Purpose: Colorectal carcinogenesis is thought to be related to abdominal obesity and insulin resistance. To investigate whether visceral fat accumulation contributes to colorectal carcinogenesis, we examined its accumulation and the levels of the adipose tissue^derived hormone adiponectin in Japanese patients with colorectal adenoma. Experimental Design: Fifty-one consecutive Japanese patients ages z40 years and with colorectal adenoma were subjected to measurement of visceral fat area by computed tomography scanning and plasma adiponectin concentration. The patients also underwent the 75-g oral glucose tolerance test. Insulin resistance was calculated by the homeostasis metabolic assessment (HOMA-IR) method. The controls were 52 Japanese subjects ages z40 years and without colorectal polyp. Cigarette smokers and subjects who consumed alcohol (z30 g ethanol/d) were excluded. Results: The patients with colorectal adenoma showed significantly more visceral fat area and significantly less plasma adiponectin concentration in comparison with the controls [odds ratio (OR), 2.19; 95% confidence interval (95% CI), 1.47-3.28; P < 0.001 and OR, 0.24; 95% CI, 0.14-0.41; P < 0.001, respectively] by logistic regression analysis. HOMA-IR index was also associated with colorectal adenoma (OR 2.60; 95% CI, 1.20-5.64; P = 0.040). Visceral fat area and adiponectin were associated with adenoma number (1, 2, z 3), the size of the largest adenoma (<10 and z10 mm), and adenoma histology (tubular and tubulovillous/villous). Conclusions: These results suggest an association of visceral fat accumulation and decreased plasma adiponectin concentration with colorectal adenoma in Japanese patients. This study may offer a new insight to understanding the relationship of colorectal carcinogenesis with abdominal obesity and insulin resistance.

The proliferation of hepatic stellate cells (HSCs) is a critical step in hepatic fibrogenesis. Platelet‐derived growth factor (PDGF) is the most potent mitogen for HSCs. We investigated the role of nonphagocytic NAD(P)H oxidase–derived reactive oxygen species (ROS) in PDGF‐induced HSC proliferation. The human HSC line, LI‐90 cells, murine primary‐cultured HSCs, and PDGF‐BB were used in this study. We examined the mechanism of PDGF‐BB‐induced HSC proliferation in relation to the role of a ROS scavenger and diphenylene iodonium, an inhibitor of NAD(P)H oxidase. We also measured ROS production with the aid of chemiluminescence. We showed that PDGF‐BB induced proliferation of HSCs through the intracellular production of ROS. We also demonstrated that HSCs expressed key components of nonphagocytic NAD(P)H oxidase (p22phox, gp91phox, p47phox, and p67phox) at both the messenger RNA and protein levels. Diphenylene iodonium suppressed PDGF‐BB–induced ROS production and HSC proliferation. Coincubation of H2O2 and PDGF‐BB restored the proliferation of HSCs that was inhibited by diphenylene iodonium pretreatment. Phosphorylation of the mitogen‐activated protein kinase (MAPK) family constitutes a signal transduction pathway of cell proliferation. Our data demonstrate that NAD(P)H oxidase–derived ROS induce HSC proliferation mainly through the phosphorylation of p38 MAPK. Moreover, an in vivo hepatic fibrosis model also supported the critical role of NAD(P)H oxidase in the activation and proliferation of HSCs. In conclusion, NAD(P)H oxidase is expressed in HSCs and produces ROS via activation of NAD(P)H oxidase in response to PDGF‐BB. ROS further induce HSC proliferation through the phosphorylation of p38 MAPK. (HEPATOLOGY 2005;41:1272–1281.)

Nitric oxide subserves diverse physiologic roles in the nervous system. NO is produced from at least three different NO synthase (NOS) isoforms: neuronal NOS (nNOS), endothelial NOS, and immunologic NOS (iNOS). We show that nNOS is the predominant isoform constitutively expressed in glia. NO derived from nNOS in glia inhibits the transcription factor nuclear factor B (NFB) as NOS inhibitors enhance basal NFB activation. Pyrrolidine dithiocarbamate (PDTC) is an inhibitor of NFB in most cells; however, we show that PDTC is also a potent scavenger of NO through formation of mononitrosyl iron complexes with PDTC. In Jurkat cells, a human T-cell lymphoma cell line, tumor necrosis factor-␣ (TNF-␣) induces NFB activation that is inhibited by PDTC. Contrary to the results in Jurkat cells, PDTC did not inhibit tumor necrosis factor-␣-induced NFB activation in astrocytes; instead PDTC itself induces NFB activation in astrocytes, and this may be related to scavenging of endogenously produced NO by the PDTC iron complex. In astrocytes PDTC also dramatically induces the NFBdependent enzyme, iNOS, supporting the physiologic relevance of endogenous NO regulation of NFB. NFB activation in glia from mice lacking nNOS responds more rapidly to PDTC compared with astrocytes from wild-type mice. Our data suggest that nNOS in astrocytes regulates NFB activity and iNOS expression, and indicate a novel regulatory role for nNOS in tonically suppressing central nervous system, NFBregulated genes.Nitric oxide is a potent messenger molecule with diverse physiologic activities, including regulation of vascular tone, neurotransmission, and killing of microorganisms and tumor cells (1-3). NO is produced from L-arginine (L-Arg) by the enzyme NO synthase (NOS). A family of related NOS proteins are the products of different genes and include neuronal NOS (nNOS, type 1), immunologic NOS (iNOS, type 2), and endothelial NOS (eNOS, type 3) (3). nNOS occurs in discreet neuronal populations in the brain and also is localized to the sarcoplasmic reticulum of skeletal muscle (4). eNOS primarily has endothelial cell localizations, but also is localized to a variety of other tissue types, including CA1 pyramidal cells of the hippocampus (5). Both nNOS and eNOS are constitutively expressed and are calcium-calmodulin-dependent enzymes (3, 4). iNOS is expressed in response to cytokines, lipopolysaccharide (LPS), and a host of other agents (6, 7). iNOS has been localized to a variety of cell types upon appropriate immunologic stimulation (6, 7). The key to regulation of NO production by iNOS is through regulation of transcription (8, 9).Characterization of the promoter region of the gene for iNOS reveals a complex pattern of regulation (8-12). Upstream from the transcription start site are distinct regulatory regions, including LPS-related response elements, binding sites for NFB, and ␥-interferon motifs (8-11). Recent studies indicate that NO transcriptionally inhibits iNOS mRNA expression in astrocytes (13). However, the mechanism by which NO transc...