Effect of salicylic acid and diclofenac on the medium‐chain and long‐chain acyl‐CoA formation in the liver and brain of mouse

Medium‐chain and long‐chain acyl‐CoA esters are key metabolites in fatty acid metabolism. Effects of salicylic acid on the in vivo formation of acyl‐CoAs in mouse liver and brain were investigated. Further, inhibition of the medium‐chain and long‐chain acyl‐CoA synthetases by salicylic acid and diclofenac was determined in mouse liver and brain mitochondria. Acyl‐CoA esters were analyzed by liquid chromatography–tandem mass spectrometry. The amounts of medium‐chain acyl‐CoAs (C₆, C₈ and C₁₀) were less than long‐chain acyl‐CoAs (C_16:0, C_18:0, C_18:1 and C_20:4) in both liver and brain. The administration of salicylic acid decreased the levels of both the medium‐chain (C₆, C₈ and C₁₀) and long‐chain acyl‐CoAs (C_16:0, C_18:0, C_18:1 and C_20:4) in liver. In brain, however, only long‐chain acyl‐CoAs were decreased. The level of salicylyl‐CoA detected in brain was about 12% of that in liver. Salicylic acid had a strong inhibitory activity (IC₅₀ = 0.1 mm ) for the liver mitochondrial formation of hexanoyl‐CoA from hexanoic acid, whereas diclofenac was weak (IC₅₀ = 4.4 mm ). In contrast, diclofenac (IC₅₀ = 1.4 mm ) inhibited the liver mitochondrial long‐chain acyl‐CoA synthetases more potently than salicylic acid (IC₅₀ = 25.5 mm ). Similar inhibitory activities for the acyl‐CoA synthetases were obtained in the case of the brain and liver mitochondria, except for the weak inhibition of brain medium‐chain acyl‐CoA synthetases by salicylic acid (IC₅₀ = 1.8 mm ). These findings suggest that salicylic acid and diclofenac exhibit different mechanisms of inhibition of fatty acid metabolism depending on the length of the acyl chain and tissues, and they may contribute to the further understanding of the toxic effects associated with these drugs. Copyright © 2009 John Wiley & Sons, Ltd.     

利洛司酮对子宫内膜异位症大鼠血清黄体生成素和雌二醇水平的影响

目的 :观察利洛司酮对子宫内膜异位症大鼠血清黄体生成素 (LH)和雌二醇 (E2 )水平的影响。方法 :2 0只子宫内膜异位症大鼠 ,随机分成 4组 ,灌胃给予利洛司酮 2 0 ,80mg·kg- 1,米非司酮 5 0mg·kg- 1和精制花生油 4mL·kg- 1,每日 1次 ,共 2 1d。采集用药d 19,2 0 ,2 1及停药 2 4h的血样本 ,用大鼠睾丸间质细胞睾酮法 (RICT法 )及放射免疫分析(RIA)法分别测定血清LH和E2 的水平。结果 :对照组大鼠给药d 19,2 0 ,2 1及停药 2 4h ,这 4d的血清LH和E2 水平均有周期性变化 ,出现一个动情前期的LH峰和E2 峰 ;利洛司酮 2 0 ,80mg·kg- 1及米非司酮 5 0mg·kg- 1组大鼠血清LH和E2 水平未见周期性变化 ,也未见动情前期的LH峰和E2 峰。结论 :和米非司酮一样 ,利洛司酮可抑制LH和E2 的分泌 ,取消动情前期的LH峰和E2 峰     

Tissue specific basal expression of soluble murine epoxide hydrolase and effects of clofibrate on the mRNA levels in extrahepatic tissues and liver

 The soluble epoxide hydrolase mRNA level in liver was increased eight-fold upon administration of the hypolipidemic drug and peroxisome proliferator clofibrate for 7 days to mice. The soluble epoxide hydrolase mRNA was back at control levels within 1–2 days after clofibrate withdrawal. The highest expression was in liver, intestine and kidney. Lower levels were found in heart and muscle and very low levels were found in testes, lung, brain and spleen. The mRNA levels were increased in liver, kidney and heart by clofibrate. Received: 17 January 1995/Accepted: 12 June 1995     

西红花酸对大鼠酒精性脂肪肝的改善作用及机制探讨

目的:研究西红花酸对大鼠酒精性脂肪肝的改善作用,探讨其可能的作用机制.方法:SD大鼠ig酒精10周,建立大鼠酒精性脂肪肝模型,同时给予西红花酸(50 mg·kg-1,ig,qd)进行预防治疗,测定血清丙氨酸氨基转移酶(ALT),血清和肝脏三酰甘油(TG)水平,肝脏中游离脂肪酸(FFA)含量,极低密度脂蛋白(VLDL)分泌速率,线粒体和过氧化物酶体脂肪酸β-氧化速度,苯胺羟化酶(ANH),乙醇脱氢酶(ADH),乙醛脱氢酶(ALDH)活性等生化指标并进行病理组织学观察.结果:西红花酸能够降低血清ALT和TG水平,升高脂肪酸线粒体Bβ-氧化能力,降低肝脏TG和FFA水平,此外西红花酸还可使微粒体ANH活性降低,使胞浆中AI)H和ALDH活性升高,但对VLDL分泌速率和过氧化物酶体β-氧化没有影响.结论:西红花酸对酒精性脂肪肝的作用机制与加速肝脏线粒体脂肪酸氧化,减轻肝脏脂肪堆积,加速乙醇和乙醛的清除,调控酒精代谢过程,提高机体抗氧化能力有关.     

小檗碱对非酒精性脂肪肝大鼠肝脏脂肪沉积的改善作用及相关机制研究

目的探究小檗碱对非酒精性脂肪肝(NAFLD)大鼠肝脏脂肪沉积的改善作用及相关机制。方法采用高脂饮食喂养8周的方法建立NAFLD大鼠模型。将成功建立的NAFLD大鼠随机分为模型组(n=18)、阳性对照组(n=18)及实验组(n=18)。另选择18只未加任何干预的正常大鼠作为对照组。阳性对照组大鼠灌胃10 mg·kg-1·d-1罗格列酮,实验组灌胃162 mg·kg-1·d-1小檗碱,对照组与模型组灌胃等量生理盐水,连续干预4周。采用全自动生化分析仪检测大鼠血清丙氨酸氨基转移酶(ALT)、天冬氨酸氨基转移酶(AST)、总胆固醇(TC)、甘油三酯(TG)及血清游离脂肪酸(FFA)含量;采用苏木精-伊红(HE)染色和油红O染色观察大鼠肝脏病理学变化和脂肪沉积情况;采用蛋白质印迹法检测各组大鼠肝组织肝X受体α(LXRα)、脂肪酸合成酶(FAS)蛋白表达。结果对照组、模型组、阳性对照组及实验组大鼠血清ALT水平分别为(45.68±5.64),(71.61±5.25),(54.78±3.82),(63.37±5.16)U·L-1;AST水平分别为(216.24±55.28),(336.56±73.12),(252.42±33.56),(286.48±48.59)U·L-1;TC水平分别为(1.32±0.31),(4.05±1.12),(1.81±0.67),(2.63±0.94)mmol·L-1;TG水平分别为(0.28±0.14),(0.81±0.18),(0.47±0.15),(0.63±0.17)mmol·L-1;FFA水平分别为(227.45±48.16),(446.56±53.72),(271.37±28.87),(319.36±55.64)μmoL·L-1;大鼠肝组织中LXRα蛋白相对表达量分别为0.32±0.11,1.21±0.13,0.41±0.09,0.96±0.04;FAS蛋白相对表达量分别为0.28±0.09,1.28±0.11,0.45±0.08,0.93±0.07,差异均有统计学意义(均P<0.05)。结论小檗碱可改善NAFLD大鼠脂质代谢和肝功能,减轻肝脏组织病变程度,减少脂肪沉积,抑制LXRα/FAS信号通路可能是其作用机制之一。     

The effect of long-term concurrent administration of chlorpromazine and lithium on the striatal and frontal cortical dopamine metabolism in rats

The effects of lithium and chlorpromazine chronically administered alone and together on the dopamine metabolism in the rat striatum and frontal cortex were investigated by measurement of the levels of dopamine (DA) and its main metabolite, homovanillic acid (HVA). Long-term chlorpromazine administration caused a significant increase in the striatal DA level and a decrease in that of HVA and HVA/DA ratio without any changes in those of the frontal cortex. The prolonged administration of lithium elevated the striatal levels of both HVA and DA, but no change in the frontal cortex was observed. The concurrent administration of chlorpromazine and lithium caused a significant increase in the frontal cortical DA level and a decrease in that of HVA and HVA/DA ratio. The striatal DA and HVA levels increased under the effect of the combined treatment, while the HVA/DA ratio remained unchanged.     

头顶一颗珠水提取物对非酒精性脂肪肝大鼠肝脏结构及功能的影响

目的：探讨头顶一颗珠对非酒精性脂肪肝（NAFLD）大鼠肝脏结构及功能的影响,阐明头顶一颗珠干预NAFLD的作用机制。方法：采用复合高脂饮食结合四氯化碳溶液腹腔注射建立NAFLD大鼠模型,模型复制成功后动物随机分为正常组、模型组、头顶一颗珠水提取物高、中、低剂量组、多烯磷脂酰胆碱组,连续灌胃给药4周,实验前及实验过程中每周称取大鼠体质量1次,实验结束称取肝湿重,计算肝指数,并观察动物肝脏的质地弹性及颜色、形态等,全自动生化分析仪测定肝酶谱,HE染色行大鼠肝脏病理组织学观察,免疫组化（SP）法检测GRP94蛋白表达,RT-PCR（逆转录聚合酶链反应）法检测GRP94 mRNA基因表达。结果：与正常组比较,模型组大鼠肝脏形态,光镜下结构,体质量、肝湿重和肝指数,肝酶谱,内质网应激等相关指标有显著异常的变化;与模型组比较,头顶一颗珠水提取物各剂量组大鼠肝脏肉眼形态,肝脏病理组织学不同程度改善,ALT、AST、ALP等肝酶谱指标及肝组织GRP94蛋白及基因表达不同程度下降,差异均有统计学意义（P<0.05或P<0.01）;结论：头顶一颗珠水提取物治疗NAFLD疗效明显,可有效逆转肝损伤,从多个层次防治NAFLD。     

Binding of cadmium and mercury by metallothionein in the kidneys and liver of rats following repeated administration

Rats were injected subcutaneously with either cadmium chloride (0.5 mg Cd/kg) or mercuric chloride (0.5 and 0.25 mg Hg/kg) every other day over a period of 6 to 7 weeks. Levels of metals and metallothionein were determined in liver and kidneys. Both cadmium and metallothionein accumulated in these organs during the period of exposure. Mercury and metallothionein accumulated only in the kidneys. Mercury did not accumulate in the liver, nor did it cause an increase of metallothionein in the liver. The molar ratio of 1.6 (metal to metallothionein) in liver was constant for cadmium. In the kidneys this ratio varied from 1 to 3 for both metals, depending on the level of the metal; This ratio was 0.1 for liver mercury.This work was partly supported by the Polish-American agreement No. 05-009-2 with National Institute for Occupational Safety and Health, PHS, USA.     

Effect of somatostatin analogs on gastric acid secretion in dogs and rats

The effects of several superactive analogs of somatostatin on gastric acid response to various exogenous and endogenous stimulants were investigated in conscious dogs and rats with gastric fistulae (GF). The inhibition was compared to that induced by somatostatin-14 (S-S-14) at two dose levels. Several octapeptide analogs of somatostatin including (RC-160) and (RC-121), which were superactive in tests on suppression of GH levels, were 4-5 times more potent than S-S-14 in inhibiting desglugastrin-stimulated gastric acid secretion in GF dogs. The analog RC-160 also reduced the rise in serum gastrin levels and gastric acid secretion induced by sham feeding (SF) in dogs with gastric and esophageal fistulae (EF), but did not decrease food consumption. Gastric acid secretion induced by histamine (80μg/kg/h) in dogs was not affected by 1-5μg/kg/h of analog RC-121 or by 5μg/kg/h of S-S-14. Analogs RC-160, RC-121, and RC-98-I and others also powerfully inhibited desglugastrin-induced gastric acid secretion in GF rats. Hexapeptide cyclo(-Pro-Phe-D-Trp-Lys-Thr-Phe) was only about half as potent as S-S-14 in dogs but its activity was higher in rats. The results indicate that octapeptide analogs which are superactive in GH-inhibition tests are also more potent than S-S-14 in suppressing gastric acid secretion. These findings may be of clinical value.     

Effect of lipopolysaccharide on alteration of phospholipids and their fatty acid composition in spleen and thymus by in vitro metabolic labeling

Lipopolysaccharide (LPS) is an endotoxin, a potent stimulator of immune response and induction of LPS leads to acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). ARDS is a life‐threatening disease worldwide with a high mortality rate. The immunological effect of LPS with spleen and thymus is well documented; however the impact on membrane phospholipid during endotoxemia has not yet been studied. Hence we aimed to investigate the influence of LPS on spleen and thymus phospholipid and fatty acid composition by [³²P]orthophosphate labeling in rats. The in vitro labeling was carried out with phosphate‐free medium (saline). Time course, LPS concentration‐dependent, pre‐ and post‐labeling with LPS and fatty acid analysis of phospholipid were performed. Labeling studies showed that 50 µg LPS specifically altered the major phospholipids, phosphatidylcholine and phosphatidylglycerol in spleen and phosphatidylcholine in thymus. Fatty acid analysis showed a marked alteration of unsaturated fatty acids/saturated fatty acids in spleen and thymus leading to immune impairment via the fatty acid remodeling pathway. Our present in vitro lipid metabolic labeling study could open up new vistas for exploring LPS‐induced immune impairment in spleen and thymus, as well as the underlying mechanism. Copyright © 2011 John Wiley & Sons, Ltd.     

N3系脂肪酸干预对炎症性肠病病人复发风险的影响

目的 探讨N3系脂肪酸干预对炎症性肠病病人复发风险的影响。方法 前瞻性选取2018年1月至2020年5月于沧州市人民医院就诊的炎性肠病病人216例,均接受规范化治疗,按照随机数字表法分为对照组108例,予以常规饮食干预;干预组108例,在对照组基础上予以N3系脂肪酸干预;随访观察12个月,记录两组复发情况,根据病人复发情况分为复发组和非复发组,利用Cox回归分析明确N3系脂肪酸干预对炎性肠病病人复发风险的影响。结果 随访12个月,无1例失访,共75例病人出现复发,复发率34.72%;其中干预组30例复发,复发率（27.78%）较对照组45例复发,复发率（41.67%）低（log-rankχ2=6.91,P=0.009）;复发组和未复发组C-反应蛋白（CRP）、红细胞沉降率（ESR）、肿瘤坏死因子-α(TNF-α)、氧化三甲胺（TMAO）、粪便钙卫蛋白、吸烟比例比较,差异有统计学意义（P<0.05）;Cox回归分析显示：ESR[HR=1.03,95%CI:(1.01,1.05)]、TNF-α[HR=1.05,95%CI:(1.03,1.07)]、粪便钙卫蛋白[HR=1.03,95%...     

荔枝核提取物抑制大鼠乳腺增生及调节激素水平研究

目的：探讨荔枝核提取物对大鼠乳腺增生病以及激素作用及其作用机制。方法：取健康、未孕雌性SD大鼠60只,按体重随机分为正常对照组,模型对照组,荔枝核提取物高、中、低剂量组（44、22、11g／kg）,乳结平组（3．3g／kg）,每组10只。实验结束时,观察各组大鼠乳头高度,光镜检查乳腺组织病理变化,用放射免疫法（RIA）分析测量血清雌二醇（E2）、孕酮（P）、泌乳素（PRL）的水平。结果：模型对照组大鼠乳头红肿或增生明显,导管上皮细胞层数、腺泡数明显增加,血清激素B和PRL水平明显升高,而P水平明显降低,与正常对照组比较,差异有统计学意义（P〈0．01）。乳结平组和荔枝核提取物高、中剂量组均能逆转病鼠乳头直径、高度、导管上皮细胞层数和腺泡数（P〈0．01）,并降低B和PRL水平（P〈0．01）,而提高P含量（P〈0．05或0．01）;荔枝核提取物低剂量组也能不同程度地逆转大鼠乳头红肿或乳腺组织增生（P〈0．01）,提高P含量（P〈0．05）,但B和PRL水平则未见统计学明显差异（P〉0．05）。结论：荔枝核提取物可调节乳腺增生大鼠的激素水平,改善增生乳腺的病理形态变化。推测荔枝核的部分作用机制,可能是调整下丘脑-垂体-卵巢性腺轴功能紊乱,从而有效地对抗雌激素性大鼠乳腺增生病。     

Effect of toluene and xylenes on liver glutathione and their urinary excretion as mercapturic acids in the rat

Administration of toluene and xylenes to rats caused a decrease in liver glutathione concentration. The effect was most pronounced after the administration of o-xylene. 26% of the initial glutathione level was found three hours after treatment with o-xylene (4.0 mmoles/kg).No in vitro conjugation of o-xylene with glutathione was observed, neither spontaneously nor in the presence of 105,000 g supernatant from rat liver homogenate, containing glutathione S-transferases. Thus, a metabolite of o-xylene, which is not formed during incubation with 105,000 g supernatant, reacts with glutathione.A thioether was isolated from urine of rats given o-xylene; the compound was identified as o-methylbenzyl mercapturic acid by GC-MS and NMR. Chromatographic evidence was found for the presence of benzyl mercapturic acid in the urine of toluene-treated rats. The amounts of mercapturic acids excreted in the urine after administration of toluene, p-xylene, m-xylene, and o-xylene were 0.4–0.7, 0.6, 1.3, and 10–21% of the dose, respectively.These results demonstrate the involvement of a thusfar unknown pathway in the biotransformation of toluene and xylenes.     

加味二至胶囊对大鼠复合型脂肪肝的调脂保肝作用

目的：研究加味二至胶囊对大鼠复合型脂肪肝的调脂保肝作用。方法：采用高脂饲料、酒精及四氯化碳复制大鼠复合型脂肪肝模型,实验分为空白对照组、模型组、加味二至胶囊高剂量组（MEP1）、加味二至胶囊中剂量组（MEP2）、加味二至胶囊低剂量组（MEP3）及东宝肝泰组（DB）,然后测定各组肝脏指数,血清脂质TC、TG、HDL及LDL含量,测定血清ALT及AST含量,肝匀浆中游离脂肪酸、SOD及MDA含量。结果：模型组大鼠肝脏指数,血清脂质TC、TG、LDL,血清转氨酶ALT、AST含量较空白对照组明显升高,HDL较空白对照组显著降低;与空白对照组相比模型组大鼠SOD活性显著降低,MDA含量显著升高。与模型组相比各治疗组肝脏指数,血清脂质TC、TG、LDL,血清转氨酶ALT、AST含量均显著降低,HDL含量显著升高。与模型组相比,各治疗组SOD活性显著提高,MDA含量明显降低。结论：加味二至胶囊具有较好的降脂保肝作用,其作用机制可能与提高抗氧化能力有关。     

荔枝核皂苷对高脂血症-脂肪肝大鼠的降血糖调血脂作用

目的 :研究荔枝核皂苷和罗格列酮对高脂血症 脂肪肝大鼠血糖血脂的影响。方法 :采用高脂血症 脂肪肝大鼠模型 ,观察荔枝核皂苷和罗格列酮、格列齐特对病鼠空腹血糖 (FBG)、口服葡萄糖耐量试验 (OGTT)后 2h血糖 (2hBG)以及给药后 2h空腹血清血糖 (FSG)、总胆固醇 (TC)、三酰甘油 (TG)、高密度脂蛋白 胆固醇 (HDL C)、低密度脂蛋白 胆固醇 (LDL C)、血清尿素氮 (BUN)、肌酐 (Cr)、丙氨酸氨基转移酶 (ALT)、天冬氨酸氨基转移酶 (AST)及镜检肝组织病理学等指标的影响。结果 :荔枝核皂苷和罗格列酮能显著改善高脂血症 脂肪肝致胰岛素抵抗 (IR)模型大鼠的IGT ,降低OGTT后 2hBG和FSG(P <0 .0 5 ) ;并能显著降低病鼠TC、TG、LDL C含量(P <0 .0 5～ 0 .0 1) ,显著提高HDL C含量 (P <0 .0 5 ) ;降低病鼠ALT、AST活性和BUN、Cr含量 (P<0 .0 5 ) ,改善肝细胞脂肪变性 (P <0 .0 1)。结论 :荔枝核皂苷和罗格列酮能提高胰岛素的敏感性 ,调整高脂血症 脂肪肝所致的糖脂代谢障碍 ,并具有改善病鼠肝肾功能的作用。     

Levels of plasma-free fatty acids and liver triglycerides in rats treated with adrenaline or theophylline: effects exerted by administration of uridine diphosphate glucose

Adrenaline or theophylline administration to rats causes increased levels of plasma-free fatty acids and liver triglycerides; however, plasma FFA and liver triglyceride values are reduced in animals treated either with adrenaline or theophylline if they receive UDPG pretreatment. The protective effect exerted by UDPG in animals receiving the combined treatment is attributable to a decrease of cAMP-dependent lipolytic activity. Furthermore, the antilipemic lowering lipid effect exhibited by UDPG is linked to the intact nucleotide molecule, because compounds structurally associated to UDPG, like uridine, UMP, UDP or glucose- 1-phosphate, are incapable of affecting the increased lipolytic activity observed in adrenaline injected rats.     

Synergistic effect of quercetin and quinic acid by alleviating structural degeneration in the liver,kidney and pancreas tissues of STZ-induced diabetic rats: A mechanistic study

The aim of this study was to investigate the synergistic effects of quercetin (QE) and quinic acid (QA) on a STZ-induced diabetic rat model to determine their potential role in alleviating diabetes and its associated complications. In our study design, diabetic rats were treated with single and combined doses of QE and QA for 45 days to analyse their effects on liver, kidney and pancreas tissues. The study result showed that QE and QA treated groups down-regulated hyperglycaemia and oxidative stress by up-regulating insulin and C-peptide levels. Moreover, histological observations of the liver, kidney and pancreas of diabetic rats treated with single and combined doses of QE and QA showed a significant improvement in the structural degeneration. Interestingly, the combination dose of QE and QA (50 mg/kg) exhibited maximum inhibition of the pro-apoptotic protein Bax expression and demonstrate enhancement of the anti-apoptotic protein Bcl-2 expression in the kidney tissues, suggesting a protective role in the kidneys of diabetic rats. Taken together, these results indicates the synergistic effects of QE and QA in ameliorating hyperglycaemia, hyperlipidemia and insulin resistance in diabetic rats and therefore, open a new window of research on the combinatorial therapy of flavonoids.     

Hepatoprotective role of bis-demethoxy curcumin analog on the expression of matrix metalloproteinase induced by alcohol and polyunsaturated fatty acid in rats

Liver fibrosis is one of the major health problems worldwide. Chronic alcohol abuse is one of the main causes of fibrosis. Ingestion of polyunsaturated fatty acids (PUFA) along with alcohol further aggravates the toxicity of alcohol. Fibrosis results due to increased deposition of extra cellular matrix (ECM). The degree of abnormal ECM degradation depends on the ratio of active matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). The present work studied the influence of bis-desmethoxy curcumin analog (BDMC-A) on the expression of MMPs and TIMPs during alcohol and ΔPUFA induced liver toxicity. Male albino Wistar rats were used for the study. The MMP expression was found to be increased in alcohol as well as ΔPUFA treated rats and decreased in alcohol + ΔPUFA treated rats. The levels of TIMPs and the collagen were increased in alcohol, ΔPUFA, and alcohol + ΔPUFA groups. Administration of BDMC-A significantly decreased the levels of collagen and TIMPs; and positively modulated the expression of MMPs. From this study, it is concluded that BDMC-A influences MMPs, TIMPs expression, and acts as an efficient anti-fibrotic agent.     

Effect of ursodeoxycholic acid on the pharmacokinetics of midazolam and CYP3A in the liver and intestine of rats

1. The elimination half-life of midazolam administered intravenously (5 mg kg^?1) or orally (15 mg kg^?1) was significantly decreased by 70% and 73%, respectively, 24 h after a single oral administration of ursodeoxycholic acid (UDCA, 300 mg kg^?1) in rats. In the liver there was a significant enhancement of the hydroxylation of midazolam in the microsomes and expression of cytochrome P450 (CYP) 3A1 messenger RNA (mRNA) and CYP3A2 mRNA.

2. The C_max and area under the curve (AUC)_0–∞ of midazolam were significantly (1.8–2.3 fold) increased by the single oral treatment with UDCA (100 and 300 mg kg^?1). Thus, the oral bioavailability, estimated from the AUC_0–∞, of midazolam administered intravenously and orally was significantly (1.8- and 2.3-fold, respectively) increased by the treatment with UDCA.

3. Repeated administration of UDCA (300 mg kg^?1 day^?1) for 7 days did not alter the pharmacokinetics of midazolam administered intravenously or orally, and the expression of mRNA for CYP3As in the rat liver.

4. The study has shown that a single administration of UDCA in rats induces significant hepatic CYP3A activity and increases significantly the oral bioavailability of midazolam. Such effects on the pharmacokinetics of midazolam were little observed on the repeated administration of UDCA.

     

Modulatory effects of fisetin, a bioflavonoid, on hyperglycemia by attenuating the key enzymes of carbohydrate metabolism in hepatic and renal tissues in streptozotocin-induced diabetic rats

Fisetin (3, 7, 3′, 4′-tetrahydroxyflavone) is a bioflavonoid found in fruits and vegetables. It exhibits a wide variety of pharmacological properties, including antioxidant, antiinflammatory and anticarcinogenic effects. Recently we have reported the hypoglycemic actions of fisetin. Oral administration of fisetin (10 mg/kg body weight) to diabetic rats for 30 days established a significant (P < 0.05) decline in blood glucose and glycosylated hemoglobin levels and a significant (P < 0.05) increase in plasma insulin level. In the present study the activities of key enzymes of carbohydrate metabolism were assayed to establish the modulatory actions of fisetin in maintaining the glucose homeostasis. The altered activities of key enzymes of carbohydrate metabolism such as hexokinase, pyruvate kinase, lactate dehydrogenase, glucose-6-phosphatase, fructose-1,6-bisphosphatase, glucose-6-phosphate dehydrogenase, glycogen synthase and glycogen phosphorylase in liver and kidney tissues of diabetic rats were significantly (P < 0.05) reverted to near normalcy by the administration of fisetin. Thus, fisetin regulates carbohydrate metabolism by modulating the key regulatory enzymes in the hepatic and renal tissues of diabetic rats.