T1839 Farnesoid X-Receptor Agonists Inhibit Colonic Secretion In Vitro and In Vivo.

Analgesia is commonly mediated through the mu or kappa opioid receptor agonism. Unfortunately, selective mu or kappa receptor agonists often cause harmful side effects. Recently, ligands exhibiting dual agonism to the opioid receptors, such as to mu and kappa, or to mu and delta, have been suggested to temper undesirable adverse effects while retaining analgesic activity. Herein we report an introduction of various 6,5-fused rings to C2 of the salvinorin scaffold via an ester linker. In vitro studies showed that some of these compounds have dual agonism on kappa and mu opioid receptors, while some have triple agonism on kappa, mu, and delta. In vivo studies on the lead dual kappa and mu opioid receptor agonist, compound 10, showed that it produced analgesic activity while avoiding anxiogenic effects in murine models, thus providing further strong evidence for the therapeutic advantages of dual opioid receptor agonists over selective opioid receptor agonists.

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From Theory to Clinical Practice in the Use of GLP-1 Receptor Agonists and DPP-4 Inhibitors Therapy

Experimental Diabetes Research ◽

10.1155/2011/898913 ◽

2011 ◽

Vol 2011 ◽

pp. 1-8 ◽

Cited By ~ 14

Author(s):

Ilaria Dicembrini ◽

Laura Pala ◽

Carlo Maria Rotella

Keyword(s):

Cell Function ◽

Lifestyle Modification ◽

Cell Mass ◽

Beta Cell Mass ◽

Minimal Risk ◽

Dipeptidyl Peptidase 4 ◽

Receptor Agonists ◽

Dipeptidyl Peptidase 4 Inhibitors

Promoting long-term adherence to lifestyle modification and choice of antidiabetic agent with low hypoglycemia risk profile and positive weight profile could be the most effective strategy in achieving sustained glycemic control and in reducing comorbidities. From this perspective, vast interest has been generated by glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 inhibitors (DPP-4i). In this review our ten-year clinical and laboratory experience byin vitroandin vivostudies is reported. Herein, we reviewed available data on the efficacy and safety profile of GLP-1 receptor agonists and DPP-4i. The introduction of incretin hormone-based therapies represents a novel therapeutic strategy, because these drugs not only improve glycemia with minimal risk of hypoglycemia but also have other extraglycemic beneficial effects. In clinical studies, both GLP-1 receptor agonists and DPP-4i, improveβcell function indexes. All these agents showed trophic effects on beta-cell mass in animal studies. The use of these drugs is associated with positive or neucral effect on body weight and improvements in blood pressure, diabetic dyslipidemia, hepatic steazosis markets, and myocardial function. These effects have the potential to reduce the burden of cardiovascular disease, which is a major cause of mortality in patients with diabetes.

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Abstract 76: MicroRNA-144 Regulates Hepatic ABCA1 and Plasma HDL Following Activation of the Nuclear Receptor FXR

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.33.suppl_1.a76 ◽

2013 ◽

Vol 33 (suppl_1) ◽

Author(s):

Thomas Vallim ◽

Elizabeth Tarling ◽

Tammy Kim ◽

Mete Civelek ◽

Angel Baldan ◽

...

Keyword(s):

Lipid Metabolism ◽

Nuclear Receptor ◽

Molecular Mechanisms ◽

Lipoprotein Metabolism ◽

Density Lipoprotein ◽

Hdl Cholesterol ◽

Farnesoid X Receptor ◽

Abca1 Protein

Rationale The bile acid receptor Farnesoid-X-Receptor (FXR) regulates many aspects of lipid metabolism by various complex and not fully understood molecular mechanisms. We set out to investigate the molecular mechanisms for FXR-dependent regulation of lipid and lipoprotein metabolism. Objective To identify FXR-regulated microRNAs that were subsequently involved in regulating lipid metabolism. Methods and Results ATP binding cassette transporter A1 (ABCA1) is a major determinant of plasma High Density Lipoprotein (HDL)-cholesterol levels. Here we show that activation of the nuclear receptor FXR in vivo increases hepatic levels of miR-144, which in turn lower hepatic ABCA1 and plasma HDL levels. We identified two complementary sequences to miR-144 in the 3’ untranslated region (UTR) of ABCA1 mRNA that are necessary for miR-144-dependent regulation. Overexpression of miR-144 in vitro decreased both cellular ABCA1 protein and cholesterol efflux to lipid-poor apolipoprotein A-I (ApoA-I) protein, whilst overexpression in vivo reduced hepatic ABCA1 protein and plasma HDL- cholesterol. Conversely, silencing miR-144 in mice increased hepatic ABCA1 protein and HDL- cholesterol. In addition, we utilized tissue-specific FXR deficient mice to show that induction of miR-144 and FXR-dependent hypolipidemia requires hepatic, but not intestinal FXR. Finally, we identified functional FXR response elements (FXREs) upstream of the miR-144 locus, consistent with direct FXR regulation. Conclusion In conclusion, we have identified a pathway involving FXR, miR-144 and ABCA1 that together regulate plasma HDL cholesterol. This pathway may be therapeutically targeted in the future in order to increase HDL levels.

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Glucagon-like Peptide 1 Receptor Agonists, Diabetic Retinopathy and Angiogenesis: The AngioSafe Type 2 Diabetes Study

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgz069 ◽

2019 ◽

Vol 105 (4) ◽

pp. e1549-e1560 ◽

Cited By ~ 7

Author(s):

Bénédicte Gaborit ◽

Jean-Baptiste Julla ◽

Samaher Besbes ◽

Matthieu Proust ◽

Clara Vincentelli ◽

...

Keyword(s):

Type 2 Diabetes ◽

Diabetic Retinopathy ◽

Fundus Photography ◽

Endothelial Cell Proliferation ◽

Receptor Agonists ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

Abstract Aims Recent trials provide conflicting results on the association between glucagon-like peptide 1 receptor agonists (GLP-1RA) and diabetic retinopathy (DR). The aim of the AngioSafe type 2 diabetes (T2D) study was to determine the role of GLP-1RA in angiogenesis using clinical and preclinical models. Methods We performed two studies in humans. In study 1, we investigated the effect of GLP-1RA exposure from T2D diagnosis on the severity of DR, as diagnosed with retinal imaging (fundus photography). In study 2, a randomized 4-week trial, we assessed the effect of liraglutide on circulating hematopoietic progenitor cells (HPCs), and angio-miRNAs. We then studied the experimental effect of Exendin-4, on key steps of angiogenesis: in vitro on human endothelial cell proliferation, survival and three-dimensional vascular morphogenesis; and in vivo on ischemia-induced neovascularization of the retina in mice. Results In the cohort of 3154 T2D patients, 10% displayed severe DR. In multivariate analysis, sex, disease duration, glycated hemoglobin (HbA1c), micro- and macroangiopathy, insulin therapy and hypertension remained strongly associated with severe DR, while no association was found with GLP-1RA exposure (o 1.139 [0.800–1.622], P = .47). We further showed no effect of liraglutide on HPCs, and angio-miRNAs. In vitro, we demonstrated that exendin-4 had no effect on proliferation and survival of human endothelial cells, no effect on total length and number of capillaries. Finally, in vivo, we showed that exendin-4 did not exert any negative effect on retinal neovascularization. Conclusions The AngioSafe T2D studies provide experimental and clinical data confirming no effect of GLP-1RA on angiogenesis and no association between GLP-1 exposure and severe DR.

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Guggulsterone, a farnesoid X receptor antagonist lowers plasma trimethylamine-N-oxide levels: An evidence from in vitro and in vivo studies

Human & Experimental Toxicology ◽

10.1177/0960327118817862 ◽

2018 ◽

Vol 38 (3) ◽

pp. 356-370 ◽

Cited By ~ 4

Author(s):

A Gautam ◽

YN Paudel ◽

SAZ Abidin ◽

U Bhandari

Keyword(s):

Hepatic Injury ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Farnesoid X Receptor ◽

Lipoprotein Cholesterol ◽

In Vivo Studies ◽

Low Density Lipoprotein Cholesterol ◽

Pro Inflammatory Cytokines

The current study investigated the role of guggulsterone (GS), a farnesoid X receptor antagonist, in the choline metabolism and its trimethylamine (TMA)/flavin monooxygenases/trimethylamine- N-oxide (TMAO) inhibiting potential in a series of in vitro and in vivo studies as determined by high-performance liquid chromatography (HPLC), mass spectroscopy (MS), and liquid chromatography (LC)-MS techniques. Atherosclerosis (AS) was successfully induced in a group of experimental animals fed with 2% choline diet for 6 weeks. Serum lipid profiles such as total cholesterol, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and very low-density lipoprotein cholesterol were measured. Pro-inflammatory cytokines levels, markers for a hepatic injury, and oxidative stress markers were assessed. Interestingly, GS reduced the level of TMA/TMAO in both in vitro and in vivo studies as demonstrated by the peaks obtained from HPLC, MS, and LC–MS. Furthermore, GS exhibited cardioprotective and antihyperlipidemic effects as evidenced by the attenuation of levels of several serum lipid profiles and different atherogenic risk predictor indexes. GS also prevented hepatic injury by successfully restoring the levels of hepatic injury biomarkers to normal. Similarly, GS inhibited the production of pro-inflammatory cytokines levels, as well as GS, enhanced antioxidant capacity, and reduced lipid peroxidation. Histopathological study of aortic sections demonstrated that GS maintained the normal architecture in AS-induced rats. On the basis of results obtained from current investigation, we suggest that GS might have a great therapeutic potential for the treatment of AS.

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Synergistic tumor inhibition of colon cancer cells by nitazoxanide and obeticholic acid, a farnesoid X receptor ligand

Cancer Gene Therapy ◽

10.1038/s41417-020-00239-8 ◽

2020 ◽

Author(s):

Junhui Yu ◽

Kui Yang ◽

Jianbao Zheng ◽

Wei Zhao ◽

Xuejun Sun

Keyword(s):

Colon Cancer ◽

Cancer Cells ◽

Farnesoid X Receptor ◽

Colon Cancer Cells ◽

Antitumor Effects ◽

Colorectal Tumorigenesis ◽

Tumor Inhibition ◽

Combination Study

Abstract The tumor-suppressive role of Farnesoid X receptor (FXR) in colorectal tumorigenesis supports restoring FXR expression as a novel therapeutic strategy. However, the complicated signaling network and tumor heterogeneity hinder the effectiveness of FXR agonists in the clinical setting. These difficulties highlight the importance of identifying drug combinations with potency and specificity to enhance the antitumor effects of FXR agonists. In this study, we found that the β-catenin level affected the antitumor effects of the FXR agonist OCA on colon cancer cells. Mechanistic studies identified a novel FXR/β-catenin complex in colon cancer cells. Furthermore, the depletion of β-catenin expedited FXR nuclear localization and enhanced its occupancy of the SHP promoter and thereby sensitized colon cancer cells to OCA. Furthermore, we utilized a drug combination study and identified that the antiparasitic drug nitazoxanide (NTZ) abrogated β-catenin expression and acted synergistically with OCA in colon cancer cells. The combination of OCA plus NTZ exerts synergistic tumor inhibition in CRC both in vitro and in vivo by cooperatively upregulating SHP expression. In conclusion, our study offers useful evidence for the clinical use of FXR agonists combined with β-catenin inhibitors in combating CRC.

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