Recent evidence indicates that inflammatory cytokines are involved in changes of blood glucose concentrations and hepatic glucose metabolism in infectious diseases, including sepsis. However, little is known regarding how cytokines interact with glucoregulatory hormones such as insulin. The objective of the present study is to investigate if and how cytokines influence insulin-stimulated glycogen metabolism in the liver. Interleukin 1␤ (IL-1␤) and interleukin 6 (IL-6) markedly inhibited the increase of glycogen deposition stimulated by insulin in primary rat hepatocyte cultures; however, tumor necrosis factor ␣ had no effect. Labeling experiments revealed that both cytokines counteracted insulin action by decreasing The regulation of carbohydrate metabolism, including glucose input and output, is one of the liver' s most important functions in the homeostasis of glucose concentration. Classical hormones such as insulin, glucagon, glucocorticoid, and adrenaline, contribute largely to the maintenance of glucose concentration as well as to general physiological homeostasis. During septic shock associated with severe infectious diseases, there are marked changes in blood glucose and its metabolism in various organs including liver, adipose tissue and skeletal muscle. 1 These alterations come mainly from imbalanced, and usually increased, concentrations of glucoregulatory and stress hormones. 2,3 However, such a change in the hormone concentrations does not explain every alteration occurring in the blood and tissues, 4 implying that additional factors contribute to the changes of glucose metabolism.Recently, considerable attention has been given to the effects of inflammatory cytokines in the liver. 5 These cytokines are produced by lymphocytes, macrophages, or other cells as part of the inflammatory reactions to trauma, infection, and malignancy; these cells also mediate the interaction among different cells and tissues. The administration of interleukin 1 (IL-1), tumor necrosis factor ␣ (TNF␣), or a combination of both results in hyperglycemia followed by hypoglycemia in animals. 4,[6][7][8] The administration of TNF␣ to rats impairs insulin action on peripheral glucose consumption and hepatic glucose output, 9 suggesting that cytokines are involved in the decreased tissue sensitivity to insulin. 10,11 Furthermore, it is reported that IL-1␤ stimulated glycogen degradation concomitantly with the decrease of glycogen synthase activity 12 and that IL-1␣ and IL-6 inhibited glycogen synthesis and stimulated glycogen degradation 13 in isolated rat hepatocytes. Ritchie 14 demonstrated that IL-6, but not IL-1, stimulated [ 14 C]-glucose release from [ 14 C]-glycogenlabeled hepatocytes.Accumulating evidence indicates that cytokines are potential mediators of abnormalities in glucose homeostasis, interacting with above glucoregulatory hormones and modifying their actions. However, it is obscure which cytokines interact with glucoregulatory hormones in hepatic glucose metabolism. In the present study, we investigate the effec...

Overexpressed LPCAT1 protein in gastric mucosa appears to play important roles in the tumorigenic process of gastric cancer by converting LPC to PC.

The aim of this study was to investigate the inhibitory effect of TSU68 [(Z)-5-[(1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-propanoic acid; SU6668], an inhibitor of vascular endothelial growth factor receptor 2, plateletderived growth factor receptor B, and fibroblast growth factor receptor 1 (FGFR1), on colon cancer liver metastasis, and to test the hypothesis that TSU68 modulates the microenvironment in the liver before the formation of metastasis. First, we implanted the highly metastatic human colon cancer TK-4 orthotopically into the cecal walls of nude mice, followed by twice-daily administration of TSU68 (400 mg/kg/d) or vehicle. Five weeks of treatment with TSU68 significantly inhibited liver metastasis compared with the control group (P < 0.001). Next, we analyzed the gene expression profile in premetastatic liver using microarrays. Microarray and quantitative reverse transcription-PCR analysis showed that mRNA levels for the chemokine CXCL1 were significantly increased in tumorbearing mice compared with non-tumor-bearing mice. Moreover, CXCL1 expression was significantly decreased by TSU68 treatment. CXCR2 expression was detected predominantly on tumor cells in orthotopic tumors compared with ectopic tumors. The number of migrating neutrophils in premetastatic liver was significantly decreased in the TSU68-treated group (P < 0.001). The amount of interleukin-12 (IL-12) p40 in the portal vein was significantly decreased by TSU68 (P = 0.02). Blockade of both CXCR2 and IL-12 p40 with a neutralizing antibody significantly inhibited liver metastasis. These results suggest that the CXCL1/CXCR2 axis is important in cancer metastasis and that TSU68 may modulate the premetastatic niche in the target organ through suppression of the inflammatory response, which might be an alternative mechanism used by antiangiogenic agents. [Cancer Res 2008;68(23):9754-62]

Our study is the largest report of patients harboring MORC2 variants. We revealed a clinical and mutational spectrum of Japanese patients with MORC2 variants. More attention should be paid to cognitive impairment, and the responsible mechanism requires further research for elucidation.

A reduced expression level of the cyclin-dependent kinase inhibitor p27Kip1 is associated with increased tumor malignancy and poor prognosis in individuals with various types of cancer. To investigate the basis for this relation, we applied microarray analysis to screen for genes differentially expressed between p27 +/À and parental (p27 +/+ ) HCT116 human colon carcinoma cells. Expression of the gene for G protein-coupled receptor 48 (GPR48) was increased in the p27 +/À cells. Forced expression of GPR48 increased both in vitro invasive activity and lung metastasis potency of HCT116 cells. In contrast, depletion of endogenous GPR48 by RNA interference reduced the invasive potential of HeLa and Lewis lung carcinoma cells not only in vitro but also in vivo. Moreover, GPR48 expression was significantly associated with lymph node metastasis and inversely correlated with p27 expression in human colon carcinomas. GPR48 may thus play an important role in invasiveness and metastasis of carcinoma and might therefore represent a potential prognostic marker or therapeutic target. (Cancer Res 2006; 66(24): 11623-31)