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
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
Medicine, Research & Experimental
Sydney Stern, Dongdong Liang, Linhao Li, Ritika Kurian, Caitlin Lynch, Srilatha Sakamuru, Scott Heyward, Junran Zhang, Kafayat Ajoke Kareem, Young Wook Chun, Ruili Huang, Menghang Xia, Charles C. Hong, Fengtian Xue, Hongbing Wang
Summary: CN06 is a dual activator of CAR and Nrf2, enhancing the bioactivation of CPA and decreasing the cytotoxicity of DOX in vitro. In a multicellular coculture model, CN06 increased the toxicity of CPA/DOX towards TNBC cells, while protecting cardiomyocytes from DOX-induced cardiotoxicity by selectively activating Nrf2-antioxidant signaling.
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
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
Pharmacology & Pharmacy
Maike Gaehrs, Dieter Schrenk
Summary: NDL-PCBs can suppress UV-induced apoptosis in rat hepatocytes by activating CAR and PXR, and the effects on apoptosis by CAR or PXR activators are specific to CAR or PXR.
Article
Nutrition & Dietetics
Xuan Xiang, Houfu Wang, Wentao Zhou, Chenyu Wang, Peng Guan, Gang Xu, Qiang Zhao, Liuqin He, Yulong Yin, Tiejun Li
Summary: This study investigated the regulatory mechanism of different dietary levels of endogenous glutathione (GSH) supplementation on the intestinal barrier and antioxidant function in a paraquat-induced stress-weaned piglet model. The results showed that dietary 0.06% GSH supplementation improved the growth performance and reduced diarrhea rate of weaned piglets. GSH also protected against oxidative stress damage by regulating intestinal morphology, organelle, and permeability, as well as modulating antioxidant and anti-inflammatory gene expression.
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
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
Pharmacology & Pharmacy
Yu Siong Ho, Pablo Torres-Vergara, Jeffrey Penny
Summary: This study investigated the effects of NR3C1, NR1I3, NR1I2 and NR2B1 activation on porcine brain endothelial cells (PBECs). The results showed that NR1I2 agonist Rifampicin up-regulated ABCG2 activity, while NR1I2 antagonist L-sulforaphane counteracted this effect. NR1I3 agonist and inverse agonist down-regulated ABCB1, ABCG2 and ABCC5 activity. NR3C1 agonist increased ABCB1, ABCG2 and ABCC5 activity and protein expression, which was counteracted by NR3C1 antagonist. NR1I3 and NR3C1 were found to regulate ABCC5 activity and protein expression in BBB endothelial cells.
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
Article
Toxicology
Amina Shehu, Junjie Zhu, Jianhua Li, Jie Lu, Deborah McMahon, Wen Xie, Frank J. Gonzalez, Xiaochao Ma
Summary: This study identified PXR and CAR as key modulators of COBI hepatotoxicity, which potentiate COBI hepatotoxicity through CYP3A4-dependent pathways. These findings can guide the safe use of COBI in the clinic by targeting PXR and CAR.
TOXICOLOGICAL SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Monicah N. Bwayi, Efren Garcia-Maldonado, Sergio C. Chai, Boer Xie, Shirish Chodankar, Andrew D. Huber, Jing Wu, Kavya Annu, William C. Wright, Hyeong-Min Lee, Jayaraman Seetharaman, Jingheng Wang, Cameron D. Buchman, Junmin Peng, Taosheng Chen
Summary: The interactions between nuclear receptors can fundamentally change our understanding of their biology. In this study, the molecular basis of crosstalk between the pregnane X receptor (PXR) and constitutive androstane receptor (CAR) is revealed, demonstrating the formation of a novel heterodimer and mutual inhibition. These findings not only change the perceived functional relationship between PXR and CAR, but also provide new perspectives for elucidating their role and designing approaches to regulate them.
NUCLEIC ACIDS RESEARCH
(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
Biochemistry & Molecular Biology
Hironobu Yagishita, Hideaki Kagaya, Mitsuru Saito, Kazuyuki Numakura, Ryohei Yamamoto, Ryuichiro Sagehashi, Tomonori Habuchi, Shigeru Satoh, Masatomo Miura
Summary: The study evaluated the effects of NR1I2 and ABCB1 genetic polymorphisms on everolimus pharmacokinetics in Japanese renal transplant patients. The results showed significant correlations between different genotypes, gender, age, and liver function with the dose-adjusted AUC(0-12) of everolimus. Therefore, age and liver function should be considered when evaluating dose reductions for everolimus.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Gastroenterology & Hepatology
Jianliang Xu, P. Jaya Kausalya, Noemi Van Hul, Matias J. Caldez, Shiyi Xu, Alicia Ghia Min Ong, Wan Lu Woo, Safiah Mohamed Ali, Philipp Kaldis, Walter Hunziker
Summary: The study highlights the crucial role of Tjp2 in maintaining liver tissue barriers and bile transport processes. Deficiency in Tjp2 can lead to the formation of a model for cholestatic liver disease, and certain drugs such as ursodeoxycholic acid and 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene can partially alleviate this damage.
Article
Pharmacology & Pharmacy
Walaa A. Abualsunun, Cigdem Sahin, Carolyn L. Cummins, Micheline Piquette-Miller
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
(2020)
Article
Biochemistry & Molecular Biology
Amila Omeragic, Michael F. Saikali, Sydney Currier, David J. Volsky, Carolyn L. Cummins, Reina Bendayan
Article
Biochemistry & Molecular Biology
Lin Lin, Adam H. Metherel, Mathieu Di Miceli, Zhen Liu, Cigdem Sahin, Xavier Fioramonti, Carolyn L. Cummins, Sophie Laye, Richard P. Bazinet
JOURNAL OF LIPID RESEARCH
(2020)
Article
Cell & Tissue Engineering
Adil Rasheed, Sarah A. Shawky, Ricky Tsai, Richard G. Jung, Trevor Simard, Michael F. Saikali, Benjamin Hibbert, Katey J. Rayner, Carolyn L. Cummins
Summary: Activation of LXR in EOCs leads to the production of secreted factors that reduce early atherosclerosis development by decreasing monocyte adhesion to activated endothelial cells. This finding has potential implications for the treatment of cardiovascular disease in both mice and human patients.
STEM CELLS TRANSLATIONAL MEDICINE
(2021)
Article
Pharmacology & Pharmacy
Mohammad Ali Amini, Taksim Ahmed, Fuh-Ching Franky Liu, Azhar Z. Abbasi, Chesarahmia Dojo Soeandy, Rui Xue Zhang, Preethy Prashad, Carolyn L. Cummins, Andrew M. Rauth, Jeffrey T. Henderson, Xiao Yu Wu
Summary: This study successfully developed a polymer-lipid hybrid nanoparticle (PLN) system with size and shape transformability and investigated its mechanisms of cellular uptake and intracellular trafficking. The findings suggest that the transformability of PLNs and lipid-biology interplay can enhance drug penetration and retention in tumor cells and intracellular targets.
EXPERT OPINION ON DRUG DELIVERY
(2021)
Article
Multidisciplinary Sciences
Rodney K. Rousseau, Leah Szadkowski, Colin M. Kovacs, Michael F. Saikali, Rabea Nadeem, Fat Malazogu, Sanja Huibner, Carolyn L. Cummins, Rupert Kaul, Sharon L. Walmsley
Summary: The study revealed that during long-term treated HIV infection, immunologic non-responders (INRs) show elevated CD8 activation and CD4 gut homing. Gut-focused interventions may be needed in the context of INRs, and CD8 activation could serve as a surrogate endpoint for clinical interventions.
Article
Endocrinology & Metabolism
Sandra Pereira, Jessy Moore, Jia-Xu Li, Wen Qin Yu, Husam Ghanim, Filip Vlavcheski, Yemisi Deborah Joseph, Paresh Dandona, Allen Volchuk, Carolyn L. Cummins, Evangelia Tsiani, Adria Giacca
Summary: The study demonstrated that the chemical chaperone PBA prevented hepatic insulin resistance caused by elevated plasma FFA without affecting ER stress markers. Moreover, PBA also increased circulating FGF21 and decreased fetuin-A, leading to Akt activation.
ENDOCRINE CONNECTIONS
(2021)
Article
Chemistry, Medicinal
Cigdem Sahin, Lilia Magomedova, Thais A. M. Ferreira, Jiabao Liu, Jens Tiefenbach, Priscilla S. Alves, Fellipe J. G. Queiroz, Andressa S. de Oliveira, Mousumi Bhattacharyya, Julie Grouleff, Patricia C. N. Nogueira, Edilberto R. Silveira, Daniel C. Moreira, Jose Roberto Souza de Almeida Leite, Guilherme D. Brand, David Uehling, Gennady Poda, Henry Krause, Carolyn L. Cummins, Luiz A. S. Romeiro
Summary: Metabolic diseases are increasing at alarming rates globally. This study explored the potential use of phenolic lipid derivatives from cashew nut shell liquid as drugs for the treatment of diabetes and obesity. The compounds showed PPAR activity and tissue-specific effects, making them promising candidates for further development.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biology
Idit Dotan, Jiaqi Yang, Jiro Ikeda, Ziv Roth, Evan Pollock-Tahiri, Harsh Desai, Tharini Sivasubramaniyam, Sonia Rehal, Josh Rapps, Yu Zhe Li, Helen Le, Gedaliah Farber, Edouard Alchami, Changting Xiao, Saraf Karim, Marcela Gronda, Michael F. Saikali, Amit Tirosh, Kay-Uwe Wagner, Jacques Genest, Aaron D. Schimmer, Vikas Gupta, Mark D. Minden, Carolyn L. Cummins, Gary F. Lewis, Clinton Robbins, Jenny Jongstra-Bilen, Myron Cybulsky, Minna Woo
Summary: Deficiency of macrophage Jak2 accelerates atherosclerosis primarily due to defects in cholesterol efflux from macrophages.
COMMUNICATIONS BIOLOGY
(2022)
Article
Endocrinology & Metabolism
Laura L. Gathercole, Nikolaos Nikolaou, Shelley E. Harris, Anastasia Arvaniti, Toryn M. Poolman, Jonathan M. Hazlehurst, Denise Kratschmar, Marijana Todorcevic, Ahmad Moolla, Niall Dempster, Ryan C. Pink, Michael F. Saikali, Liz Bentley, Trevor M. Penning, Claes Ohlsson, Carolyn L. Cummins, Matti Poutanen, Alex Odermatt, Roger D. Cox, Jeremy W. Tomlinson
Summary: AKR1D1 controls bile acid homeostasis in vivo, and altering its activity can affect insulin tolerance and lipid homeostasis in a sex-dependent manner.
JOURNAL OF ENDOCRINOLOGY
(2022)
Review
Endocrinology & Metabolism
Jia-Xu Li, Carolyn L. Cummins
Summary: Glucocorticoid therapies are effective in treating inflammatory diseases but can lead to adverse metabolic effects such as diabetes mellitus. Activating glucocorticoid receptors in multiple tissues increases hepatic glucose production and inhibits peripheral glucose uptake. Effective management strategies for the metabolic effects are currently lacking.
NATURE REVIEWS ENDOCRINOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Jiabao Liu, Cigdem Sahin, Samar Ahmad, Lilia Magomedova, Minhao Zhang, Zhengping Jia, Adam H. Metherel, Arturo Orellana, Gennady Poda, Richard P. Bazinet, Liliana Attisano, Carolyn L. Cummins, Hui Peng, Henry M. Krause
Summary: The nuclear receptor PPAR-α is an important target in the brain for the treatment of cognitive disorders. Researchers have identified an endogenous ligand, 7(S)-HDHA, that activates PPAR-α and promotes neuronal growth and synaptic plasticity.
Article
Genetics & Heredity
Muntasir Kamal, Levon Tokmakjian, Jessica Knox, Duhyun Han, Houtan Moshiri, Lilia Magomedova, Ken C. Q. Nguyen, Hong Zheng, Andrew R. Burns, Brittany Cooke, Jessica Lacoste, May Yeo, David H. Hall, Carolyn L. Cummins, Peter J. Roy
Summary: This study reveals the existence of a polar lipid barrier established by P-glycoprotein PGP-14 and sphingomyelin synthase SMS-5 in the pharyngeal cuticle of the nematode C. elegans. Loss of these proteins significantly affects the nematode's response to xenobiotics.
Article
Multidisciplinary Sciences
Waqar Arif, Bhoomika Mathur, Michael F. Saikali, Ullas V. Chembazhi, Katelyn Toohill, You Jin Song, Qinyu Hao, Saman Karimi, Steven M. Blue, Brian A. Yee, Eric L. Van Nostrand, Sushant Bangru, Grace Guzman, Gene W. W. Yeo, Kannanganattu V. Prasanth, Sayeepriyadarshini Anakk, Carolyn L. Cummins, Auinash Kalsotra
Summary: This study reveals that SRSF1 deficiency leads to detrimental R-loop formation and genotoxicity, causing impaired gene expression, metabolism, and lipid trafficking in liver cells, ultimately resulting in NASH pathology. SRSF1 plays a crucial role in maintaining genome stability and tissue homeostasis.
NATURE COMMUNICATIONS
(2023)
Review
Endocrinology & Metabolism
Florian Le Billan, Gloria Umogbai, Carolyn L. Cummins
Summary: Steroid hormones not only regulate gene transcription but also modulate the alternative splicing of pre-mRNA, acting through binding to nuclear receptors. The effect of steroid hormones on alternative splicing is time-, gene-, and tissue-specific. Mechanisms by which steroid hormones regulate alternative splicing include the recruitment of dual-function proteins, transcriptional regulation of splicing factor levels, alternative splicing of splicing factors or transcription factors, and regulation of elongation rate.