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1.
Int J Mol Sci ; 24(5)2023 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-36902397

RESUMO

Inhibition of thioredoxin reductase (TrxR) is a crucial strategy for the discovery of antineoplastic drugs. 6-Shogaol (6-S), a primary bioactive compound in ginger, has high anticancer activity. However, its potential mechanism of action has not been thoroughly investigated. In this study, we demonstrated for the first time that 6-S, a novel TrxR inhibitor, promoted oxidative-stress-mediated apoptosis in HeLa cells. The other two constituents of ginger, 6-gingerol (6-G) and 6-dehydrogingerduone (6-DG), have a similar structure to 6-S but fail to kill HeLa cells at low concentrations. 6-Shogaol specifically inhibits purified TrxR1 activity by targeting selenocysteine residues. It also induced apoptosis and was more cytotoxic to HeLa cells than normal cells. The molecular mechanism of 6-S-mediated apoptosis involves TrxR inhibition, followed by an outburst of reactive oxygen species (ROS) production. Furthermore, TrxR knockdown enhanced the cytotoxic sensitivity of 6-S cells, highlighting the physiological significance of targeting TrxR by 6-S. Our findings show that targeting TrxR by 6-S reveals a new mechanism underlying the biological activity of 6-S and provides meaningful insights into its action in cancer therapeutics.


Assuntos
Antineoplásicos , Tiorredoxina Dissulfeto Redutase , Humanos , Células HeLa , Tiorredoxina Dissulfeto Redutase/metabolismo , Estresse Oxidativo , Inibidores Enzimáticos/farmacologia , Espécies Reativas de Oxigênio/farmacologia , Antineoplásicos/farmacologia , Apoptose
2.
J Exp Med ; 220(3)2023 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-36547668

RESUMO

Androgen deprivation therapy (ADT) is a systemic therapy for advanced prostate cancer (PCa); although most patients initially respond to ADT, almost all cancers eventually develop castration-resistant PCa (CRPC). Currently, most research focuses on castration-resistant tumors, and the role of tumors in remission is almost completely ignored. Here, we report that odorant-binding protein (OBP2A) released from tumors in remission during ADT catches survival factors, such as CXCL15/IL8, to promote PCa cell androgen-independent growth and enhance the infiltration of myeloid-derived suppressor cells (MDSCs) into tumor microenvironment, leading to the emergence of castration resistance. OBP2A knockdown significantly inhibits CRPC and metastatic CRPC development and improves therapeutic efficacy of CTLA-4/PD-1 antibodies. Treatment with OBP2A-binding ligand α-pinene interrupts the function of OBP2A and suppresses CRPC development. Furthermore, α-pinene-conjugated doxorubicin/docetaxel can be specifically delivered to tumors, resulting in improved anticancer efficacy. Thus, our studies establish a novel concept for the emergence of PCa castration resistance and provide new therapeutic strategies for advanced PCa.


Assuntos
Antagonistas de Androgênios , Androgênios , Monoterpenos Bicíclicos , Resistencia a Medicamentos Antineoplásicos , Lipocalinas , Neoplasias de Próstata Resistentes à Castração , Humanos , Masculino , Antagonistas de Androgênios/uso terapêutico , Androgênios/deficiência , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/metabolismo , Receptores Androgênicos , Microambiente Tumoral , Monoterpenos Bicíclicos/uso terapêutico , Lipocalinas/genética , Lipocalinas/metabolismo , Linhagem Celular Tumoral , Animais , Camundongos , Anticorpos/uso terapêutico , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Inibidores de Checkpoint Imunológico/uso terapêutico
3.
Arch Biochem Biophys ; 727: 109303, 2022 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-35660410

RESUMO

Natural products derived from the daily diet are garnering increasing attention for neurodegenerative disease (ND) treatment. Hispolon (His), a small molecule from Phellinus linteus, has been reported to have various pharmacological activities. Here, we evaluated its protective effect on a neuron-like rat pheochromocytoma cell line (PC12). Results showed that His could restore cell death induced by oxidative damage. Nuclear factor-erythroid 2 (NF-E2)-related factor 2 (Nrf2) plays a significant role in maintaining cellular redox homeostasis. After treatment with His, some Nrf2-governed antioxidant genes were upregulated in a dose-dependent manner. However, the protective effect of His on PC12 cells was easily terminated by Nrf2 knockdown, demonstrating that Nrf2 is a critical component in this cytoprotective process. Taken together, our study showed that His was not only an effective activator of Nrf2 but also a promising candidate for ND treatment.


Assuntos
Catecóis , Fator 2 Relacionado a NF-E2 , Doenças Neurodegenerativas , Animais , Ratos , Catecóis/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Células PC12 , Transdução de Sinais
4.
Pharmaceutics ; 14(3)2022 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-35335873

RESUMO

Androgen deprivation therapy (ADT) is a systemic therapy for advanced prostate cancer (PCa). Although most patients initially respond to ADT, almost all cancers eventually develop castration resistance. Castration-resistant PCa (CRPC) is associated with a very poor prognosis, and the treatment of which is a serious clinical challenge. Accumulating evidence suggests that abnormal expression and activation of various kinases are associated with the emergence and maintenance of CRPC. Many efforts have been made to develop small molecule inhibitors to target the key kinases in CRPC. These inhibitors are designed to suppress the kinase activity or interrupt kinase-mediated signal pathways that are associated with PCa androgen-independent (AI) growth and CRPC development. In this review, we briefly summarize the roles of the kinases that are abnormally expressed and/or activated in CRPC and the recent advances in the development of small molecule inhibitors that target kinases for the treatment of CRPC.

5.
mBio ; 12(3)2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33975938

RESUMO

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein mediates viral entry into cells expressing angiotensin-converting enzyme 2 (ACE2). The S protein engages ACE2 through its receptor-binding domain (RBD), an independently folded 197-amino-acid fragment of the 1,273-amino-acid S-protein protomer. The RBD is the primary SARS-CoV-2 neutralizing epitope and a critical target of any SARS-CoV-2 vaccine. Here, we show that this RBD conjugated to each of two carrier proteins elicited more potent neutralizing responses in immunized rodents than did a similarly conjugated proline-stabilized S-protein ectodomain. Nonetheless, the native RBD is expressed inefficiently, limiting its usefulness as a vaccine antigen. However, we show that an RBD engineered with four novel glycosylation sites (gRBD) is expressed markedly more efficiently and generates a more potent neutralizing responses as a DNA vaccine antigen than the wild-type RBD or the full-length S protein, especially when fused to multivalent carriers, such as a Helicobacter pylori ferritin 24-mer. Further, gRBD is more immunogenic than the wild-type RBD when administered as a subunit protein vaccine. Our data suggest that multivalent gRBD antigens can reduce costs and doses, and improve the immunogenicity, of all major classes of SARS-CoV-2 vaccines.IMPORTANCE All available vaccines for coronavirus disease 2019 (COVID-19) express or deliver the full-length SARS-CoV-2 spike (S) protein. We show that this antigen is not optimal, consistent with observations that the vast majority of the neutralizing response to the virus is focused on the S-protein receptor-binding domain (RBD). However, this RBD is not expressed well as an independent domain, especially when expressed as a fusion protein with a multivalent scaffold. We therefore engineered a more highly expressed form of the SARS-CoV-2 RBD by introducing four glycosylation sites into a face of the RBD normally occluded in the full S protein. We show that this engineered protein, gRBD, is more immunogenic than the wild-type RBD or the full-length S protein in both genetic and protein-delivered vaccines.


Assuntos
Enzima de Conversão de Angiotensina 2/genética , Vacinas contra COVID-19/imunologia , Imunogenicidade da Vacina , Receptores de Coronavírus/genética , Enzima de Conversão de Angiotensina 2/imunologia , Animais , Sítios de Ligação , Vacinas contra COVID-19/química , Feminino , Engenharia Genética , Glicosilação , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Domínios Proteicos , Ratos , Ratos Sprague-Dawley , Receptores de Coronavírus/imunologia , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Vacinas Conjugadas/genética , Vacinas Conjugadas/imunologia , Vacinas Sintéticas/química , Vacinas Sintéticas/imunologia
6.
PLoS Pathog ; 17(4): e1009501, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33836016

RESUMO

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein mediates infection of cells expressing angiotensin-converting enzyme 2 (ACE2). ACE2 is also the viral receptor of SARS-CoV (SARS-CoV-1), a related coronavirus that emerged in 2002-2003. Horseshoe bats (genus Rhinolophus) are presumed to be the original reservoir of both viruses, and a SARS-like coronavirus, RaTG13, closely related to SARS-CoV-2, has been identified in one horseshoe-bat species. Here we characterize the ability of the S-protein receptor-binding domains (RBDs) of SARS-CoV-1, SARS-CoV-2, pangolin coronavirus (PgCoV), RaTG13, and LyRa11, a bat virus similar to SARS-CoV-1, to bind a range of ACE2 orthologs. We observed that the PgCoV RBD bound human ACE2 at least as efficiently as the SARS-CoV-2 RBD, and that both RBDs bound pangolin ACE2 efficiently. We also observed a high level of variability in binding to closely related horseshoe-bat ACE2 orthologs consistent with the heterogeneity of their RBD-binding regions. However five consensus horseshoe-bat ACE2 residues enhanced ACE2 binding to the SARS-CoV-2 RBD and neutralization of SARS-CoV-2 pseudoviruses by an enzymatically inactive immunoadhesin form of human ACE2 (hACE2-NN-Fc). Two of these mutations impaired neutralization of SARS-CoV-1 pseudoviruses. An hACE2-NN-Fc variant bearing all five mutations neutralized both SARS-CoV-2 pseudovirus and infectious virus more efficiently than wild-type hACE2-NN-Fc. These data suggest that SARS-CoV-1 and -2 originate from distinct bat species, and identify a more potently neutralizing form of soluble ACE2.


Assuntos
Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/imunologia , COVID-19/imunologia , COVID-19/virologia , Quirópteros/metabolismo , SARS-CoV-2/genética , Animais , COVID-19/genética , Quirópteros/genética , Especificidade de Hospedeiro/genética , Especificidade de Hospedeiro/imunologia , Humanos , Modelos Moleculares , Mutação , Ligação Proteica/genética , Ligação Proteica/fisiologia , Receptores Virais/metabolismo , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/metabolismo
7.
Arch Biochem Biophys ; 706: 108857, 2021 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-33781769

RESUMO

Accumulating evidence has demonstrated that cellular antioxidant systems play essential roles in retarding oxidative stress-related diseases, such as Parkinson's disease. Because nuclear factor erythroid 2-related factor 2 (Nrf2) is a chief regulator of cellular antioxidant systems, small molecules with Nrf2-activating ability may be promising neuroprotective agents. Avenanthramide-2c (Aven-2c), avenanthramide-2f (Aven-2f) and avenanthramide-2p (Aven-2p) are the most abundant avenanthramides in oats, and they have been documented to possess multiple pharmacological benefits. In this work, we synthesized these three compounds and evaluated their cytoprotective effect against oxidative stress-induced PC12 cell injuries. Aven-2c displayed the best protective potency among them. Aven-2c conferred protection on PC12 cells by scavenging free radicals and activating the Nrf2-ARE signaling pathway. Pretreatment of PC12 cells with Aven-2c efficiently enhanced Nrf2 nuclear accumulation and evoked the expression of a set of cytoprotective molecules. The mechanistic study also supports that Nrf2 activation is the molecular basis for the cellular action of Aven-2c. Collectively, this study demonstrates that Aven-2c is a potent Nrf2 agonist, shedding light on the potential usage of Aven-2c in the treatment of neuroprotective diseases.


Assuntos
Elementos de Resposta Antioxidante , Antioxidantes/farmacologia , Fator 2 Relacionado a NF-E2/genética , Fármacos Neuroprotetores/farmacologia , Transdução de Sinais/genética , ortoaminobenzoatos/farmacologia , Animais , Avena/química , Sobrevivência Celular/efeitos dos fármacos , Regulação da Expressão Gênica , Glutamato-Cisteína Ligase/genética , Glutamato-Cisteína Ligase/metabolismo , Heme Oxigenase (Desciclizante)/genética , Heme Oxigenase (Desciclizante)/metabolismo , Peróxido de Hidrogênio/antagonistas & inibidores , Peróxido de Hidrogênio/farmacologia , NAD(P)H Desidrogenase (Quinona)/genética , NAD(P)H Desidrogenase (Quinona)/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Oxidopamina/antagonistas & inibidores , Oxidopamina/farmacologia , Células PC12 , Extratos Vegetais/química , Ratos , Tiorredoxina Redutase 1/genética , Tiorredoxina Redutase 1/metabolismo , Tiorredoxinas/genética , Tiorredoxinas/metabolismo
8.
bioRxiv ; 2020 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-33236008

RESUMO

The SARS-coronavirus 2 (SARS-CoV-2) spike (S) protein mediates viral entry into cells expressing the angiotensin-converting enzyme 2 (ACE2). The S protein engages ACE2 through its receptor-binding domain (RBD), an independently folded 197-amino acid fragment of the 1273-amino acid S-protein protomer. The RBD is the primary SARS-CoV-2 neutralizing epitope and a critical target of any SARS-CoV-2 vaccine. Here we show that this RBD conjugated to each of two carrier proteins elicited more potent neutralizing responses in immunized rodents than did a similarly conjugated proline-stabilized S-protein ectodomain. Nonetheless, the native RBD expresses inefficiently, limiting its usefulness as a vaccine antigen. However, we show that an RBD engineered with four novel glycosylation sites (gRBD) expresses markedly more efficiently, and generates a more potent neutralizing responses as a DNA vaccine antigen, than the wild-type RBD or the full-length S protein, especially when fused to multivalent carriers such as an H. pylori ferritin 24-mer. Further, gRBD is more immunogenic than the wild-type RBD when administered as a subunit protein vaccine. Our data suggest that multivalent gRBD antigens can reduce costs and doses, and improve the immunogenicity, of all major classes of SARS-CoV-2 vaccines.

9.
bioRxiv ; 2020 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-32637954

RESUMO

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein mediates infection of cells expressing angiotensin-converting enzyme 2 (ACE2). ACE2 is also the viral receptor of SARS-CoV (SARS-CoV-1), a related coronavirus that emerged in 2002-2003. Horseshoe bats (genus Rhinolophus ) are presumed to be the original reservoir of both viruses, and a SARS-like coronavirus, RaTG13, closely related SARS-CoV-2, has been isolated from one horseshoe-bat species. Here we characterize the ability of S-protein receptor-binding domains (RBDs) of SARS-CoV-1, SARS-CoV-2, and RaTG13 to bind a range of ACE2 orthologs. We observed that the SARS-CoV-2 RBD bound human, pangolin, and horseshoe bat ( R. macrotis) ACE2 more efficiently than the SARS-CoV-1 or RaTG13 RBD. Only the RaTG13 RBD bound rodent ACE2 orthologs efficiently. Five mutations drawn from ACE2 orthologs of nine Rhinolophus species enhanced human ACE2 binding to the SARS-CoV-2 RBD and neutralization of SARS-CoV-2 by an immunoadhesin form of human ACE2 (ACE2-Fc). Two of these mutations impaired neutralization of SARS-CoV-1. An ACE2-Fc variant bearing all five mutations neutralized SARS-CoV-2 five-fold more efficiently than human ACE2-Fc. These data narrow the potential SARS-CoV-2 reservoir, suggest that SARS-CoV-1 and -2 originate from distinct bat species, and identify a more potently neutralizing form of ACE2-Fc.

10.
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
11.
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.


Assuntos
Fator 2 Relacionado a NF-E2/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Fármacos Neuroprotetores/farmacologia , Células PC12/efeitos dos fármacos , Sesquiterpenos/farmacologia , Animais , Antioxidantes/metabolismo , Asteraceae/química , Citoproteção/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Neuroproteção , Estresse Oxidativo/efeitos dos fármacos , Ratos , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
12.
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.


Assuntos
Elementos de Resposta Antioxidante/efeitos dos fármacos , Antioxidantes/farmacologia , Ácido Clorogênico/farmacologia , Fator 2 Relacionado a NF-E2/genética , Fármacos Neuroprotetores/farmacologia , Espécies Reativas de Oxigênio/antagonistas & inibidores , Animais , Benzotiazóis/antagonistas & inibidores , Compostos de Bifenilo/antagonistas & inibidores , Diferenciação Celular/efeitos dos fármacos , Regulação da Expressão Gênica , Glutationa/agonistas , Glutationa/metabolismo , Heme Oxigenase (Desciclizante)/genética , Heme Oxigenase (Desciclizante)/metabolismo , Peróxido de Hidrogênio/antagonistas & inibidores , Peróxido de Hidrogênio/farmacologia , NAD(P)H Desidrogenase (Quinona)/genética , NAD(P)H Desidrogenase (Quinona)/metabolismo , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Fator 2 Relacionado a NF-E2/metabolismo , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Células PC12 , Picratos/antagonistas & inibidores , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Ácidos Sulfônicos/antagonistas & inibidores , Tiorredoxina Redutase 1/genética , Tiorredoxina Redutase 1/metabolismo , Tiorredoxinas/genética , Tiorredoxinas/metabolismo
13.
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).

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.


Assuntos
Fator 2 Relacionado a NF-E2/metabolismo , Xantonas/farmacologia , Animais , Western Blotting , Caspase 3/metabolismo , Radicais Livres/metabolismo , L-Lactato Desidrogenase/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Células PC12 , Ratos , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais/efeitos dos fármacos
15.
ACS Chem Neurosci ; 9(12): 3108-3116, 2018 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-29989791

RESUMO

Honokiol (Hon), a polyphenol and main active ingredient from the bark of Magnolia officinalis, has been documented as having multiple pharmacological functions, including neuroprotection. However, the mechanisms underlying its neuroprotective effects are not well-defined. In this study, we reported that Hon attenuates the H2O2- or 6-hydroxydopamine (6-OHDA)-induced apoptosis of PC12 cells by increasing the glutathione level and upregulating a multitude of cytoprotective proteins, including heme oxygenase 1, NAD(P)H:quinone oxidoreductase 1, thioredoxin 1, and thioredoxin reductase 1. Further studies reveal that Hon promotes transcription factor Nrf2 nuclear translocation and activation. Moreover, the cytoprotection of Hon was antagonized by silence of Nrf2 expression, highlighting the fact that Nrf2 is critically engaged in the cellular functions of Hon. Taken together, our study identified that Hon is an effective agonist of Nrf2 in the neuronal system and displays potent neuroprotection against oxidative stress-mediated PC12 cell damage. These findings indicate that Hon is promising for further development as a therapeutic drug against oxidative stress-related neurodegenerative disorders.


Assuntos
Compostos de Bifenilo/farmacologia , Lignanas/farmacologia , Fator 2 Relacionado a NF-E2/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Adrenérgicos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Glutationa/efeitos dos fármacos , Glutationa/metabolismo , Heme Oxigenase (Desciclizante)/efeitos dos fármacos , Heme Oxigenase (Desciclizante)/metabolismo , Peróxido de Hidrogênio/farmacologia , NAD(P)H Desidrogenase (Quinona)/efeitos dos fármacos , NAD(P)H Desidrogenase (Quinona)/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Neurônios/metabolismo , Oxidantes/farmacologia , Oxidopamina/farmacologia , Células PC12 , Ratos , Tiorredoxina Redutase 1/efeitos dos fármacos , Tiorredoxina Redutase 1/metabolismo , Tiorredoxinas/efeitos dos fármacos , Tiorredoxinas/metabolismo
16.
Chem Sci ; 8(4): 2966-2972, 2017 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-28451363

RESUMO

Oxidation of methionine residues to methionine sulfoxide (MetSO) may cause changes in protein structure and function, and may eventually lead to cell damage. Methionine sulfoxide reductases (Msrs) are the only known enzymes that catalyze the reduction of MetSO back to methionine by taking reducing equivalents from the thioredoxin system, and thus protect cells from oxidative damage. Nonetheless, a lack of convenient assays for the enzymes hampers the exploration of their functions. We report the discovery of Msr-blue, the first turn-on fluorescent probe for Msr with a >100-fold fluorescence increment from screening a rationally-designed small library. Intensive studies demonstrated the specific reduction of Msr-blue by the enzymes. Msr-blue is ready to determine Msr activity in biological samples and live cells. Importantly, we disclosed a decline of Msr activity in a Parkinson's model, thus providing a mechanistic linkage between the loss of function of Msrs and the development of neurodegeneration. The strategy for the discovery of Msr-blue would also provide guidance for developing novel probes with longer excitation/emission wavelengths and specific probes for Msr isoforms.

17.
Food Funct ; 8(3): 997-1007, 2017 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-28271112

RESUMO

Oxidative stress represents a disorder of the redox equilibrium between the production of free radicals and the capability of cells to eliminate them. As subversion of this redox balance is thought to initiate various diseases, living cells maintain a redox equilibrium diligently. More and more pieces of evidence show that oxidative stress has already become a common risk factor in the pathogenesis of neurodegenerative disorders. So, considerable importance has been given to the prevention of oxidative stress as a potential therapeutic strategy. It is well known that the Nrf2-ARE pathway represents one of the most important cellular endogenous defense mechanisms against oxidative stress. Activation of Nrf2 signaling induces the transcriptional regulation of multiple ARE-dependent antioxidant defense genes. Here, we showed that cardamonin (CD), a chalcone isolated from Alpinia katsumadai, attenuated cell death induced by hydrogen peroxide (H2O2) and 6-hydroxydopamine (6-OHDA) in PC12 cells. Pretreatment of PC12 cells with CD dose-dependently upregulated the expression of phase II antioxidant molecules governed by Nrf2. In contrast, CD failed to provide neuroprotection after silencing Nrf2 expression, indicating that this cytoprotection may be mediated by the activation of transcription factor Nrf2. Our results demonstrate that CD is a novel small molecule activator of Nrf2 in PC12 cells, and suggest that CD may be a potential candidate for the prevention of oxidative stress-mediated neurodegenerative disorders.


Assuntos
Alpinia/química , Antioxidantes/metabolismo , Chalconas/farmacologia , Fator 2 Relacionado a NF-E2/genética , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Animais , Desintoxicação Metabólica Fase II , NAD(P)H Desidrogenase (Quinona)/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Neurônios/citologia , Neurônios/enzimologia , Neurônios/metabolismo , Células PC12 , Ratos , Espécies Reativas de Oxigênio/metabolismo , Tiorredoxinas/metabolismo
18.
Arch Biochem Biophys ; 619: 16-26, 2017 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-28249720

RESUMO

Plumbagin (PLB), a natural naphthoquinone from the traditional folk medicines Plumbago zeylanica, Dionaea muscipula, or Nepenthes gracilis, has been documented possessing a wide variety of pharmacological activities. Although PLB demonstrates anticancer activity in multiple types of malignant cells, the cellular targets of PLB have not been well defined and remained only partially understood. We reported here that PLB selectively inhibits TrxR and elicits reactive oxygen species in human promyelocytic leukemia HL-60 cells, which leads to elevation of GSSG/GSH ratio and decrease of cellular thiol pool. As a consequence, PLB disturbs the cellular redox homeostasis, induces oxidative stress-mediated apoptosis and eventually selectively kills HL-60 cells. Inhibition of TrxR by PLB thus discloses an unprecedented mechanism underlying the anticancer efficacy of PLB, and sheds light in considering the usage of PLB as a promising cancer therapeutic agent.


Assuntos
Naftoquinonas/química , Tiorredoxina Dissulfeto Redutase/metabolismo , Antineoplásicos/química , Apoptose , Caspase 3/metabolismo , Sobrevivência Celular , Células HEK293 , Células HL-60 , Células HeLa , Células Hep G2 , Humanos , Oxirredução , Estresse Oxidativo , Ligação Proteica , Espécies Reativas de Oxigênio/metabolismo
19.
Expert Opin Ther Pat ; 27(5): 547-556, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-27977313

RESUMO

INTRODUCTION: Mammalian thioredoxin reductases (TrxRs) are selenocysteine-containing homodimeric flavin enzymes that catalyze the NADPH-dependent reduction of oxidized thioredoxins. Increasing evidence indicates that TrxRs are potential targets for anticancer drug development. This review summarizes patented inhibitors of mammalian TrxRs with an emphasis on those having potential applications in treatment of cancer. Areas covered: A background introduction of TrxR as well as the relevance of TrxR and cancer is provided in the first part of this review. Then, a brief discussion of TrxR assays is followed in the second part. The patented TrxRs' inhibitors that were categorized into four classes, i. e., metal complexes, Michael acceptors, sulfur/selenium-containing compounds and others, are summarized in the third part of the review. Expert opinion: There is currently no clinical anticancer drug that specifically targets TrxR. One major hurdle in finding a successful TrxR inhibitor as a therapeutic drug is the specific inhibition of TrxR by an inhibitor. As most inhibitors described in literature and patents target the selenol group in the C-terminus of TrxR enzymes, it is hard to avoid cross interactions of such inhibitors with thiols. Novel strategies are proposed to achieve discovery of highly selective inhibitors of TrxR enzymes.


Assuntos
Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores , Animais , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Humanos , Terapia de Alvo Molecular , Neoplasias/enzimologia , Patentes como Assunto , Tiorredoxina Dissulfeto Redutase/metabolismo
20.
Biochim Biophys Acta Mol Basis Dis ; 1863(1): 129-138, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27777067

RESUMO

Thioredoxin reductase (TrxR) and thioredoxin (Trx) are two major components of the thioredoxin system, which plays essential roles in regulating cellular redox signaling. Mammalian TrxRs are essential seleno-flavoenzymes with a conserved penultimate selenocysteine (Sec) residue at the C-terminus, and have attracted considerable interests as promising targets for anticancer drugs. Securinine (SCR), a major active alkaloid lactone from the Chinese herbal medicine Securinega suffruticosa, has been established clinical success in treatment of neurological disorders. Recently, increasing evidence demonstrates that SCR has potential cytotoxicity to various types of tumor cells, which enables this old central nervous system drug as a potential cancer therapeutic agent. However, the mechanism underlying the anticancer activity of SCR is not well defined. We reported here that SCR inhibits both the purified TrxR and the enzyme in intact cells. SCR elicits accumulation of reactive oxygen species (ROS), elevation of oxidized glutathione and Trx, disturbs redox homeostasis, and eventually leads to oxidative stress-mediated HeLa cell apoptosis. Importantly, pharmacological inhibition or knockdown of TrxR sensitizes the cells to SCR treatment, underpinning the physiological significance of targeting TrxR by SCR. Our discovery discloses a novel mechanism underlying the anticancer activity of SCR and provides basic data for further development of SCR as a cancer chemotherapeutic drug.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Azepinas/farmacologia , Inibidores Enzimáticos/farmacologia , Compostos Heterocíclicos de Anel em Ponte/farmacologia , Lactonas/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Piperidinas/farmacologia , Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores , Antineoplásicos Fitogênicos/química , Azepinas/química , Linhagem Celular Tumoral , Inibidores Enzimáticos/química , Euphorbiaceae/química , Compostos Heterocíclicos de Anel em Ponte/química , Humanos , Lactonas/química , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Oxirredução/efeitos dos fármacos , Piperidinas/química , Espécies Reativas de Oxigênio/metabolismo , Tiorredoxina Dissulfeto Redutase/metabolismo
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