Review
Medicine, General & Internal
Jonathan Seckl
Summary: 11 beta-HSDs are enzymes that convert active 11-hydroxy glucocorticoids to their inert 11-keto forms. 11 beta-HSD2 inactivates glucocorticoids and has important roles in the kidney and developing foetal brain. In contrast, 11 beta-HSD1 amplifies active glucocorticoid levels in the brain and is associated with age-related cognitive decline.
JOURNAL OF INTERNAL MEDICINE
(2023)
Article
Pharmacology & Pharmacy
Cristina Gomez, Zerin Alimajstorovic, Nantia Othonos, Denise V. Winter, Sarah White, Gareth G. Lavery, Jeremy W. Tomlinson, Alexandra J. Sinclair, Alex Odermatt
Summary: This study compares the abilities of GUDCA/G7oxoLCA ratio and urinary (5α-THF+THF)/THE ratio to detect pharmacological 11 beta-HSD1 inhibition in humans. Results suggest that GUDCA/G7oxoLCA ratio is a more reliable biomarker for 11 beta-HSD1 inhibition.
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
Article
Chemistry, Multidisciplinary
Rahul Singh, Vijay Kumar Bhardwaj, Pralay Das, Rituraj Purohit
Summary: Aminoarylbenzosuberene (AAB) molecules were analyzed in silico to develop potent inhibitors for 11 beta-Hydroxysteroid dehydrogenase (11 beta-HSD1) protein. AAB4 molecule showed stronger interactions and binding affinity compared to the standard inhibitors.
CHEMICAL COMMUNICATIONS
(2022)
Article
Pharmacology & Pharmacy
Silvia G. Inderbinen, Michael Zogg, Manuel Kley, Martin Smiesko, Alex Odermatt
Summary: The study discovered a species-specific inhibition of 11 beta-HSD2 by azole antifungals, with human enzyme being most sensitive, while mouse and zebrafish enzymes showing weak inhibition. Structural differences in the C-terminal region and substrate binding pocket were identified as key factors contributing to the observed differences in sensitivity to the inhibitors. This information could aid in future evaluations of 11 beta-HSD2 inhibitors and in selecting appropriate animal models for efficacy and safety studies.
TOXICOLOGY AND APPLIED PHARMACOLOGY
(2021)
Article
Endocrinology & Metabolism
Eva Kathrin Lamade, Ferdinand Hendlmeier, Stefan A. Wudy, Stephanie H. Witt, Marcella Rietschel, Michaela Coenen, Maria Gilles, Michael Deuschle
Summary: The study revealed time-specific alteration of fetoplacental 11 beta-HSD2 activity, peaking in the morning to protect fetus from maternal glucocorticoids. Acute affective or anxiety disorders were found to impact fetoplacental 11 beta-HSD2 activity.
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
(2021)
Article
Endocrinology & Metabolism
Nicola Wheelan, Jonathan R. Seckl, Joyce L. W. Yau
Summary: This study investigates how a deficiency of 11β-HSD1 and aging modulates fear conditioning and PTSD-like memory in mice. The results indicate that a deficiency of 11β-HSD1 protects young adult mice against amnesia for the conditioning context and hypermnesia for a salient tone, but only prevents contextual amnesia in aged mice.
PSYCHONEUROENDOCRINOLOGY
(2022)
Article
Pharmacology & Pharmacy
Hongguo Guan, Yiyan Wang, Huitao Li, Qiqi Zhu, Xiaoheng Li, Guang Liang, Ren-Shan Ge
Summary: WZS08 is a potent inhibitor of rat, mouse, and human 11 beta-hydroxysteroid dehydrogenase 1, effectively treating non-alcoholic fatty liver disease in mice by reducing liver fat content and improving liver morphology.
FRONTIERS IN PHARMACOLOGY
(2021)
Review
Pharmacology & Pharmacy
Jiangang Cao, Yawen Chen, Hui Wang
Summary: Basal glucocorticoid levels play a crucial role in regulating fetal development and determining future outcomes. Adverse prenatal environments have been found to result in abnormal maternal glucocorticoid levels during pregnancy. 11 beta-hydroxysteroid dehydrogenases (11 beta-HSDs), which are present in target organs of glucocorticoids and mineralocorticoids, are involved in fetal physiological and pathological development by activating or inactivating glucocorticoids. Several pathways can be affected by prenatal adverse environments, leading to abnormal local glucocorticoid levels, changes in fetal developmental programming and homeostasis, and increased susceptibility to various diseases after birth. This review provides a theoretical basis for the early prevention and treatment of fetal-originated diseases.
Article
Pharmacology & Pharmacy
Michael Weingartner, Simon Stucheli, Denise Kratschmar, Julia Birk, Petra Klusonova, Karen E. Chapman, Gareth G. Lavery, Alex Odermatt
Summary: The study found that the plasma ratio of UDC-Tau to 7oxoLC-Tau can serve as a biomarker for decreased 11 beta-HSD1 oxoreduction activity in different mouse models. Enzyme product to substrate ratios were more reliable markers of 11 beta-HSD1 activity than absolute levels due to large inter-individual variations in bile acid concentrations. The persistence of oxoreduction activity in the face of cofactor loss indicates the existence of an alternative NADPH source in the endoplasmic reticulum.
BRITISH JOURNAL OF PHARMACOLOGY
(2021)
Article
Pharmacology & Pharmacy
Congcong Zhao, Shaowei Wang, Yingna Zhai, Mengyun Wang, Yunbing Tang, Huitao Li, Young Jun Im, Ren-shan Ge
Summary: Per- and polyfluoroalkyl substances (PFAS), including PFOA and PFOS, can inhibit the activity of 1113-hydroxysteroid dehydrogenase 2 (1113-HSD2) and lead to the accumulation of active glucocorticoids. The inhibitory effect of PFAS is determined by the carbon-chain length, with PFDA and PFOS being the most potent inhibitors.
Article
Pharmacology & Pharmacy
Zhixin Wu, Yinxian Wen, Hao Xiao, Jiayong Zhu, Bin Li, Yangfan Shangguan, Hangyuan He, Hui Wang, Liaobin Chen
Summary: Epidemiological investigations have shown an increased risk of osteoporosis in individuals treated with dexamethasone during pregnancy. Decreased peak bone mass and increased bone local active corticosterone were observed in prenatal dexamethasone exposure (PDE) offspring, with further decrease and increase after chronic stress. Injection of 118-HSD2 overexpression lentivirus partially alleviated bone loss induced by PDE. Dexamethasone inhibited 118HSD2 expression and aggravated the inhibitory effect of corticosterone on osteogenic differentiation, while overexpression of 118-HSD2 partially alleviated this effect.
PHARMACOLOGICAL RESEARCH
(2022)
Article
Nutrition & Dietetics
Yuki Nouchi, Eiji Munetsuna, Hiroya Yamada, Mirai Yamazaki, Yoshitaka Ando, Genki Mizuno, Miyuki Ikeya, Itsuki Kageyama, Takuya Wakasugi, Atsushi Teshigawara, Yuji Hattori, Yoshiki Tsuboi, Hiroaki Ishikawa, Koji Suzuki, Koji Ohashi
Summary: This study aimed to elucidate the molecular mechanism by which maternal high-fructose corn syrup (HFCS) intake increases circulating GC levels in rat offspring. By giving female Sprague Dawley rats HFCS solution, it was found that HFCS led to a decrease in activity of GC-metabolizing enzyme 11 beta-Hsd2 and an increase in renal miR-27a expression. These findings suggest that the elevation of circulating GC levels in offspring induced by maternal HFCS consumption may be explained by a decrease in 11 beta-Hsd2 activity via renal miR-27a expression.
Article
Multidisciplinary Sciences
Callam T. Davidson, Eileen Miller, Morwenna Muir, John C. Dawson, Martin Lee, Stuart Aitken, Alan Serrels, Scott P. Webster, Natalie Z. M. Homer, Ruth Andrew, Valerie G. Brunton, Patrick W. F. Hadoke, Brian R. Walker
Summary: Glucocorticoids inhibit angiogenesis by activating the glucocorticoid receptor. The inhibition of glucocorticoid-activating enzyme 11 beta-HSD1 reduces tissue-specific glucocorticoid action and promotes angiogenesis in murine models of myocardial infarction. This study demonstrates that 11 beta-HSD1 inhibition increases SCC tumour growth, likely through suppression of inflammatory/immune cell signalling and extracellular matrix deposition.
Article
Biochemistry & Molecular Biology
Justine M. Webster, Michael S. Sagmeister, Chloe G. Fenton, Alex P. Seabright, Yu-Chiang Lai, Simon W. Jones, Andrew Filer, Mark S. Cooper, Gareth G. Lavery, Karim Raza, Ramon Langen, Rowan S. Hardy
Summary: Glucocorticoids are important anti-inflammatory therapies, but their use is limited due to metabolic adverse effects like muscle wasting. The enzyme 11 beta-HSD1 plays a role in modulating glucocorticoid responses in muscle. Knocking out 11 beta-HSD1 prevented muscle atrophy associated with glucocorticoid therapy in a model of chronic inflammation, suggesting a potential strategy to refine the safety of glucocorticoids.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Mohamad Hafizi Abu Bakar, Mohamad Shamil Faris Mohamad Khalid, Nor Shafiqah Nor Shahril, Khairul Anuar Shariff, Thiruventhan Karunakaran
Summary: Celastrol improves glucose tolerance, lipid profiles, and insulin sensitivity, reduces hepatic glucose production, attenuates inflammation, mitigates oxidative stress, and inhibits 11 beta-HSD1 activity in adipose tissues, highlighting its potential in combating metabolic syndrome induced by high fructose consumption.