Biomedical subjects

Zhenyuan Song

Publications and source records attributed to Zhenyuan Song.

23 records · Page 2Linked to original sources

PubMed2003

S-adenosylmethionine (SAMe) protects against acute alcohol induced hepatotoxicity in mice.

Although S-Adenosylmethionine (SAMe) has beneficial effects in many hepatic disorders, the effects of SAMe on acute alcohol-induced liver injury are unknown. In the present study, we investigated effects of SAMe on liver injury in mice induced by acute alcohol administration. Male C57BL/6 mice received ethanol (5 g/kg BW) by gavage every 12 hrs for a total of 3 doses. SAMe (5 mg/kg BW) was administrated i.p. once a day for three days before ethanol administration. Subsequent serum ALT level, hepatic lipid peroxidation, enzymatic activity of CYP2E1 and hepatic mitochondrial glutathione levels were measured colorimetrically. Intracellular SAMe concentration was measured by high-performance liquid chromatography (HPLC). Histopathological changes were assessed by H&E staining. Our results showed that acute ethanol administration caused prominent microvesicular steatosis with mild necrosis and an elevation of serum ALT activity. SAMe treatment significantly attenuated the liver injury. In association with the hepatocyte injury, acute alcohol administration induced significant decreases in both hepatic SAMe and mitochondrial GSH levels along with enhanced lipid peroxidation. SAMe treatment attenuated hepatic SAMe and mitochondrial GSH depletion and lipid peroxidation following acute alcohol exposure. These results demonstrate that SAMe protects against the liver injury and attenuates the mitochondrial GSH depletion caused by acute alcohol administration. SAMe may prove to be an effective therapeutic agent in many toxin-induced liver injuries including those induced by alcohol.

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PubMed2003

S-adenosylmethionine (AdoMet) modulates endotoxin stimulated interleukin-10 production in monocytes.

IL-10 is produced by a large variety of cells including monocytes, macrophages, B and T lymphocytes, as well as natural killer cells and is an important suppressor for both immunoproliferative and inflammatory responses. IL-10 exerts antifibrotic effects in the liver, and decreased monocyte synthesis of IL-10 is well documented in alcoholic cirrhosis. Intracellular deficiency of S-adenosylmethionine (AdoMet) is a hallmark of toxin-induced liver injury. Although the administration of exogenous AdoMet attenuates this injury, the mechanisms of its actions are not fully established. This study was performed to investigate the effect of exogenous AdoMet on IL-10 production in LPS-stimulated RAW 264.7 cells, a murine macrophage cell line. Our results demonstrated that exogenous AdoMet administration enhanced both protein production and gene expression of IL-10 in RAW 264.7 cells. Ethionine, an inhibitor for methionine adenosyltransferases, inhibited LPS-stimulated IL-10 both at the protein and mRNA levels. Exogenous AdoMet increased the intracellular cAMP concentration as early as 3 h and continued for 24 h after AdoMet treatment; however, the inhibitors for both adenylyl cyclase and PKA did not significantly affect IL-10 production. On the basis of these results, we conclude that AdoMet administration may exert its anti-inflammatory and hepatoprotective effects, at least in part, by enhancing LPS-stimulated IL-10 production.

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PubMed2003

Diabetes enhances lipopolysaccharide-induced cardiac toxicity in the mouse model.

Diabetic patients have a higher rate of mortality from sepsis than do their nondiabetic septic counterparts. The hypothesis in this study is that chronic diabetes may make cardiovascular systems more sensitive to septicemia. To test this hypothesis, the authors investigated the effect of diabetes on endotoxin- induced cardiac toxicity. Diabetes was induced in FVB mice by injecting a single dose (150 mg/kg) of streptozotocin. Two months after streptozotocin treatment, the diabetic mice were treated with lipopolysaccharide by intraperitoneal injection at 2 mg/kg. Cardiac toxicity was evaluated by measuring levels of serum cardiac enzymes and cardiac morphology at 1 h, 4.5 h, and 24 h after lipopolysaccharide treatment. Serum and cardiac tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) were detected by enzyme-linked immunosorbent assay methods at 1 h and 4.5 h after lipopolysaccharide treatment. Lipopolysaccharide treatment did not significantly affect the diabetic manifestations, including decreased body weight gain and increased glycated hemoglobin and serum triglyceride levels. However, diabetes significantly enhanced lipopolysaccharide-induced cardiac toxicity, which was demonstrated by significant increases in the levels of cardiac enzymes such as creatine phosphokinase and troponin T, abnormal morphological changes examined under light microscope with hematoxylin and eosin staining, and oxidative damage to proteins detected by 3-nitrotyrosine staining. Lipopolysaccharide treatment significantly increased serum and cardiac TNF-alpha and IL-6 concentrations. Diabetes did not alter the effect of lipopolysaccharide on serum and cardiac TNF-alpha elevation, but it significantly enhanced lipopolysaccharideinduced cardiac IL-6 production. These results suggest that diabetes significantly enhances endotoxin-induced cardiac toxicity, possibly through mechanisms that involve inflammatory/acute-phase cytokines.

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PubMed2002

Monocyte activation in alcoholic liver disease.

Activated monocytes and macrophages have been postulated to play an important role in the pathogenesis of alcoholic liver disease (ALD). Monocyte activation can be documented by measurement of neopterin, adhesion cell molecules, and certain proinflammatory cytokines and chemokines. We first became interested in the role of monocytes and monocyte-derived cytokines in ALD in relation to altered zinc metabolism that occurs regularly in ALD. Patients with ALD have hypozincemia, which responds poorly to oral zinc supplementation. We have shown that in ALD monocytes make a low-molecular-weight substance that, when injected into rabbits, causes prominent hypozincemia. Subsequently, multiple cytokines [especially tumor necrosis factor (TNF) and interleukin (IL)-8] have been shown to be overproduced by monocytes in ALD. We initially showed that monocytes in ALD spontaneously produce TNF and overproduce TNF in response to a lipopolysaccharide (LPS) stimulus, and this could be attenuated by antioxidants in vitro and in vivo. Alterations in the endotoxin-binding protein LPS-binding protein, in CD14, and in the endotoxin receptor Toll-like receptor 4 all may play roles in enhanced proinflammatory cytokine signaling in ALD. Moreover, several groups have documented increased TNF receptor density in monocytes in ALD. Inadequate negative regulation of TNF occurs at multiple levels in ALD. This includes decreased monocyte production of the important antiinflammatory cytokine IL-10 and blunted response to the antiinflammatory properties of adenosine. Finally, generation of reactive oxygen species (which occurs during alcohol metabolism) and products of lipid peroxidation induce production of cytokines, such as TNF and IL-8. In conclusion, there are multiple overlapping potential mechanisms for enhanced proinflammatory cytokine production by monocytes in ALD. We postulate that activation of monocytes and macrophages with subsequent proinflammatory cytokine production plays an important role in certain metabolic complications of ALD and is a component of the liver injury of ALD.

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PubMed2002

S-Adenosylmethionine, cytokines, and alcoholic liver disease.

Hepatic deficiency of S-adenosylmethionine (AdoMet) is a critical acquired metabolic abnormality in alcoholic liver disease (ALD) and in many experimental models of hepatotoxicity. Subnormal AdoMet, elevated serum tumor necrosis factor (TNF), and endotoxemia (LPS) are hallmarks of ALD and experimental liver injury. AdoMet deficiency is attributed to its subnormal synthesis, but mechanisms for increased TNF are not known. AdoMet deficiency may affect the critical balance of proinflammatory (e.g., TNF) and antiinflammatory [e.g., interleukin (IL)-10] cytokines. Rats maintained on a choline-deficient diet with limited amounts of methionine (MCD diet) developed AdoMet deficiency. When challenged with LPS, rats fed MCD diet had significantly increased serum TNF levels and worse liver injury compared with findings for controls. Exogenous AdoMet attenuated liver injury and serum TNF levels. Results of in vitro studies with the use of RAW 264.7 cells demonstrated that exogenous AdoMet supplementation lowered LPS-induced TNF formation in a dose-dependent manner, and AdoMet deficiency enhanced TNF secretion and TNF gene expression. AdoMet also dose-dependently decreased LPS-stimulated TNF production from monocytes obtained from patients with alcoholic hepatitis. Finally, AdoMet supplementation stimulated production of the antiinflammatory cytokine IL-10. Interleukin-10 plays a critical role in the modulation of TNF production, and IL-10 may inhibit hepatic fibrosis. This article will review (1) the role of AdoMet in ALD/liver injury, (2) the role of TNF/proinflammatory cytokines in ALD, (3) potential roles of AdoMet in TNF/proinflammatory cytokine regulation in ALD, and (4) conclusions and future directions.

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