Dietary choline increases brown adipose tissue activation markers and improves cholesterol metabolism in female APOE*3-Leiden.CETP mice.

OBJECTIVES: Studies in mice have recently linked increased dietary choline consumption to increased incidence of obesity-related metabolic diseases, while several clinical trials have reported an anti-obesity effect of high dietary choline intake. Since the underlying mechanisms by which choline affects obesity are incompletely understood, the aim of the present study was to investigate the role of dietary choline supplementation in adiposity. METHODS: Female APOE*3-Leiden.CETP mice, a well-established model for human-like lipoprotein metabolism and cardiometabolic diseases, were fed a Western-type diet supplemented with or without choline (1.2%, w/w) for up to 16 weeks. RESULTS: Dietary choline reduced body fat mass gain, prevented adipocyte enlargement, and attenuated adipose tissue inflammation. Besides, choline ameliorated liver steatosis and damage, associated with an upregulation of hepatic genes involved in fatty acid oxidation. Moreover, choline reduced plasma cholesterol, as explained by a reduction of plasma non-HDL cholesterol. Mechanistically, choline reduced hepatic VLDL-cholesterol secretion and enhanced the selective uptake of fatty acids from triglyceride-rich lipoprotein (TRL)-like particles by brown adipose tissue (BAT), consequently accelerating the clearance of the cholesterol-enriched TRL remnants by the liver. CONCLUSIONS: In APOE*3-Leiden.CETP mice, dietary choline reduces body fat by enhancing TRL-derived fatty acids by BAT, resulting in accelerated TRL turnover to improve hypercholesterolemia. These data provide a mechanistic basis for the observation in human intervention trials that high choline intake is linked with reduced body weight.

Choline and butyrate beneficially modulate the gut microbiome without affecting atherosclerosis in APOE*3-Leiden.CETP mice.

BACKGROUND AND AIMS: Choline has been shown to exert atherogenic effects in Apoe-/- and Ldlr-/- mice, related to its conversion by gut bacteria into trimethylamine (TMA) that is converted by the liver into the proinflammatory metabolite trimethylamine-N-oxide (TMAO). Since butyrate beneficially modulates the gut microbiota and has anti-inflammatory and antiatherogenic properties, the aim of the present study was to investigate whether butyrate can alleviate choline-induced atherosclerosis. To this end, we used APOE*3-Leiden.CETP mice, a well-established atherosclerosis-prone model with human-like lipoprotein metabolism. METHODS: Female APOE*3-Leiden.CETP mice were fed an atherogenic diet alone or supplemented with choline, butyrate or their combination for 16 weeks. RESULTS: Interestingly, choline protected against fat mass gain, increased the abundance of anti-inflammatory gut microbes, and increased the expression of gut microbial genes involved in TMA and TMAO degradation. Butyrate similarly attenuated fat mass gain and beneficially modulated the gut microbiome, as shown by increased abundance of anti-inflammatory and short chain fatty acid-producing microbes, and inhibited expression of gut microbial genes involved in lipopolysaccharide synthesis. Both choline and butyrate upregulated hepatic expression of flavin-containing monooxygenases, and their combination resulted in highest circulating TMAO levels. Nonetheless, choline, butyrate and their combination did not influence atherosclerosis development, and TMAO levels were not associated with atherosclerotic lesion size. CONCLUSIONS: While choline and butyrate have been reported to oppositely modulate atherosclerosis development in Apoe-/- and Ldlr-/- mice as related to changes in the gut microbiota, both dietary constituents did not affect atherosclerosis development while beneficially modulating the gut microbiome in APOE*3-Leiden.CETP mice.

Negative regulators of Wnt signaling in non-small cell lung cancer: Theoretical basis and therapeutic potency.

Significant advances in the treatment of non-small cell lung cancer (NSCLC) have been made over the past decade, and they predominantly involve molecular targets such as epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements. However, despite the initial good response, drug resistance eventually develops. The Wnt signaling pathway has recently been considered important in embryonic development and tumorigenesis in many cancers, particularly NSCLC. Moreover, the aberrant Wnt pathway plays a significant role in NSCLC and is associated with cancer cell proliferation, metastasis, invasion and drug resistance, and the suppression of canonical or noncanonical Wnt signaling through various biological or pharmacological negative regulators has been proven to produce specific anticancer effects. Thus, blocking the Wnt pathway via its negative regulators may overcome the resistance of current treatment methods and lead to new treatment strategies for NSCLC. Therefore, in this review, we summarize recent studies on the role of negative regulators in Wnt signaling in NSCLC and the therapeutic potency of these molecules as agents and targets for NSCLC treatments.

A new proposal of utilizing intraoperative electron radiation therapy on the surface of liver to prevent postoperative liver metastasis of pancreatic cancer.

Pancreatic cancer is a lethal cancer with high rate of liver metastasis worldwide, whereas its treatment choices are limited to a large extent. The limitation of current therapeutic strategies calls for an effective approach which can lower the postoperative liver metastasis rate in order to improve the overall prognosis and survival rate. Comprehensively considering the basic knowledge and clinical practice of tumor treatment worldwide, we proposed three points of hypotheses. Basically, the existing evidences indicated that tumor cells shedding from pancreatic cancer localized in the marginal liver preferentially through the Portal vein. Then, the percentage depth dose distribution of electron radiation is consistent with the marginal distribution of liver metastasis from pancreatic cancer. Based on the characteristics of liver metastasis of pancreatic cancer and the percentage depth dose of electron radiation, we provide a new propose of preventing postoperative liver metastasis in a way of prophylactic intraoperative electron radiation therapy on the surface of liver. Intraoperative electron radiation is relatively easy to control radiation dose and treatment area under direct vision, effectively inhibiting the metastasis and growth of cancer cells and preventing further deterioration of pancreatic cancer patients' condition. Therefore, this hypothesis has an important clinical significance for postoperative rehabilitation and improvement of patients' survival.

Application of NMR metabolomics to search for human disease biomarkers in blood.

Recently, nuclear magnetic resonance spectroscopy (NMR)-based metabolomics analysis and multivariate statistical techniques have been incorporated into a multidisciplinary approach to profile changes in small molecules associated with the onset and progression of human diseases. The purpose of these efforts is to identify unique metabolite biomarkers in a specific human disease so as to (1) accurately predict and diagnose diseases, including separating distinct disease stages; (2) provide insights into underlying pathways in the pathogenesis and progression of the malady and (3) aid in disease treatment and evaluate the efficacy of drugs. In this review we discuss recent developments in the application of NMR-based metabolomics in searching disease biomarkers in human blood samples in the last 5 years.