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1.
Redox Biol ; 38: 101766, 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-33126057

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible disease characterized by an increase in differentiation of fibroblasts to myofibroblasts and excessive accumulation of extracellular matrix in lung tissue. Pharmacological activation of NRF2 has proved to be a valuable antifibrotic approach, however the detailed mechanisms of how NRF2 mediates antifibrotic function remain unclear. In this study, we found that the antifibrotic function of sulforaphane (SFN), an NRF2 activator, was largely dependent on LOC344887, a long noncoding RNA. Two functional AREs were identified in both the promoter and intron 1 of LOC344887, which defines LOC344887 as a novel anti-fibrotic NRF2 target gene. RNA-seq analysis revealed that LOC344887 controls genes and signaling pathways associated with fibrogenesis. Deletion or downregulation of LOC344887 enhanced expression of CDH2/N-cadherin, as well as a number of other fibrotic genes and blunted the antifibrotic effects of SFN. Furthermore, LOC344887-mediated downregulation of fibrotic genes may involve the PI3K-AKT signaling pathway, as pharmacologic inhibition of PI3K activity blocked the effects of LOC344887 knockdown. Our findings demonstrate that NRF2-mediated LOC344887 upregulation contributes to the antifibrotic potential of SFN by repressing the expression of CDH2 and other fibrotic genes, providing novel insight into how NRF2 controls the regulatory networks of IPF. This study provides a better understanding of the molecular mechanisms of NRF2 activators against pulmonary fibrosis and presents a novel therapeutic axis for prevention and intervention of fibrosis-related diseases.

2.
Toxicol Appl Pharmacol ; 402: 115138, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32682831

RESUMO

Chronic low dose arsenic exposure continues to be a worldwide health concern because of its prevalence and link to increased cancer risk, including non-small cell lung cancer (NSCLC). Mortality of NSCLC patients increases with the development of a metastatic lesion compared to when the tumor is localized; however, the exact mechanism for what causes NSCLC cells to metastasize in the context of environmental toxicant exposure has yet to be fully elucidated. One proposed contributor to metastasis in NSCLC is nuclear factor (erythroid-derived 2)-like 2 (NRF2), a transcription factor with known oncogenic properties that has proved to be critical for arsenic carcinogenesis. Here, we demonstrate that chronic arsenic exposure enhances the invasive and migratory capacity of immortalized lung epithelial cells via NRF2-dependent upregulation of SRY-box 9 (SOX9), another transcription factor linked with cell proliferation, epithelial-mesenchymal transition, and metastasis. We identified a functional antioxidant response element (ARE) in the promoter region of SOX9, suggesting that it is an NRF2 target gene, with mutation of the ARE preventing NRF2 binding. Pharmacological induction or inhibition of NRF2 increased or decreased SOX9 expression, respectively. Furthermore, we demonstrate that hyperactivation of NRF2 via knockout of Kelch-like ECH-associated protein 1 (KEAP1), its negative regulator, contributes to proliferation; while, inhibition of NRF2 or direct knockdown of SOX9 slowed the ability of NSCLC cells to proliferate, migrate, and invade. Overall, this study suggests that NRF2-mediated SOX9 upregulation can contribute to the metastatic potential of both environmentally and genetically driven lung tumors.

3.
Org Lett ; 22(4): 1557-1562, 2020 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-32045253

RESUMO

A mild, versatile organophotoredox protocol has been developed for the preparation of diverse, enantioenriched α-deuterated α-amino acids. Distinct from the well-established two-electron transformations, this radical-based strategy offers the unrivaled capacity of the convergent unification of readily accessible feedstock carboxylic acids and a chiral methyleneoxazolidinone fragment and the simultaneous highly diastereo-, chemo-, and regioselective incorporation of deuterium. Furthermore, the approach has addressed the long-standing challenge of the installation of sterically demanding side chains into α-amino acids.


Assuntos
Aminoácidos/síntese química , Ácidos Carboxílicos/química , Oxazolidinonas/química , Aminoácidos/química , Catálise , Radicais Livres/química , Estrutura Molecular , Oxirredução , Processos Fotoquímicos , Estereoisomerismo
4.
Chem Res Toxicol ; 33(2): 614-624, 2020 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-31878777

RESUMO

Dioxins, mostly through activation of aryl hydrocarbon receptor (AhR), are potent toxic substances widely distributed in the environment, while moderated suppression of AhR also exhibits anti-tumor effects. Therefore, the proper modulation of AhR activity may counteract AhR-mediated toxicities and certain diseases. In this investigation, we identified several novel AhR moderate agonists and antagonists using chemical biology approaches. The mechanisms and mode of interactions with AhR by these hits were also revealed using both experimental and computational studies. The newly identified AhR moderate agonists and antagonists were predicted to bind to AhR and modulate AhR signaling. The structure-activity relationships of moderate agonists and antagonists and their unique binding features with AhR have created a solid framework for further optimization of the next generation of AhR modulators.

5.
Org Lett ; 21(9): 3086-3092, 2019 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-30978030

RESUMO

An approach for efficient synthesis of C-glycosyl amino acids is described. Different from typical photoredox-catalyzed reactions of imines, the new process follows a pathway in which α-imino esters serve as electrophiles in chemoselective addition reactions with nucleophilic glycosyl radicals. The process is highlighted by the mild nature of the reaction conditions, the highly stereoselectivity attending C-C bond formation, and its applicability to C-glycosylations using both armed and disarmed pentose and hexose derivatives.

6.
Chemistry ; 25(35): 8225-8228, 2019 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-30986322

RESUMO

A metal- and oxidant-free catalytic method for accessing structurally diverse thioesters from readily accessible, widespread aldehydes, is described. A strategy of a simple organic 9,10-phenanthrenequinone-promoted hydrogen atom transfer (HAT) with visible light was successfully implemented to selectively generate acyl radicals without inducing crossover reactivity of thioester products. The preparative power of the method was demonstrated by broad substrate scope and wide functional group tolerance, and enabled the late-stage modification of complex structures, which are difficult to achieve with the existing protocols.

7.
ACS Appl Mater Interfaces ; 10(16): 13914-13923, 2018 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-29617104

RESUMO

Heterogeneous organometallic catalysts with well-defined active sites and hierarchical pores hold tremendous promise for efficient and eco-friendly chemical processes. However, the simple and scalable preparation of these materials remains difficult to date, which has hampered a more broad application scope. Herein, we reported a low-cost, rapid, and scalable aerosol-assisted assembly approach for the synthesis of a well-defined PdDPP (PdCl2(PPh2(CH2)2))_ complex-containing benzene-bridged organosilica-based catalyst with a hierarchical bimodal micro-macroporous structure. This novel material was realized by using Pd(II) organometallic silane (Pd[PPh2(CH2)2Si(OEt)3]2Cl2) as the active species, organosilane 1,4-bis(triethoxysilyl)benzene (Ph[Si(OEt)3]2) as the silicate scaffold and the surfactant cetyltrimethylammonium bromide and the inorganic salt NaCl as the dual templates on a home-built aerosol spraying-instrument. Multiple techniques including X-ray photoelectron spectroscopy and solid-state NMR spectra revealed that the organopalladium complex with a well-defined molecular configuration of major trans model and minor cis model existed in the phenyl-functionalized silica material. As expected, it efficiently promoted a variety of important carbon-carbon cross-coupling transformations including Tsuji-Trost, Sonogashira, and Suzuki reactions in pure water without the assistance of any additives. In comparison with the homogeneous catalyst PdCl2(PPh2CH3)2, it even exhibited enhanced activity and selectivity in some cases owing to the unique confinement effect and the shape selectivity generated from the hierarchical porous structure. Meanwhile, it was easily recycled and reused eight times without the loss of its activity.

8.
ACS Synth Biol ; 6(6): 921-927, 2017 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-28221778

RESUMO

A new synthetic biology engineering strategy integrating chemical reactivity sensing and small molecule induced protein dimerization has been developed to generate artificial Fe2+ signaling circuitry to control tailored cellular events in mammalian cells. The dual function probe ABA-FE18 (Fe2+-sensing and protein dimerization) derived from ABA was developed and used to control gene activation, signal transduction, and cytoskeletal remodeling in response to Fe2+. This technology was utilized to design signal circuitry incorporating "AND" and "OR" biologic gates that enables mammalian cells to translate different combinations of Fe2+ and H2O2 signals into predefined biological outputs.


Assuntos
Ferro , Proteínas Recombinantes de Fusão/genética , Transdução de Sinais/genética , Biologia Sintética/métodos , Animais , Técnicas Biossensoriais , Linhagem Celular , Humanos , Ferro/química , Ferro/metabolismo , Modelos Moleculares , Multimerização Proteica/genética , Proteínas Recombinantes de Fusão/metabolismo
9.
Am J Physiol Lung Cell Mol Physiol ; 312(5): L609-L624, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28213473

RESUMO

Inflammation is a prominent pathological feature in pulmonary arterial hypertension, as demonstrated by pulmonary vascular infiltration of inflammatory cells, including T and B lymphocytes. However, the contribution of the adaptive immune system is not well characterized in pulmonary hypertension caused by chronic hypoxia. CD4+ T cells are required for initiating and maintaining inflammation, suggesting that these cells could play an important role in the pathogenesis of hypoxic pulmonary hypertension. Our objective was to test the hypothesis that CD4+ T cells, specifically the T helper 17 subset, contribute to chronic hypoxia-induced pulmonary hypertension. We compared indices of pulmonary hypertension resulting from chronic hypoxia (3 wk) in wild-type mice and recombination-activating gene 1 knockout mice (RAG1-/-, lacking mature T and B cells). Separate sets of mice were adoptively transferred with CD4+, CD8+, or T helper 17 cells before normoxic or chronic hypoxic exposure to evaluate the involvement of specific T cell subsets. RAG1-/- mice had diminished right ventricular systolic pressure and arterial remodeling compared with wild-type mice exposed to chronic hypoxia. Adoptive transfer of CD4+ but not CD8+ T cells restored the hypertensive phenotype in RAG1-/- mice. Interestingly, RAG1-/- mice receiving T helper 17 cells displayed evidence of pulmonary hypertension independent of chronic hypoxia. Supporting our hypothesis, depletion of CD4+ cells or treatment with SR1001, an inhibitor of T helper 17 cell development, prevented increased pressure and remodeling responses to chronic hypoxia. We conclude that T helper 17 cells play a key role in the development of chronic hypoxia-induced pulmonary hypertension.


Assuntos
Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/imunologia , Hipóxia/complicações , Hipóxia/imunologia , Células Th17/imunologia , Transferência Adotiva , Animais , Pressão Sanguínea/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Contagem de Células , Movimento Celular/efeitos dos fármacos , Doença Crônica , Feminino , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/fisiopatologia , Proteínas de Homeodomínio/metabolismo , Hipertensão Pulmonar/fisiopatologia , Interleucina-17/farmacologia , Interleucina-6/metabolismo , Pulmão/metabolismo , Depleção Linfocítica , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos Endogâmicos C57BL , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Sístole/efeitos dos fármacos , Sístole/fisiologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Células Th17/efeitos dos fármacos
10.
Bioconjug Chem ; 27(2): 302-8, 2016 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-26284503

RESUMO

Fluorogenic sensors capable of spatiotemporally detecting Fe(2+) in biological systems are highly valuable in the study of iron biology. Toward this end, a new "off-on" Fe(2+)-selective fluorescent probe has been developed by incorporating an Fe(2+)-induced N-O cleavage of acylated hydroxylamine moiety into the naphthalimide fluorophore. The probe displays facile response (within 15 min) and good selectivity toward Fe(2+) with >27-fold enhancement of fluorescence intensity and high sensitivity of as low as 0.5 µM with a noticeable 3-fold fluorescence enhancement. These features of the probe have been transformed into in the convenient detection of endogenous, basal level of labile Fe(2+) pools in living cells. Furthermore, we have demonstrated the capacity of the probe for the studies of important Fe(2+) related biological functions. It can respond to the Zn(2+)-induced Fe(2+) flux, an important event observed in stroke, and facilely detect the elevated level of Fe(2+) in the brain tissue of a rat undergoing ischemic stroke at the ischemic site.


Assuntos
Encéfalo/metabolismo , Corantes Fluorescentes/química , Ferro/análise , Naftalimidas/química , Imagem Óptica , Acidente Vascular Cerebral/metabolismo , Zinco/análise , Animais , Encéfalo/patologia , Fluorescência , Corantes Fluorescentes/metabolismo , Ferro/metabolismo , Masculino , Naftalimidas/metabolismo , Imagem Óptica/métodos , Ratos , Ratos Sprague-Dawley , Acidente Vascular Cerebral/patologia , Zinco/metabolismo
11.
Org Biomol Chem ; 13(24): 6742-8, 2015 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-25997534

RESUMO

We describe a new theranostic strategy for selective delivery and spatiotemporal monitoring of mechlorethamine, a DNA alkylating agent. A photo-responsive prodrug is designed and composed of a photolabile o-nitrophenylethyl group, a DNA alkylating mechlorethamine drug and a coumarin fluorophore. Masking of the "N" in mechlorethamine in a positively charged state in the prodrug renders it inactive, non-toxic, selective and non-fluorescent. Indeed, the stable prodrug shows negligible cytotoxicity towards normal cells with and without UV activation and is completely non-fluorescent. However, upon photo-irradiation, the active mechlorethamine is released and induces efficient DNA cross-links, accompanied by a strong fluorescence enhancement (152 fold). Furthermore, DNA cross-linking activity from the release can be transformed into anticancer activity observed in in vitro studies of tumor cells. Importantly, the drug release progress and the movement can be conveniently monitored by fluorescence spectroscopy. The mechanistic study proves that the DNA cross-linking activity is mainly due to the release of DNA alkylating mechlorethamine. Altogether, the studies show the power of the theranostic strategy for efficient therapy in cancer treatment.


Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Cumarínicos/administração & dosagem , Corantes Fluorescentes/administração & dosagem , Mecloretamina/administração & dosagem , Pró-Fármacos/administração & dosagem , Nanomedicina Teranóstica/métodos , Antineoplásicos Alquilantes/química , Antineoplásicos Alquilantes/farmacologia , Linhagem Celular , Cumarínicos/química , Cumarínicos/farmacologia , DNA/química , Preparações de Ação Retardada/química , Corantes Fluorescentes/química , Corantes Fluorescentes/farmacologia , Células HeLa , Humanos , Mecloretamina/química , Mecloretamina/farmacologia , Neoplasias/tratamento farmacológico , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Raios Ultravioleta
12.
J Am Chem Soc ; 136(40): 13963-6, 2014 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-25255467

RESUMO

Herein we describe a novel, hollow-structured zeolitic imidazolate framework (ZIF-8-H) nanosphere as a highly efficient catalyst for [3+3] cycloaddition reactions. The programmed installation of acidic Zn(2+) species and basic imidazolate moieties creates a synergistic catalytic system. Appropriate positioning of these functionalities in the catalytic system makes it possible to bring two substrates into close proximity and activate them cooperatively. Moreover, the flexible shell and the surface mesopores of ZIF-8-H provide the capacity for favorable binding of various sized substrates, stabilizing intermediates via their multiple force networks and the increased accessibility of the active sites. These features render ZIF-8-H a more highly active promoter than its homogeneous precursors, bulk ZIF-8 and ZIF-8-N nanoparticles. Finally, the robust catalyst can be easily recovered and reused 10 times without loss of catalytic activity.


Assuntos
Imidazóis/química , Nanosferas/química , Zeolitas/química , Catálise , Reação de Cicloadição , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química
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