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RISS 인기검색어
- 검색키워드
- 저자 : 마라하타아누 (검색결과 1 건)
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마라하타아누 전북대학교 의학전문대학원 2014 국내박사
In my study, three parts are included. I have been focusing the pharmacokinetic profiles and its associated biological effect/dynamic effects. Therefore my thesis is composed of the following three parts. Part I: 4-Phenylbutyric acid regulates CCl4-induced Acute Hepatic Lipid Accumulation in a Mouse Model: A Mechanism-based PK/PD study We aimed to document ER stress as a possible clinical biomarker and to introduce 4-PBA as a therapeutic chemical for alleviation of ER stress-related diseases. Male C57B/L mice at eight weeks were used. Mice were divided into three groups: non-treatment, CCl4 alone, and CCl4+ 4-PBA. Treatment with 4-PBA inhibited ER stress by upregulating expression of GRP78 and CHOP, thereby preventing hepatic lipid accumulation. Further, liver triglyceride accumulation was lowered along with decreases in lipid peroxidation and cytochrome P450 2E1 activity. We also studied mechanism-based pharmacokinetic and pharmacodynamic profiles, introducing ER stress-related proteins GRP78 and CHOP, along with serum apolipoprotein B and triglyceride levels, as novel biomarkers for ER stress-induced hepatic lipid accumulation. ER stress and its clinical relevance for therapeutic approaches were well correlated with the activity of the ER stress regulator 4-PBA, which may be a promising drug for treatment of hepatic lipid accumulation. Part II: IC87114 alleviates asthma by inhibiting ER stress through IRE1 dependent pathways by modulating NF-B signaling pathways PI3K plays a pivotal role in the recruitment and activation of certain inflammatory cells. Using mice sensitized with ovalbumin (OVA) and LPS and challenged with OVA only, we investigated the effect of IC87114 on pathogenesis of asthma. Our data show that the increased numbers of inflammatory cells, increased airway hyperresponsiveness, levels and mRNA expression of IL-4, IL-5, IL-8, IL-13 and IL-17 in the bal fluid after LPS plus OVA inhalation were significantly reduced by administration of IC87114 in a time dependent manner. The LPS plus OVA mice showed that the expressions of ER stress markers in lungs were significantly increased compared with the control. IC87114 significantly reduced the increases in ER stress through IRE1 dependent specific pathway. Thus, inhibiting mRNA of spliced XBP1. Moreover, LPS plus OVA induced increases of NF-B were lowered by IC87114 treatment. The degradation of IB was also significantly decreased by IC87114 in LPS plus OVA treated mice. These results suggest that inhibition of PI3K relief asthma by decreasing UPR through IRE1/XBP1 specific pathway through modulation of NF-B/IB signaling pathway. Part III: Soybean greatly reduces valproic acid plasma concentrations: A food–drug interaction study The aim of this study was to investigate the effects of soy on the pharmacokinetics and pharmacodynamics of valproic acid (VPA). In a preclinical study, rats were pretreated with two different amounts of soy extract for five days (150 mg/kg and 500 mg/kg), which resulted in decreases of 57% and 65% in the Cmax of VPA, respectively, while the tmax and MRT of VPA were not different between groups. In addition, the AUC of valproic acid decreased to 83% in the soy pretreatment groups. Interestingly, the excretion rate of VPA glucuronide (VPAG) was higher in the soy-fed groups. Levels of UDP-glucuronosyltransferase (UGT) UGT1A3, UGT1A6, UGT2B7 and UGT2B15 were elevated in the soy-treated group, and GABA concentrations were elevated in the brain after VPA administration; however, this was less pronounced in the group that was pretreated with soy extract than for the untreated group. This is the first study to report the effects of soy pretreatment on the pharmacokinetics and pharmacodynamics of VPA in rodents.
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