compound in rosemary, activates antioxidant responsive element (ARE)-mediated transcription via activation of Nrf2. In the present study, we discovered that CA strongly promotes neurite outgrowth of PC12h cells. NGF as well as CA activated Nrf2, whereas CA and NGF-mediated neuronal differentiation was suppressed by Nrf2 knockdown. On the other hand, CA activated TrkA-downstream kinase Erk1/2 independently of Nrf2. CA-induced p62/ZIP expression in an Nrf2-dependent manner, while the CA-induced neural differentiation was suppressed by p62/ZIP knockdown. Furthermore, CA-induced ARE activation was attenuated both by p62/ZIP knockdown and a Trk signal inhibitor. These results suggest that the CA induction of p62/ZIP by Nrf2 enhances TrkA signaling which subsequently potentiates Nrf2 pathway. This is the first demonstration that activation of the Nrf2-p62/ZIP pathway by a low-molecular natural electrophilic compound plays important roles in TrkA-mediated neural differentiation and may represent the common molecular mechanism for neurotrophic activities of electrophilic compounds.

  K Iida , J Mimura , K Itoh , C Ohyama , Y Fujii Kuriyama , T Shimazui , H Akaza and M. Yamamoto
 

Down-regulation of carcinogen detoxifying enzymes might be a critical factor in tumour formation by increasing the carcinogen concentration in the target organ. Previous reports revealed that the expression of UGT1A mRNA is either lost or decreased in certain human cancer tissues, including urinary bladder cancer. To elucidate this down-regulation mechanism, we used an N-nitrosobutyl (4-hydroxybutyl) amine (BBN)-induced mouse urinary bladder carcinogenesis model. Similar to human cancer, the expressions of Ugt1a6, Ugt1a9 and total Ugt1a mRNA in the BBN-induced bladder cancer were markedly decreased compared with those of normal mice. BBN down-regulated the basal Ugt1a mRNA expression in a time-dependent manner and this was reversible in the first 2 weeks of BBN treatment. However, after 4 weeks of BBN treatment the repression became persistent after the cessation of BBN treatment. Aryl hydrocarbon receptor (AhR) regulates the constitutive and inducible expression of Ugt1a mRNA. We found that the constitutive Ugt1a mRNA expression is decreased in the bladder of AhR knockout (KO) mice. Furthermore, BBN-induced Ugt1a down-regulation was lost in AhR KO mice, and the canonical AhR target gene Cyp1a1 was similarly down-regulated by BBN in the bladder. These results demonstrate that BBN repressed Ugt1a mRNA expression via suppression of AhR signaling pathway during BBN-induced carcinogenesis.

 
 
 
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