Article
Agriculture, Multidisciplinary
Ya-Long Zheng, Zhi-Shan Tu, Hong-Mei Cui, Shuai Yan, De-Chen Duan, Wei Tang, Fang Dai, Bo Zhou
Summary: In this study, a redox-based strategy was proposed to intervene in the reprogramming of cancer cell energy metabolism by inhibiting mitochondrial antioxidant enzyme TrxR2 to generate reactive oxygen species (ROS). The strategy induced a preferential energy crisis and selectively killed cancer cells with high antitumor efficacy in vivo.
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Xuefeng Liu, Hongmei Cui, Mi Li, Zuohu Chai, Haibo Wang, Xiaojie Jin, Fang Dai, Yongqi Liu, Bo Zhou
Summary: Compared to normal cells, cancer cells have intrinsic oxidative stress, making them more susceptible to the production of reactive oxygen species (ROS) by pro-oxidative anticancer agents (PAAs). However, PAAs also generate ROS in normal cells, limiting their clinical application due to narrow therapeutic window and toxic side effects. In this study, a selective ROS-generating agent, 2c, was designed using three series of dietary curcumin analogs. It showed potent selectivity in killing non-small cell lung cancer cells and inhibited tumor growth in mice. This work highlights a practical strategy of targeting thioredoxin reductase (TrxR) overexpressed in cancer cells to develop PAAs capable of generating ROS selectively.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Xiuli Chen, Shibo Sun, Sheng Huang, Han Yang, Qing Ye, Lin Lv, Yanshan Liang, Jinjun Shan, Jianqiang Xu, Wukun Liu, Tonghui Ma
Summary: Gold(I) selenium N-heterocyclic carbene complexes H7 and H8 exhibit stronger antibacterial effects against multidrug-resistant Gram-negative bacteria by irreversibly inhibiting the activity of TrxR and inducing oxidative stress. In vivo experiments demonstrate that H7 and H8 have better antibacterial activity than auranofin, and can promote wound healing and prolong the survival time of patients with Carbapenem-resistant Acinetobacter baumannii induced peritonitis.
Article
Biochemistry & Molecular Biology
Junmin Zhang, Yaxiong Chen, Jianguo Fang
Summary: The inhibition of thioredoxin reductase (TrxR) is vital for the development of antineoplastic drugs and radiosensitizers. In this study, it is found that micheliolide (MCL), derived from Michelia, not only induces oxidative stress-mediated apoptosis in HeLa cells but also sensitizes ionizing radiation (IR) treatment by targeting TrxR. Mechanistic studies reveal that MCL covalently binds to TrxR at position 498 to inhibit its biological function. Knockdown of TrxR enhances the cytotoxicity and radiation response induced by MCL, supporting the potential of MCL as a prospective radiosensitizer and cancer chemotherapeutic agent.
FREE RADICAL BIOLOGY AND MEDICINE
(2022)
Article
Chemistry, Multidisciplinary
Hang Zou, Jing Zhang, Changmeng Wu, Benzhao He, Yubing Hu, Herman H. Y. Sung, Ryan T. K. Kwok, Jacky W. Y. Lam, Lei Zheng, Ben Zhong Tang
Summary: TBP-Au, a powerful aggregation-induced emission luminogen, combines an anticancer Au(I) moiety with an ME-active photosensitizer to enhance anticancer efficacy, enabling superior two-photon fluorescence imaging in tumor tissues and efficient facilitation of ROS-determined photodynamic therapy.
Article
Biochemistry & Molecular Biology
Junmin Zhang, Qianhe Xu, Di Ma
Summary: This study found that beta-Lapachone can selectively kill human promyelocytic leukemia HL-60 cells by inhibiting TrxR and increasing oxidative stress. Overexpression of TrxR reduced the effectiveness of beta-Lapachone, while knockdown of the enzyme increased its cytotoxicity. This discovery contributes to the understanding of the mechanism of action of beta-Lapachone and supports its potential as an anticancer drug candidate.
FREE RADICAL BIOLOGY AND MEDICINE
(2022)
Article
Biochemistry & Molecular Biology
Miao Zhong, Lingzhen Chen, Yue Tao, Jintao Zhao, Bingbing Chang, Fang Zhang, Jingwen Tu, Wenqing Cai, Baoxin Zhang
Summary: Inhibiting TrxR activity to induce tumor cell apoptosis is a significant therapeutic strategy. Piperine, a natural product, has shown potential in suppressing tumor cell proliferation. To develop a compound with higher activity, we synthesized 22 Piperine analogs and found that B5 had significant cytotoxicity and inhibited TrxR activity. Further investigation revealed B5's selective inhibition of TrxR activity by binding to Sec residues, leading to cellular oxidative stress and apoptosis.
BIOORGANIC CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Dongzhu Duan, Yanru Wang, Dabo Pan, Xiaojie Jin, Yunyun Yan, Peng Song, Le Wang, Jian Xiao, Zihua Wang, Xiaoling Wang
Summary: Sinomenine, a new inhibitor for TrxR, demonstrates anticancer activity by decreasing thiols content, increasing reactive oxygen species levels, and inducing oxidative stress-mediated cancer cell apoptosis. Knockdown of TrxR1 enhances cell sensitivity to sinomenine.
BIOORGANIC CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Hecheng Wang, Shibo Sun, Yan Ren, Rui Yang, Jianli Guo, Yu Zong, Qiuxian Zhang, Jing Zhao, Wei Zhang, Weiping Xu, Shui Guan, Jianqiang Xu
Summary: Cadmium is a toxic heavy metal that poses severe hazards to human health. Selenium has been found to reduce cadmium toxicity, but it is unclear whether this protective effect is related to selenoproteins in nerve cells. This study found that cadmium inhibited the activity of selenoprotein thioredoxin reductase 1 (TrxR1) and decreased its expression, causing cellular oxidative stress. Selenium supplementation ameliorated cadmium-induced cytotoxicity by increasing cellular TrxR activity and upregulating TrxR1 protein level. This study sheds light on the mechanism of cadmium-induced cytotoxicity and the role of TrxR1 in selenium-mitigated cytotoxicity of cadmium in neuroblast cells.
BIOLOGICAL TRACE ELEMENT RESEARCH
(2023)
Article
Biochemistry & Molecular Biology
Giulia Gorini, Francesca Magherini, Tania Fiaschi, Lara Massai, Matteo Becatti, Alessandra Modesti, Luigi Messori, Tania Gamberi
Summary: The study revealed that the gold(III) complexes Au(2)phen, Auoxo6, and AuL12 exhibit similar mechanisms in promoting apoptosis, including potent inhibition of thioredoxin reductase, disruption of the cell redox balance, impairment of the mitochondrial membrane potential, and associated metabolic changes. The findings also highlighted the significant contribution of ASK1 and AKT pathways to the apoptotic signaling induced by gold(III) compounds. Overall, the observed effects can be attributed to gold(III) reduction and the subsequent formation and release of gold(I) species that inhibit enzymes responsible for intracellular redox homeostasis, particularly thioredoxin reductase.
Article
Biochemistry & Molecular Biology
Junmin Zhang, Qianhe Xu, Hong-Ying Yang, Minghao Yang, Jianguo Fang, Kun Gao
Summary: Natural products have diverse structures and novelty, leading to unique physiological activities and new action mechanisms, making them important sources for innovative drugs and lead compounds. This study demonstrates that Santamarine targets TrxR to weaken cellular antioxidative function, inducing tumor cell oxidative stress-mediated apoptosis. TrxR plays a key role in the physiological effect of Santamarine on cells, revealing a previously unrecognized mechanism of antitumor activity.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Namasthee Harris-Gauthier, Annika Traa, Abdelrahman AlOkda, Alibek Moldakozhayev, Ulrich Anglas, Sonja K. Soo, Jeremy M. Van Raamsdonk
Summary: Mild impairment of mitochondrial function can increase lifespan in genetic model organisms. The upregulation of genes involved in the mitochondrial thioredoxin system, mediated by the mitochondrial unfolded protein response, is specifically required for the longevity of mitochondrial mutants. The mitochondrial thioredoxin system also plays a role in stress resistance.
Article
Pharmacology & Pharmacy
Xuefeng Liu, Yihua Wang, Yalong Zheng, Dechen Duan, Fang Dai, Bo Zhou
Summary: This study found that 6-DHS, a compound found in ginger, has antiangiogenic activity and its ability to inhibit angiogenesis is dependent on the presence and number of Michael acceptor units. 6-DHS inhibits angiogenesis by generating reactive oxygen species, which is important for preventing tumor growth and metastasis.
EUROPEAN JOURNAL OF PHARMACOLOGY
(2022)
Article
Pharmacology & Pharmacy
Ines Marmol, Javier Quero, Paula Azcarate, Elena Atrian-Blasco, Carla Ramos, Joana Santos, Maria Concepcion Gimeno, Maria Jesus Rodriguez-Yoldi, Elena Cerrada
Summary: This paper describes the synthesis of new N-heterocyclic carbene (NHC) gold(I) derivatives and their screening for antimicrobial and anticancer activities. The compounds showed greater activity against bacteria than against colon cancer cells. The mechanism of action of one of the compounds, 1b, was evaluated and it was found to inhibit dihydrofolate reductase (DHFR) activity in E. coli cells and cause structural changes in the bacteria.
Article
Multidisciplinary Sciences
Petra Kameritsch, Miriam Singer, Christoph Nuernbergk, Natalia Rios, Anibal M. Reyes, Kjestine Schmidt, Julian Kirsch, Holger Schneider, Susanna Mueller, Kristin Pogoda, Ruicen Cui, Thomas Kirchner, Cor de Wit, Baerbel Lange-Sperandio, Ulrich Pohl, Marcus Conrad, Rafael Radi, Heike Beck
Summary: The study reveals the crucial role of endothelial TrxR2 in regulating the steady-state concentration of peroxynitrite and maintaining vascular integrity. Deletion of the TrxR2 gene leads to increased vascular stiffness, hypertrophy, and renal abnormalities. Loss of TrxR2 results in elevated peroxynitrite levels in both vascular endothelial cells and vessels, indicating a potential disruption of vascular homeostasis.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
