- Dual-biomarker-triggered fluorescence probes for differentiating cancer cells and revealing synergistic antioxidant effects under oxidative stress
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Hydrogen sulfide (H2S) and human NAD(P)H:quinine oxidoreductase 1 (hNQO1) are potential cancer biomarkers and also vital participants in cellular redox homeostasis. Simultaneous detection of these two biomarkers would benefit the diagnostic precision of related cancers and could also help to investigate their crosstalk in response to oxidative stress. Despite this importance, fluorescent probes that can be activated by the dual action of H2S detection and hNQO1 activity have not been investigated. To this end, dual-biomarker-triggered fluorescent probes 1 and 2 were rationally constructed by installing two chemoselective triggering groups into one fluorophore. Probe 1 provides a small turn-on fluorescence response toward H2S but a much larger response to both H2S and hNQO1 in tandem. By contrast, fluorescence probe 2 is activated only in the presence of both H2S and hNQO1. Probe 2 exhibits a large fluorescence turn-on (>400 fold), high sensitivity, excellent selectivity as well as good biocompatibility, enabling the detection of both endogenous H2S and hNQO1 activity in living cells. Bioimaging results indicated that probe 2 could differentiate HT29 and HepG2 cancer cells from HCT116, FHC and HeLa cells owing to the existence of relatively high endogenous levels of both biomarkers. Expanded investigations using 2 revealed that cells could generate more endogenous H2S and hNQO1 upon exposure to exogenous hydrogen peroxide (H2O2), implying the synergistic antioxidant effects under conditions of cellular oxidative stress.
- Zhang, Changyu,Zhang, Qiang-Zhe,Zhang, Kun,Li, Lu-Yuan,Pluth, Michael D.,Yi, Long,Xi, Zhen
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- Photoactivated fluorescent probe as well as preparation method and application thereof
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The invention relates to a fluorescent probe as well as a preparation method and application thereof, which belongs to the field of small organic molecule fluorescent probes. The probe capable of performing fluorescence labeling on the protein is synthesized, and the fluorescent probe does not have fluorescence or has weak fluorescence, and can perform a light cyclization reaction with the primary amine compound under the light induction so as to generate the fluorescent product; compared with a traditional micromolecular dye for carrying out fluorescence labeling on protein, the fluorescent probe can reduce interference of fluorescence of the dye on labeling, and can carry out time-space controlled labeling through photoactivation.
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Paragraph 0035-0038
(2021/09/08)
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- Compounds for treating spinal muscular atrophy
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Provided herein are compounds, compositions thereof and uses therewith for treating spinal muscular atrophy. In a specific embodiment, provided herein are compounds of a form that may be used to modulate the inclusion of exon 7 of SMN2 into mRNA that is transcribed from the SMN2 gene. In another specific embodiment, provided herein are compounds of a form that may be used to modulate the inclusion of exon 7 of SMN1 into mRNA that is transcribed from the SMN1 gene. In yet another embodiment, provided herein are compounds of a form that may be used to modulate the inclusion of exon 7 of SMN1 and SMN2 into mRNA that is transcribed from the SMN1 and SMN2 genes, respectively.
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Page/Page column 319; 320
(2017/05/02)
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- Discovery and Optimization of Small Molecule Splicing Modifiers of Survival Motor Neuron 2 as a Treatment for Spinal Muscular Atrophy
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The underlying cause of spinal muscular atrophy (SMA) is a deficiency of the survival motor neuron (SMN) protein. Starting from hits identified in a high-throughput screening campaign and through structure-activity relationship investigations, we have developed small molecules that potently shift the alternative splicing of the SMN2 exon 7, resulting in increased production of the full-length SMN mRNA and protein. Three novel chemical series, represented by compounds 9, 14, and 20, have been optimized to increase the level of SMN protein by >50% in SMA patient-derived fibroblasts at concentrations of 160 nM. Daily administration of these compounds to severe SMA Δ7 mice results in an increased production of SMN protein in disease-relevant tissues and a significant increase in median survival time in a dose-dependent manner. Our work supports the development of an orally administered small molecule for the treatment of patients with SMA.
- Woll, Matthew G.,Qi, Hongyan,Turpoff, Anthony,Zhang, Nanjing,Zhang, Xiaoyan,Chen, Guangming,Li, Chunshi,Huang, Song,Yang, Tianle,Moon, Young-Choon,Lee, Chang-Sun,Choi, Soongyu,Almstead, Neil G.,Naryshkin, Nikolai A.,Dakka, Amal,Narasimhan, Jana,Gabbeta, Vijayalakshmi,Welch, Ellen,Zhao, Xin,Risher, Nicole,Sheedy, Josephine,Weetall, Marla,Karp, Gary M.
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p. 6070 - 6085
(2016/07/26)
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- COMPOUNDS FOR TREATING SPINAL MUSCULAR ATROPHY
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Provided herein are compounds, compositions thereof and uses therewith for treating spinal muscular atrophy. In a specific embodiment, provided herein are compounds of a form that may be used to modulate the inclusion of exon 7 of SMN2 into mRNA that is transcribed from the SMN2 gene. In another specific embodiment, provided herein are compounds of a form that may be used to modulate the inclusion of exon 7 of SMN1 into mRNA that is transcribed from the SMN1 gene. In yet another embodiment, provided herein are compounds of a form that may be used to modulate the inclusion of exon 7 of SMN1 and SMN2 into mRNA that is transcribed from the SMN1 and SMN2 genes, respectively.
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Paragraph 00578; 00579
(2013/07/19)
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