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  • 1
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    Online Resource
    Hepatocyte Nuclear Factor 4α Suppresses the Development of Hepatocellular Carcinoma
    American Association for Cancer Research (AACR) ; 2010
    In:  Cancer Research Vol. 70, No. 19 ( 2010-10-01), p. 7640-7651
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 19 ( 2010-10-01), p. 7640-7651
    Abstract: Hepatocyte nuclear factor 4α (HNF4α) is a transcription factor that plays a key role in hepatocyte differentiation and the maintenance of hepatic function, but its role in hepatocarcinogenesis has yet to be examined. Here, we report evidence of a suppressor role for HNF4α in liver cancer. HNF4α expression was progressively decreased in the diethylinitrosamine-induced rat model of liver carcinogenesis. In human liver tissues, HNF4α expression was decreased in cirrhotic tissue and further decreased in hepatocarcinoma relative to healthy tissue. Notably, an inverse correlation existed with epithelial-mesenchymal transition (EMT). Enforced expression of HNF4α attenuated hepatocyte EMT during hepatocarcinogenesis, alleviated hepatic fibrosis, and blocked hepatocellular carcinoma (HCC) occurrence. In parallel, stem cell marker gene expression was inhibited along with cancer stem/progenitor cell generation. Further, enforced expression of HNF4α inhibited activation of β-catenin, which is closely associated with EMT and hepatocarcinogenesis. Taken together, our results suggest that the inhibitory effect of HNF4α on HCC development might be attributed to suppression of hepatocyte EMT and cancer stem cell generation through an inhibition of β-catenin signaling pathways. More generally, our findings broaden knowledge on the biological significance of HNF4α in HCC development, and they imply novel strategies for HCC prevention through the manipulation of differentiation-determining transcription factors in various types of carcinomas. Cancer Res; 70(19); 7640–51. ©2010 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-10-0824
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 2
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    Abstract 134: HNF4α inhibits liver cancer metastasis via suppression of NF-кB activity
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 19_Supplement ( 2014-10-01), p. 134-134
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 134-134
    Abstract: BACKGROUND & AIMS: Hepatocyte nuclear factor 4α (HNF4α) is a liver enriched transcription factor and is indispensable for liver development. However, the role of HNF4α in hepatocellular carcinoma (HCC) metastasis remains largely unknown. METHODS: 429 HCC tissues were involved in the correlation analysis of HNF4α levels with tumor features and patient outcomes. Effect of HNF4α on HCC metastasis was monitored through in vivo imaging system. Expression of HNF4α, RelA(p65) or microRNAs in human HCCs was determined by Real-time PCR, western blot or immunohistochemistry. Point mutation and ChIP assay were performed to detect the interaction of HNF4α with the promoter of target microRNA. 3’UTR reporter assay was conducted to determine the regulation of RelA by microRNAs. RESULTS: Reduced HNF4α expression correlated well with the aggressive clinicopathological characteristics of HCC and predicted poor prognosis of patients. HNF4α levels were even lower in metastatic HCCs, and ectopic HNF4α expression suppressed the metastasis of hepatoma cells both in vitro and in vivo. HNF4α suppressed HCC metastasis through inhibiting RelA expression and NFκB activity. miR-7 and miR-124, which were transcriptionally up-regulated by HNF4α, repressed RelA expression via interaction with RelA-3’UTR. Herein, HNF4α suppresses NF-κB activity and RelA expression via a miR-7 and miR-124-dependent manner. Moreover, combination of HNF4α and NF-κB exhibited more powerful predictive efficiency of patient prognosis. CONCLUSIONS: Considering the importance of HNF4α and NF-κB in chronic liver disease, the suppression of NF-κB by HNF4α is not only essential in connecting hepatic inflammation and tumorigenesis, but also indicates novel strategy in HCC prevention and therapy. Citation Format: Bei-Fang Ning, Jiao Liu, Wen-Ping Xu, Chuan Yin, Xin Zhang, Wei-Fen Xie. HNF4α inhibits liver cancer metastasis via suppression of NF-кB activity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 134. doi:10.1158/1538-7445.AM2014-134
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2014-134
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 3
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    The HLF/IL-6/STAT3 feedforward circuit drives hepatic stellate cell activation to promote liver fibrosis
    BMJ ; 2018
    In:  Gut Vol. 67, No. 9 ( 2018-09), p. 1704-1715
    Details
    In: Gut, BMJ, Vol. 67, No. 9 ( 2018-09), p. 1704-1715
    Abstract: Liver fibrosis is a wound-healing response that disrupts the liver architecture and function by replacing functional parenchyma with scar tissue. Recent progress has advanced our knowledge of this scarring process, but the detailed mechanism of liver fibrosis is far from clear. Methods The fibrotic specimens of patients and HLF (hepatic leukemia factor) PB/PB mice were used to assess the expression and role of HLF in liver fibrosis. Primary murine hepatic stellate cells (HSCs) and human HSC line Lx2 were used to investigate the impact of HLF on HSC activation and the underlying mechanism. Results Expression of HLF was detected in fibrotic livers of patients, but it was absent in the livers of healthy individuals. Intriguingly, HLF expression was confined to activated HSCs rather than other cell types in the liver. The loss of HLF impaired primary HSC activation and attenuated liver fibrosis in HLF PB/PB mice. Consistently, ectopic HLF expression significantly facilitated the activation of human HSCs. Mechanistic studies revealed that upregulated HLF transcriptionally enhanced interleukin 6 (IL-6) expression and intensified signal transducer and activator of transcription 3 (STAT3) phosphorylation, thus promoting HSC activation. Coincidentally, IL-6/STAT3 signalling in turn activated HLF expression in HSCs, thus completing a feedforward regulatory circuit in HSC activation. Moreover, correlation between HLF expression and alpha-smooth muscle actin, IL-6 and p-STAT3 levels was observed in patient fibrotic livers, supporting the role of HLF/IL-6/STAT3 cascade in liver fibrosis. Conclusions In aggregate, we delineate a paradigm of HLF/IL-6/STAT3 regulatory circuit in liver fibrosis and propose that HLF is a novel biomarker for activated HSCs and a potential target for antifibrotic therapy.
    Type of Medium: Online Resource
    ISSN: 0017-5749 , 1468-3288
    URL: Article
    URL: Article
    DOI: 10.1136/gutjnl-2016-313392
    DOI: 10.1136/gutjnl-2016-313392.supp1
    RVK:
    XA 10000
    Language: English
    Publisher: BMJ
    Publication Date: 2018
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  • 4
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    842 Adenovirus-Mediated Hepatocyte Nuclear Factor 4a Prevents the Development of Hepatocellular Carcinoma in Rats
    Elsevier BV ; 2010
    In:  Gastroenterology Vol. 138, No. 5 ( 2010-5), p. S-797-
    Details
    In: Gastroenterology, Elsevier BV, Vol. 138, No. 5 ( 2010-5), p. S-797-
    Type of Medium: Online Resource
    ISSN: 0016-5085
    URL: Article
    DOI: 10.1016/S0016-5085(10)63670-0
    RVK:
    XA 44500
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2010
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  • 5
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    Prourokinase Mutant That Induces Highly Effective Clot Lysis Without Interfering With Hemostasis
    Ovid Technologies (Wolters Kluwer Health) ; 2002
    In:  Circulation Research Vol. 90, No. 7 ( 2002-04-19), p. 757-763
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 90, No. 7 ( 2002-04-19), p. 757-763
    Abstract: Prourokinase (proUK) is a zymogenic plasminogen activator that at pharmacological doses is prone to nonspecific activation to urokinase. This has handicapped therapeutic exploitation of its fibrin-specific physiological properties. To attenuate this susceptibility without compromising specific activation of proUK on a fibrin clot, a Lys300→His mutation (M5) was developed. M5 had a lower intrinsic activity and, therefore, remained stable in plasma at a 4-fold higher concentration than did proUK. M5 had a higher 2-chain activity and induced more rapid plasminogen activation and fibrin-specific clot lysis in vitro. Sixteen dogs embolized with radiolabeled clots were infused with saline, proUK, tissue plasminogen activator, or M5. The lower intrinsic activity allowed a higher infusion rate with M5, which induced the most rapid and efficient clot lysis (50% clot lysis by ≈600 μg/kg M5 versus ≈1200 μg/kg proUK). In association with this, M5 caused neither a significant increase in the primary bleeding time nor secondary bleeding (total blood loss). By contrast, these measurements increased 4-fold and 5-fold, respectively, with proUK and 〉 5-fold and 8-fold, respectively, with tissue plasminogen activator. Clot lysis by M5 and hemostasis were further evaluated in 6 rhesus monkeys. M5 again induced rapid clot lysis without a significant increase in the primary bleeding time, and secondary bleeding did not occur. In conclusion, a site-directed mutation designed to improve the stability of proUK in blood at therapeutic concentrations induced superior clot lysis in vitro and in vivo without causing significant interference with hemostasis.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/01.RES.0000014825.71092.BD
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2002
    detail.hit.zdb_id: 1467838-X
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  • 6
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    Abstract 2463: Suppression of hepatocyte nuclear factor 4α by nuclear factor κB in hepatoma cells
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 19_Supplement ( 2014-10-01), p. 2463-2463
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 2463-2463
    Abstract: BACKGROUND & AIMS: HCC predominantly arises from cirrhotic liver where there usually has been repeated wound-healing response upon chronic inflammation. However, the mechanistic link between hepatic inflammation and carcinogenesis remains largely unknown. METHODS: Expression of HNF4α, RelA(p65) or microRNAs in human HCCs was determined by Real-time PCR, western blot or immunohistochemistry. 3′UTR reporter assay was conducted to determine the regulation of HNF4α by microRNAs. The recombinant adenoviruses carrying HNF4α gene were injected into diethylinitrosamine(DEN)-administrated Wistar rats through tail vein. Tissue microarray was utilized to assess the expression of HNF4α and RelA HCC tissues. RESULTS: Overexpression or interference of RelA remarkably decreased or increased HNF4α expression in hepatoma cells respectively, suggesting a negative regulation of HNF4α by NF-κB. Interestingly, ecotopic RelA expression dramatically reduced the activation of HNF4α-3′UTR indicating microRNA could be involved in the feedback regulation. MiR-21 was predicted to be regulated by NF-κB using Targetscan analysis, and overexpression of RelA evidently enhanced the miR-21 expression. Delivery of miR-21 mimic notably suppressed HNF4α-3′UTR activity and HNF4α expression. Moreover, treatment of miR-21 inhibitor increased HNF4α levels and attenuated the down-regulation of HNF4α by RelA. Consistently, downregulation of HNF4α and upregulation of RelA was detected during DEN-induced rat hepatocarcingenesis, negative correlation of HNF4α and RelA was also observed in human HCCs. CONCLUSIONS: These findings not only broaden the knowledge on hepatic inflammation and cancer initiation, but also indicates novel strategy in HCC prevention. Note: This abstract was not presented at the meeting. Citation Format: Bei-Fang Ning, Xin Zhang, Wei-Fen Xie. Suppression of hepatocyte nuclear factor 4α by nuclear factor κB in hepatoma cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2463. doi:10.1158/1538-7445.AM2014-2463
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2014-2463
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 7
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    Soporific effect of modified Suanzaoren Decoction on mice models of insomnia by regulating Orexin-A and HPA axis homeostasis
    Elsevier BV ; 2021
    In:  Biomedicine & Pharmacotherapy Vol. 143 ( 2021-11), p. 112141-
    Details
    In: Biomedicine & Pharmacotherapy, Elsevier BV, Vol. 143 ( 2021-11), p. 112141-
    Type of Medium: Online Resource
    ISSN: 0753-3322
    URL: Article
    DOI: 10.1016/j.biopha.2021.112141
    RVK:
    XA 10000
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2021
    detail.hit.zdb_id: 1501510-5
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  • 8
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    Effect of Oral Methylprednisolone on Decline in Kidney Function or Kidney Failure in Patients With IgA Nephropathy : The TESTING Randomized Clinical Trial
    American Medical Association (AMA) ; 2022
    In:  JAMA Vol. 327, No. 19 ( 2022-05-17), p. 1888-
    Details
    In: JAMA, American Medical Association (AMA), Vol. 327, No. 19 ( 2022-05-17), p. 1888-
    Type of Medium: Online Resource
    ISSN: 0098-7484
    URL: Article
    DOI: 10.1001/jama.2022.5368
    RVK:
    XA 10000
    Language: English
    Publisher: American Medical Association (AMA)
    Publication Date: 2022
    detail.hit.zdb_id: 2958-0
    detail.hit.zdb_id: 2018410-4
    SSG: 5,21
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  • 9
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    Pharmacokinetics and Pharmacodynamics of Multiple-Dose Intravenous Nemonoxacin in Healthy Chinese Volunteers
    American Society for Microbiology ; 2015
    In:  Antimicrobial Agents and Chemotherapy Vol. 59, No. 3 ( 2015-03), p. 1446-1454
    Details
    In: Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 59, No. 3 ( 2015-03), p. 1446-1454
    Abstract: This study evaluated the safety and pharmacokinetic/pharmacodynamic profiles of nemonoxacin in healthy Chinese volunteers following multiple-dose intravenous infusion once daily for 10 consecutive days. The study was composed of two stages. In the open-label stage, 500 mg or 750 mg of nemonoxacin ( n = 12 each) was administered at an infusion rate of 5.56 mg/min. In the second stage, with a randomized double-blind placebo-controlled design, 500, 650, or 750 mg of nemonoxacin ( n = 16 in each cohort; 12 subjects received the drug and the other 4 subjects received the placebo) was given at an infusion rate of 4.17 mg/min. The results showed that, in the first stage, the maximal nemonoxacin concentrations (mean ± SD) at steady state ( C max_ss ) were 9.60 ± 1.84 and 11.04 ± 2.18 μg/ml in the 500-mg and 750-mg cohorts, respectively; the areas under the concentration-time curve at steady state (AUC 0–24_ss ) were 44.03 ± 8.62 and 65.82 ± 10.78 μg · h/ml in the 500-mg and 750-mg cohorts, respectively. In the second stage, the nemonoxacin C max_ss values were 7.13 ± 1.47, 8.17 ± 1.76, and 9.96 ± 2.23 μg/ml in the 500-mg, 650-mg, and 750-mg cohorts, respectively; the AUC 0–24_ss values were 40.46 ± 9.52, 54.17 ± 12.10, and 71.34 ± 17.79 μg · h/ml in the 500-mg, 650-mg, and 750-mg cohorts, respectively. No accumulation was found after the 10-day infusion with any regimen. The drug was well tolerated. A Monte Carlo simulation indicated that the cumulative fraction of response of any dosing regimen was nearly 100% against Streptococcus pneumoniae . The probability of target attainment of nemonoxacin therapy was 〉 98% when the MIC of nemonoxacin against S. pneumoniae was ≤1 mg/liter. It is suggested that all of the studied intravenous nemonoxacin dosing regimens should have favorable clinical and microbiological efficacies in future clinical studies. (This study has been registered at ClinicalTrials.gov under registration no. NCT01944774.)
    Type of Medium: Online Resource
    ISSN: 0066-4804 , 1098-6596
    URL: Article
    DOI: 10.1128/AAC.04039-14
    RVK:
    XA 24552
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2015
    detail.hit.zdb_id: 1496156-8
    SSG: 12
    SSG: 15,3
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  • 10
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    Daily point-of-care ultrasound-assessment of central venous catheter-related thrombosis in critically ill patients: a prospective multicenter study
    Springer Science and Business Media LLC ; 2023
    In:  Intensive Care Medicine Vol. 49, No. 4 ( 2023-04), p. 401-410
    Details
    In: Intensive Care Medicine, Springer Science and Business Media LLC, Vol. 49, No. 4 ( 2023-04), p. 401-410
    Type of Medium: Online Resource
    ISSN: 0342-4642 , 1432-1238
    URL: Article
    DOI: 10.1007/s00134-023-07006-x
    RVK:
    XA 10000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 1459201-0
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