Article
Crystallography
Miaomiao Gao, Kaili Nie, Meng Qin, Haijun Xu, Fang Wang, Luo Liu
Summary: The study compared HSDHs from two superfamilies, explored their structural and functional differences, and found that different enzymes have different ways of processing substrates, further confirming this conclusion.
Review
Biochemistry & Molecular Biology
Andrea J. Detlefsen, Ryan D. Paulukinas, Trevor M. Penning
Summary: Steroid hormone-transforming enzymes play a crucial role in regulating the functions of steroid hormones. Mutations in these enzymes can cause endocrine disorders and have significant impacts on sexual development and other severe disorders. This review focuses on disease-associated germline coding mutations in the aldo-keto reductase (AKR) superfamily, uncovering the effects of these mutations on androgen metabolism, bile acid deficiency, and other diseases. However, further research is needed to fully understand the relationship between AKR mutations and diseases.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Biotechnology & Applied Microbiology
Zhiyong Liu, Rongzhen Zhang, Wenchi Zhang, Yan Xu
Summary: This review discusses the inherent features and catalytic characteristics of steroidogenic enzymes, and explores the progress in protein redesign to improve their biosynthetic efficiency and catalytic ability.
CRITICAL REVIEWS IN BIOTECHNOLOGY
(2023)
Review
Oncology
Matti Poutanen, Malin Hagberg Thulin, Pirkko Harkonen
Summary: Sex steroids are major promoters of breast and prostate cancer growth. Current treatment methods include inhibiting sex steroid biosynthesis and blocking sex steroid receptor interactions. Enzyme inhibitors have been developed, but there is still potential for discovering new targets and mechanisms for more effective therapies.
NATURE REVIEWS CANCER
(2023)
Review
Oncology
Matti Poutanen, Malin Hagberg Thulin, Pirkko Harkonen
Summary: This review highlights the importance of inhibiting sex steroid biosynthesis to restrict their availability for receptor binding in the treatment of breast and prostate cancers. It discusses current therapies and potential new targets and mechanisms for more efficient treatment.
NATURE REVIEWS CANCER
(2023)
Article
Chemistry, Organic
Christopher C. J. Fitzgerald, Malcolm D. McLeod
Summary: This study reports a new stable isotope label for sulfate metabolites, which enables the synthesis of various SIL-steroid conjugates suitable for mass spectrometry detection and internal standards. The method was applied to investigate the mass spectrometry behavior of steroid bis(sulfate) compounds through collision-induced dissociation experiments.
ORGANIC & BIOMOLECULAR CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Wonwoong Lee, Hyunjung Lee, You Lee Kim, Yong Chan Lee, Bong Chul Chung, Jongki Hong
Summary: A gas chromatography-tandem mass spectrometry-dynamic multiple reaction monitoring method combined with solid-phase extraction and microwave-assisted derivatization was developed to analyze 20 endogenous steroids in human plasma. This method provided sufficient detection sensitivities and reliable quantification results, and was successfully applied to profile steroid metabolism pathways in patients with chronic superficial gastritis, intestinal metaplasia, and gastric cancer. The statistical significances of steroid plasma levels between different gastric disorder groups were investigated, providing comprehensive insights into the potential biomarkers for the development of gastric cancer and metabolic syndrome.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Oncology
Nuria Camina, Trevor M. Penning
Summary: The activation of the NRF2 transcription factor plays a crucial role in detoxifying electrophilic carcinogens and preventing cancer, yet can also potentially exacerbate carcinogenesis in certain contexts. Understanding the activation of the NRF2-KEAP1 signaling pathway, its epigenetic regulation, and its role in oncogenesis is essential for elucidating the mechanisms of cancer development.
BRITISH JOURNAL OF CANCER
(2022)
Article
Endocrinology & Metabolism
Ryan D. Paulukinas, Clementina A. Mesaros, Trevor M. Penning
Summary: Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women, characterized by hyperandrogenism. Research suggests that Aldo-keto reductase family 1 member C3 (AKR1C3) plays a significant role in the conversion of androgens in adipocytes, contributing to the hyperandrogenic profile of PCOS. This finding highlights AKR1C3 as a potential therapeutic target for mitigating the symptoms of PCOS, particularly through the modulation of 11-oxygenated androgens formed in adipocytes.
Article
Chemistry, Medicinal
Joseph D. Romano, Yun Hao, Jason H. Moore, Trevor M. Penning
Summary: ComptoxAI is a new data infrastructure that utilizes computational and artificial intelligence research to predict toxicology. It features a graph structured knowledge base that can quickly answer complex questions and includes various real-world use cases.
CHEMICAL RESEARCH IN TOXICOLOGY
(2022)
Review
Chemistry, Medicinal
Trevor M. Penning, Anthony L. Su, Karam El-Bayoumy
Summary: This article provides an overview of the reduction mechanism and catalytic role of enzymes in the chemical reactions of nitro-containing substances, as well as the genotoxicity of the reduction products in terms of their ability to form covalent DNA adducts and cause oxidative damage to DNA. The regulation of nitroreductases and future research directions are also discussed.
CHEMICAL RESEARCH IN TOXICOLOGY
(2022)
Article
Environmental Sciences
Lin Ma, Dongxiao Sun, Guangli Xiu, Philip Lazarus, Anil Vachani, Trevor M. Penning, Alexander S. Whitehead, Joshua E. Muscat
Summary: 8-iso-prostaglandin F2 alpha is a commonly used biomarker for oxidative stress and lung cancer risk. This study developed a rapid method for measuring 8-isoprostane in blood and tested its discriminatory ability in lung cancer patients, benign lung nodule patients, and patients with COPD or asthma. The results suggest that the method can effectively differentiate between these groups.
INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH
(2022)
Article
Chemistry, Medicinal
Anthony L. Su, Clementina A. Mesaros, Jacek Krzeminski, Karam El-Bayoumy, Trevor M. Penning
Summary: This study found that human aldo-keto reductases (AKRs) 1C1-1C3 are capable of catalyzing the nitroreduction of 1-NP and 1,8-DNP, resulting in the formation of respective amine products. Among the three isoforms, AKR1C1 exhibited the highest catalytic efficiency for 1-AP formation, while AKR1C3 had the highest catalytic efficiency for 1,8-ANP formation. These findings expand the role of AKR1C1-1C3 in the metabolic activation of nitroarenes.
CHEMICAL RESEARCH IN TOXICOLOGY
(2022)
Article
Chemistry, Medicinal
Holger Moustakas, Mihir S. Date, Manoj Kumar, Terry W. Schultz, Daniel C. Liebler, Trevor M. Penning, Daniel T. Salvito, Anne Marie Api
Summary: Integrating computational chemistry and toxicology can enhance the read-across analog approach in chemical safety assessment by filling data gaps. Recent advances have focused on improving the grouping of chemicals for toxicity prediction via read-across. Each human health endpoint requires a different approach for analog selection, and this study describes six rule-based schemes to fill the data gap for each endpoint using read-across.
CHEMICAL RESEARCH IN TOXICOLOGY
(2022)
Article
Chemistry, Medicinal
Anthony L. Su, Trevor M. Penning
Summary: 1-Nitropyrene (1-NP), a constituent of diesel exhaust, is a group 2A probable human carcinogen that can cause cancer through the covalent binding of electrophiles generated during nitroreduction to DNA. We discovered that aldo-keto reductases (AKRs) 1C1-1C3 and nuclear factor erythroid 2-related factor 2 (NRF2) play a significant role in the nitroreduction of 1-NP. Pharmacological and genetic experiments revealed that inhibiting AKR1C1 and AKR1C2 decreased nitroreduction, while activating NRF2 increased nitroreduction in certain cell lines. Moreover, NRF2 expression levels influenced the amount of 1-aminopyrene (1-AP) production, indicating the importance of NRF2 in 1-NP metabolic activation.
CHEMICAL RESEARCH IN TOXICOLOGY
(2023)
Review
Biochemistry & Molecular Biology
Andrea J. Detlefsen, Ryan D. Paulukinas, Trevor M. Penning
Summary: Steroid hormone-transforming enzymes play a crucial role in regulating the functions of steroid hormones. Mutations in these enzymes can cause endocrine disorders and have significant impacts on sexual development and other severe disorders. This review focuses on disease-associated germline coding mutations in the aldo-keto reductase (AKR) superfamily, uncovering the effects of these mutations on androgen metabolism, bile acid deficiency, and other diseases. However, further research is needed to fully understand the relationship between AKR mutations and diseases.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Toxicology
Seon Hwa Lee, Mizuki Tsutsui, Atsushi Matsunaga, Tomoyuki Oe
Summary: This study found that lipid hydroperoxide-induced insulin resistance can be prevented by pyridoxamine (PM), which scavenges reactive aldehydes. The results showed that treating cells with PM restored the decreased glucose uptake caused by the reactive aldehydes and identified modifications that could disturb the interaction between insulin receptor substrate 1 (IRS1) and activated IR, leading to insulin resistance.
TOXICOLOGICAL RESEARCH
(2023)
Article
Food Science & Technology
Sawaka Ono, Yusuke Hatakawa, Seon Hwa Lee, Tomoyuki Oe
Summary: In this study, a validated analytical method was developed to detect dipeptides in fermented brown rice and rice bran. The method successfully screened and quantified five dipeptides in the samples, with much higher concentrations compared to related materials. The method was simple, robust, and could be applied to other functional foods.
FOOD ANALYTICAL METHODS
(2023)
Article
Biochemistry & Molecular Biology
Seon Hwa Lee, Kazuyuki Takahashi, Yusuke Hatakawa, Tomoyuki Oe
Summary: Oxidative stress and lipid peroxidation can lead to various pathological states, such as neurodegenerative diseases and cancer. Reactive aldehydes derived from lipid peroxidation, including ONE, HNE, and MG, can modify cellular components like DNA and proteins, exerting multiple biological effects. GPx1, an intracellular antioxidant enzyme, is inhibited by these reactive aldehydes through modification of its GSH-binding sites, which reduces its activity and amplifies cellular oxidative stress. This study highlights the importance of oxidative damage and reactive aldehydes in cellular oxidative stress and their impact on GPx1 activity.
FREE RADICAL BIOLOGY AND MEDICINE
(2023)
Article
Chemistry, Medicinal
Krishnaiah Maddeboina, Sravan K. Jonnalagadda, Ahmed Morsy, Ling Duan, Yashpal S. Chhonker, Daryl J. Murry, Trevor M. Penning, Paul C. Trippier
Summary: AKR1C3 is overexpressed in castration-resistant prostate cancer and drives proliferation and aggressiveness by producing androgens. The study reports the optimization of AKR1C3 inhibitors and the discovery of a potent inhibitor, 5r, with high selectivity for AKR1C3. A prodrug strategy was used to improve pharmacokinetics, and the prodrug 4r was converted to the active form, 5r. In vivo experiments showed increased exposure and concentration of 5r compared to direct administration of the free acid. The prodrug 4r effectively reduced tumor volume without toxicity.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Letter
Endocrinology & Metabolism
Trevor M. Penning, Andrea J. Detlefsen
Article
Endocrinology & Metabolism
Ryan D. Paulukinas, Trevor M. Penning
Summary: Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women, characterized by insulin resistance and hyperandrogenism. The study found that AKR1C3, induced by insulin, plays a role in promoting lipid overload through the induction of FASN in PCOS adipocytes. It was also discovered that AKR1C3 stabilizes AR and interacts with it, leading to the formation of lipid droplets. These findings suggest that AKR1C3 could be a therapeutic target for bifunctional inhibitors to reduce cardiometabolic disease in PCOS.
