Article
Biochemistry & Molecular Biology
Andrew D. Huber, William C. Wright, Wenwei Lin, Kinjal Majumder, Jonathan A. Low, Jing Wu, Cameron D. Buchman, David J. Pintel, Taosheng Chen
Summary: This study found that mutating a single residue in the PXR receptor can convert the antagonist SPA70 into an agonist. Molecular dynamics simulations revealed that in certain cases, the action of SPA70 is similar to that of agonists, further elucidating the relationship between the structure and activity of the PXR receptor.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2021)
Review
Biochemistry & Molecular Biology
Morgane M. Thibaut, Laure B. Bindels
Summary: This review summarizes the immune-modulatory actions of bile acid-responsive receptors and discusses the contribution of microbiota-derived bile acids to intestinal and hepatic inflammation through these receptors.
TRENDS IN MOLECULAR MEDICINE
(2022)
Review
Biochemistry & Molecular Biology
Sarah Da Won Bae, Romario Nguyen, Liang Qiao, Jacob George
Summary: CAR is a receptor that is predominantly expressed in the liver and interacts with key signaling pathways related to drug, energy, and bilirubin metabolism. While studies in animal models suggest a potential role of CAR in tumorigenesis, recent research has shown species differences and a possible tumor-suppressive role of CAR in liver cancer in humans. This review highlights the need for further exploration of CAR's role in human diseases, particularly cancers, with a focus on its emerging functions in liver cancer.
BIOCHIMICA ET BIOPHYSICA ACTA-REVIEWS ON CANCER
(2021)
Article
Biochemistry & Molecular Biology
Hangxing Huang, Change Cao, Zhimin Miao, Xiaoli Yang, Yong Lai
Summary: In this study, it was found that scutellarin can affect the expression of CYP3A4 and CYP2C19 in HepG2 and Caco-2 cells by regulating nuclear receptors PXR and CAR. Scutellarin inhibits the expression of CYP3A4 through PXR, and up-regulates CYP2C19 through CAR.
CURRENT MOLECULAR PHARMACOLOGY
(2023)
Article
Pharmacology & Pharmacy
Daniel Rizzolo, Bo Kong, Stephanie Piekos, Liming Chen, Xiaobo Zhong, Jie Lu, Jian Shi, Hao-jie Zhu, Qian Yang, Albert Li, Linhao Li, Hongbing Wang, Anna Siemiatkowska, Celine Park, Leonid Kagan, Grace L. Guo
Summary: Fibroblast growth factors 15 and 19 are important in maintaining bile acid homeostasis, and are currently being tested as potential treatments for certain liver diseases. This study found that long-term elevations of these growth factors can lead to increased expression of drug metabolizing enzymes, affecting drug metabolism and pharmacokinetics. The overexpression of Fgf15 was also found to cause a switch in the expression pattern of these enzymes in male mice, similar to the pattern observed in female mice. This change was associated with differences in growth hormone secretion and STAT5 signaling.
DRUG METABOLISM AND DISPOSITION
(2022)
Article
Plant Sciences
Mingyue Ma, Na Wei, Jieren Yang, Tingting Ding, Anping Song, Lerong Chen, Shuguo Zheng, Huanhuan Jin
Summary: This study aimed to investigate the effect of Schisandrin B (Sch B) on activated hepatic stellate cells (HSCs) senescence in hepatic fibrosis and its underlying mechanism. The results showed that Sch B could alleviate hepatic fibrosis and promote the senescence of activated HSCs, possibly through the induction of NCOA4-mediated ferritinophagy to enhance the aging process.
PHARMACEUTICAL BIOLOGY
(2023)
Article
Environmental Sciences
Yu-Sheng Shi, Yi Zhao, Xue-Nan Li, Mu-Zi Li, Jin-Long Li
Summary: Phthalates, extensively used in plastics production, have been proven to cause lung injury. Lycopene (LYC) is an effective preventive measure against phthalates-induced toxicity. However, the role of phthalates in the pathogenesis of lung injury and whether LYC can alleviate phthalate-induced lung toxicity by modulating nuclear xenobiotic receptors (NXRs) response have not been thoroughly researched. This study investigates the toxicity of the representative phthalate di (2-ethylhexyl) phthalate (DEHP) and the antagonistic role of LYC in DEHP-induced lung injury. It was found that DEHP exposure caused alveoli destruction and damage to alveolar epithelial cells type II. Mechanistically, DEHP exposure increased nuclear accumulation of aryl hydrocarbon receptor (AHR) and its downstream genes, as well as Constitutive androstane receptor (CAR) and its downstream gene level. LYC supplementation relieved lung injury from DEHP exposure by inhibiting the activation of NXRs. The study confirms the important role of NXRs in phthalates-induced lung injury and suggests LYC as an effective strategy for mitigating the toxicity effects of phthalates.
Article
Pharmacology & Pharmacy
Yoshihiro Kobashigawa, Mana Namikawa, Mitsuhiro Sekiguchi, Yuki Inada, Soichiro Yamauchi, Yuu Kimoto, Kyo Okazaki, Yuya Toyota, Takashi Sato, Hiroshi Morioka
Summary: The constitutive active/androstane receptor (CAR) is a nuclear receptor involved in drug metabolism regulation. A novel system was developed for rapid evaluation of drug interactions with CAR, using differential scanning fluorometry (DSF) to confirm direct interactions. This method is easy to set up and beneficial for drug discovery purposes.
BIOLOGICAL & PHARMACEUTICAL BULLETIN
(2021)
Article
Biochemistry & Molecular Biology
Mireia Lopez-Riera, Rebeca Ortega, Luisa Hueso, Maria Carmen Montesinos, Mari Carmen Gomez-Cabrera, Maria Jesus Sanz, Jose T. Real, Laura Piqueras
Summary: This study demonstrates that CAR agonists can inhibit the early inflammatory response that precedes atherosclerosis by targeting various steps in the leukocyte recruitment cascade. This suggests that CAR agonists may serve as a new therapeutic approach to control inflammation associated with cardiovascular diseases.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Gyun-Sik Oh, Si-Ryong Kim, Eun-Sook Lee, Jin Yoon, Min-Kyung Shin, Hyeon Kyoung Ryu, Dong Seop Kim, Seung-Whan Kim
Summary: NCOA6 is a transcriptional coactivator of nuclear receptors and other transcription factors. It regulates hepatic gluconeogenesis by modulating glucagon/cAMP-dependent gluconeogenic gene transcription through an interaction with CREB.
MOLECULES AND CELLS
(2022)
Article
Pharmacology & Pharmacy
Congrong Niu, Bill Smith, Yurong Lai
Summary: This study characterized the gene induction by ligands of CAR and AhR in human hepatocytes, showing distinct effects on metabolizing enzyme and drug transporter genes. Different inducers had varying degrees of effects on specific genes, highlighting the importance of assessing transporter gene inductions alongside metabolizing enzyme genes.
FRONTIERS IN PHARMACOLOGY
(2021)
Article
Nutrition & Dietetics
Dicson Sheeja Malar, Mani Iyer Prasanth, Kanika Verma, Anchalee Prasansuklab, Tewin Tencomnao
Summary: In this study, the mode of toxicity of Phenanthrene (Phe) in human keratinocytes was investigated, along with the protective effect of the ethanol extract of Hibiscus sabdariffa calyxes (HS). The results showed that Phe induced cytotoxicity through CAR/PXR/RXR-mediated activation of CYP1A1, leading to alterations in phase I and II metabolism genes. However, pre-treatment with HS extract inhibited CYP1A1 and attenuated the pathological changes caused by Phe exposure.
Article
Biochemistry & Molecular Biology
Bhaswati Banerjee, Olayemi Joseph Olajide, Giulia Bortolussi, Andres F. Muro
Summary: Bilirubin is a byproduct of heme metabolism, and Ugt1a1 is the enzyme responsible for its elimination. Dysfunctional Ugt1a1 can lead to the accumulation of unconjugated bilirubin in the brain, causing neuronal damage and death. Understanding alternative bilirubin detoxification mechanisms is crucial for developing new therapeutic strategies. Activation of alternative clearance pathways can partially improve hyperbilirubinemic conditions in the absence of Ugt1a1.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Pharmacology & Pharmacy
Zhe Shi, Xue Li, Yu-Man Zhang, Yi-Yao Zhou, Xiu-Feng Gan, Qiao-Ying Fan, Chen-Qing He, Tong Shi, Shu-Yun Zhang
Summary: This study investigates the molecular mechanisms of the inflammatory response in pyrene-caused mice liver injury and reveals the crucial role of the CAR gene in this process, leading to increased levels of SAAs and Th17 cells. Our findings suggest that serum SAAs may serve as a convenient biomarker for early diagnosis of liver inflammatory response caused by polycyclic aromatic hydrocarbons, including pyrene.
BRITISH JOURNAL OF PHARMACOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Shin-Hun Juang, Min-Tsang Hsieh, Pei-Ling Hsu, Ju-Ling Chen, Hui-Kang Liu, Fong-Pin Liang, Sheng-Chu Kuo, Chen-Yuan Chiu, Shing-Hwa Liu, Chen-Hsi Chou, Tian-Shung Wu, Hsin-Yi Hung
Summary: In the study, 6,7-diprenoxycoumarin was identified as the most effective CAR activator, with modifications at the 6 position and unsaturated chains generally beneficial. The research also indicated that mimicking natural occurring coumarins for modification shed light on CAR studies.