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The Role of Peroxisome Proliferator-activated Receptor Alpha in Bile Acid and Anti-inflammatory Regulation in Treating Chronic Cholestatic Liver Diseases
Başlık:
The Role of Peroxisome Proliferator-activated Receptor Alpha in Bile Acid and Anti-inflammatory Regulation in Treating Chronic Cholestatic Liver Diseases
Yazar:
Alsuwayt, Bader, author.
ISBN:
9780438047013
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (139 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 79-10(E), Section: B.
Advisors: Nisanne Ghonem Committee members: Timothy Maher; Alejandro Pino Figueroa; Iman Zaghloul.
Özet:
Cholestatic liver disease is an accumulation of bile in the liver due to a blockage in bile excretion. The most common available treatment for cholestasis patients is ursodeoxycholic acid (UDCA) but is not effective in some patients. Another drug is obeticholic acid (OCA) which is used alone or in combination with UDCA. It is effective in decreasing biochemical markers such as alkaline phosphatase (ALP), but the Food and Drug Administration (FDA) plans to monitor its effect on primary biliary cholangitis (PBC) patients over time. The objectives of this research were to determine the mechanisms of a peroxisome proliferator-activated receptor alpha (PPARalpha) agonist that can attenuate cholestatic liver diseases. Chenodeoxycholic acid (CDCA) is one of the primary bile acids (BAs) and is more toxic compared to other BAs. Chenodeoxycholic acid (500, 1000 muM), decreased cell viability of HepaRG cells to 51 % and 31 %, respectively. Treatment of cells with 500 muM CDCA significantly down-regulated bile salt export pump (BSEP) expression and multidrug resistance protein 3 (MDR3) expression and led to a significant increase in alkaline phosphatase (ALP) activity and interleukin-8 (IL-8) concentration compared to the control group. Pretreatment of HepaRG cells with different concentrations of the PPARalpha agonist fenofibrate (5, 25, 50, 125 muM) for 2 hours significantly improved cell viability in a concentration-dependent manner. In HepaRG cell line, fenofibrate (50, 125 muM) significantly induced MDR3 and BSEP mRNA expression, reduced ALP activity to two-fold compare to five-fold in CDCA alone. Also, fenofibrate (50, 125 muM) significantly decreased IL-8 production to 59 % and 53 %, respectively, compared to CDCA (500 muM). In the human monocyte-macrophages (THP-1) cell line, pretreatment with fenofibrate (50, 125 muM) for 2 hours significantly decreased LPS-stimulated TNF-alpha, IL-1beta and IL-8 production in 8 and 24 hours. In addition, in THP-1-Lucia NF-kappaB cell lines stimulated with LPS (10 ng/mL) for 3, 6 and 24 hours, fenofibrate (125 and 250 muM) and Wy-14643 (50 muM) significantly reduced NF-kappaB activity induced by LPS (10 ng/mL). The THP-1 cells pretreated with fenofibrate (125 and 250 muM) for 2 hours resulted in a significant decrease in NF-kappaB p65 / p50 binding activity induced by LPS (10 ng/mL). Moreover, pretreatment of THP-1 cells with fenofibrate (50, 125 muM) for 2 hours significantly decreased the phosphorylation of IKBalpha, c-Jun and increased IKBalpha protein expression compared to LPS (100 ng/mL). Pretreatment with Fenofibrate (50, 125 muM) for 2 hours significantly decreased NF-kappaB p65 and NF-kappaB p50 protein expression in nuclear extracts induced by LPS (100 ng/mL). When the cells were pretreated with GW6471 (PPARalpha antagonist, 10 muM) for 1 hour, the effect of fenofibrate (50 muM) in reducing TNF-alpha production was abolished. Thus, fenofibrate has anti-cholestatic liver effects by reducing cholestatic liver markers in an in vitro cholestatic liver model. These data suggested that fenofibrate was able to reduce human hepatic inflammation by reducing pro-inflammatory cytokines production. Therefore, fenofibrate might be beneficial in treating cholestatic liver diseases by its anti-inflammatory mechanisms.
Notlar:
School code: 0308
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
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XX(682484.1) | 682484-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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