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1.
Chem Commun (Camb) ; 55(78): 11762-11765, 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31513186

RESUMO

A water-soluble turn-on fluorescent probe has been rationally designed and synthesized to distinguish Cys from Hcy and GSH in less than five seconds. It has high sensitivity and strong anti-interference ability to other amino acids and ions. Its ultra-rapid detection of Cys in aqueous systems could be attributed to dual response sites imparted by the probe.

2.
Eur J Pharm Sci ; 138: 104994, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31302210

RESUMO

Dihydromyricetin (DMY), a flavanonol compound found as the most abundant and bioactive constituent in Ampelopsis grossedentata (Hand-Mazz) W.T. Wang, possesses numerous pharmacological activities, such as antioxidant, anti-inflammation, anticancer, anti-microbial, hypoglycemic and hypolipidemic effects, and so on. Recently, DMY shows a promising potential to develop as an agent for the prevention and treatment of Type 2 diabetes mellitus (T2DM). However, the low oral bioavailability of DMY was one of the special concerns to be resolved for its clinical applications. In this study, DMY phospholipid complex (DMY-HSPC COM) was prepared by the solvent evaporation technique and optimized with DMY combination ratio. Scanning electron microscopy (SEM), X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and Fourier transform infrared spectrophotometry (FT-IR) were carried to characterize the formation of DMY-HSPC COM. The particle size, zeta potential, drug loading and solubility of DMY-HSPC COM were further investigated. The phospholipid complex technology could significantly improve the solubility of DMY. Pharmacokinetic study results of DMY-HSPC COM in healthy SD rats and T2DM rats demonstrated that the oral bioavailability was significantly increased when compared with pure DMY as well, which could be attributed to the improvement of the aqueous solubility of the complex, absorption promotion and a probable decrease in intestinal and hepatic metabolism. In addition, when compared with healthy SD rats, pharmacokinetic parameters of pure DMY and DMY-HSPC COM showed significant difference in T2DM rats. Thus, phospholipid complex technology holds a promising potential for increasing the oral bioavailability of DMY.

3.
J Agric Food Chem ; 67(29): 8227-8234, 2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31299148

RESUMO

The mechanisms underlying neurodegenerative diseases are not fully understood yet. However, an increasing amount of evidence has suggested that these disorders are related to oxidative stress. We reported herein that lipoamide (LM), a neutral amide derivative of lipoic acid (LA), could resist oxidative stress-mediated neuronal cell damage. LM is more potent than LA in alleviating hydrogen peroxide- or 6-hydroxydopamine-induced PC12 cell injury. Our results reveal that LM promotes the nuclear accumulation of NFE2-related factor 2 (Nrf2), following with the activation of expression of Nrf2-governed antioxidant and detoxifying enzymes. Notably, silencing Nrf2 gene annuls the protection of LM, which demonstrates that Nrf2 is engaged in this cytoprotection. Our findings suggest that LM might be used as a potential therapeutic candidate for oxidative stress-related neurological disorders.


Assuntos
Fator 2 Relacionado a NF-E2/metabolismo , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Ácido Tióctico/análogos & derivados , Animais , Elementos de Resposta Antioxidante/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/genética , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Células PC12 , Ratos , Transdução de Sinais/efeitos dos fármacos , Ácido Tióctico/farmacologia
4.
Nat Commun ; 10(1): 2745, 2019 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-31227705

RESUMO

Small molecule probes are indispensable tools to explore diverse cellular events. However, finding a specific probe of a target remains a high challenge. Here we report the discovery of Fast-TRFS, a specific and superfast fluorogenic probe of mammalian thioredoxin reductase, a ubiquitous enzyme involved in regulation of diverse cellular redox signaling pathways. By systematically examining the processes of fluorophore release and reduction of cyclic disulfides/diselenides by the enzyme, structural factors that determine the response rate and specificity of the probe are disclosed. Mechanistic studies reveal that the fluorescence signal is switched on by a simple reduction of the disulfide bond within the probe, which is in stark contrast to the sensing mechanism of published probes. The favorable properties of Fast-TRFS enable development of a high-throughput screening assay to discover inhibitors of thioredoxin reductase by using crude tissue extracts as a source of the enzyme.


Assuntos
Descoberta de Drogas/métodos , Corantes Fluorescentes/química , Imagem Molecular/métodos , Sondas Moleculares/química , Tiorredoxina Redutase 1/metabolismo , Animais , Produtos Biológicos/farmacologia , Misturas Complexas , Dissulfetos/química , Corantes Fluorescentes/metabolismo , Células HeLa , Ensaios de Triagem em Larga Escala/métodos , Humanos , Microscopia Intravital/métodos , Microscopia de Fluorescência/métodos , Sondas Moleculares/metabolismo , Oxirredução , RNA Interferente Pequeno/metabolismo , Proteínas Recombinantes/metabolismo , Especificidade por Substrato , Tiorredoxina Redutase 1/antagonistas & inibidores , Tiorredoxina Redutase 1/genética
5.
Chemistry ; 25(48): 11228-11232, 2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31241789

RESUMO

Herein, a strategy for the selective derivatization of 3-nitrotyrosine-containing proteins using the classic azo coupling reaction as the key step is described. This novel approach featured multiple advantages and was successfully applied to detect picomole levels of protein tyrosine nitration in biological samples.

6.
Food Funct ; 10(7): 4143-4152, 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31241085

RESUMO

Costunolide (COS) is a natural sesquiterpene lactone originally isolated from Inula helenium (Compositae). Although COS is known for its multiple pharmacological activities, neuroprotection of COS has not been fully elucidated. Increasing evidence demonstrates that oxidative stress is strongly associated with the progression and pathogenesis of neurodegenerative diseases. As NF-E2 related factor 2 (Nrf2) is an important transcription factor for the regulation of cellular redox homeostasis, small molecules with the ability to activate the Nrf2 pathway are promising neuroprotective agents. Herein, we investigated the potential mechanism of Nrf2-mediated neuroprotection against oxidative damage by COS in the neuron-like rat pheochromocytoma cell line (PC12 cells). Our results demonstrated that COS could activate Nrf2 to counteract the oxidative injuries of PC12 cells. COS facilitated the Nrf2 nuclear translocation, and knockdown of Nrf2 almost abrogated the cytoprotection of COS, demonstrating that activation of Nrf2 acted as an essential step in this cytoprotective process. After treatment with COS, a range of antioxidant genes governed by Nrf2 were upregulated, and subsequently the expressions and activities of these gene products were also induced. Furthermore, COS attenuates the cellular reactive oxygen species level and restores cellular thiol homeostasis, supporting that COS was involved in maintaining the cellular redox balance. Taken together, our study indicates that COS provides neuroprotection via activating the Nrf2 signaling pathway in PC12 cells.

7.
Anal Chem ; 91(13): 8524-8531, 2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31177768

RESUMO

Finding specific small molecule probes of a biological target is extremely desired but remains a big challenge. We reported herein a highly selective fluorescent probe derivatized from the nile blue fluorophore, NBL-SS, for thioredoxin (Trx), a ubiquitous redox-regulating protein essentially involved in cell growth, differentiation, and death. NBL-SS displayed multiple favorable properties, such as red emission, fast response, and high fluorescence signal, which enabled the probe to readily image Trx functions in live cells and in vivo. The fluorophore-dependent selectivity indicates that manipulation of weak interactions between probes and their target biomacromolecules could further improve the probes' specificity. In addition, our discovery, i.e., the preference reduction of simple disulfide bonds by Trx over glutathione, also advances the development of disulfide cleavage-based probes, prodrugs, and theranostic agents.

8.
ACS Chem Neurosci ; 10(6): 2956-2966, 2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31116948

RESUMO

The nuclear factor erythroid 2-related factor 2 (Nrf2), a master transcription factor controlling a series of cytoprotective genes, is closely associated with scavenging the reactive oxygen species and maintaining the intracellular redox balance. Accumulating evidence has indicated that activation of Nrf2 is efficient to block or retard oxidative stress mediated neurodegenerative disorders. Small molecules that contribute directly or indirectly to the Nrf2 activation thus are promising therapeutic agents. Herein, we screened xanthohumol and its analogues, and two analogues (11 and 12) were disclosed to possess low cytotoxicity and rescue PC12 cells from the hydrogen peroxide or 6-hydroxydopamine induced injuries. Molecular mechanism studies demonstrated that compounds 11 and 12 are potent Nrf2 activators by promoting the nuclear accumulation of Nrf2 and enhancing the cellular antioxidant defense system. More importantly, genetically silencing the Nrf2 expression shuts down the observed cytoprotection conferred by both compounds, supporting the critical involvement of Nrf2 for the cellular actions of compounds 11 and 12.

9.
Biofactors ; 45(4): 616-626, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30951611

RESUMO

Chlorogenic acid (CA), the ester of caffeic acid and quinic acid, is one of the most abundant polyphenols in coffee, and has multiple pharmacological functions. The present study is designed to explore the protection provided by CA against hydrogen peroxide (H2 O2 )-induced oxidative damages in the rat pheochromocytoma cells, and the underlying mechanisms engaged in this process. CA displays robust free radical-scavenging activity in vitro. More importantly, CA strikingly rescues the cells from the H2 O2 -mediated oxidative insults. Mechanistic studies revealed that CA upregulates a panel of phase II cytoprotective species, such as heme oxygenase-1, NAD(P)H: quinone oxidoreductase 1, glutathione, thioredoxin reductase 1, and thioredoxin 1. This neuroprotection is dependent on the activation of the transcription factor Nuclear factor erythroid 2-related factor 2 (Nrf2), as knockdown of Nrf2 abolishes such effect. Our results demonstrate that CA provides dual neuroprotection via directly neutralizing free radicals and indirectly inducing expression of Nrf2-driven cytoprotective enzymes, and suggest a potential therapeutic usage of CA as a neuroprotective agent. Coffee is one of the most popular drinks in the world, and our discovery may also contribute to understanding the beneficial effects of regular coffee consumption. © 2019 BioFactors, 45 (4):616-626, 2019.

10.
Free Radic Biol Med ; 135: 216-226, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30880248

RESUMO

Cancer is considered as one of the highly mortal diseases globally. This is largely due to the lack of efficacious medicines for tumors, and thus development of potent anticancer agents is urgently needed. The thioredoxin (Trx) system is crucial to the survival ability of cells and its expression is up-regulated in many human tumors. Recently, increasing evidence has been established that mammalian thioredoxin reductase (TrxR), a selenocysteine-containing protein and the core component of the thioredoxin system, is a promising therapeutic target. The sesquiterpene lactone compound cynaropicrin (CYN), a major component of Cynara scolymus L., has shown multiple pharmacological functions, especially the anticancer effect, in many experimental models. Most of these functions are concomitant with the production of reactive oxygen species (ROS). Nevertheless, the target of this promising natural anticancer product in redox control has rarely been explored. In this study, we showed that CYN induces apoptosis of Hela cells. Mechanistic studies demonstrated that CYN impinges on the thioredoxin system via inhibition of TrxR, which leads to Trx oxidation and ROS accumulation in HeLa cells. Particularly, the cytotoxicity of CYN is enhanced through the genetic knockdown of TrxR, supporting the pharmacological effect of CYN is relevant to its inhibition of TrxR. Together, our studies reveal an unprecedented mechanism accounting for the anticancer effect of CYN and identify a promising therapeutic agent worthy of further development for cancer therapy.

11.
Toxicol Appl Pharmacol ; 370: 106-116, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30898620

RESUMO

The selenoprotein thioredoxin reductase (TXNRD) is a promising therapeutic target for cancer. To discover novel TXNRD inhibitors, a library of α, ß-unsaturated carbonyl compounds were applied in structure-based virtual screening for the selection of hit compounds. Fifteen top-ranked compounds were further validated experimentally, exhibiting potent inhibition of TXNRD and remarkable cytotoxicity to cancer cells. The further binding mode analysis indicated that multiple noncovalent interactions between the inhibitors and the active pocket of TXNRD facilitated the formation of covalent bonds between the Sec498 on TXNRD and the α, ß-unsaturated carbonyl groups on inhibitors. Results from both simulations and experiments demonstrated that Sec498 is the prime interaction site for the inhibition of TXNRD. Taking compound 7 as an example, the inhibition of TXNRD by compounds promoted oxidative stress-mediated apoptosis of cancer cells. Given these findings, novel TXNRD inhibitors may be discovered and introduced to the growing fields of small molecule drugs against TXNRD.

12.
Org Lett ; 21(5): 1551-1554, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30789736

RESUMO

A pair of enantiomeric polyketides, (+)- and (-)-alternamgin (1), featuring an unprecedented 6/6/6/6/5/6/6 seven ring backbone, were isolated from the endophytic fungi Alternaria sp. MG1. The relative configuration of 1 was determined using X-ray diffraction, and the absolute configurations of (±)-1 were confirmed by comparing the experimental and calculated ECD data. Plausible biosynthetic pathways for 1 were proposed. Compound (-)-1 exhibited moderate necrosis rates to Hela and HepG2 cells, but (+)-1 only showed similar necrosis rates to HepG2 cells.


Assuntos
Alternaria/química , Policetídeos/isolamento & purificação , Células Hep G2/efeitos dos fármacos , Humanos , Estrutura Molecular , Necrose , Policetídeos/química , Estereoisomerismo , Difração de Raios X
13.
J Pharmacol Exp Ther ; 369(2): 212-222, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30760494

RESUMO

Ibrutinib (IBT), the first-in-class inhibitor of Bruton's tyrosine kinase (BTK), has demonstrated clinical activity against various B-cell malignancies. Aside from its therapeutic mechanism through BTK inhibition, IBT has other target sites reported for cancer therapy, leading us to investigate whether IBT has unreported targets. Our study revealed that IBT can inhibit SMMC-7721 cells through irreversible inhibition of mammalian thioredoxin reductase enzymes. Further study demonstrated that IBT can cause cellular reactive oxygen species elevation and induce cancer cell apoptosis. The discovery of a new target of IBT sheds light on better understanding its anticancer mechanisms and provides a theoretical foundation for its further use in clinical therapy.

14.
Biofactors ; 45(3): 381-392, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30633833

RESUMO

Accumulating evidence demonstrates that oxidative stress is involved in the pathogenesis and progression of neurodegeneration. As NF-E2-related factor 2 (Nrf2) plays a crucial role in maintaining cellular redox homeostasis, small molecules with the ability in activation of Nrf2 pathway are promising neuroprotective agents. Mangiferin (Mg) is a xanthone glucoside extracted from mangoes and papayas, and has been reported to possess multiple pharmacological activities. In this study, we investigated neuroprotective effects of Mg in the neuron-like rat pheochromocytoma cell line (PC12 cells). Mg scavenges different kinds of free radicals in vitro and attenuates hydrogen peroxide- or 6-hydroxydopamine-induced cell death. After treatment with Mg, a range of antioxidant genes governed by Nrf2 were upregulated, and the expressions and activities of these gene products were also elevated. Moreover, knockdown of Nrf2 antagonized the protective effect of Mg, indicating that Nrf2 is an essential factor in this cytoprotective process. In summary, our study demonstrates that Mg is a potent antioxidant that can provide neuroprotection against oxidative stress-mediated damage of PC12 cells. © 2019 BioFactors, 45(3):381-392, 2019.

15.
Chem Commun (Camb) ; 55(10): 1502-1505, 2019 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-30648177

RESUMO

A ratiometric fluorescent probe of methionine sulfoxide reductase, Msr-Ratio, was disclosed for monitoring the enzyme activity in vitro and in live cells. The probe displayed favorable properties such as a nearly 400-fold fluorescence change, fast response rate (<30 min), large Stokes shift (120 nm), and green emission (550 nm).

16.
J Agric Food Chem ; 67(7): 1839-1846, 2019 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-30688448

RESUMO

Fusarium, a large genus of filamentous fungi, is widely distributed in soil and plants. Fusarium is a prolific source of novel chemical constituents with various bioactivities. In search for antibiotics from soil and endophytic fungi, the secondary metabolites of Fusarium avenaceum SF-1502 and Fusarium proliferatum AF-04 were investigated. An alkaloid (1), a depsipeptide (6), and five sesquiterpenoids (7-11) were isolated from the extracts of the soil fungus F. avenaceum SF-1502. Three alkaloids (2-4), a depsipeptide (5), three sesquiterpenoids (9, 11, and 12), a sesterterpene (13), and four 1,4-naphthoquinones (14-17) were also separated from the extract of the green Chinese onion derived fungus F. proliferatum AF-04. Fusaravenin (1) represents the first example of a natural naphthoisoxazole-type zwitter-ionic alkaloid, a naphthoisoxazole formic acid connected with a morpholino carbon skeleton. Cyclonerotriol B (7) is a new cyclonerane sesquiterpene. Another new sesquiterpene, 3ß-hydroxy-ß-acorenol (12), possesses an acorane framework. The known compounds 9 and 11 were found from both fungi. The structures of the new compounds were determined via extensive HR-ESI-MS and comparison between experimental and calculated NMR results. The biological properties of 1-5 and 7-17 were evaluated against eight anthropogenic bacteria, while 1 and 7-11 were also screened for inhibitory effects against four plant pathogen bacteria. The known compounds 8, 9, and 14-17 showed potent antibacterial activities toward some of the tested anthropogenic bacteria.


Assuntos
Alcaloides/isolamento & purificação , Depsipeptídeos/isolamento & purificação , Fusarium/química , Naftoquinonas/isolamento & purificação , Sesquiterpenos/isolamento & purificação , Microbiologia do Solo , Alcaloides/química , Alcaloides/farmacologia , Antibacterianos , Depsipeptídeos/química , Depsipeptídeos/farmacologia , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Estrutura Molecular , Naftoquinonas/química , Naftoquinonas/farmacologia , Sesquiterpenos/química , Sesquiterpenos/farmacologia , Espectrometria de Massas por Ionização por Electrospray
17.
Med Res Rev ; 39(1): 5-39, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29727025

RESUMO

Mammalian thioredoxin reductase (TrxR) enzymes are homodimeric flavin proteins sharing a unique yet essential selenocysteine residue at their C-terminus. TrxRs, together with their endogenous substrate thioredoxins, play a crucial role in regulating diverse cellular redox events. A wealth of evidence from both clinic observations and bench studies supports that overactivation/dysfunction of TrxRs has a close link to the onset and development of various diseases, such as cancer and neurodegeneration. Thus, an increasing interest has been attracted to find small molecule modulators of TrxRs during the past years. Herein, we briefly discussed the relevance of targeting TrxRs inhibition for cancer treatment, and presented the small molecule inhibitors of mammalian TrxRs published in the nonpatent literatures from 2011 to 2016. The mechanisms of inhibition by different classes of molecules were summarized, and some inhibitors with promising anticancer activity were further discussed. We expect this work would be a comprehensive reference in the medicinal chemistry, and have a broad audience across multiple disciplines.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Mamíferos/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores , Animais , Antineoplásicos/química , Inibidores Enzimáticos/química , Humanos , Bibliotecas de Moléculas Pequenas/química , Tiorredoxina Dissulfeto Redutase/metabolismo
18.
ACS Appl Mater Interfaces ; 10(39): 33010-33021, 2018 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-30209950

RESUMO

Transportation of exogenous copper ions into cancer cells by copper carriers has gained increasing interest for cancer chemotherapy. We disclosed herein a redox-dependent copper carrier, 2,2'-dithiodipyridine (DPy), which binds copper ions and carries the cargo into cells. The cellular reducing environment cleaved the disulfide bond in DPy to facilitate unloading copper ions. The elevated copper level then elicits oxidative stress and subsequently promotes the reformation of DPy. Further mechanistic studies revealed that the DPy/copper combination predominantly targets the cellular redox-regulating systems, including the thioredoxin system and the glutathione system, to induce the oxidative stress-mediated death of tumor cells. The discovery of DPy as a cleavable and recyclable copper shuttle provides a proof of concept for designing novel biomaterials for copper transportation as potential anticancer agents.

19.
Chem Asian J ; 13(23): 3593-3600, 2018 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-30204305

RESUMO

The selenoprotein thioredoxin reductase (TrxR) enzymes are the only identified proteins that maintain thioredoxin (Trx) proteins in a reduced state under physiological conditions, and consequently play a pivotal role in the regulation of various cellular redox signaling pathways involved in cell differentiation, growth, and death. The elevated expression of TrxR enzymes has been observed in different types of cancer cells, and this overexpression is of pathological significance in maintaining tumor phenotypes, such as uncontrolled proliferation and resistance to apoptosis. Herein, we discuss recent advances in the study of TrxR, including classic assays of TrxR, the emerging chemical tools of TrxR, and small molecules that target TrxR as potential anticancer agents.

20.
J Cell Biochem ; 119(11): 8981-8995, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30076654

RESUMO

Osteolysis is a serious complication of several chronic inflammatory diseases and is closely associated with a local chronic inflammatory reaction with a variety of causes. However, similarities exist in the mechanisms of their pathological processes. Inflammatory factors and oxidative stress-induced nuclear factor κB (NF-κB) and mitogen-activated protein kinases (MAPKs) signaling pathways play a center role in bone erosion. Dihydromyricetin (DMY) is a natural compound with anti-inflammatory and antioxidative effect, which are commonly used in chronic pharyngitis and alcohol use disorders. In the current study, we identified that DMY attenuated lipopolysaccharide (LPS)-induced oxidative stress through inhibiting the production of reactive oxygen species (ROS) and nitric oxide (NO), downregulated COX-2 and iNOS, and promoted the activity of the antioxidative system by activating superoxide dismutase (SOD) and Nrf2/HO-1 pathway. To further investigate the underlying mechanism, we found that DMY inhibits osteoclast (OC) differentiation and bone resorption activity through blocking the RANKL-induced activation of the NF-κB and MAPKs signaling pathways and then downregulated c-Fos and NFATc1, which is essential for OC differentiation. Furthermore, DMY inhibited LPS-induced osteolysis in vivo. Collectively, these results indicate that DMY might be a promising prophylactic antiosteoclastic/resorptive agent in preventing or treating bone lysis diseases.

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