Review
Food Science & Technology
Jie Zhang, Petr Pavek, Rajamanikkam Kamaraj, Li Ren, Tiehua Zhang
Summary: As a review, this paper summarizes the types and mechanisms of plant-derived pregnane X receptor (PXR) modulators and provides crystal structure information related to PXR binding. Furthermore, it summarizes the agonists, partial agonists, and antagonists of PXR from botanical sources. Further research is needed to screen more plant-derived PXR antagonists for antagonizing PXR function.
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION
(2023)
Article
Pharmacology & Pharmacy
Dajana Lichtenstein, Alexandra Lasch, Jimmy Alarcan, Almut Mentz, Joern Kalinowski, Felix F. Schmidt, Oliver Poetz, Philip Marx-Stoelting, Albert Braeuning
Summary: In real life, organisms are exposed to complex mixtures of chemicals at low concentration levels, whereas research on toxicological effects is mostly focused on single compounds at comparably high doses. Mixture effects deviating from the assumption of additivity, especially synergistic effects, are of concern. This study demonstrates the enhanced triglyceride accumulation in human liver cells caused by a mixture of fatty chemicals at low concentrations, revealing potentially synergistic effects. Mathematical modeling and transcript pattern analysis further support the existence of more than additive behavior in mixture effects.
Article
Pharmacology & Pharmacy
Caitlin Lynch, Srilatha Sakamuru, Ruili Huang, Jake Niebler, Stephen S. Ferguson, Menghang Xia
Summary: The study identified a group of potential PXR activators, with 11 compounds significantly inducing CYP3A4 mRNA expression in cells. Etomidoline was found to potentially be a selective agonist of PXR.
BIOCHEMICAL PHARMACOLOGY
(2021)
Review
Cell Biology
Juan Pablo Rigalli, Dirk Theile, Julie Nilles, Johanna Weiss
Summary: PXR interacts with RXRα to regulate drug metabolism, immune function, and cancer pathogenesis; its activity is regulated by coactivator and corepressor proteins; studies indicate cell- and ligand-specific differences in PXR activation.
Article
Cell Biology
Enni-Kaisa Mustonen, Tatu Pantsar, Azam Rashidian, Juliander Reiner, Matthias Schwab, Stefan Laufer, Oliver Burk
Summary: This study aimed to identify small-molecule kinase inhibitors that can also act as PXR antagonists. Through computational screening and experimental validation, four novel PXR antagonists and one agonist were identified. Further experiments showed that these compounds can directly bind to PXR and disrupt its interaction with coregulatory proteins.
Article
Biochemistry & Molecular Biology
Claudia Finamore, Carmen Festa, Bianca Fiorillo, Francesco Saverio Di Leva, Rosalinda Roselli, Silvia Marchiano, Michele Biagioli, Lucio Spinelli, Stefano Fiorucci, Vittorio Limongelli, Angela Zampella, Simona De Marino
Summary: A series of novel 1,2,4-oxadiazole derivatives were synthesized and their pharmacological and in vitro pharmacokinetic properties were evaluated. Compounds 5 and 11 were identified as the first examples of nonsteroidal dual FXR/PXR modulators, showing potential in the treatment of inflammatory disorders.
Article
Nutrition & Dietetics
Halima Sultana, Ayaka Kato, Ai Ohashi, Rie Takashima, Tomoko Katsurai, Shoko Sato, Masafumi Monma, Yusuke Ohsaki, Tomoko Goto, Michio Komai, Hitoshi Shirakawa
Summary: PXR acts as a key regulator of defense against foreign substances and can be activated by dietary supplements, impacting drug metabolism efficiency through interactions with drugs and nutrients.
Article
Chemistry, Medicinal
Yongtao Li, Wenwei Lin, Sergio C. Chai, Jing Wu, Kavya Annu, Taosheng Chen
Summary: In this study, a selective and potent PXR antagonist was discovered through structural optimization of a series of compounds. This finding provides novel PXR inhibitors for basic research and future clinical studies and sheds light on reducing compound's binding affinity to PXR.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Ivana Mejdrova, Jan Dusek, Krystof Skach, Alzbeta Stefela, Josef Skoda, Karel Chalupsky, Klara Dohnalova, Ivona Pavkova, Thales Kronenberger, Azam Rashidian, Lucie Smutna, Vojtech Duchoslav, Tomas Smutny, Petr Pavek, Radim Nencka
Summary: The nuclear constitutive androstane receptor (CAR, NR1I3) plays significant roles in hepatic functions and has been proposed as a target for metabolic or liver disease therapy. However, current CAR agonists have limited selectivity. We discovered derivatives that directly activate human CAR and are selective, non-toxic, and show in vivo activity, highlighting CAR as a therapeutic target.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Endocrinology & Metabolism
Bin Yang, Vasily M. Gelfanov, Kimberley El, Alex Chen, Rebecca Rohlfs, Barent DuBois, Ann Maria Kruse Hansen, Diego Perez-Tilve, Patrick J. Knerr, David 'Alessio, Jonathan E. Campbell, Jonathan D. Douros, Brian Finan
Summary: This study reports the discovery of a potent, specific, and long-acting GIPR peptide antagonist that effectively blocks GIP action in vitro, ex vivo in human islets, and in vivo in mice while producing additive weight-loss when combined with a GLP-1R agonist in DIO mice.
MOLECULAR METABOLISM
(2022)
Article
Multidisciplinary Sciences
Aditya S. Vaidya, Francis C. Peterson, James Eckhardt, Zenan Xing, Sang-Youl Park, Wim Dejonghe, Jun Takeuchi, Oded Pri-Tal, Julianna Faria, Dezi Elzinga, Brian F. Volkman, Yasushi Todoroki, Assaf Mosquna, Masanori Okamoto, Sean R. Cutler
Summary: The study designed a pan receptor antagonist, ANT, by modifying the agonist structure, and demonstrated that ANT effectively blocks ABA signaling and accelerates seed germination in multiple species, showing great potential for application.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(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
Biochemistry & Molecular Biology
Ziyue Guan, Xueqin Chen, Sui Fang, Yonghua Ji, Zhaobing Gao, Yueming Zheng
Summary: CCT128930 is identified as a novel and potent TRPM7 channel antagonist, which can inhibit TRPM7 independently of intracellular Mg2+, and has subtype selectivity towards TRPM7 compared to TRPM6 and TRPM8 isoforms in mammalian cells.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2021)
Article
Microbiology
Nagender Ledala, Mishika Malik, Karim Rezaul, Sara Paveglio, Anthony Provatas, Aaron Kiel, Melissa Caimano, Yanjiao Zhou, Jonathan Lindgren, Kristyna Krasulova, Peter Illes, Zdenek Dvorak, Sandhya Kortagere, Sabine Kienesberger, Amar Cosic, Lisa Poeltl, Ellen L. Zechner, Subho Ghosh, Sridhar Mani, Justin D. Radolf, Adam P. Matson
Summary: In this study, it was shown that bacterial indole acts as a multifunctional mitigator of pathogenicity by suppressing toxin production, enhancing conversion of tilimycin to tilivalline, and activating PXR.
Article
Gastroenterology & Hepatology
Kyle L. Flannigan, Kristoff M. Nieves, Holly E. Szczepanski, Alex Serra, Joshua W. Lee, Laurie A. Alston, Hena Ramay, Sridhar Mani, Simon A. Hirota
Summary: The pregnane X receptor (PXR) plays an important role in regulating intestinal inflammation and fibrosis. Microbiota-derived indole-3-propionic acid (IPA) influences PXR signaling. Deletion of PXR exacerbates fibrosis, suggesting that microbiota metabolites may be a vital determinant in the progression of fibrotic complications in inflammatory bowel diseases (IBDs).
CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Yiannis Drosos, Jacquelyn A. Myers, Beisi Xu, Kaeli M. Mathias, Emma C. Beane, Sandi Radko-Juettner, Robert J. Mobley, Margaret E. Larsen, Federica Piccioni, Xiaotu Ma, Jonathan Low, Baranda S. Hansen, Samuel T. Peters, Natarajan Bhanu, Sandeep K. Dhanda, Taosheng Chen, Santhosh A. Upadhyaya, Shondra M. Pruett-Miller, David E. Root, Benjamin A. Garcia, Janet F. Partridge, Charles W. M. Roberts
Summary: Disruption of antagonism between SWI/SNF chromatin remodelers and polycomb repressor complexes drives the formation of numerous cancer types. Loss of the H3K36 methyltransferase NSD1 causes resistance to EZH2 inhibition. H3K36me2 itself has an essential role in the activation of polycomb target genes.
Article
Biochemistry & Molecular Biology
Huan Sun, Ka Yang, Xue Zhang, Yingxue Fu, Jay Yarbro, Zhiping Wu, Ping-Chung Chen, Taosheng Chen, Junmin Peng
Summary: Chemoproteomics is a crucial platform for studying the mode of action of compounds. This study presents a pooling strategy to enhance throughput and applies it to a drug library. The findings demonstrate that pooling chemoproteomics screening is an efficient method for dissecting the molecular targets of compound libraries.
Article
Chemistry, Medicinal
Andrew D. Huber, Yongtao Li, Wenwei Lin, Annalise N. Galbraith, Ashutosh Mishra, Shaina N. Porter, Jing Wu, Rebecca R. Florke Gee, Wei Zhuang, Shondra M. Pruett-Miller, Junmin Peng, Taosheng Chen
Summary: This study describes the discovery of a molecule, SJPYT-195, which can reduce the protein level of PXR by acting as a molecular glue degrader of GSPT1, a translation termination factor. The findings provide insights into the chemical determinants of drug-induced GSPT1 degradation and also present assays and cell models for the discovery of PXR degraders.
ACS MEDICINAL CHEMISTRY LETTERS
(2022)
Review
Pharmacology & Pharmacy
Shyaron Poudel, Andrew D. Huber, Taosheng Chen
Summary: PXR and CAR are ligand-activated transcription factors that regulate drug metabolizing enzymes and transporters. They not only play important roles in drug efficacy, toxicity, and interactions, but also respond to a wide range of stimuli and are implicated in various diseases. Recent research has provided new insights into their biology and potential clinical applications.
DRUG METABOLISM AND DISPOSITION
(2023)
Article
Chemistry, Medicinal
Anand Divakaran, Cole R. Scholtz, Huda Zahid, Wenwei Lin, Elizabeth C. Griffith, Richard E. Lee, Taosheng Chen, Daniel A. Harki, William C. K. Pomerantz
Summary: Targeted protein degradation is a powerful tool for controlling cellular protein concentrations. In this study, the researchers designed a selective inhibitor of the first BRD4 bromodomain and developed a selective degrader for BRD4. This approach allowed for specific degradation of BRD4 without inhibiting other BET family members such as BRD2/3.
ACS MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Multidisciplinary Sciences
Giridhar Sekar, Geetika Singh, Xingping Qin, Cristina D. Guibao, Brittany Schwam, Zintis Inde, Christy R. Grace, Weixing Zhang, P. Jake Slavish, Wenwei Lin, Taosheng Chen, Richard E. Lee, Zoran Rankovic, Kristopher Sarosiek, Tudor Moldoveanu
Summary: The small molecule SJ572946 selectively activates BAK over BAX, showing cytotoxic effects on cancer cells, and can be used in combination with other apoptotic inducers and BH3 mimetics.
Article
Chemistry, Medicinal
Yongtao Li, Wenwei Lin, Sergio C. Chai, Jing Wu, Kavya Annu, Taosheng Chen
Summary: In this study, a selective and potent PXR antagonist was discovered through structural optimization of a series of compounds. This finding provides novel PXR inhibitors for basic research and future clinical studies and sheds light on reducing compound's binding affinity to PXR.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Multidisciplinary Sciences
Wenwei Lin, Andrew D. Huber, Shyaron Poudel, Yongtao Li, Jayaraman Seetharaman, Darcie J. Miller, Taosheng Chen
Summary: The promiscuity of ligand-binding in detoxification systems is beneficial for body protection but a challenge for drug development. Through X-ray crystallography, we found that expanding the ligand-binding pocket of the PXR receptor can enhance binding affinity. However, this expansion is an unfavorable event, and engineering ligands to avoid clashes with the receptor can reduce safety liabilities. Therefore, engineering the ligand-binding pocket of PXR can potentially improve drug development.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Multidisciplinary Sciences
Jennifer L. Kamens, Stephanie Nance, Cary Koss, Beisi Xu, Anitria Cotton, Jeannie W. Lam, Elizabeth A. R. Garfinkle, Pratima Nallagatla, Amelia M. R. Smith, Sharnise Mitchell, Jing Ma, Duane Currier, William C. Wright, Kanisha Kavdia, Vishwajeeth R. Pagala, Wonil Kim, LaShanale M. Wallace, Ji-Hoon Cho, Yiping Fan, Aman Seth, Nathaniel Twarog, John K. Choi, Esther A. Obeng, Mark E. Hatley, Monika L. Metzger, Hiroto Inaba, Sima Jeha, Jeffrey E. Rubnitz, Junmin Peng, Taosheng Chen, Anang A. Shelat, R. Kiplin Guy, Tanja A. Gruber
Summary: Proteasome inhibition is found to be effective in KMT2Ar infant acute lymphoblastic leukemia, leading to the depletion of histone modifications and downregulation of KMT2A gene expression signature. A cohort of relapsed/refractory KMT2Ar patients treated with this approach showed a high overall response rate. This innovative treatment approach is now being evaluated in a multi-institutional upfront trial for infants with newly diagnosed ALL.
NATURE COMMUNICATIONS
(2023)
Article
Multidisciplinary Sciences
Giovanni Quarato, Luigi Mari, Nicholas J. Barrows, Mao Yang, Sebastian Ruehl, Mark J. Chen, Cliff S. Guy, Jonathan Low, Taosheng Chen, Douglas R. Green
Summary: The degradation of defective mitochondria is regulated by the ubiquitin-proteasome system and lysosomal activities, which play essential roles in maintaining cellular homeostasis. Activation of the PINK1-Parkin axis following mitochondrial damage triggers a BAX- and BAK-independent cytochrome c release process, leading to apoptosis mediated by APAF1 and caspase 9. This process is initiated by UPS-dependent outer mitochondrial membrane degradation and can be reversed by proteasome inhibitors. Autophagy machinery recruitment to the outer mitochondrial membrane protects cells from apoptosis by mediating the lysosomal degradation of dysfunctional mitochondria. The study highlights the major role of the autophagy machinery in counteracting abnormal noncanonical apoptosis and identifies autophagy receptors as key regulators of this process.
Article
Oncology
Mika B. Jekabsons, Mollie Merrell, Anna G. Skubiz, Noah Thornton, Sandra Milasta, Douglas Green, Taosheng Chen, Yan-Hong Wang, Bharathi Avula, Ikhlas A. Khan, Yu-Dong Zhou
Summary: Gene expression signatures associated with breast cancer metastases suggest that metabolic re-wiring is important for metastatic growth in lungs, bones, and other organs. Flux analysis is necessary to conclusively establish phenotypes, as pathway fluxes depend on additional factors. This study assessed the metabolic phenotypes of breast cancer cell lines with different metastatic potentials, as well as lung and bone-homing lines, and found differences in ATP production, nutrient consumption, and anabolic fluxes.
CANCER & METABOLISM
(2023)
Article
Multidisciplinary Sciences
Jie Fang, Shivendra Singh, Changde Cheng, Sivaraman Natarajan, Heather Sheppard, Ahmed Abu-Zaid, Adam D. Durbin, Ha Won Lee, Qiong Wu, Jacob Steele, Jon P. Connelly, Hongjian Jin, Wenan Chen, Yiping Fan, Shondra M. Pruett-Miller, Jerold E. Rehg, Selene C. Koo, Teresa Santiago, Joseph Emmons, Stefano Cairo, Ruoning Wang, Evan S. Glazer, Andrew J. Murphy, Taosheng Chen, Andrew M. Davidoff, Carolina Armengol, John Easton, Xiang Chen, Jun Yang
Summary: A improved MYC-driven hepatoblastoma-like murine model is developed and characterized in this study, which recapitulates the pathological features of embryonal type of hepatoblastoma and shows transcriptomics resembling the high-risk gene signatures of the human disease. Single-cell RNA-sequencing and CRISPR-Cas9 screening are used to identify distinct subpopulations of hepatoblastoma cells and druggable targets shared with human hepatoblastoma. The study also reveals genetic modifiers of chemotherapy response and suggests a potential therapeutic strategy for human hepatoblastoma.
NATURE COMMUNICATIONS
(2023)
Article
Pharmacology & Pharmacy
Rebecca R. Florke Gee, Andrew D. Huber, Jing Wu, Richa Bajpai, Allister J. Loughran, Shondra M. Pruett-Miller, Taosheng Chen
Summary: This study identified FBXO44 as a novel E3 ligase for PXR, which regulates the protein abundance of PXR and has downstream effects on CYP3A4 levels and drug-drug interactions.
ACTA PHARMACEUTICA SINICA B
(2023)
Article
Cell Biology
Ping-Chung Chen, Xian Han, Timothy I. Shaw, Yingxue Fu, Huan Sun, Mingming Niu, Zhen Wang, Yun Jiao, Brett J. W. Teubner, Donnie Eddins, Lauren N. Beloate, Bing Bai, Joseph Mertz, Yuxin Li, Ji-Hoon Cho, Xusheng Wang, Zhiping Wu, Danting Liu, Suresh Poudel, Zuo-Fei Yuan, Ariana Mancieri, Jonathan Low, Hyeong-Min Lee, Mary H. Patton, Laurie R. Earls, Elizabeth Stewart, Peter Vogel, Yawei Hui, Shibiao Wan, David A. Bennett, Geidy E. Serrano, Thomas G. Beach, Michael A. Dyer, Richard J. Smeyne, Tudor Moldoveanu, Taosheng Chen, Gang Wu, Stanislav S. Zakharenko, Gang Yu, Junmin Peng
Summary: The study reveals the causative role of U1 snRNP dysfunction to neurodegeneration in Alzheimer's disease and demonstrates the synergy between RNA splicing defect and amyloid cascade. By generating a mouse model with perturbed U1 snRNP activity, the authors recapitulate RNA splicing defects, neuron hyperexcitability, neurodegeneration, and cognitive decline.
