Author Correction: B-cell translocation gene 2 enhances fibroblast growth factor 21 production by inducing Kruppel-like factor 15.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

B-cell translocation gene 2 enhances fibroblast growth factor 21 production by inducing Kruppel-like factor 15.

Fibroblast growth factor 21 (FGF21) is a hormone that is vital for the regulation of metabolic homeostasis. In the present study, we report that Kruppel-like factor 15 (KLF15) is a novel mediator of b-cell translocation gene 2 (BTG2)-induced FGF21 biosynthesis. The expression levels of hepatic Fgf21, Btg2, and Klf15, and the production of serum FGF21 increased significantly in fasted and forskolin (FSK)-treated mice.

Melatonin ameliorates alcohol-induced bile acid synthesis by enhancing miR-497 expression.

Alcoholic liver disease is a major cause of chronic liver disease worldwide, and cannabinoid receptor type 1 (CB1R) is involved in a diverse metabolic diseases. B-cell translocation gene 2 (BTG2) and yin yang 1 (YY1) are a potent regulator of biological conditions. Melatonin plays a crucial role in regulating diverse physiological functions and metabolic homeostasis.

Inhibition of cereblon by fenofibrate ameliorates alcoholic liver disease by enhancing AMPK.

Alcohol consumption exacerbates alcoholic liver disease by attenuating the activity of AMP-activated protein kinase (AMPK). AMPK is activated by fenofibrate, a peroxisome proliferator-activated receptor α (PPARα) agonist, and inhibited by direct interaction with cereblon (CRBN), a component of an E3 ubiquitin ligase complex. Based on these preliminary findings, we investigated that CRBN would be up-regulated in the liver by alcohol consumption and that CRBN deficiency would ameliorate hepatic steatosis and pro-inflammatory responses in alcohol-fed mice by increasing AMPK activity.

B-cell translocation gene 2 promotes hepatic hepcidin production via induction of Yin Yang 1.

Hepcidin is a peptide hormone secreted in the liver and plays a key role in maintaining iron homeostasis. Here, we demonstrate that B-cell translocation gene 2 (BTG2) is a key player in hepatic hepcidin regulation via induction of Yin Yang 1 (YY1). Hepatic hepcidin gene expression significantly enhanced by fasting states and glucagon exposure led to induction of gluconeogenic gene expression, and elevated serum hepcidin production in mice.

ERK1/2 antagonize AMPK-dependent regulation of FcεRI-mediated mast cell activation and anaphylaxis.

Background: Extracellular signal-regulated kinases 1/2 (ERK1/2) make important contributions to allergic responses via their regulation of degranulation, eicosanoid production, and cytokine expression by mast cells, yet the mechanisms underlying their positive effects on FcεRI-dependent signaling are not fully understood. Recently, we reported that mast cell activation and anaphylaxis are negatively regulated by AMP-activated protein kinase (AMPK). However, little is known about the relationship between ERK1/2-mediated positive and the AMPK-mediated negative regulation of FcεRI signaling in mast cells.

B-cell translocation gene 2 regulates hepatic glucose homeostasis via induction of orphan nuclear receptor Nur77 in diabetic mouse model.

B-cell translocation gene 2 (BTG2) is a member of an emerging gene family that is involved in cellular functions. In this study, we demonstrate that BTG2 regulates glucose homeostasis via upregulation of Nur77 in diabetic mice. Hepatic BTG2 gene expression was elevated by fasting and forskolin.

Emodin Isolated from Polygoni cuspidati Radix Inhibits TNF-α and IL-6 Release by Blockading NF-κB and MAP Kinase Pathways in Mast Cells Stimulated with PMA Plus A23187.

Emodin, a naturally occurring anthraquinone derivative isolated from Polygoni cuspidati radix, has several beneficial pharmacologic effects, which include anti-cancer, anti-diabetic, and anti-inflammatory activities. In this study, the authors examined the effect of emodin on the production of proinflammatory cytokines, such as, tumor necrosis factor (TNF)-α and interleukin (IL)-6, in mouse bone marrow-derived mast cells (BMMCs) stimulated with phorbol 12-myristate 13-acetate (PMA) plus the calcium ionophore A23187. To investigate the mechanism responsible for the regulation of pro-inflammatory cytokine production by emodin, the authors assessed its effects on the activations of transcriptional factor nuclear factor-κB (NF-κB) and mitogen-activated protein kinases (MAPKs).

Pinusolide improves high glucose-induced insulin resistance via activation of AMP-activated protein kinase.

Adenosine monophosphate (AMP)-activated protein kinase (AMPK) plays a crucial role in the maintenance of cellular energy homeostasis, and several natural compounds that activate AMPK possibly enhance glucose uptake by muscle cells. In this study, we found that pinusolide stimulated AMPK phosphorylation and glucose uptake and these effects were significantly reduced by siRNA LKB1 or compound C, suggesting that enhanced glucose uptake by pinusolide is predominantly accomplished via an LKB1-mediated AMPK activation pathway. An insulin resistance state was induced by exposing cells to 30mM glucose, as indicated by reduced insulin-stimulated tyrosine phosphorylation of IRS-1 and glucose uptake.

Manassantin B isolated from Saururus chinensis inhibits cyclooxygenase-2-dependent prostaglandin D2 generation by blocking Fyn-mediated nuclear factor-kappaB and mitogen activated protein kinase pathways in bone marrow derived-mast cells.

The authors investigated the effect of manassantin B (Man B) isolated from Saururus chinensis (S. chinensis) on cyclooxygenase-2 (COX-2)-dependent prostaglandin D2 (PGD2) generation in mouse bone marrow derived-mast cells (BMMCs). Man B inhibited the generation of PGD2 dose-dependently by inhibiting COX-2 expression in immunoglobulin E (IgE)/Ag-stimulated BMMCs.

B-cell translocation gene 2 positively regulates GLP-1-stimulated insulin secretion via induction of PDX-1 in pancreatic β-cells.

Glucagon-like peptide-1 (GLP-1) is a potent glucoincretin hormone and an important agent for the treatment of type 2 diabetes. Here we demonstrate that B-cell translocation gene 2 (BTG2) is a crucial regulator in GLP-1-induced insulin gene expression and insulin secretion via upregulation of pancreatic duodenal homeobox-1 (PDX-1) in pancreatic β-cells. GLP-1 treatment significantly increased BTG2, PDX-1 and insulin gene expression in pancreatic β-cells.

Low molecular weight fucoidan improves endoplasmic reticulum stress-reduced insulin sensitivity through AMP-activated protein kinase activation in L6 myotubes and restores lipid homeostasis in a mouse model of type 2 diabetes.

Low molecular weight fucoidan (LMWF) is widely used to treat metabolic disorders, but its physiologic effects have not been well determined. In the present study, we investigated the metabolic effects of LMWF in obese diabetic mice (leptin receptor-deficient db/db mice) and the underlying molecular mechanisms involved in endoplasmic reticulum (ER) stress-responsive L6 myotubes. The effect of LMWF-mediated AMP-activated protein kinase (AMPK) activation on insulin resistance via regulation of the ER stress-dependent pathway was examined in vitro and in vivo.

AMP-activated protein kinase negatively regulates FcεRI-mediated mast cell signaling and anaphylaxis in mice.

Background: Aggregation of FcεRI activates a cascade of signaling events leading to mast cell activation, followed by inhibitory signals that turn off the activating signals. However, the overall view of negative signals in mast cells is still incomplete. Although AMP-activated protein kinase (AMPK), which is generally known as a regulator of energy metabolism, is also associated with anti-inflammation, little is known about the role of AMPK in mast cells.

Inhibitory cross-talk between the AMPK and ERK pathways mediates endoplasmic reticulum stress-induced insulin resistance in skeletal muscle.

Background And Purpose: Endoplasmic reticulum (ER) stress has been implicated in the pathogeneses of insulin resistance and type 2 diabetes, and extracellular signal-regulated kinase (ERK) antagonist is an insulin sensitizer that can restore muscle insulin responsiveness in both tunicamycin-treated muscle cells and type 2 diabetic mice. The present study was undertaken to determine whether the chemical or genetic inhibition ER stress pathway targeting by ERK results in metabolic benefits in muscle cells.

Experimental Approach: ER stress was induced in L6 myotubes using tunicamycin (5 μg·mL(-1) ) or thapsigargin (300 nM) and cells were transfected with siRNA ERK or AMPKα2.

Glyceollin improves endoplasmic reticulum stress-induced insulin resistance through CaMKK-AMPK pathway in L6 myotubes.

Glyceollin has been shown to have antidiabetic properties, although its molecular mechanism is not known. Here, we have investigated the metabolic effects of glyceollin in animal models of insulin resistance and in endoplasmic reticulum (ER) stress-responsive muscle cells. db/db mice were treated with glyceollin for 4weeks and triglycerides, total cholesterol, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) levels were measured.

Tanshinone IIA improves endoplasmic reticulum stress-induced insulin resistance through AMP-activated protein kinase.

The aim of the present study was to determine the effect of Tanshinone IIA (Tan IIA) on endoplasmic reticulum (ER) stress-induced insulin resistance in L6 myotubes and db/db mice. ER stress markers, RNA-activated protein kinase-like ER resident kinase (PERK), JNK, and AMPK activity were determined in tunicamycin-treated L6 myotubes. Insulin resistance was monitored using glucose uptake assays in vitro and blood glucose levels in vivo.

Effect of Curculigo orchioides on reflux esophagitis by suppressing proinflammatory cytokines.

This study was performed to investigate effects of Curculigo orchioides rhizome (curculiginis rhizome) on acute reflux esophigitis (RE) in rats that are induced by pylorus and forestomach ligation operation. Proinflammatory cytokine, as well as tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 were all assayed and the expression of TNF-α and COX2 analyzed by RT-PCR. The esophagic tissue damage of reflux esophagitis rat was increased compared to that of normal intact group.

B-cell translocation gene-2 increases hepatic gluconeogenesis via induction of CREB.

Hepatic gluconeogenesis is mediated by the network of transcriptional factors and cofactors. Here, we show that B-cell translocation gene-2 (BTG2) plays a crucial cofactor in hepatic gluconeogenesis via upregulation of the cyclic AMP (cAMP) response element binding (CREB) in hepatocytes. cAMP/dexamethasone (Dex) significantly increased BTG2 and other gluconeogenic genes such as Nur77, phosphoenolpyruvate carboxykinase (PEPCK), and glucose-6-phosphatase (G6Pase) in hepatocytes.

Orphan nuclear receptor small heterodimer partner negatively regulates growth hormone-mediated induction of hepatic gluconeogenesis through inhibition of signal transducer and activator of transcription 5 (STAT5) transactivation.

Growth hormone (GH) is a key metabolic regulator mediating glucose and lipid metabolism. Ataxia telangiectasia mutated (ATM) is a member of the phosphatidylinositol 3-kinase superfamily and regulates cell cycle progression. The orphan nuclear receptor small heterodimer partner (SHP: NR0B2) plays a pivotal role in regulating metabolic processes.

Heat-processed Gynostemma pentaphyllum extract improves obesity in ob/ob mice by activating AMP-activated protein kinase.

Gynostemma pentaphyllum is widely used in Asian countries as a herbal medicine to treat dyslipidemia, type 2 diabetes and inflammation. An ethanol extract of G. pentaphyllum lessened obesity by activating AMP-activated protein kinase (AMPK).

Natural vanadium-containing Jeju groundwater inhibits immunoglobulin E-mediated anaphylactic reaction and suppresses eicosanoid generation and degranulation in bone marrow derived-mast cells.

The high-affinity receptor for immunoglobulin E (IgE) (FcεRI)-mediated activation of mast cells plays an important role in various allergic diseases. To assess the anti-allergic activity of natural vanadium-containing Jeju groundwater (JW), an in vivo passive cutaneous anaphylaxis (PCA) animal model and in vitro mouse bone marrow-derived mast cells (BMMCs) was used. JW inhibited cyclooxygenase-2 (COX-2)-dependent prostaglandin D(2) (PGD(2)) generation in a dose-dependent manner, with a concomitant reduction of COX-2 protein expression in IgE-induced BMMCs.

Improved insulin sensitivity by rapamycin is associated with reduction of mTOR and S6K1 activities in L6 myotubes.

This study was designed to evaluate the role of mammalian target of rapamycin (mTOR)/p70S61 kinase (S6K1) pathways in ER stress-induced insulin resistance in L6 myotubes. Pretreatment with 5μg/ml of tunicamycin or 600nM thapsigargin for 3h decreased insulin-mediated tyrosine phosphorylation of IRS-1 and glucose uptake, and increased the level of mTOR/S6K1 phosphorylation in L6 myotubes. However, the inhibition of mTOR activity by rapamycin (inhibitor of several intracellular pathways including S6K1 pathways) reversed the ER stress-reduced tyrosine phosphorylation of IRS-1 and glucose uptake.

Saucerneol F, a new lignan, inhibits iNOS expression via MAPKs, NF-κB and AP-1 inactivation in LPS-induced RAW264.7 cells.

Saucerneol F (SF), a new tetrahydrofuran-type sesquilignan isolated from Saururus chinensis, dose-dependently inhibited nitric oxide (NO) production, with concomitant reduction of inducible nitric oxide synthase (iNOS) protein and mRNA expression in lipopolysaccharide (LPS)-stimulated murine macrophage RAW264.7 cells. To elucidate the molecular mechanism underlying the inhibition of iNOS expression by SF, we assessed the effects of SF on nuclear factor-κB (NF-κB) DNA-binding activity, NF-κB-dependent reporter gene activity, inhibitory factor-κB (IκB) phosphorylation and degradation, and p65 nuclear translocation.

Citreorosein, a naturally occurring anthraquinone derivative isolated from Polygoni cuspidati radix, attenuates cyclooxygenase-2-dependent prostaglandin D2 generation by blocking Akt and JNK pathways in mouse bone marrow-derived mast cells.

In this study, we examined the effects of citreorosein (CIT), an anthraquinone component of Polygoni cuspidati radix (P. cuspidati, Polygonaceae), on cyclooxygenase (COX)-2 dependent prostaglandin (PG)D2 generation in mast cells, central effector cells of allergy and other inflammatory diseases. CIT strongly inhibited COX-2-dependent PGD2 generation in a concentration-dependent manner in mouse bone marrow-derived mast cells (BMMCs) stimulated with stem cell factor (SCF)/IL-10/LPS.

New dammarane-type glucosides as potential activators of AMP-activated protein kinase (AMPK) from Gynostemma pentaphyllum.

AMP-activated protein kinase (AMPK) is a key sensor and regulator of glucose, lipid, and energy metabolism throughout the body. Activation of AMPK improves metabolic abnormalities associated with metabolic diseases including obesity and type-2 diabetes. The oriental traditional medicinal herbal plant, Gynostemma pentaphyllum, has shown a wide range of beneficial effects on glucose and lipid metabolism.