Regulatory lipid vicinal diols counteract the biological activity of epoxy fatty acids and can act as biomarkers and mechanisms for disease progression

McReynolds, Cindy B.; Hammock, Bruce G.; Morisseau, Christophe

doi:10.1016/j.pharmthera.2023.108454

“…In rodent studies, sEHIs have shown promising results for controlling various inflammatory diseases, such as hypertension, atherosclerosis, diabetes, COPD, liver regeneration, fibrosis, sepsis, asthma, subarachnoid hemorrhage, arthritis, and neuropathic pain ( 27 , 41 , 57 , 96 – 104 ). Thus, sEH is a critical cause of and biomarker for inflammation in many systems ( 40 , 50 , 53 , 84 , 99 , 105 – 107 ). The human sEHI EC5026 is in clinical development as an analgesic for neuropathic pain as a nonaddictive opioid alternative ( 42 ).…”

Section: Discussionmentioning

confidence: 99%

Enhancing cancer immunotherapy via inhibition of soluble epoxide hydrolase

Kelly,

Wang,

Rothenberger

et al. 2024

Proc. Natl. Acad. Sci. U.S.A.

4

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Cancer therapy, including immunotherapy, is inherently limited by chronic inflammation-induced tumorigenesis and toxicity within the tumor microenvironment. Thus, stimulating the resolution of inflammation may enhance immunotherapy and improve the toxicity of immune checkpoint inhibition (ICI). As epoxy-fatty acids (EpFAs) are degraded by the enzyme soluble epoxide hydrolase (sEH), the inhibition of sEH increases endogenous EpFA levels to promote the resolution of cancer-associated inflammation. Here, we demonstrate that systemic treatment with ICI induces sEH expression in multiple murine cancer models. Dietary omega-3 polyunsaturated fatty acid supplementation and pharmacologic sEH inhibition, both alone and in combination, significantly enhance anti-tumor activity of ICI in these models. Notably, pharmacological abrogation of the sEH pathway alone or in combination with ICI counter-regulates an ICI-induced pro-inflammatory and pro-tumorigenic cytokine storm. Thus, modulating endogenous EpFA levels through dietary supplementation or sEH inhibition may represent a unique strategy to enhance the anti-tumor activity of paradigm cancer therapies.

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Harnessing Cooperative Multivalency in Thioguanine for Surface‐Enhanced Raman Scattering (SERS)‐Based Differentiation of Polyfunctional Analytes Differing by a Single Functional Group

Nguyen,

Tan,

Leong

et al. 2024

Angewandte Chemie

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Small‐molecule receptors are increasingly employed to probe various functional groups for (bio)chemical analysis. However, differentiation of polyfunctional analogs sharing multiple functional groups remains challenging for conventional mono‐ and bidentate receptors because their insufficient number of binding sites limits interactions with the least reactive yet property‐determining functional group. Herein, we introduce 6‐thioguanine (TG) as a supramolecular receptor for unique tridentate receptor‐analyte complexation,achieving ≥ 95% identification accuracy among 16 polyfunctional analogs across three scenarios: glycerol derivatives, disubstituted propanes, and vicinal diols. Crucially, we demonstrate distinct spectral changes induced by the tridentate interaction between TG’s three anchoring points and all the analyte’s functional groups, even the least reactive ones. Notably, H‐bond networks formed in the TG‐analyte complexes demonstrate additive effect in binding strength originating from good bond linearity, cooperativity, and resonance, thus strengthens complexation events and amplifies the differences in spectral changes induced among analytes. It also enhances spectral consistency by selectively form a sole configuration that is stronger than the respective analyte‐analyte interaction. Finally, we achieve 95.4% accuracy for multiplex identification of a mixture consisting of multiple polyfunctional analogs. We envisage that extension to other multidentate non‐covalent interactions enables the development of interference‐free small molecule‐based sensors for various (bio)chemical analysis applications.

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Harnessing Cooperative Multivalency in Thioguanine for Surface‐Enhanced Raman Scattering (SERS)‐Based Differentiation of Polyfunctional Analytes Differing by a Single Functional Group

Nguyen,

Tan,

Leong

et al. 2024

Angew Chem Int Ed

0

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Small‐molecule receptors are increasingly employed to probe various functional groups for (bio)chemical analysis. However, differentiation of polyfunctional analogs sharing multiple functional groups remains challenging for conventional mono‐ and bidentate receptors because their insufficient number of binding sites limits interactions with the least reactive yet property‐determining functional group. Herein, we introduce 6‐thioguanine (TG) as a supramolecular receptor for unique tridentate receptor‐analyte complexation,achieving ≥ 95% identification accuracy among 16 polyfunctional analogs across three scenarios: glycerol derivatives, disubstituted propanes, and vicinal diols. Crucially, we demonstrate distinct spectral changes induced by the tridentate interaction between TG’s three anchoring points and all the analyte’s functional groups, even the least reactive ones. Notably, H‐bond networks formed in the TG‐analyte complexes demonstrate additive effect in binding strength originating from good bond linearity, cooperativity, and resonance, thus strengthens complexation events and amplifies the differences in spectral changes induced among analytes. It also enhances spectral consistency by selectively form a sole configuration that is stronger than the respective analyte‐analyte interaction. Finally, we achieve 95.4% accuracy for multiplex identification of a mixture consisting of multiple polyfunctional analogs. We envisage that extension to other multidentate non‐covalent interactions enables the development of interference‐free small molecule‐based sensors for various (bio)chemical analysis applications.

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Regulatory lipid vicinal diols counteract the biological activity of epoxy fatty acids and can act as biomarkers and mechanisms for disease progression

Cited by 9 publications

References 83 publications

Enhancing cancer immunotherapy via inhibition of soluble epoxide hydrolase

Enhancing cancer immunotherapy via inhibition of soluble epoxide hydrolase

Harnessing Cooperative Multivalency in Thioguanine for Surface‐Enhanced Raman Scattering (SERS)‐Based Differentiation of Polyfunctional Analytes Differing by a Single Functional Group

Harnessing Cooperative Multivalency in Thioguanine for Surface‐Enhanced Raman Scattering (SERS)‐Based Differentiation of Polyfunctional Analytes Differing by a Single Functional Group

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