Ming Song

Polyphenols and gastrointestinal diseases

Purpose of review This article will review the role of polyphenols in gastrointestinal diseases. Ingested polyphenols are concentrated in the gastrointestinal tract and are not well absorbed into the rest of the body. Thus, the high luminal concentrations achieved support a potential for therapeutic uses in the gastrointestinal tract. Additionally, there is great interest from the general public in complementary and alternative medicine. Recent findings Dietary polyphenols are a major source of antioxidants consumed by humans. Polyphenols possess not only antioxidant properties but also antiviral, antibacterial, antiinflammatory and anticarcinogenic effects, as well as the ability to modulate certain signaling pathways such as nuclear factor-κB activation. Green tea polyphenols have been shown to have efficacy in various models of inflammatory bowel disease. Silymarin, or milk thistle, is hepatoprotective against many forms of experimental liver injury and is widely used in human liver diseases, such as hepatitis C and alcoholic cirrhosis, with an excellent safety profile (but with unclear efficacy). Summary Substantial in-vitro and animal studies support the beneficial effects of polyphenols in many gastrointestinal diseases. Well designed multicenter trials in humans, such as those called for in the 2005 National Institutes of Health Requests for Applications for Silymarin Centers, will be critical for defining the safety, appropriate dosing and therapeutic efficacy of such agents.

High fructose feeding induces copper deficiency in Sprague-Dawley rats: a novel mechanism for obesity related fatty liver.

BACKGROUND & AIMS Dietary copper deficiency is associated with a variety of manifestations of the metabolic syndrome, including hyperlipidemia and fatty liver. Fructose feeding has been reported to exacerbate complications of copper deficiency. In this study, we investigated whether copper deficiency plays a role in fructose-induced fatty liver and explored the potential underlying mechanism(s). METHODS Male weanling Sprague-Dawley rats were fed either an adequate copper or a marginally copper deficient diet for 4 weeks. Deionized water or deionized water containing 30% fructose (w/v) was also given ad lib. Copper and iron status, hepatic injury and steatosis, and duodenum copper transporter-1 (Ctr-1) were assessed. RESULTS Fructose feeding further impaired copper status and led to iron overload. Liver injury and fat accumulation were significantly induced in marginal copper deficient rats exposed to fructose as evidenced by robustly increased plasma aspartate aminotransferase (AST) and hepatic triglyceride. Hepatic carnitine palmitoyl-CoA transferase I (CPT I) expression was significantly inhibited, whereas hepatic fatty acid synthase (FAS) was markedly up-regulated in marginal copper deficient rats fed with fructose. Hepatic antioxidant defense system was suppressed and lipid peroxidation was increased by marginal copper deficiency and fructose feeding. Moreover, duodenum Ctr-1 expression was significantly increased by marginal copper deficiency, whereas this increase was abrogated by fructose feeding. CONCLUSIONS Our data suggest that high fructose-induced nonalcoholic fatty liver disease (NAFLD) may be due, in part, to inadequate dietary copper. Impaired duodenum Ctr-1 expression seen in fructose feeding may lead to decreased copper absorption, and subsequent copper deficiency.

The Use of Selected Nutrition Supplements and Complementary and Alternative Medicine in Liver Disease

Almost all patients with liver disease, especially advanced liver disease, have some evidence of malnutrition, including mineral/vitamin deficiency. A major health trend in the United States has been the significant growth in the use of complementary and alternative medicine (CAM), including nutrition supplements and herbal agents. In the 1990s, the United States government created the National Center for Complementary and Alternative Medicine (NCCAM), as well as the Office on Dietary Supplements, to extend our knowledge in these areas. CAM users are often highly educated and frequently use CAM therapy for chronic diseases, including chronic liver disease. Indeed, most studies suggest that patients with chronic liver disease frequently use nutrition supplements and CAM agents in addition to their traditional medicines. The purpose of this review is to provide an update on the role of nutrition supplements and herbals in liver disease. This article will focus mainly on 7 selected agents (vitamin E, zinc, magnesium, S-adenosylmethionine, betaine, silymarin, and glycyrrhizin), for which there have been not only in vitro and animal studies but also human clinical trials, and we will review both potential efficacy and safety issues.

Tetrathiomolybdate Protects against Bile Duct Ligation-Induced Cholestatic Liver Injury and Fibrosis

Tetrathiomolybdate (TM), a potent copper-chelating drug, was initially developed for the treatment of Wilsons disease. Our working hypothesis is that the fibrotic pathway is copper-dependent. Because biliary excretion is the major pathway for copper elimination, a bile duct ligation (BDL) mouse model was used to test the potential protective effects of TM. TM was given in a daily dose of 0.9 mg/mouse by means of intragastric gavage 5 days before BDL. All the animals were killed 5 days after surgery. Plasma liver enzymes and total bilirubin were markedly decreased in TM-treated BDL mice. TM also inhibited the increase in plasma levels of tumor necrosis factor (TNF)-α and transforming growth factor (TGF)-β1 seen in BDL mice. Cholestatic liver injury was markedly attenuated by TM treatment as shown by histology. Hepatic collagen deposition was significantly decreased, and it was paralleled by a significant suppression of hepatic smooth muscle α-actin and fibrogenic gene expression in TM-treated BDL mice. Although the endogenous antioxidant ability was enhanced, oxidative stress as shown by malondialdehyde and 4-hydroxyalkenals, hepatic glutathione/oxidized glutathione ratio, was not attenuated by TM treatment, suggesting the protective mechanism of TM may be independent of oxidative stress. In summary, TM attenuated BDL-induced cholestatic liver injury and fibrosis in mice, in part by inhibiting TNF-α and TGF-β1 secretion. The protective mechanism seems to be independent of oxidative stress. Our data provide further evidence that TM might be a potential therapy for hepatic fibrosis.

Fructose Induced Endotoxemia in Pediatric Nonalcoholic Fatty Liver Disease

In preclinical studies of fructose-induced NAFLD, endotoxin appears to play an important role. We retrospectively examined samples from three pediatric cohorts (1) to investigate whether endotoxemia is associated with the presence of hepatic steatosis; (2) to evaluate postprandial endotoxin levels in response to fructose beverage in an acute 24-hour feeding challenge, and (3) to determine the change of fasting endotoxin amounts in a 4-week randomized controlled trial comparing fructose to glucose beverages in NAFLD. We found that adolescents with hepatic steatosis had elevated endotoxin levels compared to obese controls and that the endotoxin level correlated with insulin resistance and several inflammatory cytokines. In a 24-hour feeding study, endotoxin levels in NAFLD adolescents increased after fructose beverages (consumed with meals) as compared to healthy children. Similarly, endotoxin was significantly increased after adolescents consumed fructose beverages for 2 weeks and remained high although not significantly at 4 weeks. In conclusion, these data provide support for the concept of low level endotoxemia contributing to pediatric NAFLD and the possible role of fructose in this process. Further studies are needed to determine if manipulation of the microbiome or other methods of endotoxin reduction would be useful as a therapy for pediatric NAFLD.

Modest fructose beverage intake causes liver injury and fat accumulation in marginal copper deficient rats

Dietary fructose and copper interaction may play an important role in the pathogenesis of nonalcoholic fatty liver disease. In this study, whether or not modest fructose consumption (3% fructose, w/v) (which is more closely related to the American lifestyle with regard to sugar beverage consumption) affects copper status, and causes liver injury and fat accumulation in marginal copper deficient rats was investigated.

Copper Deficiency Exacerbates Bile Duct Ligation-Induced Liver Injury and Fibrosis in Rats

Copper levels are elevated in a variety of liver fibrosis conditions. Lowering copper to a certain level protects against fibrosis. However, whether severe copper deficiency is protective against liver fibrosis is not known. The purpose of the present study is to evaluate this question by inducing severe copper deficiency using the copper chelator, tetrathiomolybdate (TM), in a bile duct ligation (BDL) rat model. Male Sprague-Dawley rats were divided into four groups: sham, sham plus TM, BDL, and BDL plus TM. TM was given in a daily dose of 10 mg/kg by body weight by means of intragastric gavage, beginning 5 days after BDL. All animals were killed 2 weeks after surgery. Severe copper deficiency was induced by TM overdose in either sham or BDL rats, as shown by decreased plasma ceruloplasmin activity. Liver injury and fibrosis were exacerbated in BDL rats with TM treatment, as illustrated by robustly increased plasma aspartate aminotransferase and hepatic collagen accumulation. Iron stores, as measured by plasma ferritin, were significantly increased in copper-deficient BDL rats. Moreover, hepatic heme oxygenase-1 expression was markedly down-regulated by copper deficiency in BDL rats. In addition, hepatic gene expression involving mitochondrial biogenesis and β-oxidation was significantly up-regulated in BDL rats, and this increase was abolished by copper deficiency. In summary, severe copper deficiency exacerbates BDL-induced liver injury and liver fibrosis, probably caused by increased iron overload and decreased antioxidant defenses and mitochondrial dysfunction.

Effects of Dietary Different Doses of Copper and High Fructose Feeding on Rat Fecal Metabolome

The gut microbiota plays a critical role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Increased fructose consumption and inadequate copper intake are two critical risk factors in the development of NAFLD. To gain insight into the role of gut microbiota, fecal metabolites, obtained from rats exposed to different dietary levels of copper with and without high fructose intake for 4 weeks, were analyzed by comprehensive two-dimensional gas chromatography time-of-flight mass spectrometry (GC × GC-TOF MS). In parallel, liver tissues were assessed by histology and triglyceride assay. Our data showed that high fructose feeding led to obvious hepatic steatosis in both marginal copper deficient rats and copper supplementation rats. Among the 38 metabolites detected with significant abundance alteration between groups, short chain fatty acids were markedly decreased with excessive fructose intake irrespective of copper levels. C15:0 and C17:0 long chain fatty acids, produced only by bacteria, were increased by either high copper level or high fructose intake. In addition, increased fecal urea and malic acid paralleled the increased hepatic fat accumulation. Collectively, GC × GC-TOF MS analysis of rat fecal samples revealed distinct fecal metabolome profiles associated with the dietary high fructose and copper level, with some metabolites possibly serving as potential noninvasive biomarkers of fructose induced-NAFLD.

Kupffer cell depletion protects against the steatosis, but not the liver damage, induced by marginal-copper, high-fructose diet in male rats

High-fructose feeding impairs copper status and leads to low copper availability, which is a novel mechanism in obesity-related fatty liver. Copper deficiency-associated hepatic iron overload likely plays an important role in fructose-induced liver injury. Excess iron in the liver is distributed throughout hepatocytes and Kupffer cells (KCs). The aim of this study was to examine the role of KCs in the pathogenesis of nonalcoholic fatty liver disease induced by a marginal-copper high-fructose diet (CuMF). Male weanling Sprague-Dawley rats were fed either a copper-adequate or a marginally copper-deficient diet for 4 wk. Deionized water or deionized water containing 30% fructose (wt/vol) was also given ad libitum. KCs were depleted by intravenous administration of gadolinium chloride (GdCl3) before and/or in the middle of the experimental period. Hepatic triglyceride accumulation was completely eliminated with KC depletion in CuMF consumption rats, which was associated with the normalization of elevated plasma monocyte chemoattractant protein-1 (MCP-1) and increased hepatic sterol regulatory element binding protein-1 expression. However, hepatic copper and iron content were not significantly affected by KC depletion. In addition, KC depletion reduced body weight and epididymal fat weight as well as adipocyte size. Plasma endotoxin and gut permeability were markedly increased in CuMF rats. Moreover, MCP-1 was robustly increased in the culture medium when isolated KCs from CuMF rats were treated with LPS. Our data suggest that KCs play a critical role in the development of hepatic steatosis induced by marginal-copper high-fructose diet.

EIder: A compound identification tool for gas chromatography mass spectrometry data

We report software entitled EIder (EI mass spectrum identifier) that provides users with eight literature reported spectrum matching algorithms for compound identification from gas chromatography mass spectrometry (GC-MS) data. EIder calculates retention index according to experimental conditions categorized by column class, column type and data type, where 9 empirical distribution functions of the absolute retention index deviation to its mean value were constructed using the National Institute of Standards and Technology (NIST) 2011 retention index database to improve the accuracy of compound identification. EIder filters compound candidates based on elementary composition and derivatization reagent, and automatically adds the molecular information of the native compound to each derivatized compound using a manually created database. When multiple samples are analyzed together, EIder performs cross-sample alignment and provides an option of using an average mass spectrum for compound identification. Furthermore, a suite of graphical user interfaces are implemented in EIder to allow users to both manually and automatically modify the identification results using experimental information at various analysis stages. Analysis of three types of GC-MS datasets indicates that the developed EIder software can improve the accuracy of compound identification.