Review
Cell Biology
Leonida Rakateli, Rosanna Huchzermeier, Emiel P. C. van der Vorst
Summary: Xenobiotic receptors play a crucial role in both chemical sensing and detoxification as well as lipid metabolism regulation, particularly in relation to dyslipidemia.
Article
Dermatology
Baochang Lai, Xinya Xie, Fan Li, Qi Cui, Erle Dang, Wenhuan Luo, Ning Wang, Yan Zheng, Gang Wang, Lei Xiao, Nanping Wang
Summary: The study demonstrates that CAR plays a pathogenic role in psoriasis and has the potential to be a target for its treatment. Xenobiotics and proinflammatory cytokines affect the expression of CAR and its target genes, further promoting the development of psoriatic skin lesions.
JOURNAL OF INVESTIGATIVE DERMATOLOGY
(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.
Review
Pharmacology & Pharmacy
Xiaoyin Ye, Tong Zhang, Han Han
Summary: The activation of FXR receptor can reduce bile acid synthesis and alleviate cholestasis, but the unresponsiveness of some patients and side effects of UDCA or OCA treatment limit their effectiveness. Therefore, researchers have begun to investigate the role of PPARα receptor in regulating bile acid metabolism and transport, and have found its anti-inflammatory effects that can improve the physiological status of patients with cholestatic liver disorders.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Genetics & Heredity
Fan-Cheng Kong, Chun-Lai Ma, Li-Qin Lang, Ming-Kang Zhong
Summary: This study aimed to investigate the pharmacogenomic associations of polymorphisms of xenobiotic receptors with the CBZ response in epilepsy patients, revealing a potentially relevant interaction between the CAR rs2502815 polymorphism and the CBZ response.
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
Ya-Di Zhu, Xiao-Qing Guan, Jing Chen, Sheng Peng, Moshe Finel, Ying-Yuan Zhao, Rui-Min Wang, Hui-Chang Bi, Ming Lei, Dan-Dan Wang, Guang-Bo Ge
Summary: NBIF is identified as a potent natural inducer of UGT1A1, mainly activating and up-regulating PPAR alpha and PPAR gamma to induce UGT1A1 expression. This finding suggests that NBIF could be a promising lead compound for the development of more efficacious UGT1A1 inducers to treat hyperbilirubinaemia and UGT1A1-associated drug toxicities.
FRONTIERS IN PHARMACOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Katerina Cizkova, Tereza Foltynkova, Jiri Hanyk, Zbynek Kamencak, Zdenek Tauber
Summary: The study found that PPAR alpha plays an important role in the differentiation of intestinal cells, but the differentiation of intestinal epithelium may be independent of PPAR alpha.
Article
Immunology
Xiaohua Wu, Bei Cheng, Xiaojuan Guo, Qinqin Wu, Shan Sun, Ping He
Summary: The biochemical mechanisms of Chlamydia pneumoniae (Cpn)-induced foam cell formation in early atherosclerosis involve upregulation of SR-A1 and ACAT1, as well as downregulation of ABCA1/G1 expression by both PPAR alpha and PPAR gamma pathways.
MICROBIAL PATHOGENESIS
(2021)
Article
Pharmacology & Pharmacy
Tomomi Morikawa, Tatsuki Fukami, Saki Gotoh-Saito, Masataka Nakano, Miki Nakajima
Summary: This study demonstrated the regulation of human AADAC by PPAR alpha through binding to DR1, and the significance of AADAC in lipid accumulation.
BIOCHEMICAL PHARMACOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Doudou Luo, Wenxuan Ye, Ling Chen, Xiaoqian Yuan, Yali Zhang, Caixia Chen, Xin Jin, Yu Zhou
Summary: Astrocyte inflammation activation hinders motor function recovery after cerebral ischemia, and the molecular mechanism is not clearly understood. This study investigates the role of PPARa in astrocyte inflammation activation after cerebral ischemia and explores the underlying mechanism. The results show that PPARa dysfunction promotes astrocyte inflammatory activation, while PPARa activation preserves lysosome function and restores autophagic flux in astrocytes after oxygen-glucose deprivation/reoxygenation (OGD/R).
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
Chemistry, Multidisciplinary
Jie Yang, Xiao Yang, Yi-fei Zhang, Jia-ning Tian, Shi-cheng Fan, Yue Gao, Hui-lin Li, Cheng-hui Cai, Min Huang, Hui-chang Bi
Summary: In this study, it was found that activation of PPARa leads to hepatomegaly in mice, with hepatocyte hypertrophy around the central vein area and hepatocyte proliferation around the portal vein area. The study also revealed that the upregulation of PPARa targets is higher in the central vein area compared to the portal vein area, while the upregulation of proliferation-related proteins mainly occurs in the portal vein area. These findings provide new insights into the understanding of PPARa activation-induced liver enlargement and regeneration.
ACTA PHARMACOLOGICA SINICA
(2023)
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
Nutrition & Dietetics
Jia Liu, Qinyu Yao, Xinya Xie, Qi Cui, Tingting Jiang, Ziwei Zhao, Xiong Du, Baochang Lai, Lei Xiao, Nanping Wang
Summary: This study demonstrates that PCB2 attenuates nicotine-induced hepatocyte pyroptosis and liver damage by activating PPAR gamma.
Review
Pharmacology & Pharmacy
Kouichi Yoshinari, Ryota Shizu
Summary: PXR and CAR are transcription factors highly expressed in the liver and play important roles in xenobiotic metabolism and liver functions. PXR activation enhances hepatocyte proliferation, while CAR activation is associated with liver tumorigenesis. Additionally, PXR may have antitumor effects by targeting inflammatory cytokine signals, angiogenesis, and epithelial-mesenchymal transition.
DRUG METABOLISM AND DISPOSITION
(2022)
Article
Pharmacology & Pharmacy
Daigo Asano, Syoya Hamaue, Hamim Zahir, Hideyuki Shiozawa, Yumi Nishiya, Takako Kimura, Miho Kazui, Naotoshi Yamamura, Marie Ikeguchi, Takahiro Shibayama, Shin-Ichi Inoue, Tsuyoshi Shinozuka, Toshiyuki Watanabe, Chizuko Yahara, Nobuaki Watanabe, Kouichi Yoshinari
Summary: This study assessed the human metabolites of DS-1971a and identified a human disproportionate metabolite M1 formed by CYP2C8-mediated metabolism. Species differences in the formation of M1 provide new insights into the metabolism of cyclohexane-containing substrates by CYP2C8.
DRUG METABOLISM AND DISPOSITION
(2022)
Article
Pharmacology & Pharmacy
Yasushi Yamazoe, Yoshiya Yamamura, Kouichi Yoshinari
Summary: A ligand-accessible space in the CYP2C9 active site was reconstituted as a fused grid-based template, and the interaction between CYP2C9 and its ligands was studied. The results suggest that contacts with the template walls stabilize the ligand binding, and trigger-residue movement initiates CYP2C9 reactions.
DRUG METABOLISM AND PHARMACOKINETICS
(2022)
Article
Chemistry, Medicinal
Yuki Hagiwara, Harumi Kumagai, Niels Ouwerkerk, Linda Gijzen, Rumaisha Annida, Marleen Bokkers, Remko van Vught, Kouichi Yoshinari, Yoshifumi Katakawa, Kei Motonaga, Tomokazu Tajiri
Summary: The aim of this study was to develop an in vitro drug permeability methodology that accurately mimics the gastrointestinal environment using a three-dimensional (3D) Caco-2 tubules and a microphysiological system. The methodology was confirmed by measuring the permeability of propranolol and subsequently applied to solifenacin and bile acids. This model provides an alternative testing system for drug absorption in a closely resembling environment to the human gastrointestinal tract.
JOURNAL OF PHARMACEUTICAL SCIENCES
(2022)
Article
Pharmacology & Pharmacy
Daigo Asano, Koichi Nakamura, Yumi Nishiya, Hideyuki Shiozawa, Hideo Takakusa, Takahiro Shibayama, Shin-Ichi Inoue, Tsuyoshi Shinozuka, Takakazu Hamada, Chizuko Yahara, Nobuaki Watanabe, Kouichi Yoshinari
Summary: This study assessed the pharmacokinetics of the human disproportionate metabolite M1 in PXB-mice and showed that the metabolite profile in PXB-mice is remarkably similar to that in humans. Furthermore, the PBPK model incorporating parameters from PXB-mice provided a more accurate prediction of exposure to M1 compared to the observed value in PXB-mice. This study highlights the usefulness of PBPK modeling in predicting exposure to human disproportionate metabolites.
DRUG METABOLISM AND DISPOSITION
(2023)
Article
Oncology
Yuichiro Kanno, Nao Saito, Ryota Saito, Tomohiro Kosuge, Ryota Shizu, Tomofumi Yatsu, Takuomi Hosaka, Kiyomitsu Nemoto, Keisuke Kato, Kouichi Yoshinari
Summary: This study investigated the selective mechanism of selective androgen receptor modulators (SARMs) using the synthetic steroid YK11. The results suggested that gene selective regulation by SARMs is achieved through differential DNA-binding and/or cofactor recruitment by ligands. These findings provide novel insights into the mechanism of action of SARMs.
EXPERIMENTAL CELL RESEARCH
(2022)
Article
Biochemistry & Molecular Biology
Yuichiro Kanno, Nao Saito, Naoya Yamashita, Kazuki Ota, Ryota Shizu, Takuomi Hosaka, Kiyomitsu Nemoto, Kouichi Yoshinari
Summary: This study found that HER2-activated AHR can upregulate the expression of Delta Np63, thus contributing to the maintenance of breast cancer stem cells.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Food Science & Technology
Takumi Sato, Ryota Shizu, Yoshie Miura, Takuomi Hosaka, Yuichiro Kanno, Takamitsu Sasaki, Kouichi Yoshinari
Summary: This study identified possible direct and indirect activators of rCAR by measuring Cyp2b1 mRNA levels and performing reporter assays. It demonstrated the usefulness of these methods in evaluating rCAR activation by chemicals.
FOOD AND CHEMICAL TOXICOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Ryota Shizu, Yuta Otsuka, Chizuru Ishii, Kanako Ezaki, Kouichi Yoshinari
Summary: The nuclear receptor PPAR alpha controls fatty acid metabolism and can be inhibited by the xenobiotic receptor CAR, preventing lipid metabolism. Activation of PPAR alpha increases gene expression related to fatty acid metabolism. PPAR alpha binds to the promoter region of the CAR gene and induces its activity. CAR functions as a negative feedback factor for PPAR alpha activation.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Toxicology
Tomomi Yoda, Tomoaki Tochitani, Toru Usui, Mami Kouchi, Hiroshi Inada, Takuomi Hosaka, Yuichiro Kanno, Izuru Miyawaki, Kouichi Yoshinari
Summary: In this study, the researchers investigated the mechanism of hepatotoxicity caused by DSP-0640 and found that CYP1A1 inhibition-mediated AHR activation is involved in the hepatotoxicity. This discovery reveals a novel mechanism for drug-induced hepatotoxicity.
JOURNAL OF TOXICOLOGICAL SCIENCES
(2022)
Meeting Abstract
Oncology
Yuichiro Kanno, Nao Saito, Naoya Yamashita, Kouichi Yoshinari
Article
Toxicology
Hideaki Yokoyama, Taku Masuyama, Yuki Tanaka, Iori Tsubakihara, Kazuma Kondo, Kouichi Yoshinari
Summary: This study found that pharmacological inhibition of DGAT1 increased plasma ALT and AST activity in rats, and the accumulation of DAG and resultant PKC activation in enterocytes played a key role in this elevation.
JOURNAL OF TOXICOLOGICAL SCIENCES
(2022)
Article
Toxicology
Susumu Kodama, Nao Yoshii, Akihiro Ota, Jun-ichi Takeshita, Kouichi Yoshinari, Atsushi Ono
Summary: The study established mammalian one-hybrid assay systems for five rat-derived nuclear receptors and evaluated a large number of compounds for their activating profiles. Results showed that compounds activating PXR were associated with a high frequency of liver hypertrophy-related endpoints, as well as statistically significant associations with blood clotting factors.
JOURNAL OF TOXICOLOGICAL SCIENCES
(2021)
Meeting Abstract
Toxicology
K. Yoshinari, Y. Kanno, T. Hosaka, R. Shizu, T. Sasaki
TOXICOLOGY LETTERS
(2021)