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Fibroblast growth factor 21 (FGF21) is expressed in several organs, including the liver, adipose tissue, and cardiovascular system, and plays an important role in cross-talk with other organs by binding to specific FGF receptors and their co-receptors. FGF21 represents a potential target for the treatment of obesity, type 2 diabetes mellitus, and non-alcoholic steatohepatitis (NASH). The production of FGF21 in skeletal muscle was recently suggested to be beneficial for metabolic health through its autocrine and paracrine effects. However, the regulatory mechanisms of FGF21 in skeletal muscle remain unclear. In the present study, we showed that berberine regulated FGF21 production in C2C12 myotubes in a dose-dependent manner. We also examined the effects of A-674563, a selective Akt1 inhibitor, on the berberine-mediated regulation of FGF21 expression in C2C12 myotubes. Berberine significantly increased the secretion of FGF21 in C2C12 myotubes, while A-674563 attenuated this effect. Moreover, a pre-treatment with A-674563 effectively suppressed berberine-induced increases in Bmal1 expression in C2C12 myotubes, indicating that the up-regulation of Bmal1 after the berberine treatment was dependent on Akt1. Additionally, berberine-induced increases in FGF21 secretion were significantly attenuated in C2C12 cells transfected with Bmal1 siRNA, indicating the contribution of the core clock transcription factor BMAL1 to Akt-regulated FGF21 in response to berberine. Collectively, these results indicate that berberine regulates the expression of FGF21 through the Akt1 pathway in C2C12 myotubes. Moreover, the core clock gene Bmal1 may participate in the control of the myokine FGF21. Berberine stimulated Akt1-dependent FGF21 expression in C2C12 myotubes. The up-regulation of FGF21 through the modulation of PI3K/AKT1/BMAL1 in response to berberine may be involved in the regulation of cellular function (such as Glut1 expression) by acting in an autocrine and/or paracrine manner in skeletal muscle. [ABSTRACT FROM AUTHOR]

Three new sesquiterpenes, phlebidiol, phlebioic acid, and phlebiolide, as well as the known compound tremetriol, were isolated from cultures of the basidiomycete Phlebia tremellosa. The structures of all isolated compounds were established by extensive spectroscopic analyses, including those involving extensive two-dimensional nuclear magnetic resonance. The absolute configurations of phlebidiol, phlebioic acid, and phlebiolide were determined by comparisons of experimental and calculated electronic circular dichroism spectra. Phlebidiol and phlebioic acid have previously unreported carbon skeletons, for which we propose the skeletal names "seco-sterpurane" and "phlebiane," respectively. Phlebiolide is also the second published example of a merulane sesquiterpene. [ABSTRACT FROM AUTHOR]

Abstract: Retinoid X receptor (RXR) ligands have a wide range of beneficial effects in mouse models of Alzheimer's disease (AD). Recently accumulated evidence suggests that early neuroinflammation may be a therapeutic target for AD treatment. We therefore investigated the anti-inflammatory effects of the prenylated flavanoids SPF1 and SPF2, which were previously isolated from root of Sophora tonkinensis and identified as potent ligands for RXR, and potential mechanisms involved. SPF1 and SPF2 efficiently reduced interleukin (IL)-1β messenger RNA (mRNA) and IL-6 mRNA levels in lipopolysaccharide-stimulated and tumor necrosis factor-α-stimulated RAW264.7 cells, whereas SPF3—which has a structure similar to SPF1 and SPF2 but no RXR ligand activity—did not exhibit such effects. Intriguingly, the liver X receptor (LXR) ligand T0901317 reduced proinflammatory cytokine mRNA levels, and these effects were potentiated by SPF1. With regard to the mechanism underlying the anti-inflammatory effects, SPF1 induced significant amounts of activating transcription factor 3 (ATF3) mRNA and protein, and this effect was potentiated by T0901317. SPF1 also reduced translocation of nuclear factor κB (NF-κB) into nuclei. The production of proinflammatory cytokines was significantly inhibited by SPF1, and this effect was primarily exerted via RXR/LXR heterodimers. The effects of SPF1 may partly depend on the induction of ATF3, which may bind to the p65 subunit of NF-κB, resulting in reduced translocation of NF-κB into nuclei and reduced NF-κB transcription. Although inflammatory effects mediated by RXR/LXR heterodimers have not been thoroughly investigated, the above-described results shed light on the mechanism of the anti-inflammatory effect via RXR/LXR heterodimer.Graphical abstract: [ABSTRACT FROM AUTHOR]

Neuronal cell death induced by amyloid-β (Aβ) oligomers is implicated in neuronal degeneration and is a leading cause of Alzheimer's disease (AD). Therefore, to identify effective therapeutic agents for AD, we investigated the neuroprotective effects of two naturally occurring retinoid X receptor (RXR) agonists (SPF1 and SPF2), isolated from the root of Sophora tonkinensis Gagnep., on the Aβ25-35-induced cytotoxicity against nerve growth factor-differentiated rat pheochromocytoma (PC12) cells. Pretreatment with SPFs significantly prevented Aβ25-35-induced apoptosis in PC12 cells, similarly to the synthetic RXR agonist bexarotene. These effects were blocked by the RXR antagonist PA452. When the effects of SPFs were studied in the presence of the liver X receptor (LXR) agonist T0901317, the protective effects of SPFs were enhanced, suggesting that RXR/LXR heterodimers may play a key role in the neuroprotective effects of SPFs. SPFs and T0901317 induced ATP-binding cassette transporter 1 (ABCA1) protein expression in PC12 cells when administered alone or in combination. Intriguingly, a functional inhibitor of ABCA1 cyclosporine A negated the neuroprotective effects of SPFs or T0901317. Taken together, these results demonstrate that the RXR agonists SPF1 and SPF2 protect PC12 cells from Aβ25-35-induced neurotoxicity in an RXR-dependent manner and that their effects are markedly enhanced by the LXR agonist T0901317, in part related to ABCA1 function. These results suggest a novel approach to the treatment or prevention of AD. [ABSTRACT FROM AUTHOR]

The clock system has been identified as one of the major mechanisms controlling cellular functions. Circadian clock gene oscillations also actively participate in the functions of various cell types including bone-related cells. Previous studies demonstrated that clock genes were expressed in bone tissue and also that their expression exhibited circadian rhythmicity. Recent findings have shown that sympathetic tone plays a central role in biological oscillations in bone. Adrenergic receptor (AR) signaling regulates the expression of clock genes in cancellous bone. Furthermore, α-AR signaling in osteoblasts is known to negatively regulate the expression of bone morphogenetic protein-4 (Bmp4) by up-regulating nuclear factor IL-3 (Nfil3)/e4 promoter-binding protein 4 (E4BP4). The ablation of α-AR signaling also increases the expression of the Bmp4 gene in bone. The findings of transient overexpression and siRNA experiments have supported the involvement of the transcription factor CCAAT/enhancer-binding protein delta (C/EBPδ, Cebpd) in Nfil3 and Bmp4 expression in MC3T3-E1 cells. These findings suggest that the effects of Cebpd are due to the circadian regulation of Bmp4 expression, at least in part, by the up-regulated expression of the clock gene Nfil3 in response to α-AR signaling in osteoblasts. Therefore, AR signaling appears to modulate cellular functionality through the expression of clock genes that are circadian rhythm regulators in osteoblasts. The expression of clock genes regulated by the sympathetic nervous system and clock-controlled genes that affect bone metabolism are described herein. [ABSTRACT FROM AUTHOR]

In the original publication of the article, Table 1 and Fig. 1 were incorrectly published. [ABSTRACT FROM AUTHOR]

The article Sesquiterpenes with new carbon skeletons from the basidiomycete Phlebia tremellosa, written by Ken ichi Nakashima, Junko Tomida, Takao Hirai, Yoshiaki Kawamura and Makoto Inoue was originally published Online First without Open Access. [ABSTRACT FROM AUTHOR]