BACKGROUND There is considerable evidence indicating that the severity of hepatic damage in individuals with cholestatic liver disease is causally associated with the extent of intrahepatic oxidative ...stress. Increased levels or accelerated generation of reactive oxygen species and toxic degradative products of lipid peroxidation have been reported in the plasma of individuals with chronic liver disease and animal models of liver disease. Hence, by virtue of their increased presence in the circulation, it is not unreasonable to suppose that they may account for extrahepatic tissue damage in chronic liver disease. MATERIALS AND METHODS This hypothesis was tested by determining plasma levels of the ubiquitous antioxidant glutathione (GSH) and lipid peroxides (LP), together with assessment of the extent of lipid peroxidation in the kidney, brain, and heart, in 24 day chronically bile duct ligated (CBDL) rats. The extent of lipid peroxidation in tissues was based on measurement of conjugated dienes, lipid peroxides, and malondialdehyde (MDA) content. Data were compared with identical data collected from unoperated control, pair fed, 24 day bile duct manipulated (sham operated), and pair fed sham operated rats. RESULTS In CBDL rats, total and reduced plasma GSH levels were almost half those determined in all control rats. Plasma, kidney, and heart LP levels were significantly increased in CBDL rats compared with controls. MDA levels were significantly higher in the kidney, brain, and heart homogenates prepared from CBDL rats compared with MDA content measured in tissue homogenates prepared from the four groups of control rats. CONCLUSIONS Our data show that experimental cholestatic liver disease is associated with increased lipid peroxidation in the kidney, brain, and heart. Hence we have concluded that the oxidative stress in cholestatic liver disease is a systemic phenomenon probably encompassing all tissues and organs, even those separated by the blood-brain barrier.
Buprenorphine is a widely used analgesic for relief of postoperative pain in rats. The effect of repeated doses of buprenorphine throughout the postoperative pain and stress response is unknown. This ...investigation tested the hypotheses that (a) daily analgesic doses of buprenorphine for 7 d ameliorate the stress response after laparotomy in rats and (b) preoperative buprenorphine better ameliorates the response than do peri- and postoperative administration. Postoperative effects on body weight, daily food and water consumption, and daily fecal and urinary outputs were monitored in groups of rats treated for 7 d with analgesic doses of buprenorphine initiated at different time points relative to the time of laparotomy. Analgesic doses of buprenorphine had no effect on the study parameters in healthy unoperated rats. Daily injection of buprenorphine delayed the time at which the preoperative body weight was restored without decreasing the postoperative changes in daily food consumption, water intake, and fecal and urinary outputs in the operated rats. The effects of daily analgesic doses of buprenorphine for 7 d on body weight, daily food, and water consumption, and fecal and urinary outputs were minimal and less statistically significant than the changes caused by surgery itself. However, this dosing regimen seems to delay the restoration of body weight after abdominal surgery in rats.
BACKGROUND: Kupffer cells are essential for normal hepatic homeostasis and when stimulated, they secrete reactive oxygen species, nitric oxide, eicosanoids, and cytokines. Some of these products are ...cytotoxic and attack nucleic acids, thiol proteins, or membrane lipids causing lipid peroxidation. Hydrophobic bile acids, such as deoxycholic acid (DCA), can damage hepatocytes by solubilising membranes and impairing mitochondrial function, as well as increasing the generation of reactive oxygen species. OBJECTIVES: The hypothesis that hydrophobic bile acids could stimulate Kupffer cells to increase their capacity to generate reactive oxygen species by measuring cellular lipid peroxidation was tested. Because the hydrophilic bile acid, ursodeoxycholic acid (UDCA) can block hydrophobic bile acid induced cellular phenomena, it was also hypothesised that UDCA could antagonise macrophage activation by hydrophobic bile acids to blunt their capacity to generate reactive oxygen species. METHODS: J-774A.1 murine macrophages were incubated for 24 hours with either 10(-5) M and 10(-4) M (final concentration) DCA alone, or 10(-4) M UDCA alone, or a mixture of 10(-4) M 1:1 molar ratio of DCA and UDCA. At the end of the incubation period, the culture medium was collected for determination of cellular lipid peroxidation by measuring the malondialdehyde (MDA) content in the medium with the thiobarbituric acid reactive substances assay. RESULTS: 10(-5) M and 10(-4) M DCA increased MDA generation by cultured macrophages. 10(-4) M UDCA alone did not increase MDA generation but blocked the peroxidative actions of DCA. CONCLUSIONS: Hydrophobic bile acids, after their hepatic retention, can oxidatively activate Kupffer cells to generate reactive oxygen species. Because UDCA can block this action, the beneficial effect of UDCA is, in part, related to its ability to act as an antioxidant.
The medicinal use of extracts prepared from plant parts of the genus
Crataegus dates back to ancient times. Furthermore, it has been proposed that its antioxidant constituents account for its ...beneficial therapeutic effects. A decoction of leaves and unripe fruits from
Crataegus aronia syn. azarolus (L) (Rosaceae), the indigenous Israeli hawthorn, is used to treat cardiovascular diseases, cancer, diabetes and sexual weakness in Arab traditional medicine.
Because laboratory data on the bioactivity of extracts prepared from the indigenous Israeli hawthorn is lacking, we evaluated the antioxidant and cytotoxic potentials of an extract prepared from leaves and unripe fruits in a variety of cell and cell-free in vitro assays.
The antioxidant assays measured: (a) its ability to inhibit (i) oxidation of β-carotene, (ii) 2,2′-azobis(2-amidino-propan) dihydrochloride (AAPH)-induced plasma oxidation and (iii) iron-induced lipid peroxidation in rat liver homogenates; (b) its ability to scavenge the superoxide (O
2
−) radical; (c) its effects on the enzyme xanthine oxidase (XO) activity; (d) its effect on the redox state of glutathione (GSH) in cultured Hep G2 cells. In addition, we also evaluated the effects of the extract on cell membrane integrity and mitochondrial respiration in cultured Hep G2 cells.
Water-soluble extracts inhibited (1) oxidation of β-carotene, (2) AAPH-induced plasma oxidation and (3) Fe
2+-induced lipid peroxidation in rat liver homogenates. In addition, the extract (4) is an efficient scavenger of the O
2
− (5) increases intracellular GSH levels and (6) is not cytotoxic. Accordingly, we propose that the therapeutic benefit of
Crataegus aronia can be, at least in part, attributed to its effective inhibition of oxidative processes, efficient scavenging of O
2
− and possible increasing GSH biosynthesis.
Ethnopharmacological surveys conducted among herbal practitioners of traditional Arab medicine in Israel and the Palestinian area have revealed a large number of indigenous plant species are used as ...sources of their herbal therapies. Some of these herbal therapies are used to treat liver disease, jaundice or diabetes, conditions in which oxidative stress is prominent. No laboratory data on the bioactivity of herbal medicines in these settings exist in traditional Arab medicine. We hypothesized that the beneficial effect of these plants might be due to their antioxidant properties. Accordingly, we selected eight plants used to treat these two conditions and assessed their antioxidant potential by measuring their ability to suppress the extent of iron-induced lipid peroxidation in rat liver homogenates and their potential toxicity by evaluating their effects on mitochondrial respiration and cell membrane integrity in cultured PC12 and HepG2 cells. We found that all the extracts can suppress iron-induced lipid peroxidation and are not toxic. Of these extracts, those prepared from
Teucrium polium and
Pistacia lentiscus were the most effective in suppressing iron-induced lipid peroxidation. Further investigations are now needed to establish the exact mechanism of action and identify the active bio-ingredient(s) of each extract in order to explain their therapeutic efficacy.
In a previous study, we identified
Pistacia lentiscus was worthy for further laboratory evaluation because an aqueous extract of the plant suppressed iron-induced lipid peroxidation in rat liver ...homogenates without affecting mitochondrial respiration in cultured HepG2 and PC12 cells. The present study was undertaken to evaluate the efficacy of an aqueous extract prepared from the dried leaves of
Pistacia lentiscus in a rat model of hepatic injury caused by the hepatotoxin, thioacetamide. We assessed the impact of daily dosing on biochemical and morphological indices and the extent of oxidative stress in the livers of healthy and thioacetamide-treated rats. In healthy rats, long-term administration of the extract induced hepatic fibrosis and an inflammatory response, mild cholestasis and depletion of reduced glutathione associated with an increase in its oxidized form. In thioacetamide-treated rats, long-term administration of extract aggravated the inflammatory and fibrotic and glutathione depleting responses without affecting the extent of lipid peroxidation. Although our previous in vitro study established that extracts prepared from the leaves of
Pistacia lentiscus had antioxidant activity, this in vivo study establishes these extracts also contains hepatotoxins whose identity may be quite different from those compounds with antioxidant properties. The results of this study suggest complementing in vitro experiments with those involving animals are essential steps in establishing the safety of medicinal plants. Furthermore, these data confirm that complete reliance on data obtained using in vitro methodologies may lead to erroneous conclusions pertaining to the safety of phytopharmaceuticals.
Reactive oxygen species and reactive nitroxy species are now being recognized as regulatory molecules in signaling pathways influencing contractile and noncontractile functions of healthy vascular ...smooth muscle cells. In liver disease, oxidative stress is a systemic phenomenon, whose extent correlates with the severity of disease. A role for oxidative stress in the development of the hyperdynamic circulation in portal hypertension has been proposed. Evaluation of the limited available data indicates that it is premature to conclude that oxidative stress per se impacts on vascular smooth muscle cell function in liver disease.
The aim of this study was to assess the relationship between subtle cardiovascular abnormalities and abnormal sodium handling in cirrhosis. A total of 35 biopsy-proven patients with cirrhosis with or ...without ascites and 14 age-matched controls underwent two-dimensional echocardiography and radionuclide angiography for assessment of cardiac volumes, structural changes and systolic and diastolic functions under strict metabolic conditions of a sodium intake of 22 mmol/day. Cardiac output, systemic vascular resistance and pressure/volume relationship (an index of cardiac contractility) were calculated. Eight controls and 14 patients with non-ascitic cirrhosis underwent repeat volume measurements and the pressure/volume relationship was re-evaluated after consuming a diet containing 200 mmol of sodium/day for 7 days. Ascitic cirrhotic patients had significant reductions in (i) cardiac pre-load (end diastolic volume 106+/-9 ml; P<0.05 compared with controls), due to relatively thicker left ventricular wall and septum (P<0.05); (ii) afterload (systemic vascular resistance 992+/-84 dyn.s.cm(-5); P<0. 05 compared with controls) due to systemic arterial vasodilatation; and (iii) reversal of the pressure/volume relationship, indicating contractility dysfunction. Increased cardiac output (6.12+/-0.45 litres/min; P<0.05 compared with controls) was due to a significantly increased heart rate. Pre-ascitic cirrhotic patients had contractile dysfunction, which was accentuated when challenged with a dietary sodium load, associated with renal sodium retention (urinary sodium excretion 162+/-12 mmol/day, compared with 197+/-12 mmol/day in controls; P<0.05). Cardiac output was maintained, since the pre-load was normal or increased, despite a mild degree of ventricular thickening, indicating some diastolic dysfunction. We conclude that: (i) contractile dysfunction is present in cirrhosis and is aggravated by a sodium load; (ii) an increased pre-load in the pre-ascitic patients compensates for the cardiac dysfunction; and (iii) in ascitic patients, a reduced afterload, manifested as systemic arterial vasodilatation, compensates for a reduced pre-load and contractile dysfunction. Cirrhotic cardiomyopathy may well play a pathogenic role in the complications of cirrhosis.
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