Rhododendrol, a reductive metabolite of raspberry ketone, suppresses the differentiation of 3T3‑L1 cells into adipocytes.

Obesity is a serious medical condition worldwide, and a major risk factor for type 2 diabetes, metabolic syndrome, cancer and cardiovascular disease. In addition to changes in dietary habits and physical activity, consuming supplements to maintain good health and prevent obesity is important in modern society. Raspberry ketone (RK) is a natural phenolic ketone found in the European red raspberry ( L.

Clinical study designs and patient selection methods based on genomic biomarkers: Points-to-consider documents.

Recently, genomic biomarkers have been widely used clinically for prediction of the efficacy and safety of pharmacotherapy and diagnosis and prognosis of pathological conditions. Therefore, genomic biomarkers are anticipated to accelerate not only precision medicine for pharmacotherapy but also development of molecularly targeted drugs. Because the design of clinical studies involving biomarkers may differ from conventional clinical study designs, a concept paper focused on clinical studies and patient selection methods based on genomic biomarkers is desired to prompt innovative drug development.

Allopurinol suppresses expression of the regulatory T-cell migration factors TARC/CCL17 and MDC/CCL22 in HaCaT keratinocytes via restriction of nuclear factor-κB activation.

Recent studies have shown that sparse distribution of regulatory T cells (Tregs) in the skin might be involved in the onset of severe cutaneous adverse drug reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis. Treg migration toward epithelial cells is regulated by certain chemokines, including TARC/CCL17 and MDC/CCL22. In this study, we analyzed the effect of allopurinol (APN), a drug known to cause severe adverse reactions, on the expression of factors affecting Treg migration and the mechanisms involved.

Phosphorylated Nuclear Receptor CAR Forms a Homodimer To Repress Its Constitutive Activity for Ligand Activation.

The nuclear receptor CAR (NR1I3) regulates hepatic drug and energy metabolism as well as cell fate. Its activation can be a critical factor in drug-induced toxicity and the development of diseases, including diabetes and tumors. CAR inactivates its constitutive activity by phosphorylation at threonine 38.

Active ERK1/2 protein interacts with the phosphorylated nuclear constitutive active/androstane receptor (CAR; NR1I3), repressing dephosphorylation and sequestering CAR in the cytoplasm.

The nuclear constitutive active/androstane receptor (CAR) is inactivated and sequestered in the cytoplasm when Thr-38 is phosphorylated. Here, we have demonstrated that activated ERK1/2 interacts with phosphorylated CAR to repress dephosphorylation of Thr-38. The phosphorylation-dependent interaction between CAR and ERK1/2 was examined by co-immunoprecipitation experiments of ectopically expressed FLAG-tagged CAR T38A and CAR T38D mutants with endogenous phospho-ERK1/2 in Huh-7 cells.

Dephosphorylation of threonine 38 is required for nuclear translocation and activation of human xenobiotic receptor CAR (NR1I3).

Upon activation by therapeutics, the nuclear xenobiotic/ constitutive active/androstane receptor (CAR) regulates various liver functions ranging from drug metabolism and excretion to energy metabolism. CAR can also be a risk factor for developing liver diseases such as hepatocellular carcinoma. Here we have characterized the conserved threonine 38 of human CAR as the primary residue that regulates nuclear translocation and activation of CAR.

Induction of UGT1A1 and CYP2B6 by an antimitogenic factor in HepG2 cells is mediated through suppression of cyclin-dependent kinase 2 activity: cell cycle-dependent expression.

Hepatocyte growth factor (HGF), an antimitogenic factor for HepG2 cells, increased mRNA and protein levels of UGT1A1 and CYP2B6, as well as the endogenous cyclin-dependent kinase (CDK) inhibitors p16, p21, and p27 in HepG2 cells but not in HuH6, Caco2, or MCF7 cells. Treatment with 1,4-diamino-2,3-dicyano-1,4-bis(methylthio)butadiene (U0126) (an extracellular signal-regulated kinase inhibitor) suppressed the HGF-induced expression of UGT1A1 and CYP2B6, as well as p16, p21, and p27 in HepG2 cells. The CDK inhibitor roscovitine also enhanced the expression of UGT1A1, CYP2B6, and CYP3A4.

Up-regulation of CAR expression through Elk-1 in HepG2 and SW480 cells by serum starvation stress.

Constitutive androstane receptor (CAR) is a transcription factor regulating the expression of several genes related to drug metabolism. CAR expression was elevated in human HepG2 and SW480 cells by serum starvation. From reporter gene assays, mutagenesis, RNA interference, and chromatin immunoprecipitation assays, we identified the serum response element at -142/-139 in the CAR gene transactivated by Elk-1.

Comparison of enzymatically synthesized inulin, resistant maltodextrin and clofibrate effects on biomarkers of metabolic disease in rats fed a high-fat and high-sucrose (cafeteria) diet.

Background: While naturally occurring inulin has anti-hyperlipidemic effects in animals and humans, health effects of synthetic inulin with different degrees of fructose polymerization remain poorly understood.

Aim Of The Study: Our study aimed at distinguishing health effects of synthetic inulin with different degrees of fructose polymerization (DP) from those of resistant maltodextrin and clofibrate.

Methods: We examined effects of synthetic inulin on serum and liver lipid profiles and blood biochemical parameters in rats fed a high-fat and high-sucrose (HF, cafeteria) diet when compared to resistant maltodextrin and clofibrate.

Expression of CAR in SW480 and HepG2 cells during G1 is associated with cell proliferation.

Constitutive androstane receptor (CAR) is a transcription factor to regulate the expression of several genes related to drug-metabolism. Here, we demonstrate that CAR protein accumulates during G1 in human SW480 and HepG2 cells. After the G1/S phase transition, CAR protein levels decreased, and CAR was hardly detected in cells by the late M phase.

Transcriptional regulation of human UGT1A1 gene expression through distal and proximal promoter motifs: implication of defects in the UGT1A1 gene promoter.

Human UDP-glucuronosyltransferase (UGT)1A1 is a critical enzyme responsible for detoxification and metabolism of endogenous and exogenous lipophilic compounds, such as potentially neurotoxic bilirubin and the anticancer drug irinotecan SN-38, via conjugation with glucuronic acid. A 290-bp distal enhancer module, phenobarbital-responsive enhancer module of UGT1A1 (gtPBREM), fully accounts for constitutive androstane receptor (CAR)-, pregnane X receptor (PXR)-, glucocorticoid receptor (GR)-, and aryl hydrocarbon receptor (AhR)-mediated activation of the UGT1A1 gene. This study indicates that hepatocyte nuclear factor 1alpha (HNF1alpha) bound to the proximal promoter motif not only enhances the basal reporter activity of UGT1A1, including the distal (-3570/-3180) and proximal (-165/-1) regions, but also influences the transcriptional regulation of UGT1A1 by CAR, PXR, GR, and AhR to markedly enhance reporter activities.

Expression of hepatic UDP-glucuronosyltransferase 1A1 and 1A6 correlated with increased expression of the nuclear constitutive androstane receptor and peroxisome proliferator-activated receptor alpha in male rats fed a high-fat and high-sucrose diet.

Rats that consumed a high-fat and high-sucrose (HF1) diet or a high-fat (HF2) diet developed hepatic steatosis. The alteration in nutritional status affected hepatic cytochrome P450 and UDP-glucuronosyltransferase (UGT) levels. Messenger RNA and protein levels of UGT1A1 and UGT1A6 in the liver but not the jejunum were increased in male rats fed the HF1 diet.

Dietary inulin alleviates hepatic steatosis and xenobiotics-induced liver injury in rats fed a high-fat and high-sucrose diet: association with the suppression of hepatic cytochrome P450 and hepatocyte nuclear factor 4alpha expression.

Inulin enzymatically synthesized from sucrose is a dietary component that completely escapes glucide digestion. Supplementing inulin to a high-fat and high-sucrose diet (HF) ameliorated hypertriglycemia and hepatic steatosis in 8-week-fed rats by suppressing elevated levels of serum triacylglycerols, fatty acids, and glucose, and the accumulation of hepatic triacylglycerols and fatty acids. Inulin intake prevented phenobarbital (PB)- and dexamethasone-induced liver injuries in the HF group.