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Fibroblast growth factor 21 (FGF21), a member of the FGF subfamily that acts through the FGF receptor 1 with the co-receptor β-Klotho, functions as an important metabolic regulator of peripheral glucose tolerance and lipid homeostasis in an endocrine or autocrine and/or paracrine manner. Previous studies showed that FGF21 ameliorated and prevented the development of metabolic disorders, such as obesity and diabetes mellitus. In the present study, we demonstrated that berberine, a naturally occurring compound, stimulated FGF21 expression in brown adipose tissue (BAT). Furthermore, the up-regulated expression of FGF21 in brown adipocytes in response to berberine was due, at least in part, to the activation of the AMP-activated protein kinase pathway. We also found that berberine reversed high-fat diet-induced obesity concomitant with its regulation of the expression of Fgf21 and the core clock component brain and muscle Arnt-like 1 (Bmal1) in BAT. Berberine significantly up-regulated the gene expression and production of FGF21 in a dose-dependent manner in C3H10T1/2 brown adipocytes. Furthermore, the knockdown of Bmal1 prevented the up-regulated expression of FGF21 in response to berberine in C3H10T1/2 brown adipocytes, suggesting that Bmal1 links the regulatory mechanisms of FGF21 in response to berberine. The present results suggest that berberine stimulates the expression of FGF21 by modulating molecular clock Bmal1 in BAT, which may, in turn, attenuate diet-induced obesity. They also indicate the potential of berberine as a therapeutic agent for obesity and obesity-associated metabolic disorders related to circadian misalignments. [ABSTRACT FROM AUTHOR]

Abstract Retinoic acid receptor-related orphan receptor (ROR) α has been implicated in various physiological functions, including the immune system, inflammation, and circadian rhythms. In the present study, the synthetic RORα/γ agonist SR1078 stimulated the production and gene expression of fibroblast growth factor 21 (FGF21) in C2C12 myotubes. FGF21, a member of the FGF family, plays important roles in the regulation of peripheral glucose tolerance and lipid metabolism and improves metabolic health. The mRNA expression and secretion of FGF21 was significantly weaker in Rora -silenced cells than in cells transfected with non-targeting control siRNA. SR1078 significantly up-regulated C/EBP homologous protein (CHOP), an established marker of ER stress, in a dose-dependent manner in C2C12 myotubes, while CHOP expression was decreased in Rora -silenced C2C12 cells, suggesting that RORα is involved in the regulation of FGF21 expression and stimulates ER stress in C2C12 myotubes. The naturally occurring compound baicalein up-regulated FGF21 expression and secretion in C2C12 myotubes. Additionally, the up-regulation of CHOP mRNA and protein expression was observed in C2C12 myotubes after the baicalein treatment. Furthermore, the knockdown of RORα prevented the augmentation of FGF21 and up-regulation of CHOP in response to baicalein in C2C12 cells. Collectively, these results suggest that baicalein stimulates the ER stress response and FGF21 expression through an RORα-dependent mechanism in C2C12 myotubes, and indicate the potential of baicalein as an effective anti-obesity therapy via its ability to enhance FGF21 production. [ABSTRACT FROM AUTHOR]

Recent studies reported that serotonin (5-hydroxytryptamine, 5-HT) may be an endogenous paracrine and/or autocrine factor that is used for intercellular communication in bone cells and between multiple organs regulating bone homeostasis. In the present study, we showed that the administration of MDL11939, a selective 5-HT 2A receptor antagonist, reduced bone mass in mice. The loss of bone mass in MDL11939-treated mice was associated with impaired bone formation in vivo , as demonstrated by the lower expression of osterix ( Osx ) and osteocalcin than that in vehicle-treated mice. On the other hand, no significant differences were observed in osteoclast numbers between MDL11939- and vehicle-treated mice. The pharmacological blockade of 5-HT 2A receptor signaling significantly decreased alkaline phosphatase activity in osteoblastic cells. In addition, the knockdown of the 5-HT 2A receptor by a siRNA treatment decreased Osx , but not Runx2 gene expression in MC3T3-E1 cells. These results suggest that 5-HT 2A receptor signaling mediated bone mass by regulating osteoblast differentiation. [ABSTRACT FROM AUTHOR]

The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcriptional factor belonging to the basic helix-loop-helix-Per-Ahr/Arnt-Sim family. In this study, we evaluated the AhR agonistic activities of 12 xanthones isolated from the roots of M. cochinchinensis var. gerontogea using HepG2 cells transfected with pX4TK–Luc reporter plasmids. Gerontoxanthone B (GXB) showed the most potent activity at a concentration of 10 μM, and the activity was inhibited by AhR antagonists such as GNF-351. GXB also increased cytochrome P450 1A1 mRNA and protein levels in HepG2 cells. Similar to the AhR agonist 2,3,7,8-tetrachlorodibenzo- p -dioxin, however, GXB suppressed the IL-1β-induced mRNA level of SAA1 , an acute-phase response gene that is up-regulated AhR-dependently but XRE-independently. Thus, GXB shows XRE-dependent transcriptional activity and XRE-independent activity involving AhR. [ABSTRACT FROM AUTHOR]

Three new isocoumarins and two new phthalides, tubakialactones A–E ( 1 – 5 ), together with three known polyketides including ( R )-3,4-dihydro-4-hydroxyl-6,8-dimethoxy-4-methyl-3-methylene-1 H -2-benzopyran-1-one ( 6 ), (−)-5,7-dimethoxy-3-methyl-1(3 H )-isobenzofuranone ( 7 ), and isosclerone ( 8 ) were found in the endophytic fungus Tubakia sp. ECN-111 isolated from the leaves of Houttuynia cordata . The chemical structures of the new compounds were determined by spectroscopic analyses, including extensive 2D-NMR experiments. The absolute configuration of 3 and 7 was determined by optical rotation and circular dichroism. [ABSTRACT FROM AUTHOR]

Abstract The prevalence of obesity and its associated diseases is increasing worldwide, and the therapeutic potential of increasing energy expenditure through differentiation or activation of beige adipocytes has attracted much interest. Therefore, we explored naturally occurring compounds that induce beige adipocytes by screening for activity to induce mRNA expression of uncoupling protein 1 (UCP1) in stromal vascular fraction (SVF) cells cultured in beige adipocyte differentiation medium. Through screening, p -synephrine, a compound isolated from Citrus unshiu Marcov., was found to be an active compound that increased UCP1 mRNA expression in a dose-dependent manner from a concentration of 3.12 µM, which induced morphological changes specific for beige adipocytes. Similar effects were also observed in SVF cells prepared from db/db obese mice. While investigating the underlying mechanism of p -synephrine-induced beige adipocyte differentiation, we found that the effects of p- synephrine were abolished by the β3-adrenoceptor antagonist SR58894. Intriguingly, p -synephrine increased UCP1 mRNA levels in SVF cells cultured in beige adipocyte differentiation medium lacking insulin to an extent different from those by the β-agonist isoprenaline. Furthermore, phosphatidylinositol 3-kinase inhibitor LY294002 decreased isoprenaline-induced UCP1 mRNA levels in the early phase of beige adipocyte differentiation and p -synephrine-induced UCP1 mRNA levels in fully differentiated beige adipocytes. Thus, p -synephrine appears to elicit signals via β3-adrenoceptor combined with some part of the insulin signaling pathway, finally resulting in efficient stimulation of beige adipocyte differentiation with the support of certain beige adipocyte differentiation-inducing factors. The present results suggest the potential of p -synephrine for prophylaxis and treatment of obesity and its associated diseases. [ABSTRACT FROM AUTHOR]

Diaporthols A ( 1 ) and B ( 2 ), two diphenyl ether derivatives, were isolated from cultures of an endophytic fungus Diaporthe sp. ECN-137 obtained from the leaves of Phellodendron amurense . The structures of 1 and 2 were determined by extensive spectroscopic analyses, and the structure of 2 was confirmed by X-ray crystallographic analysis. Compounds 1 and 2 showed anti-migration activities in TGF-β1-elicited MDA-MB-231 breast cancer cells at a concentration of 20 μM. [ABSTRACT FROM AUTHOR]

Fibroblast growth factor 21 (FGF21) acts as an endocrine factor, playing important roles in the regulation of energy homeostasis, glucose and lipid metabolism. It is induced by diverse metabolic and cellular stresses, such as starvation and cold challenge, which in turn facilitate adaptation to the stress environment. The pharmacological action of FGF21 has received much attention, because the administration of FGF21 or its analogs has been shown to have an anti-obesity effect in rodent models. In the present study, we found that 3- O -acetyloleanolic acid, an active constituent isolated from the fruits of Forsythia suspensa , stimulated FGF21 production concomitant with the up-regulation of a transcription factor, nuclear receptor Nr4a1, in C2C12 myotubes. Additionally, significant increases in mFgf21 promoter activity were observed in C2C12 cells overexpressing TGR5 receptor in response to 3- O -acetyloleanolic acid treatment. Treatment with the p38 MAPK inhibitor SB203580 was effective at suppressing these stimulatory effects of 3- O -acetyloleanolic acid. Pretreatment with SB203580 also significantly repressed FGF21 mRNA abundance and FGF21 secretion in C2C12 myotubes after 3- O -acetyloleanolic acid stimulation, suggesting that p38 activation is required for the induction of FGF21 by ligand-activated TGR5 in C2C12 myotubes. These findings collectively indicated that TGR5 receptor signaling drives FGF21 expression via p38 activation, at least partly, by mediating Nr4a1 expression. Thus, the novel biological function of 3- O -acetyloleanolic acid as an agent having anti-obesity effects is likely to be mediated through the activation of TGR5 receptors. [Display omitted] • 3- O -acetyloleanolic acid, an active constituent isolated from the fruits of Forsythia suspensa , stimulated FGF21 in C2C12 myotubes. • TGR5 receptor signaling drives FGF21 expression via p38 activation. • Up-regulation of Nr4a1 after stimulation with 3- O -acetyloleanolic acid regulates FGF21. • Biological function of 3- O -acetyloleanolic acid as an agent having anti-obesity effects is likely mediated through the activation of TGR5. [ABSTRACT FROM AUTHOR]

Abstract: We have previously identified Ntan1 as a magnetism response gene by differential display screening in cultured rat hippocampal neurons. Ntan1 mRNA was ubiquitously expressed in all the mouse tissues examined but relatively abundant in brain, retina and testis. Ntan1 mRNA expression was detectable in the embryonic 12-day mouse brain and gradually increased with ageing. In situ hybridization analysis showed high localization of Ntan1 mRNA in pyramidal cell layer of CA region and granular cell layer of dentate gyrus in the hippocampus, and Purkinje and granular cell layers in the cerebellum, respectively. Ntan1 mRNA expression was significantly increased about two-fold 12h after brief exposure for 15min to magnetism at 100mT with a gradual decrease thereafter in cultured mouse hippocampal neurons. When embryonic 12-day-old or newborn mice were successively exposed to magnetic fields at 100mT for 2h, four times per day until the postnatal seventh day, Ntan1 mRNA was significantly increased about 1.5–2-fold in the hippocampus in vivo. The mice exposed to magnetic fields under the same condition showed significantly decreased locomotor activity. These results suggest that magnetic exposure affects higher order neural functions through modulation of genes expression. [Copyright &y& Elsevier]

Abstract: We investigated the effect of 5-HT receptor antagonists on mechanical hyperalgesia observed in a neuropathic pain rat model prepared by chronic constriction injury of the sciatic nerve. NAN-190, a 5-HT1A receptor antagonist, (−)-pindolol, a 5-HT1A/1B receptor antagonist, and tropisetron, a 5-HT3/4 receptor antagonist, did not affect the pain threshold in the hyperalgesic hind limb to the same extent as in the normal hind limb. However, sarpogrelate and ketanserin, 5-HT2A receptor antagonists, significantly elevated the pain threshold in the hyperalgesic hind limb, but not in the normal hind limb. In spite of its high affinity for the 5-HT2A receptor, methysergide only slightly elevated the pain threshold in the hyperalgesic hind limb. Pre-treatment with methysergide significantly antagonized the inhibitory effect of sarpogrelate on hyperalgesia. Furthermore, the 5-HT2A receptor specific binding activity of 3H-ketanserin determined for the hyperalgesic hind limb did not differ from that of the normal hind limb. From these results, we propose that the 5-HT2A receptor in the hyperalgesic hind paw function as an agonist-independent active receptor following constriction of the sciatic nerve, and that sarpogrelate and ketanserin act as inverse agonists of this receptor and suppress its activation. Methysergide may act as a neutral antagonist that blocks the effect of inverse agonists on the 5-HT2A receptor. [Copyright &y& Elsevier]