Article
Pharmacology & Pharmacy
Mallory Little, Moumita Dutta, Hao Li, Adam Matson, Xiaojian Shi, Gabby Mascarinas, Bruk Molla, Kris Weigel, Haiwei Gu, Sridhar Mani, Julia Yue Cui
Summary: In this study using genetically engineered mice, we discovered that the xenobiotic-sensing nuclear receptors PXR and CAR have bivalent hormetic functions in modulating the richness of gut microbiome. The absence of PXR or CAR increased microbial richness, while the absence of both receptors synergistically increased microbial richness. Deficiency in PXR and CAR led to an increase in pro-inflammatory bacteria and a decrease in primary taurine-conjugated bile acids, which may contribute to inflammation, oxidative stress, and cytotoxicity.
ACTA PHARMACEUTICA SINICA B
(2022)
Article
Multidisciplinary Sciences
Maru Jaime-Garza, Carlos A. Nowotny, Daniel Coutandin, Feng Wang, Mariano Tabios, David A. Agard
Summary: PP5 requires Hsp90 to dephosphorylate CRaf kinase and Cdc37. Hsp90 acts as a platform to facilitate targeted dephosphorylation by PP5 and collaborates with phosphorylated Cdc37 for the folding and activation of client kinases. The cryo-EM structure reveals how Hsp90 activates and scaffolds PP5 to dephosphorylate nearby phosphorylation sites of CRaf, showing the role of Hsp90 in post-translational modification of client kinases goes beyond folding and activation.
NATURE COMMUNICATIONS
(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
Xinran Cai, Ye Feng, Meishu Xu, Chaohui Yu, Wen Xie
Summary: Activation of the xenobiotic receptor CAR has been shown to inhibit obesity and improve insulin sensitivity, but its metabolic benefits may depend partly on the inducible coactivator Gadd45b.
ACTA PHARMACEUTICA SINICA B
(2021)
Article
Biochemistry & Molecular Biology
Jing Ge, Yan Huang, MeiWei Lv, Cong Zhang, Milton Talukder, JinYang Li, JinLong Li
Summary: Cadmium is a toxic heavy metal that poses a threat to food safety and human health. This study investigated the mechanisms of cadmium-induced kidney damage and the detoxification response. The results showed that cadmium exposure caused renal injuries and affected detoxification enzyme activities. These findings contribute to our understanding of the toxicity and detoxification mechanisms of cadmium.
JOURNAL OF INORGANIC BIOCHEMISTRY
(2022)
Article
Cell Biology
Agata Lampart, Katarzyna Dominika Sluzalska, Aleksandra Czyrek, Aleksandra Szerszen, Jacek Otlewski, Antoni Wiedlocha, Malgorzata Zakrzewska
Summary: The nuclear localization sequence (NLS) in fibroblast growth factor 1 (FGF1) is not required for its intracellular anti-apoptotic activity in differentiated cells, suggesting that the mechanism of stress response differs according to the level of cell differentiation.
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
Chemistry, Medicinal
Zuzana Rania Brozova, Jan Dusek, Norbert Palsa, Jana Maixnerova, Rajamanikkam Kamaraj, Lucie Smutna, Petr Matous, Albert Braeuning, Petr Pavek, Jiri Kunes, Nicholas Gathergood, Marcel Spulak, Milan Pour, Alejandro Carazo
Summary: A series of quinazolinone derivatives were synthesized and evaluated for their ability to selectively modulate human CAR activity. Several novel partial agonists and antagonists were identified, including 2-(3-methylphenyl) quinazolinone derivatives 7d and 8d as potent partial agonists. Compound 7l, a 2-(4-bromophenyl)quinazoline-4-thione, showed significant CAR antagonistic activity.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Review
Environmental Sciences
Jessica H. Hartman, Samuel J. Widmayer, Christina M. Bergemann, Dillon E. King, Katherine S. Morton, Riccardo F. Romersi, Laura E. Jameson, Maxwell C. K. Leung, Erik C. Andersen, Stefan Taubert, Joel N. Meyer
Summary: Caenorhabditis elegans has become a major model in biomedical and environmental toxicology, attracting research interest in various fields. However, the study of xenobiotic metabolism and transport processes in C. elegans remains underdeveloped. This review summarizes the history of C. elegans in toxicological and pharmacological studies, physical barriers to chemical uptake, and known and unknown processes of xenobiotic metabolism.
JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH-PART B-CRITICAL REVIEWS
(2021)
Article
Endocrinology & Metabolism
Johanna Saell, Maria Lindahl, Andreas M. Fritzen, Claes Fryklund, Franziska Kopietz, Emma Nyberg, Anna Warvsten, Bjorn Moren, Marc Foretz, Bente Kiens, Karin G. Stenkula, Olga Goransson
Summary: This study demonstrates that SIK2 is downregulated in obese ob/ob mice and that SIK activity is required for intact glucose uptake in primary human and mouse adipocytes. The underlying mechanism involves direct effects on the insulin signaling pathway, likely at the level of phosphatidylinositol (3,4,5)-trisphosphate (PIP3) generation or breakdown.
Review
Biotechnology & Applied Microbiology
Lin Tang, Sheng Pan, Xuyong Wei, Xiao Xu, Qiang Wei
Summary: This article summarizes the strategies of arming CAR-T cells with natural or synthetic cytokine signals to enhance their anti-tumor capacity, and summarizes the advances in CAR-T cells expressing non-cytokine proteins. It also discusses several prospective strategies for armored CAR-T therapy development, providing new insights for the innovations of the next generation of CAR-T therapy.
Article
Cell Biology
Wenjia Xie, Qingyun He, Yan Zhang, Xinxin Xu, Ping Wen, Hongdi Cao, Yang Zhou, Jing Luo, Junwei Yang, Lei Jiang
Summary: Mitochondrial fragmentation is an important pathological process in acute kidney injury (AKI), leading to cell death. This study found that phosphorylation of PKM2 contributed to its dimer formation and translocation into mitochondria. Mitochondrial PKM2 binds MYH9 to promote mitochondrial fragmentation. Modulating PKM2 abundance and activity to inhibit mitochondrial translocation may alleviate renal tubular injury and cell death.
CELL DEATH & DISEASE
(2023)
Article
Cell Biology
Haiyuan Mu, Ting Zhang, Ying Yang, Danru Zhang, Jie Gao, Junhong Li, Liang Yue, Dengfeng Gao, Bingbo Shi, Yue Han, Liang Zhong, Xinze Chen, Zhen-Bo Wang, Zhen Lin, Ming-Han Tong, Qing-Yuan Sun, Yun-Gui Yang, Jianyong Han
Summary: m(6)A modification plays essential roles in follicle development and oocyte growth, regulating oocyte meiosis by enhancing RNA stability.
CELL DEATH & DISEASE
(2021)
Review
Oncology
Justin D. Clubb, Torahito A. Gao, Yvonne Y. Chen
Summary: The development of modern synthetic-biology tools has revolutionized cellular treatments, particularly in anticancer immunotherapy. The FDA has approved six chimeric antigen receptor-modified T-cell products in the last 5 years, demonstrating the potential of engineered T cells in treating hematologic malignancies. Natural killer (NK) cells, with their potent cytotoxic activities and allogeneic capabilities, have emerged as an attractive alternative to T-cell therapies. However, both T cells and NK cells face challenges such as antigen escape, tumor microenvironment immunosuppression, and potential toxicity. Synthetic-biology strategies have been developed to address these obstacles, primarily in the T-cell context. This review explores the strategies, applications, and clinical translation opportunities and challenges for NK-cell therapies.
CLINICAL CANCER RESEARCH
(2023)
Review
Oncology
Kun Yun, Elizabeth L. Siegler, Saad S. Kenderian
Summary: CAR-T cell therapy has shown remarkable effectiveness in treating B cell hematological malignancies, but relapse remains a challenge. The similarities and differences between CARs and TCRs in terms of sensitivity, signaling pathway, killing mechanisms, and performance are not fully understood. Comparing CARs and TCRs can provide novel insights and contribute to improving the efficacy of CAR-T cell therapy.
Meeting Abstract
Pharmacology & Pharmacy
Masahiko Negishi
DRUG METABOLISM AND PHARMACOKINETICS
(2019)
Review
Cell Biology
Wi S. Lai, Melissa L. Wells, Lalith Perera, Perry J. Blackshear
WILEY INTERDISCIPLINARY REVIEWS-RNA
(2019)
Article
Toxicology
Katherine E. Pelch, Yin Li, Lalith Perera, Kristina A. Thayer, Kenneth S. Korach
TOXICOLOGICAL SCIENCES
(2019)
Article
Environmental Sciences
Olubusayo Alofe, Edwina Kisanga, Salmaan H. Inayat-Hussain, Masao Fukumura, Rolando Garcia-Milian, Lalith Perera, Vasilis Vasiliou, Shannon Whirledge
ENVIRONMENT INTERNATIONAL
(2019)
Article
Multidisciplinary Sciences
Ryota Shizu, Kosuke Yokobori, Lalith Perera, Lee Pedersen, Masahiko Negishi
SCIENTIFIC REPORTS
(2019)
Article
Endocrinology & Metabolism
Yin Li, Katherine J. Hamilton, Lalith Perera, Tianyuan Wang, Artiom Gruzdev, Tanner B. Jefferson, Austin X. Zhang, Emilie Mathura, Kevin E. Gerrish, Laura Wharey, Negin P. Martin, Jian-Liang Li, Kenneth S. Korach
Article
Chemistry, Multidisciplinary
Lalith Perera, William A. Beard, Lee G. Pedersen, David D. Shock, Samuel H. Wilson
Review
Pharmacology & Pharmacy
Riddhidev Banerjee, Lalith Perera, L. M. Viranga Tillekeratne
Summary: This review focuses on recent developments in the search for small-molecule inhibitors targeting the SARS-CoV-2 M-pro, aiming at discovering and designing drugs targeting the key target in the viral replication cycle.
DRUG DISCOVERY TODAY
(2021)
Article
Multidisciplinary Sciences
Monica C. Pillon, Meredith N. Frazier, Lucas B. Dillard, Jason G. Williams, Seda Kocaman, Juno M. Krahn, Lalith Perera, Cassandra K. Hayne, Jacob Gordon, Zachary D. Stewart, Mack Sobhany, Leesa J. Deterding, Allen L. Hsu, Venkata P. Dandey, Mario J. Borgnia, Robin E. Stanley
Summary: Nsp15 is a uridine specific endoribonuclease present in all coronaviruses. The cryo-EM structures of SARS-CoV-2 Nsp15 in the apo and UTP-bound states, together with biochemical experiments, mass spectrometry, and molecular dynamics simulations, provide insights into the catalytic mechanism of Nsp15 and its conformational dynamics.
NATURE COMMUNICATIONS
(2021)
Article
Multidisciplinary Sciences
Alexander C. Y. Foo, Peter M. Thompson, Shih-Heng Chen, Ramesh Jadi, Brianna Lupo, Eugene F. DeRose, Simrat Arora, Victoria C. Placentra, Lakshmanane Premkumar, Lalith Perera, Lars C. Pedersen, Negin Martin, Geoffrey A. Mueller
Summary: The mosquito protein AEG12 has been shown to inhibit replication of enveloped viruses such as Dengue and Zika viruses by selectively delivering unsaturated fatty acids into lipid membranes, demonstrating its potential as a broad-spectrum therapeutic agent.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Multidisciplinary Sciences
Kyungmin Kim, Thomas W. Kirby, Lalith Perera, Robert E. London
Summary: The study investigated the phosphopeptide binding characteristics of Nbs1 BRCT1/2 and identified structural homology with TopBP1 BRCT7/8 through molecular modeling. These features provide insight into the basis for interaction of SDT motifs with the BRCT1/2 domains and allowed identification of high and low affinity ligands.
SCIENTIFIC REPORTS
(2021)
Article
Oncology
Birandra K. Sinha, Lalith Perera, Ronald E. Cannon
Summary: The development of resistance to chemotherapeutics in human cancers poses a serious problem in clinical practice. Overexpression of ABC efflux proteins on tumor cell membranes is believed to be a main mechanism for clinical resistance. Nitric oxide has shown promising potential in inhibiting ATPase functions of ABC transporters, leading to reversal of resistance to various anticancer drugs. Studies suggest that tumor-specific nitric oxide donors may be useful in treating human tumors overexpressing ABC transporters, including cancer stem cells.
Article
Multidisciplinary Sciences
Joonas A. Jamsen, Akira Sassa, Lalith Perera, David D. Shock, William A. Beard, Samuel H. Wilson
Summary: The study reveals that pol mu lacks discrimination against oxidized ribonucleotide (8-oxo-rGTP) during double strand break repair, potentially leading to widespread persistent mutagenesis and genomic instability.
NATURE COMMUNICATIONS
(2021)
Article
Multidisciplinary Sciences
Huanchen Wang, Lalith Perera, Nikolaus Jork, Guangning Zong, Andrew M. Riley, Barry V. L. Potter, Henning J. Jessen, Stephen B. Shears
Summary: This study provides the analysis of ligand/enzyme crystal complexes for Arabidopsis thaliana Plant and Fungi Atypical Dual Specificity Phosphatase 1 (AtPFA-DSP1), uncovering its regioselective and efficient phosphatase activity towards inositol pyrophosphate (PP-InsP) signaling molecules. Despite lacking the traditional tripeptide motif, the WPD loop structural element still contributes to catalysis by assisting with the delivery of PP-InsP into the catalytic pocket. Functionally, it is proposed that the substrate PP-InsP substitutes for the absent aspartate/glutamate general-acid through intramolecular proton donation.
NATURE COMMUNICATIONS
(2022)
Article
Chemistry, Medicinal
Endri Karaj, Shaimaa H. Sindi, Nishanth Kuganesan, Lalith Perera, William Taylor, L. M. Viranga Tillekeratne
Summary: This article explores the renewed interest in covalent inhibitors in drug discovery and the discovery of a new class of tunable heterocyclic electrophiles capable of inducing ferroptosis. The results show that these heterocycles selectively induce ferroptosis with high potency. Further analysis suggests that these compounds can undergo thiol addition and their potential target is the GPX4 protein. Incorporation of these heterocycles into appropriate pharmacophores generates highly cytotoxic agents.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)