Novel FXR (farnesoid X receptor) modulators: Potential therapies for cholesterol gallstone disease

Yu, Donna; Andrali, Sreenath S.; Li, Hongzhi; Lin, Min; Huang, Wendong; Forman, Barry M.

doi:10.1016/j.bmc.2016.06.039

Cited by 26 publications

(25 citation statements)

References 33 publications

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“…We conducted docking studies to study the interaction between 2HF and RLIP76, ERα and HER2 by employing Schordinger Glide docking software [ 20 , 21 ]. 2HF formed hydrogen bonds with tyrosine (Y 231 ), lysine (K 268 ) and alanine (A 264 ) residues of RLIP76 with a docking score of −10.5 kcal/mol at its previously known ligand (DNP-SG)-binding site [ 7 , 10 ] (Figure 2A ).…”

Section: Resultsmentioning

confidence: 99%

2’-Hydroxyflavanone effectively targets RLIP76-mediated drug transport and regulates critical signaling networks in breast cancer

Nagaprashantha

Singhal

et al. 2018

Oncotarget

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Breast cancer (BC) is the most common cancer in women. Estrogen, epidermal growth factor receptor 2 (ERBB2, HER2), and oxidative stress represent critical mechanistic nodes associated with BC. RLIP76 is a major mercapturic acid pathway transporter whose expression is increased in BC. In the quest of a novel molecule with chemopreventive and chemotherapeutic potential, we evaluated the effects of 2'-Hydroxyflavanone (2HF) in BC. 2HF enhanced the inhibitory effects of RLIP76 depletion and also inhibited RLIP76-mediated doxorubicin transport in BC cells. RNA-sequencing revealed that 2HF induces strong reversal of the gene expression pattern in ER+MCF7, HER2+ SKBR3 and triple-negative MDA-MB-231 BC cells with minimal effects on MCF10A normal breast epithelial cells. 2HF down regulated ERα and enhanced inhibitory effects of imatinib mesylate/Gleevec in MCF7 cells. 2HF also down regulated ERα and HER2 gene networks in MCF7 and SKBR3 cells, respectively. 2HF activated TP53 and inhibited TGFβ1 canonical pathway in MCF7 and MDA-MB-231 BC cells. 2HF also regulated the expression of a number of critical prognostic genes of MammaPrint panel and their upstream targets including TP53, CDKN2A and MYC. The collective findings from this study provide a comprehensive, direct and integrated evidence for the benefits of 2HF in targeting major and clinically relevant mechanistic regulators of BC.

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Section: Resultsmentioning

confidence: 99%

2’-Hydroxyflavanone effectively targets RLIP76-mediated drug transport and regulates critical signaling networks in breast cancer

Nagaprashantha

Singhal

et al. 2018

Oncotarget

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“…However, a recent clinical study suggested that UDCA might have direct or indirect (may compete with endogenous agonist FXR) inhibitory activity toward intestinal FXR 117, 118 . While UDCA binds to FXR, it shows partial agonist or no FXR agonist activity 119, 120 . It remains to be determined if UDCA is an FXR antagonist.…”

Section: Fxr As a Drug Targetmentioning

confidence: 99%

An Intestinal Microbiota–Farnesoid X Receptor Axis Modulates Metabolic Disease

2016

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The gut microbiota is associated with metabolic diseases including obesity, insulin resistance and non-alcoholic fatty liver disease (NAFLD), as demonstrated by correlative studies and by transplant of microbiota from obese humans and mice into germ-free mice. Modification of the microbiota by treatment of high-fat diet (HFD)-fed mice with tempol or antibiotics resulted in decreased adverse metabolic phenotypes. This was due to lower levels of the genera Lactobacillus and decreased bile salt hydrolase (BSH) activity. The decreased BSH resulted in increased levels of tauro-β-muricholic acid (T-β-MCA), a substrate of BSH and a potent farnesoid X receptor (FXR) antagonist. Mice lacking expression of FXR in the intestine were resistant to HFD-induced obesity, insulin resistance and NAFLD thus confirming that intestinal FXR is involved in the potentiation of metabolic disease. A potent intestinal FXR antagonist glycine-β-muricholic acid (Gly-MCA) that is resistant to BSH, was developed that when administered to HFD-treated mice, mimics the effect of the altered microbiota on HFD-induced metabolic disease. Gly-MCA had similar effects on genetically obese leptin-deficient mice. The decreased in adverse metabolic phenotype by tempol, antibiotics and Gly-MCA was due to decreased serum ceramides. Mice lacking FXR in intestine also have lower serum ceramides, are metabolic fit and resistant to HFD-induced metabolic disease, and this is reversed by injection of C16:0 ceramide. In mouse ileum, due to the presence of endogenous FXR agonists produced in the liver, FXR target genes involved in ceramide synthesis are activated and when Gly-MCA is administered, they are repressed, which likely accounts for the decrease in serum ceramides. These studies reveal that ceramides produced in the ileum under control of FXR, influence metabolic diseases.

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“…If the levels of FXR expression are inappropriate, bile acid secretion and reabsorption disorders may occur, and bile will accumulate in the bile duct [21][22][23]. So cholesterol and bile pigments may accumulate in bile ducts, leading to the formation of stones.…”

Section: Discussionmentioning

confidence: 99%

FXR expression in a rat model of hilar cholangiocarcinoma

Zhang

Wang

2020

Preprint

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Background: To develop a rat model of hilar cholangiocarcinoma and detect Farnesyl X receptor (FXR) expression in hilar cholangiocarcinoma tissues of this model, in order to provide a new method for the treatment of hilar cholangiocarcinoma.Methods: Forty male Wistar rats (body weight, 185 ± 5 g) were randomly divided into two groups (n = 20 each) as follows: The control group was fed a standard diet, and the experimental group was injected by cholangiocarcinoma QBC939 cell suspension along the hilar bile duct into the bile duct bifurcation with microsyringe. Every day note the rats’ mental state, diet, and fur condition. At 4 weeks, one rat of the experimental group was sacrificed, and we recorded changes in hilar bile duct size, texture, and form. This procedure was repeated at 6 weeks. After 6 weeks, hilar cholangiocarcinoma developed only in the experimental group, thereby establishing an experimental model for studying QBC939-induced hilar cholangiocarcinoma. Tumor formation was confirmed by pathological examination, and hilar bile duct tissues were harvested from both the groups. A real-time polymerase chain reaction assay and an immunohistochemical assay were used to analyze the expression of FXR in hilar cholangiocarcinoma and normal hilar bile duct tissues.Results: From the second week, the rats in experimental group began to eat less, and their body mass decreased compared with controls. After 6 weeks, we detected hilar cholangiocarcinoma in 17 rats (85%) in the experimental group. In the experimental group, we found that the levels of total cholesterol, total bilirubin, and direct bilirubin were higher compared with those of the control group. Simultaneously, muddy stones emerged from the bile ducts of rats in the experimental group. The FXR/Gapdh mRNA ratio in hilar cholangiocarcinoma and normal hilar bile duct tissues differed markedly. Light microscopy revealed a granular pattern of FXR expression which reacted with the anti-FXR antibody. Each section was randomly divided into six regions, with 80 cells were observed in every region. Sections with >10% positive cells were designated positive,Sections with <10% positive cells were designated negative. Each group included 4,800 cells. In the experimental group, 1,196 cells (24.9%) were positive and 3,538 cells (73.7%) were positive in the control group, and this difference was statistically significant.Conclusion: FXR expression significantly decreased in hilar cholangiocarcinoma of rats than in those of controls, suggesting that drugs targeting FXR may be a new strategy for hilar cholangiocarcinoma.

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Novel FXR (farnesoid X receptor) modulators: Potential therapies for cholesterol gallstone disease

Cited by 26 publications

References 33 publications

2’-Hydroxyflavanone effectively targets RLIP76-mediated drug transport and regulates critical signaling networks in breast cancer

2’-Hydroxyflavanone effectively targets RLIP76-mediated drug transport and regulates critical signaling networks in breast cancer

An Intestinal Microbiota–Farnesoid X Receptor Axis Modulates Metabolic Disease

FXR expression in a rat model of hilar cholangiocarcinoma

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