MicroRNA 301A Promotes Intestinal Inflammation and Colitis-Associated Cancer Development by Inhibiting BTG1.

Background & Aims: Intestinal tissues from patients with inflammatory bowel disease (IBD) and colorectal cancer have increased expression of microRNA-301a (MIR301A) compared with tissues from patients without IBD. We studied the mechanisms of MIR301A in the progression of IBD in human tissues and mice.

Methods: We isolated intestinal epithelial cells (IECs) from biopsy samples of the colon from 153 patients with different stages of IBD activity, 6 patients with colitis-associated cancer (CAC), and 35 healthy individuals (controls), enrolled in the study in Shanghai, China.

Effects of essential amino acids on lipid metabolism in mice and humans.

Eight amino acids are considered essential for human nutrition, and three of them, including leucine, isoleucine and valine, are called as branched-chain amino acids (BCAAs). We recently discovered that dietary deficiency of any BCAA for 7 days rapidly reduces the abdominal fat mass in mice. The goal of this study was to investigate (1) whether dietary deficiency of the other five essential amino acids (EAAs), including phenylalanine, threonine, tryptophan, methionine and lysine, would produce similar effects and (2) whether an association between serum AAs and obesity was observed in humans in Chinese Han population.

Leucine deprivation inhibits proliferation and induces apoptosis of human breast cancer cells via fatty acid synthase.

Substantial studies on fatty acid synthase (FASN) have focused on its role in regulating lipid metabolism and researchers have a great interest in treating cancer with dietary manipulation of amino acids. In the current study, we found that leucine deprivation caused the FASN-dependent anticancer effect. Here we showed that leucine deprivation inhibited cell proliferation and induced apoptosis of MDA-MB-231 and MCF-7 breast cancer cells.

Knockout of inositol-requiring enzyme 1α in pro-opiomelanocortin neurons decreases fat mass via increasing energy expenditure.

Although numerous functions of inositol-requiring enzyme 1α (IRE1α) have been identified, a role of IRE1α in pro-opiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus is largely unknown. Here, we showed that mice lacking IRE1α specifically in POMC neurons (PIKO) are lean and resistant to high-fat diet-induced obesity and obesity-related insulin resistance, liver steatosis and leptin resistance. Furthermore, PIKO mice had higher energy expenditure, probably due to increased thermogenesis in brown adipose tissue.

Liver-specific Gene Inactivation of the Transcription Factor ATF4 Alleviates Alcoholic Liver Steatosis in Mice.

Although numerous biological functions of the activating transcription factor 4 (ATF4) have been identified, a direct effect of ATF4 on alcoholic liver steatosis has not been described previously. The aim of our current study is to investigate the role of ATF4 in alcoholic liver steatosis and elucidate the underlying mechanisms. Here, we showed that the expression of ATF4 is induced by ethanol in hepatocytes in vitro and in vivo, and liver-specific ATF4 knock-out mice are resistant to ethanol-induced liver steatosis, associated with stimulated hepatic AMP-activated protein kinase (AMPK) activity.

MAPK1/3 regulate hepatic lipid metabolism via ATG7-dependent autophagy.

Although many biological functions of MAPK1/ERK2-MAPK3/ERK1 (mitogen-activated protein kinase 1/3) have been reported, a direct effect of MAPK1/3 on hepatic lipid metabolism remains largely unknown. We recently showed that activation of MAPK1/3 ameliorates liver steatosis in LEPR (leptin receptor)-deficient (db/db) mice, a classic animal model for liver steatosis. Consistent with these results, knockdown of MAPK1/3 promotes liver steatosis in C57/B6J wild-type (WT) mice.

A novel function of B-cell translocation gene 1 (BTG1) in the regulation of hepatic insulin sensitivity in mice via c-Jun.

Insulin resistance is one of the major factors contributing to metabolic diseases, but the underlying mechanisms are still poorly understood. As an important cofactor, B-cell translocation gene 1 (BTG1) is involved in many physiologic processes; however, the direct effect of BTG1 on insulin sensitivity has not been described. In our study, BTG1 overexpression or knockdown improved or impaired insulin signaling in vitro, respectively.

CREB/TRH pathway in the central nervous system regulates energy expenditure in response to deprivation of an essential amino acid.

Background: In the central nervous system (CNS), thyrotropin-releasing hormone (TRH) has an important role in regulating energy balance. We previously showed that dietary deprivation of leucine in mice increases energy expenditure through CNS-dependent regulation. However, the involvement of central TRH in this regulation has not been reported.

Effects of individual branched-chain amino acids deprivation on insulin sensitivity and glucose metabolism in mice.

Objective: We recently discovered that leucine deprivation increases hepatic insulin sensitivity via general control nondepressible (GCN) 2/mammalian target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) pathways. The goal of the present study was to investigate whether the above effects were leucine specific or were also induced by deficiency of other branched chain amino acids including valine and isoleucine.

Methods: Following depletion of BCAAs, changes in metabolic parameters and the expression of genes and proteins involved in regulation of insulin sensitivity and glucose metabolism were analyzed in mice and cell lines including human HepG2 cells, primary mouse hepatocytes and a mouse myoblast cell line C2C12.

ATF4 deficiency protects hepatocytes from oxidative stress via inhibiting CYP2E1 expression.

Activating transcription factor (ATF) 4 is involved in the regulation of oxidative stress in fibroblasts and neurons. The role of ATF4 in hepatocytes, however, is unknown. The aim of this study was to investigate the role of ATF4 in hepatocytes in oxidative stress under a high-fat diet (HFD).

Aberrant expression of trefoil factor 3 is associated with colorectal carcinoma metastasis.

Background: Recent evidence has indicated that the trefoil factor family possesses pivotal roles in the progression of human cancer. Aberrant expression of trefoil factor 3 (TFF3) has been reported to correlate with an aggressive tumor phenotype. However, the clinical importance of TFF3 expression in colorectal carcinomas (CRCs) has rarely been addressed.

PRLR regulates hepatic insulin sensitivity in mice via STAT5.

Insulin resistance is one of the major contributing factors in the development of metabolic diseases. The mechanisms responsible for insulin resistance, however, remain poorly understood. Although numerous functions of the prolactin receptor (PRLR) have been identified, a direct effect on insulin sensitivity has not been previously described.

Molecular genetic analysis of sexual rejection: roles of octopamine and its receptor OAMB in Drosophila courtship conditioning.

After Drosophila males are rejected by mated females, their subsequent courtship is inhibited even when encountering virgin females. Molecular mechanisms underlying courtship conditioning in the CNS are unclear. In this study, we find that tyramine β hydroxylase (TβH) mutant males unable to synthesize octopamine (OA) showed impaired courtship conditioning, which could be rescued by transgenic TβH expression in the CNS.

Effects of ATF4 on PGC1α expression in brown adipose tissue and metabolic responses to cold stress.

Objective: We have shown previously that the expression of peroxisome proliferator activated receptor gamma coactivator (PGC1α) increases significantly in the white and brown adipose tissue of activating transcription factor 4 (ATF4) global knockout mice, which suggests that ATF4 is involved in the regulation of PGC1α expression. The goal of the current study is to investigate this possibility and elucidate the underlying cellular mechanisms.

Material/methods: The effects of ATF4 on PGC1α expression and on PGC1α promoter activity were analyzed in vivo and in vitro using mice, HIB-1B, and 293T cell line.

Effects of activating transcription factor 4 deficiency on carbohydrate and lipid metabolism in mammals.

It has been shown that the mammalian activating transcription factor 4 (ATF4) is involved in many different physiological events, such as eye development, stress response, learning, and memory. However, several recent studies have demonstrated that ATF4 also plays an important role in the regulation of lipid and glucose metabolism, energy homeostasis, insulin secretion, and sensitivity, suggesting that ATF4 is a master regulator of metabolism. This review summarizes the most recent progress in the understanding of the novel roles of ATF4 in the regulation of metabolism.

Isoleucine or valine deprivation stimulates fat loss via increasing energy expenditure and regulating lipid metabolism in WAT.

There has been a growing interest in controlling body weight by increasing dietary levels of leucine recently. By contrast, we have focused on studying the effect of deficiency of branched-chain amino acids (BCAAs) leucine on lipid metabolism. We previously have shown that mice fed a leucine-deficient diet for 7 days exhibit significant changes in lipid metabolism as demonstrated by suppressed lipogenesis in the liver and increased fat mobilization in white adipose tissue, the latter of which was found to be caused by increased lipolysis in WAT and uncoupling protein 1 expression in brown adipose tissue.

ATF4 deficiency protects mice from high-carbohydrate-diet-induced liver steatosis.

Chronic feeding of HCD (high-carbohydrate diet) is one of the major contributors to the prevailing of metabolic diseases. ATF4 (activating transcription factor 4) has been shown to play an important role in the regulation of glucose metabolism and obesity development; however, it is unclear how ATF4(-/-) mice respond to HCD. In the present study, we show that 8 weeks of HCD results in significant higher accumulation of TAGs (triacylglycerols) in livers and impairment in glucose tolerance in ATF4(+/+) mice, but not in ATF4(-/-) mice, compared with those on a normal diet.

Leucine deprivation increases hepatic insulin sensitivity via GCN2/mTOR/S6K1 and AMPK pathways.

Objective: We have previously shown that serum insulin levels decrease threefold and blood glucose levels remain normal in mice fed a leucine-deficient diet, suggesting increased insulin sensitivity. The goal of the current study is to investigate this possibility and elucidate the underlying cellular mechanisms.

Research Design And Methods: Changes in metabolic parameters and expression of genes and proteins involved in regulation of insulin sensitivity were analyzed in mice, human HepG2 cells, and mouse primary hepatocytes under leucine deprivation.

Yeast telomerase subunit Est1p has guanine quadruplex-promoting activity that is required for telomere elongation.

Telomeres are eukaryotic protein-DNA complexes found at the ends of linear chromosomes that are essential for maintaining genome integrity and are implicated in cellular aging and cancer. The guanine (G)-rich strand of telomeric DNA, usually elongated by the telomerase reverse transcriptase, can form a higher-order structure known as a G-quadruplex in vitro and in vivo. Several factors that promote or resolve G-quadruplexes have been identified, but the functional importance of these structures for telomere maintenance is not well understood.

Leucine deprivation decreases fat mass by stimulation of lipolysis in white adipose tissue and upregulation of uncoupling protein 1 (UCP1) in brown adipose tissue.

Objective: White adipose tissue (WAT) and brown adipose tissue (BAT) play distinct roles in adaptation to changes in nutrient availability, with WAT serving as an energy store and BAT regulating thermogenesis. We previously showed that mice maintained on a leucine-deficient diet unexpectedly experienced a dramatic reduction in abdominal fat mass. The cellular mechanisms responsible for this loss, however, are unclear.

KMBP2O8 (M = Sr, Ba): a new kind of noncentrosymmetry borophosphate with the three-dimensional diamond-like framework.

Two new isotypic anhydrous borophosphates, KMBP(2)O(8) (M = Sr, Ba), have been prepared under high temperature solution growth (HTSG). Investigation of single-crystal X-ray diffraction shows that they crystallize in noncentrosymmetric space group I42d with the following lattice parameters: a = 7.1095(18), c = 13.

Abrogation of hepatic ATP-citrate lyase protects against fatty liver and ameliorates hyperglycemia in leptin receptor-deficient mice.

Unlabelled: Hepatic steatosis is a hallmark of nonalcoholic fatty liver disease (NAFLD) and a key component of obesity-associated metabolic dysfunctions featuring dyslipidemia, insulin resistance, and loss of glycemic control. It has yet to be completely understood how much dysregulated de novo lipogenesis contributes to the pathogenic development of hepatic steatosis and insulin resistance. ATP-citrate lyase (ACL) is a lipogenic enzyme that catalyzes the critical reaction linking cellular glucose catabolism and lipogenesis, converting cytosolic citrate to acetyl-coenzyme A (CoA).

Reconstitution of human Ero1-Lalpha/protein-disulfide isomerase oxidative folding pathway in vitro. Position-dependent differences in role between the a and a' domains of protein-disulfide isomerase.

Protein-disulfide isomerase (PDI), a critical enzyme responsible for oxidative protein folding in the eukaryotic endoplasmic reticulum, is composed of four thioredoxin domains a, b, b', a', and a linker x between b' and a'. Ero1-Lalpha, an oxidase for human PDI (hPDI), has been determined to have one molecular flavin adenine dinucleotide (FAD) as its prosthetic group. Oxygen consumption assays with purified recombinant Ero1-Lalpha revealed that it utilizes oxygen as a terminal electron acceptor producing one disulfide bond and one molecule of hydrogen peroxide per dioxygen molecule consumed.

Product monitoring and quantitation of oligosaccharides composition in agar hydrolysates by precolumn labeling HPLC.

Since the discovery of multiple bioactivities for agarobiose oligomers, a quantitative method has been in great need to monitor the agarobiose oligomers. This report demonstrates that agarobiose oligomers can be separated with high resolution in HPLC after introducing alpha-naphthylamine into compounds. Agarobiose oligomers ranged from biose to decaose were isolated by Sephadex column.

N-(2-Nitro-phenyl-sulfon-yl)-N-(4-nitro-phenyl-sulfon-yl)methyl-amine.

In the crystal structure of the title compound, C(13)H(11)N(3)O(8)S(2), mol-ecules are linked by inter-molecular C-H⋯O hydrogen bonds into zigzag chains running parallel to the c axis. Centrosymmetrically related chains are further stabilized by aromatic π-π stacking inter-actions [centroid-centroid distance = 3.749 (3) Å] involving adjacent 4-nitro-benzene rings.