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The pruritus of cholestasis: From bile acids to opiate agonists: Relevant after all these years.

The pruritus of cholestasis is a maddening complication of liver disease. Increased opioidergic tone contributes to the pruritus of cholestasis, as evidenced by the amelioration of the symptom by opiate antagonists. Obeticholic acid, an agonist of the farnesoid receptor, has been approved for the treatment of primary biliary cholangitis, a disease characterized by cholestasis; this drug is associated with pruritus, the cause of which is unknown. In animal models, bile acids, which accumulate in the body as a result of cholestasis, have been reported to cause scratching behavior mediated by the TGR5 receptor, in an opioid-dependent manner, in laboratory animals. As obeticholic acid also binds to TGR5, the pruritus caused by this drug is likely to be mediated by the opioid system. Lisophosphatidic acid, which has been reported to be increased in patients with cholestasis and pruritus, has been described to cause scratching behavior that is prevented by an opiate antagonist in laboratory animals, suggesting an opioid-receptor mediated mechanism of scratching. In summary, evidence continues to support a role of the endogenous opioid system in the pathogenesis of the pruritus of cholestasis.

1244 related Products with: The pruritus of cholestasis: From bile acids to opiate agonists: Relevant after all these years.

ENZYMATIC ASSAY KITS (CH LIVER DISEASES Total Bile LIVER DISEASES Total Bile FDA Standard Frozen Tissu FDA Standard Frozen Tissu FDA Standard Frozen Tissu FDA Standard Frozen Tissu Human Dnak (HSP70) His ta Topoisomerase II; Clone Topoisomerase II; Clone Topoisomerase II; Clone Toludine Blue Solution

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Synthesis and Biological Evaluation of a Series of Bile Acid Derivatives as FXR Agonists for Treatment of NASH.

Farnesoid X receptor (FXR) has become a particularly attractive target for the discovery of drugs for the treatment of liver and metabolic diseases. Obeticholic acid (INT-747), a FXR agonist, has advanced into clinical phase III trials in patients with nonalcoholic steatohepatitis (NASH), but adverse effects (e.g., pruritus, LDL increase) were observed. Pruritus might be induced by Takeda G-protein-coupled receptor 5 (TGR5, GPBAR1), and there are chances to develop FXR agonists with higher selectivity over TGR5. In this letter, novel bile acids bearing different modifications on ring A and side chain of INT-747 are reported and discussed. Our results indicated that the side chain of INT-747 is amenable to a variety of chemical modifications with good FXR potency in vitro. Especially, compound 18 not only showed promising FXR potency and excellent pharmacokinetic properties, but also proved superior pharmacological efficacy in the HFD + CCl4 model.

2956 related Products with: Synthesis and Biological Evaluation of a Series of Bile Acid Derivatives as FXR Agonists for Treatment of NASH.

ENZYMATIC ASSAY KITS (CH Amplite™ Fluorimetric G Amplite™ Fluorimetric A Triglyceride Assay Kit Li Glucose Assay With the La Cultrex In Vitro Angiogen (5Z)-7-[(5-Acetyloxy-2-fo (5Z)-7-[(5-Acetyloxy-2-fo Androst-4-ene-3,17-dion-1 L-Ascorbic Acid C6H8O6 CA L-Ascorbic Acid-13C6 13C6 Ascorbic Acid Acetonide C

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Chronic infusion of taurolithocholate into the brain increases fat oxidation in mice.

Bile acids can function in the postprandial state as circulating signaling molecules in the regulation of glucose and lipid metabolism via the transmembrane receptor TGR5 and nuclear receptor FXR. Both receptors are present in the central nervous system, but their function in the brain is unclear. Therefore, we investigated the effects of intracerebroventricular (i.c.v.) administration of taurolithocholate (tLCA), a strong TGR5 agonist, and GW4064, a synthetic FXR agonist, on energy metabolism. We determined the effects of chronic i.c.v. infusion of tLCA, GW4064, or vehicle on energy expenditure, body weight and composition as well as tissue specific fatty acid uptake in mice equipped with osmotic minipumps. We found that i.c.v. administration of tLCA (final concentration in cerebrospinal fluid: 1 μM) increased fat oxidation (tLCA group: 0.083 ± 0.006 vs control group: 0.036 ± 0.023 kcal/h, F = 5.46, P = 0.04) and decreased fat mass (after 9 days of tLCA infusion: 1.35 ± 0.13 vs controls: 1.96 ± 0.23 g, P = 0.03). These changes were associated with enhanced uptake of triglyceride-derived fatty acids by brown adipose tissue and with browning of subcutaneous white adipose tissue. I.c.v. administration of GW4064 (final concentration in cerebrospinal fluid: 10 μM) did not affect energy metabolism, body composition nor bile acid levels, negating a role of FXR in the central nervous system in metabolic control. In conclusion, bile acids such as tLCA may exert metabolic effects on fat metabolism via the brain.

2336 related Products with: Chronic infusion of taurolithocholate into the brain increases fat oxidation in mice.

Anti 3 DG imidazolone Mon Beta Amyloid (42) ELISA K Beta Amyloid (1 40) ELISA Beta Amyloid (40) ELISA K Leptin ELISA Kit, Rat Lep Beta Amyloid (1 40) ELISA Thermal Shaker with cooli Brain glioblastoma tissue Brain disease spectrum (b Rat intestinal fatty acid Goat Anti-Human CKB Brain FDA Standard Frozen Tissu

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Bile acid metabolism and signaling in liver disease and therapy.

Bile acids play a critical role in the regulation of glucose, lipid, and energy metabolism through activation of the nuclear bile acid receptor farnesoid X receptor (FXR) and membrane G protein-coupled bile acid receptor-1 (Gpbar-1, aka TGR5). Agonist activation of FXR and TGR5 improves insulin and glucose sensitivity and stimulates energy metabolism to prevent diabetes, obesity, and non-alcoholic fatty liver disease (NAFLD). Bile acids have both pro- and anti-inflammatory actions through FXR and TGR5 in the intestine and liver. In the intestine, bile acids activate FXR and TGR5 to stimulate stimulate fibroblast growth factor 15 and glucagon-like peptide-1 secretion. FXR and TGR5 agonists may have therapeutic potential for treating liver-related metabolic diseases, such as diabetes and NAFLD.

2320 related Products with: Bile acid metabolism and signaling in liver disease and therapy.

ENZYMATIC ASSAY KITS (CH LIVER DISEASES Total Bile LIVER DISEASES Total Bile Androst-4-ene-3,17-dion-1 Liver disease spectrum ti Multiple diseases of live Androgen Receptor (Phosph Androgen Receptor (Phosph Rabbit Anti-Human Androge Rabbit Anti-Human Androge GST Inhibitor 2 (Ethacryn HBeAg test strip, Infecti

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Modulating bile acid pathways and TGR5 receptors for treating liver and GI diseases.

Bile acids are central signals in enterohepatic communication and also integrate microbiota-derived signals into this signaling axis. Discovery of the tissue distribution and signaling pathways activated by the natural receptors for bile acids, farnesoid X receptor and G protein-coupled bile acid receptor 1 (GPBAR1) also known as TGR5, and bile acid transporters has led to the development of therapeutic agents that target these molecules. Obeticholic acid, a selective FXR agonist, and NGM282, a non-mitogenic FGF-19 analog, are two of the agents in this pipeline. Obeticholic acid has been approved by regulatory agencies for use in patients with primary biliary cholangitis.

1246 related Products with: Modulating bile acid pathways and TGR5 receptors for treating liver and GI diseases.

ENZYMATIC ASSAY KITS (CH LIVER DISEASES Total Bile LIVER DISEASES Total Bile Androst-4-ene-3,17-dion-1 Androgen Receptor (Phosph Androgen Receptor (Phosph Rabbit Anti-Human Androge Rabbit Anti-Human Androge Androgen Receptor (Ab 650 AZD-3514 Mechanisms: Andr 17β-Acetoxy-2α-bromo-5 (5α,16β)-N-Acetyl-16-[2

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Bile acid receptors link nutrient sensing to metabolic regulation.

Non-alcoholic fatty liver disease (NAFLD) is a common liver disease in Western populations. Non-alcoholic steatohepatitis (NASH) is a more debilitating form of NAFLD characterized by hepatocellular injury and inflammation, which significantly increase the risk of end-stage liver and cardiovascular diseases. Unfortunately, there are no available drug therapies for NASH. Bile acids are physiological detergent molecules that are synthesized from cholesterol exclusively in the hepatocytes. Bile acids circulate between the liver and intestine, where they are required for cholesterol solubilization in the bile and dietary fat emulsification in the gut. Bile acids also act as signaling molecules that regulate metabolic homeostasis and inflammatory processes. Many of these effects are mediated by the bile acid-activated nuclear receptor farnesoid X receptor (FXR) and the G protein-coupled receptor TGR5. Nutrient signaling regulates hepatic bile acid synthesis and circulating plasma bile acid concentrations, which in turn control metabolic homeostasis. The FXR agonist obeticholic acid has had beneficial effects on NASH in recent clinical trials. Preclinical studies have suggested that the TGR5 agonist and the FXR/TGR5 dual agonist are also potential therapies for metabolic liver diseases. Extensive studies in the past few decades have significantly improved our understanding of the metabolic regulatory function of bile acids, which has provided the molecular basis for developing promising bile acid-based therapeutic agents for NASH treatment.

2882 related Products with: Bile acid receptors link nutrient sensing to metabolic regulation.

ENZYMATIC ASSAY KITS (CH LIVER DISEASES Total Bile LIVER DISEASES Total Bile (2S)-2-Amino-benzenebutan (1R,3S,5R)-2-Azabicyclo[3 Nycodenz, non ionic, non 6 para Toluidino 2 naphth 6 para Toluidino 2 naphth p Toluenesulfinic acid so 5 (4 Formyl 3,5 dimethoxy HMPA Linker (4 Hydroxymet 3 Tolylboronic acid CAS N

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FXR/TGR5 Dual Agonist Prevents Progression of Nephropathy in Diabetes and Obesity.

Bile acids are ligands for the nuclear hormone receptor farnesoid X receptor (FXR) and the G protein-coupled receptor TGR5. We have shown that FXR and TGR5 have renoprotective roles in diabetes- and obesity-related kidney disease. Here, we determined whether these effects are mediated through differential or synergistic signaling pathways. We administered the FXR/TGR5 dual agonist INT-767 to DBA/2J mice with streptozotocin-induced diabetes, db/db mice with type 2 diabetes, and C57BL/6J mice with high-fat diet-induced obesity. We also examined the individual effects of the selective FXR agonist obeticholic acid (OCA) and the TGR5 agonist INT-777 in diabetic mice. The FXR agonist OCA and the TGR5 agonist INT-777 modulated distinct renal signaling pathways involved in the pathogenesis and treatment of diabetic nephropathy. Treatment of diabetic DBA/2J and db/db mice with the dual FXR/TGR5 agonist INT-767 improved proteinuria and prevented podocyte injury, mesangial expansion, and tubulointerstitial fibrosis. INT-767 exerted coordinated effects on multiple pathways, including stimulation of a signaling cascade involving AMP-activated protein kinase, sirtuin 1, PGC-1α, sirtuin 3, estrogen-related receptor-α, and Nrf-1; inhibition of endoplasmic reticulum stress; and inhibition of enhanced renal fatty acid and cholesterol metabolism. Additionally, in mice with diet-induced obesity, INT-767 prevented mitochondrial dysfunction and oxidative stress determined by fluorescence lifetime imaging of NADH and kidney fibrosis determined by second harmonic imaging microscopy. These results identify the renal signaling pathways regulated by FXR and TGR5, which may be promising targets for the treatment of nephropathy in diabetes and obesity.

2484 related Products with: FXR/TGR5 Dual Agonist Prevents Progression of Nephropathy in Diabetes and Obesity.

TGR5 Receptor Agonist Anti 3 DG imidazolone Mon Obesity (Human) Antibody Obesity (Human) Antibody Rectum disease spectrum ( Kidney disease spectrum ( Brain disease spectrum (b Colon disease spectrum (c Goat Anti-Human Dual oxid Goat Anti-Human Farnesoid AccuPower DualStar qPCR P AccuPower DualStar qPCR P

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The Dietary Furocoumarin Imperatorin Increases Plasma GLP-1 Levels in Type 1-Like Diabetic Rats.

Imperatorin, a dietary furocoumarin, is found not only in medicinal plants, but also in popular culinary herbs, such as parsley and fennel. Recently, imperatorin has been shown to activate GPR119 in cells. Another GPR, GPR131, also called TGR5 or G-protein-coupled bile acid receptor 1 (GPBAR1), is known to regulate glucose metabolism. Additionally, TGR5 activation increases glucagon-like peptide (GLP-1) secretion to lower blood sugar levels in animals. Therefore, the present study aims to determine whether the effects of imperatorin on GLP-1 secretion are mediated by TGR5. First, we transfected cultured Chinese hamster ovary cells (CHO-K1 cells) with the TGR5 gene. Glucose uptake was confirmed in the transfected cells using a fluorescent indicator. Moreover, NCI-H716 cells, which secrete GLP-1, were used to investigate the changes in calcium concentrations and GLP-1 levels. In addition, streptozotocin (STZ)-induced type 1-like diabetic rats were used to identify the effects of imperatorin in vivo. Imperatorin dose-dependently increased glucose uptake in CHO-K1 cells expressing TGR5. In STZ diabetic rats, similar to the results in NCI-H716 cells, imperatorin induced a marked increase of GLP-1 secretion that was reduced, but not totally abolished, by a dose of triamterene that inhibited TGR5. Moreover, increases in GLP-1 secretion induced by imperatorin and GPR119 activation were shown in NCI-H716 cells. We demonstrated that imperatorin induced GLP-1 secretion via activating TGR5 and GPR119. Therefore, imperatorin shall be considered as a TGR5 and GPR119 agonist.

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Native Parainfluenza Viru Native Parainfluenza Viru Native Parainfluenza Viru High density (188 cases 2 High density (188 cases 2 Human interleukin 2(IL-2) Bovine prolactin-induced Goat Anti- collagen type Goat Anti-Rat Collagen, t Goat Anti-Human GOLGA6 GL Plasma Proteins: Corn Try Disease State Samples: Si

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Beneficial effects of bile acid receptor agonists in pulmonary disease models.

Bile acids act as steroid hormones, controlling lipid, glucose and energy metabolism, as well as inflammation and fibrosis. Their actions are implemented through activation of nuclear (FXR, VDR, PXR) and membrane G protein-coupled (TGR5, S1PR2) receptors. Areas covered: This review discusses the potential of FXR and TGR5 as therapeutic targets in the treatment of pulmonary disorders linked to metabolism and/or inflammation. Obeticholic acid (OCA) is the most clinically advanced bile acid-derived agonist for FXR-mediated anti-inflammatory and anti-fibrotic effects. It therefore represents an attractive pharmacological approach for the treatment of lung conditions characterized by vascular and endothelial dysfunctions. Expert opinion: Inflammation, vascular remodeling and fibrotic processes characterize the progression of pulmonary arterial hypertension (PAH) and idiopathic pulmonary fibrosis (IPF). These processes are only partially targeted by the available therapeutic options and still represent a relevant medical need. The results hereby summarized demonstrate OCA efficacy in preventing experimental lung disorders, i.e. monocrotaline-induced PAH and bleomycin-induced fibrosis, by abating proinflammatory and vascular remodeling progression. TGR5 is also expressed in the lung, and targeting the TGR5 pathway, using the TGR5 agonist INT-777 or the dual FXR/TGR5 agonist INT-767, could also contribute to the treatment of pulmonary disorders mediated by inflammation and fibrosis.

1937 related Products with: Beneficial effects of bile acid receptor agonists in pulmonary disease models.

ENZYMATIC ASSAY KITS (CH LIVER DISEASES Total Bile LIVER DISEASES Total Bile Interferon-a Receptor Typ Mouse Anti-Human Interleu GST Inhibitor 2 (Ethacryn HBeAg test strip, Infecti Anti-HBeAg (HBeAb) test s Anti-HBcAg (HBcAb) test s HBV-5 panel test, sAg sAb HCV antibody test strip, HBV-3 panel test, HBsAg H

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Long-term Administration of Nuclear Bile Acid Receptor FXR Agonist Prevents Spontaneous Hepatocarcinogenesis in Abcb4-/- Mice.

Altered bile acid (BA) signaling is associated with hepatotoxicity. The farnesoid X receptor (FXR) is a nuclear receptor that transcriptionally regulates BA homeostasis. Mice with FXR ablation present hepatocarcinoma (HCC) due to high toxic BA levels. Mice with Abcb4 ablation accumulate toxic BA within the bile ducts and present HCC. We have previously shown that intestinal specific activation of FXR by transgenic VP16-FXR chimera is able to reduce BA pool size and prevent HCC. Here we tested chemical FXR activation by administering for 15 months the dual FXR/ membrane G protein-coupled receptor (TGR5) agonist INT-767 (6α-ethyl-3α,7α,23-trihydroxy-24-nor-5β-cholan-23-sulphate) to Fxr-/- and Abcb4-/- mice. HCC number and size were significantly reduced by INT-767 administration. In contrast, no changes in HCC tumor number and size were observed in Fxr-/- mice fed with or without INT-767. Notably, INT-767 preserved the hepatic parenchyma, improved hepatic function and down-regulated pro-inflammatory cytokines. Moreover, in Abcb4-/- mice INT-767 prevented fibrosis by reducing collagen expression and deposition. Thus, long term activation of FXR is able to reduce BA pool, reprogram BA metabolism and prevent HCC. These data provide the impetus to address the bona fide therapeutic potential of FXR activation in disease with BA-associated development of HCC.

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Nuclear Membrane Receptor Goat Anti-Human Farnesoid Goat Anti- Glucogon recep Interleukin-34 IL34 (N-t Interferon-a Receptor Typ Goat Anti-Human HMGB3 HMG Goat Anti-Human F2R PAR1, Goat Anti-Mouse APOBEC1, Mouse Anti-Human Interleu GST Inhibitor 2 (Ethacryn TGR5 Receptor Agonist RANK Ligand Soluble, Huma

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