Discovery of a crystalline sulforaphane analog with good solid-state stability and engagement of the Nrf2 pathway in vitro and in vivo

Boehm, Jeffrey C.; Davis, Roderick; Murar, Claudia E.; Li, Tindy; McCleland, Brent W.; Dong, Shuping; Huang, Yan; Kerns, Jeffrey K.; Moody, Christopher J.; Wilson, A. James; Graves, Alan P.; Mentzer, Mary; Qi, Hongwei; Yonchuk, John; Kou, Jen-Pyng; Foley, Joseph; Sánchez, Yolanda; Podolin, Patricia L.; Bolognese, Brian; Booth-Genthe, Catherine; Galop, Marc; Wolfe, Lawrence A.; Carr, Robin A. E.; Callahan, James F.

doi:10.1016/j.bmc.2018.12.026

Cited by 9 publications

(9 citation statements)

References 38 publications

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“…Interestingly, this study found that SFN failed to reduce miR-200a and oxidative stress, and to restore glucose uptake in DEHP-exposed C2C12 myotubes when miR-17 was knockdown, suggesting that antioxidant effects of miR-17 was stronger than those of the small molecule Nrf2 inducer SFN. SFN is an electrophilic entity with very small molecular weight and poor aqueous, and this activator has some additional disadvantages hindering its development as a drug, such as the relatively low potency in functional assays measuring the induction of antioxidant proteins and the activation of ROS-detoxifying enzymes 64 . Precision therapeutics to target dysregulated miRNA can be an appropriate target for disease treatment.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic repression of miR-17 contributed to di(2-ethylhexyl) phthalate-triggered insulin resistance by targeting Keap1-Nrf2/miR-200a axis in skeletal muscle

et al. 2020

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Rationale: Skeletal muscle insulin resistance is detectable before type 2 diabetes is diagnosed. Exposure to di(2-ethylhexyl) phthalate (DEHP), a typical environmental endocrine-disrupting chemical, is a novel risk factor for insulin resistance and type 2 diabetes. This study aimed to explore insulin signaling regulatory pathway in skeletal muscle of the DEHP-induced insulin-resistant mice and to investigate potential therapeutic strategies for treating insulin resistance. Methods: C57BL/6J male mice were exposed to 2 mg/kg/day DEHP for 15 weeks. Whole-body glucose homeostasis, oxidative stress and deregulated miRNA-mediated molecular transduction in skeletal muscle were examined. microRNA (miRNA) interventions based on lentiviruses and adeno-associated viruses 9 (AAV9) were performed. Results: Dnmt3a-dependent promoter methylation and lncRNA Malat1-related sponge functions cooperatively downregulated miR-17 in DEHP-exposed skeletal muscle cells. DEHP suppressed miR-17 to disrupt the Keap1-Nrf2 redox system and to activate oxidative stress-responsive Txnip in skeletal muscle. Oxidative stress upregulated miR-200a, which directly targets the 3'UTR of Insr and Irs1 , leading to hindered insulin signaling and impaired insulin-dependent glucose uptake in skeletal muscle, ultimately promoting the development of insulin resistance. AAV9-induced overexpression of miR-17 and lentivirus-mediated silencing of miR-200a in skeletal muscle ameliorated whole-body insulin resistance in DEHP-exposed mice. Conclusions: The miR-17/Keap1-Nrf2/miR-200a axis contributed to DEHP-induced insulin resistance. miR-17 is a positive regulator, whereas miR-200a is a negative regulator of insulin signaling in skeletal muscle, and both miRNAs have the potential to become therapeutic targets for preventing and treating insulin resistance or type 2 diabetes.

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Section: Discussionmentioning

confidence: 99%

Epigenetic repression of miR-17 contributed to di(2-ethylhexyl) phthalate-triggered insulin resistance by targeting Keap1-Nrf2/miR-200a axis in skeletal muscle

et al. 2020

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“… 164 This may be due to the lack of stability of the compound, therefore discovery of a more stable analogue of sulforaphane may allow further studies. 165 …”

Section: Biologicsmentioning

confidence: 99%

“…164 This may be due to the lack of stability of the compound, therefore discovery of a more stable analogue of sulforaphane may allow further studies. 165 Although we are now learning more about the inflammatory profile observed in the lungs of patients with COPD, the role of increased leukocyte accumulation is still not fully understood. Environmental changes to cellular activation states or phenotypes may derive from structural cells or exposure to inhaled pollutants such as cigarette smoke.…”

Section: Other Anti-inflammatory Pathway Inhibitorsmentioning

confidence: 99%

Leukocyte Function in COPD: Clinical Relevance and Potential for Drug Therapy

Baker

Donnelly

2021

COPD

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Chronic obstructive pulmonary disease (COPD) is a progressive lung condition affecting 10% of the global population over 45 years. Currently, there are no disease-modifying treatments, with current therapies treating only the symptoms of the disease. COPD is an inflammatory disease, with a high infiltration of leukocytes being found within the lung of COPD patients. These leukocytes, if not kept in check, damage the lung, leading to the pathophysiology associated with the disease. In this review, we focus on the main leukocytes found within the COPD lung, describing how the release of chemokines from the damaged epithelial lining recruits these cells into the lung. Once present, these cells become active and may be driven towards a more pro-inflammatory phenotype. These cells release their own subtypes of inflammatory mediators, growth factors and proteases which can all lead to airway remodeling, mucus hypersecretion and emphysema. Finally, we describe some of the current therapies and potential new targets that could be utilized to target aberrant leukocyte function in the COPD lung. Here, we focus on old therapies such as statins and corticosteroids, but also look at the emerging field of biologics describing those which have been tested in COPD already and potential new monoclonal antibodies which are under review.

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“…In 2019, Boehm and co-workers [ 264 ] synthesized crystalline SFN analogues 459 and 461 . Both isothiocyanates 459 and 461 were obtained in good yields, in a two-step reaction of the appropriate amine hydrochlorides 458 or 460 , and carbon disulfide in the presence of triethylamine, using hydrogen peroxide or tosyl chloride as desulfurizing agents ( Figure 51 ).…”

Section: Synthesis Of Bifunctional Analogs Of Sulforaphane and Their ...mentioning

confidence: 99%

Sulforaphane and Its Bifunctional Analogs: Synthesis and Biological Activity

Janczewski

2022

Molecules

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For decades, various plants have been studied as sources of biologically active compounds. Compounds with anticancer and antimicrobial properties are the most frequently desired. Cruciferous plants, including Brussels sprouts, broccoli, and wasabi, have a special role in the research studies. Studies have shown that consumption of these plants reduce the risk of lung, breast, and prostate cancers. The high chemopreventive and anticancer potential of cruciferous plants results from the presence of a large amount of glucosinolates, which, under the influence of myrosinase, undergo an enzymatic transformation to biologically active isothiocyanates (ITCs). Natural isothiocyanates, such as benzyl isothiocyanate, phenethyl isothiocyanate, or the best-tested sulforaphane, possess anticancer activity at all stages of the carcinogenesis process, show antibacterial activity, and are used in organic synthesis. Methods of synthesis of sulforaphane, as well as its natural or synthetic bifunctional analogues with sulfinyl, sulfanyl, sulfonyl, phosphonate, phosphinate, phosphine oxide, carbonyl, ester, carboxamide, ether, or additional isothiocyanate functional groups, and with the unbranched alkyl chain containing 2–6 carbon atoms, are discussed in this review. The biological activity of these compounds are also reported. In the first section, glucosinolates, isothiocyanates, and mercapturic acids (their metabolites) are briefly characterized. Additionally, the most studied anticancer and antibacterial mechanisms of ITC actions are discussed.

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Discovery of a crystalline sulforaphane analog with good solid-state stability and engagement of the Nrf2 pathway in vitro and in vivo

Cited by 9 publications

References 38 publications

Epigenetic repression of miR-17 contributed to di(2-ethylhexyl) phthalate-triggered insulin resistance by targeting Keap1-Nrf2/miR-200a axis in skeletal muscle

Epigenetic repression of miR-17 contributed to di(2-ethylhexyl) phthalate-triggered insulin resistance by targeting Keap1-Nrf2/miR-200a axis in skeletal muscle

Leukocyte Function in COPD: Clinical Relevance and Potential for Drug Therapy

Sulforaphane and Its Bifunctional Analogs: Synthesis and Biological Activity

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