Metformin, an antidiabetic agent, suppresses the production of tumor necrosis factor and tissue factor by inhibiting early growth response factor-1 expression in human monocytes in vitro.

Metformin, an antidiabetic agent, has been shown to reduce atherothrombotic disease in diabetic patients independent of antihyperglycemic effect. Recent studies have demonstrated that metformin attenuates the proinflammatory responses in human vascular wall cells and macrophages. However, the detailed molecular mechanisms underlying these therapeutic effects remain unclear. In the present study, we investigated the effects of metformin on tumor necrosis factor (TNF) production and tissue factor (TF) expression in isolated human monocytes stimulated with lipopolysaccharide (LPS) or oxidized low-density lipoprotein (oxLDL). Metformin significantly inhibited both TNF production and TF expression in isolated human monocytes stimulated with LPS or oxLDL. Metformin also significantly inhibited TNF and TF mRNA in human monocytes stimulated with LPS. Although metformin did not inhibit the activation of either nuclear factor-kappaB or activator protein-1, it inhibited the expression of early growth response factor-1 (Egr-1) and phosphorylation of extracellular signal-regulated protein kinase (ERK) 1/2 in monocytes stimulated with LPS or oxLDL. These results suggest that metformin may attenuate the inflammatory responses, at least in part, by suppressing the production of both TNF and TF through the inhibition of the ERK1/2-Egr-1 pathway in human monocytes.

Before-after study of a restricted fluid infusion strategy for management of donor hepatectomy for living-donor liver transplantation.

PURPOSE: Intraoperative fluid infusion strategy remains controversial. Many animal model studies have shown that restricted fluid infusion reduces blood loss, though reports on this topic in humans are rare. The purpose of this study was to determine the effects on volume of blood loss of a restricted fluid infusion strategy for hepatectomy in donors for living donor liver transplantation. METHODS: A before-after study design was used with prospective consecutive data collection. A total of 22 patients who underwent living-donor hepatectomy were enrolled. Eleven patients who were managed before the implementation of restricted-volume fluid administration comprised the standard-volume group, and 11 who were evaluated after the implementation of the restricted-volume infusion strategy comprised the restricted-volume group. In the standard-volume group, the donors were given 10 ml x kg(-1) x h(-1) of lactated Ringer's solution and additional plasma expander corresponding to blood loss. In the restricted-volume group, the donors received 5 ml x kg(-1) x h(-1) of lactated Ringer's solution until the resection of the hepatic graft, followed by 15 ml x kg(-1) x h(-1) of lactated Ringer's solution after the completion of resection until the end of the operation. RESULTS: Intraoperative blood loss was less in the restricted-volume group (445 +/- 193 ml) than in the standard-volume group (1331 +/- 602 ml; P < 0.01). Intraoperative fluid infusion was also less in the restricted-volume group (4130 +/- 563 ml) than in the standard-volume group (5634 +/- 1260 ml; P < 0.01). There were no differences in length of hospital stay or side effects between the two groups. CONCLUSION: Our restricted-volume strategy reduced blood loss and had no adverse effects during living-donor hepatectomy.

A new enteral diet, MHN-02, which contains abundant antioxidants and whey peptide, protects against carbon tetrachloride-induced hepatitis.

BACKGROUND: Inflammatory or oxidative stress is related to various diseases, including not only inflammatory diseases, but also diabetes, cancer, and atherosclerosis. The aim of this study was to evaluate the anti-inflammatory effects of a new enteral diet, MHN-02, which contains abundant antioxidants and whey peptide. The study also investigated the ability of MHN-02 to attenuate lethality, liver injury, the production of inflammatory cytokines, and the production of oxidized products using a carbon tetrachloride-induced rat model of severe fulminant hepatitis. METHODS: Male Sprague-Dawley rats were fed either a control diet or the MHN-02 diet for 14 days and injected with 2 mL/kg of carbon tetrachloride. Survival of rats was monitored from day 0 to day 3. To evaluate liver injury, inflammation, and oxidative stress, blood and liver samples were collected, and aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, interleukin 6, tumor necrosis factor-α, and superoxide dismutase activity as a free radical scavenger were measured. A portion of the liver was evaluated histologically. RESULTS: The survival rates of rats receiving the MHN-02 diet and the control diet were 90% and 55%, respectively. In the MHN-02 diet group, levels of serum liver enzymes and serum cytokines were significantly lower than in the control group. Superoxide dismutase activity in the MHN-02 diet was significantly higher in the MHN-02 group. Pathological lesions were significantly larger in the control group. CONCLUSION: Supplementation of enteral diets containing whey peptide and antioxidants may protect against severe hepatitis.

Carvedilol, a nonselective beta-blocker, suppresses the production of tumor necrosis factor and tissue factor by inhibiting early growth response factor-1 expression in human monocytes in vitro.

Tumor necrosis factor (TNF) and tissue factor (TF) produced by monocytes and macrophages have been shown to be among the aggravating factors for chronic heart failure (CHF), because they induce cardiac dysfunction and thrombotic complications, respectively. Carvedilol, a nonselective beta-adrenoceptor antagonist with alpha(1)- adrenoceptor blockade action, has been demonstrated to improve the outcome of patients with severe CHF, suggesting that carvedilol might inhibit the production of TNF and TF. In this study, this possibility is examined using isolated human monocytes stimulated with lipopolysaccharide (LPS) in vitro. Carvedilol (10 muM) significantly inhibited LPS-induced production of TNF and TF by monocytes, whereas prazosin (a selective alpha(1)-adrenoceptor antagonist), bisoprolol (a selective beta(1)-adrenoceptor antagonist), ICI-118,551 (a selective beta(2)-adrenoceptor antagonist), and arotinolol (a nonselective beta-adrenoceptor antagonist with alpha(1)-adrenoceptor blockade action) did not. Carvedilol inhibited both expression of early growth response factor-1 (Egr-1) and phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, but it did not inhibit activation of either nuclear factor-kappaB or activator protein-1 in monocytes stimulated with LPS. These results suggest that carvedilol inhibits LPS-induced production of TNF and TF by inhibiting activation of the ERK1/2-Egr-1 pathway independent of its adrenoceptor inhibitory activities in monocytes.