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Paola Pradella
Gabriele Pozzato
DOI: http://dx.doi.org/10.1016/j.jhep.2010.08.018
Methods
Ninety-one consecutive LC patients (36 HCV, 49 alcoholics, 15 HBV) were enrolled. As controls, 25
subjects with idiopathic thrombocytopenic purpura, 10 subjects with aplastic anemia, and 40 healthy blood
donors were studied. Plasma thrombopoietin (TPO) was measured by ELISA. Reticulated platelets (RP)
were determined using the Thiazole Orange method. Plasma glycocalicin (GC) was measured using
monoclonal antibodies. Platelet associated and serum antiplatelet antibodies were detected by flow
cytometry. B-cell monoclonality in PBMC was assessed by immunoglobulin fingerprinting.
Results
Serum TPO was significantly lower in LC (29.918.1pg/ml) compared to controls (82.3 47.6 pg/ml).
The GC levels were higher in LC (any etiology) than in healthy cases. Conversely, the absolute levels of
RP were lower in LC (any etiology) than in healthy controls. The platelet-associated and serum antiplatelet antibodies were higher in HCV+ LC compared to healthy subjects (p<0.0064), alcoholic LC (p
<0.018), and HBV+ LC (p<0.0001). B-cell monoclonality was found in 27% of the HCV +LC, while it was
not found in HBV+ or alcoholic LC.
Conclusions
Patients with LC present decreased plasma TPO, accelerated platelet turnover, and reduced platelet
production. This indicates that LC thrombocytopenia is a multifactorial condition involving both increased
platelet clearance and impaired thrombopoiesis.
Author information
Abstract
BACKGROUND AND AIM:
Hepatic cirrhosis is the final stage of liver dysfunction, characterized by diffuse fibrosis, which is
the main response to the liver injury. This study is to investigate the effects of ursolic acid (UA)
on liver functions and fibrosis in bile duct ligation (BDL) mice and to determine the underlying
mechanisms.
METHODS:
Cultured hepatocytes were treated with lipopolysaccharide (LPS) in the presence or absence of
UA. The reactive oxygen species (ROS) level, protein levels of IB, iNOS and Cox-2, and NFB activation were detected, respectively. C57/BL6 and AMP-activated protein kinase
(AMPK)2(-/-) mice were subjected to BDL for 14 days. UA was administered by gavage. The
markers of liver function and oxidative stress, and liver histopathology were analyzed after
treatment.
RESULTS:
Treatment of hepatocytes with UA dose-dependently activates AMPK, which is abolished by
silence of liver kinase B1 (LKB1). LPS significantly increased ROS productions, apoptosis, NFB activation, and expressions of iNOS and Cox-2 in cultured hepatocytes. All these effects
were blocked by co-incubation with UA. Importantly, silence of LKB1, AMPK, or iNOS/Cox-2 by
small interference RNA transfection reversed UA-induced effects in cultured cells. In an animal
study, 14-day BDL induced liver fibrosis and liver injury, accompanied with increased oxidative
stress and protein expressions of iNOS and Cox-2 in liver. Treatment of UA significantly
attenuated the BDL-induced detrimental effects in wild-type mice but not in AMPK2(-/-) mice.
CONCLUSION:
UA via LKB1-AMPK signaling offers protective effects on BDL-induced liver injury in mice, which
may be related to inhibition of oxidative stress.
Author information
Abstract
BACKGROUND & AIMS:
Specific induction of cell death in activated hepatic stellate cells (HSCs) is a promising
therapeutic strategy for hepatic fibrosis. In this study, we evaluated the cell-killing effect of
ursolic acid (UA), a pentacyclic triterpenoid, in activated HSCs both in vitro and in vivo.
METHODS:
Culture-activated rat HSCs were treated with UA (0-40M), and the mechanisms of cell death
were evaluated. The cell killing effect of UA on activated HSCs in rats chronically treated with
thioacetamide (TAA) was detected by dual staining of TdT-mediated dUTP nick-end labeling
(TUNEL) and smooth muscle -actin (SMA) immunohistochemistry, and resolution of hepatic
fibrosis was evaluated. Further, the protective effects of UA on progression of hepatic fibrosis
caused by TAA and bile duct ligation (BDL) were evaluated.
RESULTS:
UA induced apoptotic cell death in culture-activated HSCs, but not in isolated hepatocytes and
quiescent HSCs. Mitochodrial permeability transition (MPT) preceded the cleavage of caspase3 and -9 following UA treatment. UA also decreased phosphorylation levels of Akt, and
diminished nuclear localization of NFB in these cells. In rats pretreated with TAA for 6weeks, a
single injection of UA induced remarkable increases in TUNEL- and SMA-dual-positive cells in
24h, and significant regression of hepatic fibrosis within 48h. Moreover, UA ameliorated hepatic
fibrogenesis caused by both chronic TAA administration and BDL.
CONCLUSIONS:
UA ameliorated experimental hepatic fibrosis most likely through specific induction of apoptosis
in activated HSCs. It is therefore postulated that UA is a potential therapeutic reagent for
resolution of hepatic fibrosis
Propranolol hydrochloride is reported to lower portal pressure and inhibit renin secretion in
patients with chronic liver disease, actions that might lessen the tendency to ascites formation.
We compared the effect of diuretics with that of the same dose of diuretics plus propranolol on
natriuresis, urine output, and daily weight loss in 13 hospitalized patients with stable chronic
liver disease, sodium retention, and ascites. The propranolol hydrochloride dose was 20 to 160
mg four times a day, titrated to reduce resting pulse by 25% or systolic BP 10 mm Hg. Diuretics
given were furosemide, 80 to 160 mg, and triamterene, 100 or 200 mg/day. Periods of time
when each regimen was received ranged from one to four days. Creatinine excretion
documented complete urine collections. Compared with diuretics alone, diuretics plus
propranolol substantially reduced resting pulse, systolic BP, and urine sodium excretion,
although not creatinine clearance. This antinatriuretic effect may limit the proposed usefulness
of propranolol for prevention of variceal bleeding in patients with cirrhosis and ascites.
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