Searching for Constitutive Androstane Receptor Modulators

Honkakoski, Paavo

doi:10.1124/dmd.121.000482

Cited by 7 publications

(5 citation statements)

References 111 publications

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“…The mice were housed in controlled environments with a 12-h light/dark cycle and provided with standard laboratory food and water ad libitum. For subcutaneous xenograft models, 150 μL of media containing 5×10 6 MDA-MB-231 cells were injected subcutaneously into the right flanks of female BALB/c-Nude mice. Once the tumor volume reached approximately 100 mm 3 (measured using a digital caliper and the formula V = length × width 2 /2), the mice were randomly grouped into four categories, each comprising five mice.…”

Section: Animal Experimentsmentioning

confidence: 99%

“…CAR serves as a master regulator of drug metabolism and disposition. It also plays a pivotal role in the development of various diseases, including cancer, liver diseases, inflammatory diseases, and metabolic disorders through the regulation of energy homeostasis and cell proliferation [6] . Existing evidence strongly suggests that CAR is a promising target for drug discovery, leading to extensive efforts to identify activators and inhibitors of CAR [7] .…”

Section: Introductionmentioning

confidence: 99%

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Timosaponin AⅢ induces drug-metabolizing enzymes by activating constitutive androstane receptor (CAR) <i>via</i> dephosphorylation of the EGFR signaling pathway

Hafiz,

Pan,

Gao

et al. 2024

J Biomed Res

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This study aimed to assess the impact of timosaponin AⅢ (T-AⅢ) on drug-metabolizing enzymes in anticancer treatment. In vivo experiments were conducted on nude mice and ICR mice. After 24 days of T-AⅢ administration, nude mice showed an induction of CYP2B10, MDR1, and CYP3A11 in the liver. In ICR mice, CYP2B10 and MDR1 were up-regulated after three days of T-AⅢ administration. In vitro assessments were performed using HepG2 cells to determine the effects and underlying mechanisms. In HepG2 cells, T-AⅢ induced the expression of CYP2B6, MDR1, and CYP3A4, along with CAR activation. CAR siRNA reversed the T-AⅢ-induced increases in CYP2B6 and CYP3A4. Furthermore, other CAR target genes showed a significant up-regulation. Up-regulation of mCAR was observed in the livers of nude mice and ICR mice. Subsequent findings demonstrated that T-AⅢ activated CAR by inhibiting ERK1/2 phosphorylation, partially reversed by the MAPK/MEK activator t-BHQ. Inhibition of the ERK1/2 signaling pathway was also observed in vivo. Lastly, T-AⅢ inhibited the phosphorylation of EGFR at Tyr1173 and Tyr845, and suppressed EGF-induced phosphorylation of EGFR, ERK, and CAR. Additionally, T-AⅢ inhibited EGFR phosphorylation in nude mice. Our results demonstrate that T-AⅢ is a novel CAR activator through inhibition of the EGFR pathway.

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Section: Animal Experimentsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Timosaponin AⅢ induces drug-metabolizing enzymes by activating constitutive androstane receptor (CAR) <i>via</i> dephosphorylation of the EGFR signaling pathway

Hafiz,

Pan,

Gao

et al. 2024

J Biomed Res

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“…Both receptors are selectively activated by BAs. Other nuclear receptors are the Pregnane-X-receptor (PXR) [31], the Constitutive Androstane Receptor (CAR) [32], the Vitamin D Receptor (VDR) [33], the sphingosine-1-phosphate receptor (S1PR) [34], and other G-protein coupled receptors, able to bind BAs in a non-exclusive manner [35].…”

Section: Bile Acids: Biochemistry and Physiologymentioning

confidence: 99%

Bile Acids and Bilirubin Role in Oxidative Stress and Inflammation in Cardiovascular Diseases

Punzo,

Silla,

Fogacci

et al. 2024

Diseases

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Bile acids (BAs) and bilirubin, primarily known for their role in lipid metabolism and as heme catabolite, respectively, have been found to have diverse effects on various physiological processes, including oxidative stress and inflammation. Indeed, accumulating evidence showed that the interplay between BAs and bilirubin in these processes involves intricate regulatory mechanisms mediated by specific receptors and signaling pathways under certain conditions and in specific contexts. Oxidative stress plays a significant role in the development and progression of cardiovascular diseases (CVDs) due to its role in inflammation, endothelial dysfunction, hypertension, and other risk factors. In the cardiovascular (CV) system, recent studies have suggested that BAs and bilirubin have some opposite effects related to oxidative and inflammatory mechanisms, but this area of research is still under investigation. This review aims to introduce BAs and bilirubin from a biochemical and physiological point of view, emphasizing their potential protective or detrimental effects on CVDs. Moreover, clinical studies that have assessed the association between BAs/bilirubin and CVD were examined in depth to better interpret the possible link between them.

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“…The constitutive androgen receptor (CAR) is a nuclear receptor that regulates the transcription of genes involved in xenobiotic metabolism [ 229 ]. CAR is mainly expressed in the liver and the intestine [ 230 ].…”

Section: Strategies To Overcome Low Slc Transporter Expression-mediat...mentioning

confidence: 99%

The Role of Solute Carrier Transporters in Efficient Anticancer Drug Delivery and Therapy

2023

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Transporter-mediated drug resistance is a major obstacle in anticancer drug delivery and a key reason for cancer drug therapy failure. Membrane solute carrier (SLC) transporters play a crucial role in the cellular uptake of drugs. The expression and function of the SLC transporters can be down-regulated in cancer cells, which limits the uptake of drugs into the tumor cells, resulting in the inefficiency of the drug therapy. In this review, we summarize the current understanding of low-SLC-transporter-expression-mediated drug resistance in different types of cancers. Recent advances in SLC-transporter-targeting strategies include the development of transporter-utilizing prodrugs and nanocarriers and the modulation of SLC transporter expression in cancer cells. These strategies will play an important role in the future development of anticancer drug therapies by enabling the efficient delivery of drugs into cancer cells.

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Searching for Constitutive Androstane Receptor Modulators

Cited by 7 publications

References 111 publications

Timosaponin AⅢ induces drug-metabolizing enzymes by activating constitutive androstane receptor (CAR) <i>via</i> dephosphorylation of the EGFR signaling pathway

Timosaponin AⅢ induces drug-metabolizing enzymes by activating constitutive androstane receptor (CAR) <i>via</i> dephosphorylation of the EGFR signaling pathway

Bile Acids and Bilirubin Role in Oxidative Stress and Inflammation in Cardiovascular Diseases

The Role of Solute Carrier Transporters in Efficient Anticancer Drug Delivery and Therapy

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