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1.
Hepatic 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) and cholesterol 7α-hydroxylase (Cyp7a1) are rate-limiting enzymes for cholesterol biosynthesis and catabolism, respectively. Involvement of inflammatory cytokines, particularly interleukin-1 (IL-1), in alterations of HMGR and Cyp7a1 gene expression during development of lead nitrate (LN)-induced hypercholesterolemia was examined in IL-1α/β-knockout (IL-1-KO) and wild-type (WT) mice. Lead nitrate treatment of WT mice led to not only a marked downregulation of the Cyp7a1 gene at 6-12 h, but also a significant upregulation of the HMGR gene at 12 h. However, such changes were not observed at significant levels in IL-1-KO mice, although a slight, transient downregulation of the Cyp7a1 gene and a minimal upregulation of the HMGR gene occurred at 6 h and 24 h, respectively. Consequently, LN treatment led to development of hypercholesterolemia at 24 h in WT mice, but not in IL-1-KO mice. Furthermore, in WT mice, significant LN-mediated increases were observed at 3-6 h in hepatic IL-1 levels, which can modulate gene expression of Cyp7a1 and HMGR. These findings indicate that, in mice, LN-mediated increases in hepatic IL-1 levels contribute, at least in part, to altered expressions of Cyp7a1 and HMGR genes, and eventually to hypercholesterolemia development.  相似文献   

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Exposure to aristolochic acid I (AAI) is associated with aristolochic acid nephropathy, Balkan endemic nephropathy, and urothelial cancer. Individual differences in xenobiotic-metabolizing enzyme activities are likely to be a reason for interindividual susceptibility to AA-induced disease. We evaluated the reductive activation and oxidative detoxication of AAI by cytochrome P450 (P450) 1A1 and 1A2 using the Cyp1a1(-/-) and Cyp1a2(-/-) single-knockout and Cyp1a1/1a2(-/-) double-knockout mouse lines. Incubations with hepatic microsomes were also carried out in vitro. P450 1A1 and 1A2 were found to (i) activate AAI to form DNA adducts and (ii) detoxicate it to 8-hydroxyaristolochic acid I (AAIa). AAI-DNA adduct formation was significantly higher in all tissues of Cyp1a1/1a2(-/-) than Cyp1a(+/+) wild-type (WT) mice. AAI-DNA adduct levels were elevated only in selected tissues from Cyp1a1(-/-) versus Cyp1a2(-/-) mice, compared with those in WT mice. In hepatic microsomes, those from WT as well as Cyp1a1(-/-) and Cyp1a2(-/-) mice were able to detoxicate AAI to AAIa, whereas Cyp1a1/1a2(-/-) microsomes were less effective in catalyzing this reaction, confirming that both mouse P450 1A1 and 1A2 are both involved in AAI detoxication. Under hypoxic conditions, mouse P450 1A1 and 1A2 were capable of reducing AAI to form DNA adducts in hepatic microsomes; the major roles of P450 1A1 and 1A2 in AAI-DNA adduct formation were further confirmed using selective inhibitors. Our results suggest that, in addition to P450 1A1 and 1A2 expression levels in liver, in vivo oxygen concentration in specific tissues might affect the balance between AAI nitroreduction and demethylation, which in turn would influence tissue-specific toxicity or carcinogenicity.  相似文献   

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The xenobiotic receptors, constitutive androstane receptor (CAR), and pregnane X receptor (PXR) regulate and alter the metabolism of xenobiotic substrates. Among the 19 functional UDP-glucuronosyltransferases (UGTs) in humans, UGT2B7 is involved in the metabolism of many structurally diverse xenobiotics and plays an important role in the clearance and detoxification of many therapeutic drugs. To examine whether this gene is regulated by CAR and PXR in vivo, transgenic mice expressing the entire UGT2B7 gene (TgUGT2B7) were created. Gene expression profiles revealed that UGT2B7 is differentially expressed in liver, kidney, adipocytes, brain, and estrogen-sensitive tissues, such as ovary and uterus. Liver UGT2B7 expression levels were decreased when TgUGT2B7 mice were treated with the CAR ligand 1,4-b-s-[2-(3,5,-dichloropyridyloxy)] (TCPOBOP) but not the PXR ligand pregnenolone 16α-carbonitrile. Although TCPOBOP decreased the levels of UGT2B7 mRNA in TgUGT2B7 mice, it had no affect on Tg(UGT2B7)Car(-/-) mice, adding support for a CAR-dependent mechanism contributing toward UGT2B7 gene suppression. Expression of promoter constructs in HepG2 cells showed the CAR-dependent inhibition was linked to hepatocyte nuclear factor-4α (HNF4α)-mediated transactivation of the UGT2B7 promoter. The inhibitory effect of CAR on UGT2B7 gene expression was validated in chromatin immunoprecipitation assays in which TCPOBOP treatment blocked HNF4α binding to the UGT2B7 promoter. These results suggest that HNF4α plays an important role in the constitutive expression of hepatic UGT2B7, and CAR acts as a negative regulator by interfering with HNF4α binding activity.  相似文献   

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Retinoid X receptor-α (RXRα) is an obligate partner for several nuclear hormone receptors that regulate important physiological processes in the liver. In this study the impact of hepatocyte RXRα deficiency on methionine and choline deficient (MCD) diet-induced steatosis, oxidative stress, inflammation, and hepatic transporters gene expression were examined. The mRNA of sterol regulatory element-binding protein (SREBP)-regulated genes, important for lipid synthesis, were not altered in wild type (WT) mice, but were increased 2.0- to 5.4-fold in hepatocyte RXRα-null (H-RXRα-null) mice fed a MCD diet for 14 days. Furthermore, hepatic mRNAs and proteins essential for fatty acid β-oxidation were not altered in WT mice, but were decreased in the MCD diet-fed H-RXRα-null mice, resulting in increased hepatic free fatty acid levels. Cyp2e1 enzyme activity and lipid peroxide levels were induced only in MCD-fed WT mice. In contrast, hepatic mRNA levels of pro-inflammatory factors were increased only in H-RXRα-null mice fed the MCD diet. Hepatic uptake transporters Oatp1a1 and Oatp1b2 mRNA levels were decreased in WT mice fed the MCD diet, whereas the efflux transporter Mrp4 was increased. However, in the H-RXRα-null mice, the MCD diet only moderately decreased Oatp1a1 and induced both Oatp1a4 and Mrp4 gene expression. Whereas the MCD diet increased serum bile acid levels and alkaline phosphatase activity in both WT and H-RXRα-null mice, serum ALT levels were induced (2.9-fold) only in the H-RXRα-null mice. In conclusion, these data suggest a critical role for RXRα in hepatic fatty acid homeostasis and protection against MCD-induced hepatocyte injury.  相似文献   

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《药学学报(英文版)》2021,11(12):3847-3856
Bile acids (BAs) are amphipathic molecules important for metabolism of cholesterol, absorption of lipids and lipid soluble vitamins, bile flow, and regulation of gut microbiome. There are over 30 different BA species known to exist in humans and mice, which are endogenous modulators of at least 6 different membrane or nuclear receptors. This diversity of ligands and receptors play important roles in health and disease; however, the full functions of each individual BA in vivo remain unclear. We generated a mouse model lacking the initiating enzymes, CYP7A1 and CYP27A1, in the two main pathways of BA synthesis. Because females are more susceptible to BA related diseases, such as intrahepatic cholestasis of pregnancy, we expanded this model into female mice. The null mice of Cyp7a1 and Cyp27a1 were crossbred to create double knockout (DKO) mice. BA concentrations in female DKO mice had reductions in serum (63%), liver (83%), gallbladder (94%), and small intestine (85%), as compared to WT mice. Despite low BA levels, DKO mice had a similar expression pattern to that of WT mice for genes involved in BA regulation, synthesis, conjugation, and transport. Additionally, through treatment with a synthetic FXR agonist, GW4064, female DKO mice responded to FXR activation similarly to WT mice.  相似文献   

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Upon inhalation, multi-walled carbon nanotubes (MWCNTs) may reach the subpleura and pleural spaces, and induce pleural inflammation and/or mesothelioma in humans. However, the mechanisms of MWCNT-induced pathology after direct intrapleural injections are still only partly elucidated. In particular, a role of the proinflammatory interleukin-1 (IL-1) cytokines in pleural inflammation has so far not been published. We examined the MWCNT-induced pleural inflammation, gene expression abnormalities, and the modifying role of IL-1α and β cytokines following intrapleural injection of two types of MWCNTs (CNT-1 and CNT-2) compared with crocidolite asbestos in IL-1 wild-type (WT) and IL-1α/β KO (IL1-KO) mice. Histopathological examination of the pleura 28?days post-exposure revealed mesothelial cell hyperplasia, leukocyte infiltration, and fibrosis occurring in the CNT-1 (Mitsui-7)-exposed group. The pleura of these mice also showed the greatest changes in mRNA and miRNA expression levels, closely followed by CNT-2. In addition, the CNT-1-exposed group also presented the greatest infiltrations of leukocytes and proliferation of fibrous tissue. WT mice were more prone to development of sustained inflammation and fibrosis than IL1-KO mice. Prominent differences in genetic and epigenetic changes were also observed between the two genotypes. In conclusion, the fibrotic response to MWCNTs in the pleura depends on the particles’ physico-chemical properties and on the presence or absence of the IL-1 genes. Furthermore, we found that CNT-1 was the most potent inducer of inflammatory responses, followed by CNT-2 and crocidolite asbestos.  相似文献   

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IL-1 and TNF-α are thought to be important bone-remodeling regulators. However, mice lacking either them or their receptors reportedly grow healthily. Here, we examined the roles of IL-1 and TNF-α in bone. Although a significant IL-1 level was detected in the tibia of non-stimulated wild-type (WT) mice, no significant physicochemical, morphological, or histological defects were detected in the tibias in mice lacking IL-1 (both α and β types) (IL-1KO) or lacking both IL-1 and TNF-α (IL-1/TNF-αKO). Injection of sub-lethal doses of lipopolysaccharide (LPS) into WT mice induced a transient hypocalcemia, increased IL-1 (in the plasma and markedly in the tibia), and increased TNF-α (markedly in the plasma, but only slightly in the tibia). LPS-induced hypocalcemia was modest in IL-1KO mice, and not detected in IL-1/TNFαKO mice. IL-1α (but not TNFα) induced hypocalcemia in both WT and IL-1KO mice. In both WT and IL-1KO mice treated with clodronate (osteoclast inhibitor), the LPS-induced hypocalcemia was markedly augmented. Nifedipine (inhibitor of both voltage-activated and capacitative Ca2 +-entry) reduced the LPS-induced hypocalcemia. These results suggest that in mice: (i) IL-1 and TNF-α may contribute little to physiological bone-formation, and (ii) a time-lag between IL-1- and TNF-α-stimulated Ca2 +-entry into cells throughout the body from the circulation and IL-1-stimulated Ca2 +-release from the bone may cause the observed transient LPS-induced hypocalcemia. Thus, the prime role of bone IL-1 may reside in the supply of Ca2 + from the bone to cells throughout the body when the need is urgent.  相似文献   

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目的探讨靶向小鼠髓样细胞触发受体1(triggering receptor expressed on myeloid cells-1,TREM-1)的小分子干扰RNA(small inter-feting RNA,siRNA)在体外对内毒素刺激小鼠巨噬细胞株RAW264.7分泌肿瘤坏死因子α(tumor necrosis factor-α,TNF-α)、白纽胞介素1p(interleukin1B,IL-1β)的抑制作用。方法合成1条靶向小鼠TREM-1分子的siRNA序列,以增强型绿色荧光蛋白(EGFP)作为报告因子,荧光显微镜观察EGFP的荧光强度,验证siRNA序列的干扰率。以pLKO1-1为载体构建针对TREM-1的pLKO1.1-TREM1-shRNA干扰质粒。将小鼠巨噬细胞株RAW264.7分为4组:空白组;内毒素组(LPS组);空质粒组(pLKO1.1组):采用脂质体法将pLKO1.1转染细胞;干扰组(siRNA组):将pLKO1.1-TREM1-shRNA转染细胞;转染72h后用内毒素刺激24h,并以实时定量PCR分别检测TREM.1、TNF-α与IL-1β的表达;以ELISA分别检测上清液中TNF-α、IL-1β含量。结果与LPS组比较,siRNA组中TREM.1、TNF—α、IL-1β的mRNA显著下降(P〈0.01),上清液中TNF-α、IL-1β含量明显降低(P〈0.01)。结论小分子干扰RNA可能通过抑制TREM-1基因的表达而减少内毒素诱导小鼠巨噬细胞264.7中TNF-α、IL-1β的分泌。  相似文献   

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BackgroundLung injury is a vital contributor of mortality in septic patients. Our previous studies have found that molecular hydrogen (H2), which has anti-oxidant, anti-inflammatory, and anti-apoptosis effects, had a therapeutic effect on a septic animal model through increasing expression of nuclear factor-erythroid 2-related factor 2 (Nrf2). The aim of this research was to investigate the effects of 2% H2 gas inhalation on sepsis-induced lung injury and its underlying mechanisms.MethodsMale wild-type (WT) and Nrf2-knockout (Nrf2-KO) ICR mice underwent sham or cecal ligation and puncture (CLP) operation. Two percent of H2 gas was inhaled for 60 min beginning at both 1 h and 6 h after sham or CLP surgery. To assess the severity of septic lung injury, the 7-day survival rate, wet/dry (W/D) weight ratio of lung tissue, lung histopathologic score, pro-inflammatory cytokines (tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), high-mobility group box 1 (HMGB1)), anti-inflammatory cytokine (interleukin 10 (IL-10)), antioxidant enzymes (superoxide dismutase (SOD), catalase (CAT), and heme oxygenase 1 (HO-1)), and an oxidative product (malondialdehyde (MDA)) were detected after sham or CLP operation. The histopathologic changes were observed in lung tissues by hematoxylin and eosin (HE) staining, and pro-inflammatory cytokines (TNF-α and IL-6), anti-inflammatory cytokine (IL-10), antioxidant enzymes (SOD and CAT), and MDA were detected in lung tissues by an enzyme-linked immunosorbent assay (ELISA).ResultsThe results indicated that 2% H2 gas treatment increased the survival rates, decreased the W/D weight ratio and the lung injury score, alleviated the injuries caused by oxidative stress and inflammation, and induced HO-1 level but reduced HMGB1 level in WT but not Krf2-KO mice. These data reveal that H2 gas could suppress lung injury in septic mice through regulation of HO-1 and HMGB1 expression and that Nrf2 plays a main role in the protective effects of H2 gas on lung damage caused by sepsis.  相似文献   

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Acanthoic acid, a pimaradiene diterpene isolated from Acanthopanax koreanum, has been reported to have anti-inflammatory activities. However, the effect of acanthoic acid on vascular inflammation has not been investigated. The aim of this study was to investigate the anti-inflammatory effects of acanthoic acid on lipopolysaccharide (LPS)-induced inflammatory response in human umbilical vein endothelial cells (HUVECs). The production of cytokines TNF-α and IL-8 was detected by ELISA. The expression of VCAM-1, ICAM-1, E-selectin, NF-κB and LXRα were detected by Western blotting. Adhesion of monocytes to HUVECs was detected by monocytic cell adhesion assay. The results showed that acanthoic acid dose-dependently inhibited LPS-induced TNF-α and IL-8 production. Acanthoic acid also inhibited TNF-α-induced IL-8 and IL-6 production. LPS-induced endothelial cell adhesion molecules, VCAM-1 and ICAM-1 were also inhibited by acanthoic acid. Acanthoic acid inhibited LPS-induced NF-κB activation. Furthermore, acanthoic acid dose-dependently up-regulated the expression of LXRα. In addition, our results showed that the anti-inflammatory effect of acanthoic acid was attenuated by transfection with LXRα siRNA. In conclusion, the anti-inflammatory effect of acanthoic acid is due to its ability to activate LXRα. Acanthoic acid may be a therapeutic agent for inflammatory cardiovascular disease.  相似文献   

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Changes in cytochrome P450 expression incurred by inflammatory disease were studied in a murine collagen antibody induced arthritis (CAIA) model and compared to bacterial lipopolysaccharide-treated mice and to cytochrome P450 changes in primary mouse hepatocytes following combination treatments with cytokines IL-1β, IL-6, or TNFα. CAIA in female mice increased serum IL-1β, IL-6 and hepatic serum amyloid A (SAA) mRNA and significantly altered cytochrome P450 mRNA and activity levels. Most cytochrome P450 isoforms were down-regulated, although some, such as Cyp3a13, were up-regulated. Cytokine effects on cytochrome P450 levels in mouse hepatocytes were compared at in vitro cytokine concentrations similar to those measured in CAIA mouse serum in vivo. In vivo and in vitro cytochrome P450 suppression by cytokines was congruent for some cytochrome P450 isoforms (Cyp1a2, Cyp2c29, and Cyp3a11) but not for others (cytochrome P450 oxidoreductase (POR) and Cyp2e1). In mouse hepatocytes, IL-6 and IL-1β in combination in vitro caused a synergistic increase in SAA mRNA expression, but not in cytochrome P450 suppression. IL-1β and IL-6 were equipotent in the suppression of cytochrome P450 gene expression, while TNFα caused mild suppression only at the highest concentrations used. TNFα in combination with IL-1β, IL-6, or both had a protective effect against IL-1β and IL-6-mediated cytochrome P450 suppression. When IL-1β or IL-6 was combined with low concentrations of TNFα, several P450 isoforms were induced rather than suppressed. These data highlight the complexities of performing in vitro-in vivo comparisons using disease models for cytochrome P450 regulation by cytokines.  相似文献   

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目的 探讨葡萄糖对HepG2细胞酰基辅酶A:胆固醇酰基转移酶2(acyl-CoA:cholesterol acyltransferase2,ACAT2)表达的调节作用及可能机制.方法 用不同浓度的葡萄糖(5.5、12.5、25.0 mmol/L)作用HepG2细胞12 h,RTPCR检测ACAT2和人肝细胞核因子-1α(hepatocyte nuclear factor 1α,HNF1α) mRNA的表达水平.将HNF1α的真核表达质粒瞬时转染HepG2,利用RT-PCR和Western blot检测高表达HNF1α对ACAT2表达的影响.利用凝胶迁移率实验(electrophoretic mobility shift assay,EMSA)观察葡萄糖对HNF1α结合于ACAT2上游调控序列活性的影响.结果 25.0 mmol/L葡萄糖可上调HepG2细胞HNF1α和ACAT2的转录水平;HepG2细胞内过表达HNF1α可增强ACAT2的表达;高糖组HNF1α与ACAT2上游调控序列的结合活性明显增高.结论 高糖可上调ACAT2的表达,其机制可能与高糖增强了HNF1α与ACAT2上游调控区域的结合活性有关.  相似文献   

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