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1.
MedComm (2020) ; 2(3): 315-340, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34766149

RESUMO

Cancer is a leading cause of death worldwide. Surgery is the primary treatment approach for cancer, but the survival rate is very low due to the rapid progression of the disease and presence of local and distant metastasis at diagnosis. Adjuvant chemotherapy and radiotherapy are important components of the multidisciplinary approaches for cancer treatment. However, resistance to radiotherapy and chemotherapy may result in treatment failure or even cancer recurrence. Radioresistance in cancer is often caused by the repair response to radiation-induced DNA damage, cell cycle dysregulation, cancer stem cells (CSCs) resilience, and epithelial-mesenchymal transition (EMT). Understanding the molecular alterations that lead to radioresistance may provide new diagnostic markers and therapeutic targets to improve radiotherapy efficacy. Patients who develop resistance to chemotherapy drugs cannot benefit from the cytotoxicity induced by the prescribed drug and will likely have a poor outcome with these treatments. Chemotherapy often shows a low response rate due to various drug resistance mechanisms. This review focuses on the molecular mechanisms of radioresistance and chemoresistance in cancer and discusses recent developments in therapeutic strategies targeting chemoradiotherapy resistance to improve treatment outcomes.

2.
MedComm (2020) ; 2(3): 453-466, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34766155

RESUMO

Colorectal cancer (CRC) is one of the most common malignancies currently. Despite advances in drug development, the survival and response rates in CRC patients are still poor. In our previous study, a library comprised of 1056 bioactive compounds was used for screening of drugs that could suppress CRC. Lomerizine 2HCl, which is an approved prophylactic drug for migraines, was selected for our studies. The results of in vitro and in vivo assays suggested that lomerizine 2HCl suppresses cell growth and promotes apoptosis in CRC cells. Moreover, lomerizine 2HCl inhibits cell migration and invasion of CRC. RNA sequencing analysis and Western blotting confirmed that lomerizine 2HCl can inhibit cell growth, migration, and invasion through PI3K/AKT/mTOR signaling pathway and induces protective autophagy in CRC. Meanwhile, autophagy inhibition by 3-methyladenine (3-MA) increases lomerizine 2HCl-induced cell apoptosis. Taken together, these results imply that lomerizine 2HCl is a potential anticancer agent, and the combination of lomerizine 2HCl and autophagy inhibitors may serve as a novel strategy to increase the antitumor efficacy of agents in the treatment of CRC.

3.
Chem Sci ; 12(35): 11793-11798, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34659717

RESUMO

A new catalytic asymmetric formal cross dehydrogenative coupling process for the construction of all-aryl quaternary stereocenters is disclosed, which provides access to rarely explored chiral tetraarylmethanes with excellent enantioselectivity. The suitable oxidation conditions and the hydrogen-bond-based organocatalysis have enabled efficient intermolecular C-C bond formation in an overwhelmingly crowded environment under mild conditions. para-Quinone methides bearing an ortho-directing group serve as the key intermediate. The precise loading of DDQ is critical to the high enantioselectivity. The chiral products have also been demonstrated as promising antiviral agents.

6.
J Cell Mol Med ; 24(21): 12525-12536, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33047871

RESUMO

Sorafenib has been approved for the treatment of certain cancers in clinic. However, the effects of sorafenib on gastric adenocarcinoma (GAC) were still limited. This study aimed to evaluate both in vitro and in vivo efficacy of sorafenib in combination with pterostilbene (PTE) on the treatment of GAC. Here, the morphological changes and cell viability were recorded in both N87 and MKN45 cells. The cell cycle profile and apoptosis were assessed by flow cytometry. Subcutaneous tumour xenografts were constructed in nude mice, and IHC staining of the dissected tumour tissues was conducted. Our results showed that PTE enhanced sorafenib's inhibitory effects on cell viability. The obvious down-regulation of cyclin D1, Cdk-2, Cdk-4, Cdk-6 and p62 and the up-regulation of LC3II, caspase-9, caspase-3 and PARP cleavages were observed for the combination treatment with PTE and sorafenib than monotherapy. The combination treatment resulted in a higher level of cell cycle arrest at G1 phase and apoptosis than either drug. Besides, drug combination significantly enhanced the inhibition of tumour growth than sorafenib or PET alone in nude mice. The percentage of Ki-67- and PCNA-positive cells was distinctly reduced, and the apoptotic cells was obviously increased when compared with single drug therapy. Altogether, PET obviously enhanced sorafenib's antitumour effects against GAC through inhibiting cell proliferation, inducing autophagy and promoting apoptosis. The combination therapy with PET and sorafenib may serve as a novel therapeutic strategy for treating GAC and deserve further clinical trials.


Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos/uso terapêutico , Sorafenibe/uso terapêutico , Estilbenos/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/patologia , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Forma Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Sorafenibe/farmacologia , Estilbenos/química , Estilbenos/farmacologia , Neoplasias Gástricas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
7.
J Am Chem Soc ; 142(42): 18150-18159, 2020 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-32991157

RESUMO

Mimicking nature's ability to orchestrate molecular self-assembly in living cells is important yet challenging. Molecular self-assembly has found wide applications in cellular activity control, drug delivery, biomarker imaging, etc. Nonetheless, examples of suborganelle-confined supramolecular self-assembly are quite rare and research in this area remains challenging. Herein, we have presented a new strategy to program supramolecular self-assembly specifically in mitochondria by leveraging on a unique enzyme SIRT5. SIRT5 is a mitochondria-localized enzyme belonging to a family of NAD+-dependent histone deacetylases. Accumulating studies suggest that SIRT5 is involved in regulating diverse biological processes, such as reactive oxygen defense, fatty acid metabolism, and apoptosis. In this study, we designed a novel class of succinylated peptide precursors that can be transformed into self-assembling building blocks through SIRT5 catalysis, leading to the formation of supramolecular nanofibers in vitro and in living cells. The increased hydrophobicity arising from self-assembly remarkably enhanced the fluorescence of nitrobenzoxadiazole (NBD) in the nanofibers. With this approach, we have enabled activity-based imaging of SIRT5 in living cells for the first time. Moreover, SIRT5-mediated peptide self-assembly was found to depolarize mitochondria membrane potential and promote ROS formation. Coincubation of the peptide with three different chemotherapeutic agents significantly boosted the anticancer activities of these drugs. Our work has thus illustrated a new way of mitochondria-confined peptide self-assembly for SIRT5 imaging and potential anticancer treatment.


Assuntos
Mitocôndrias/metabolismo , Peptídeos/metabolismo , Sirtuínas/metabolismo , Biocatálise , Células HeLa , Humanos , Microscopia Eletrônica de Transmissão , Imagem Óptica , Peptídeos/síntese química , Peptídeos/química , Conformação Proteica
8.
Genes Dis ; 7(4): 502-519, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32837984

RESUMO

The pandemic COVID-19, caused by a new coronavirus SARS-CoV-2 infection, has infected over 12 million individuals and caused more than 55,200 death worldwide. Currently, there is no specific drug to treating this disease. Here we summarized the mechanisms of antiviral therapies and the clinic findings from different countries. Antiviral chemotherapies have been conducted by in multiple cohorts in different counties. Although FDA has fast approved remdesivir for treating COVID-19, it only speeds up recovery from COVID-19 with mildly reduced mortality. The chloroquine was suggested a potential drug against SARS-CoV-2 infection due to its in vitro antiviral effects, it is imperative high-quality data from worldwide clinical trials are necessitated for an approved therapy. In terms of hydroxychloroquine (HCQ) therapy, although WHO has stopped all the clinic trials due to its strong side-effects in COVID patients, large scale clinical trials with a long-term outcome follow-up may warrant HCQ and azithromycin combination in combating the virus. Convalescent plasma (CP) therapy suggested its safety use in SARS-CoV-2 infection; but both CP immunotherapy and NK cellular therapy must be manufactured and utilized according to scrupulous ethical and controlled conditions to guarantee a possible role of these products of human origin. Further research should be conducted to define the exact mechanism of SARS-CoV-2 pathogenesis, suitable animal models or ex vivo human lung tissues aid in studying replication, transmission and spread of the novel viruses, thereby facilitating highly effective therapies.

9.
Signal Transduct Target Ther ; 5(1): 125, 2020 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-32661235

RESUMO

Stress proteins (SPs) including heat-shock proteins (HSPs), RNA chaperones, and ER associated stress proteins are molecular chaperones essential for cellular homeostasis. The major functions of HSPs include chaperoning misfolded or unfolded polypeptides, protecting cells from toxic stress, and presenting immune and inflammatory cytokines. Regarded as a double-edged sword, HSPs also cooperate with numerous viruses and cancer cells to promote their survival. RNA chaperones are a group of heterogeneous nuclear ribonucleoproteins (hnRNPs), which are essential factors for manipulating both the functions and metabolisms of pre-mRNAs/hnRNAs transcribed by RNA polymerase II. hnRNPs involve in a large number of cellular processes, including chromatin remodelling, transcription regulation, RNP assembly and stabilization, RNA export, virus replication, histone-like nucleoid structuring, and even intracellular immunity. Dysregulation of stress proteins is associated with many human diseases including human cancer, cardiovascular diseases, neurodegenerative diseases (e.g., Parkinson's diseases, Alzheimer disease), stroke and infectious diseases. In this review, we summarized the biologic function of stress proteins, and current progress on their mechanisms related to virus reproduction and diseases caused by virus infections. As SPs also attract a great interest as potential antiviral targets (e.g., COVID-19), we also discuss the present progress and challenges in this area of HSP-based drug development, as well as with compounds already under clinical evaluation.


Assuntos
Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Proteínas de Choque Térmico/genética , Ribonucleoproteínas Nucleares Heterogêneas/genética , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Pneumonia Viral/tratamento farmacológico , Antivirais/síntese química , Betacoronavirus/genética , Betacoronavirus/patogenicidade , COVID-19 , Montagem e Desmontagem da Cromatina/efeitos dos fármacos , Infecções por Coronavirus/genética , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Regulação da Expressão Gênica , Proteínas de Choque Térmico/agonistas , Proteínas de Choque Térmico/antagonistas & inibidores , Proteínas de Choque Térmico/metabolismo , Ribonucleoproteínas Nucleares Heterogêneas/agonistas , Ribonucleoproteínas Nucleares Heterogêneas/antagonistas & inibidores , Ribonucleoproteínas Nucleares Heterogêneas/metabolismo , Interações Hospedeiro-Patógeno/genética , Humanos , Terapia de Alvo Molecular/métodos , Pandemias , Pneumonia Viral/genética , Pneumonia Viral/patologia , Pneumonia Viral/virologia , RNA Polimerase II/genética , RNA Polimerase II/metabolismo , Precursores de RNA/genética , Precursores de RNA/metabolismo , SARS-CoV-2 , Índice de Gravidade de Doença , Transdução de Sinais , Transcrição Genética/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
10.
Theranostics ; 10(16): 7053-7069, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32641978

RESUMO

Lipids, the basic components of the cell membrane, execute fundamental roles in almost all the cell activities including cell-cell recognition, signalling transduction and energy supplies. Lipid metabolism is elementary for life sustentation that balances activity between synthesis and degradation. An accumulating amount of data has indicated abnormal lipid metabolism in cancer stem cells (CSCs), and that the alteration of lipid metabolism exerts a great impact on CSCs' properties such as the capability of self-renewal, differentiation, invasion, metastasis, and drug sensitivity and resistance. CSCs' formation and maintenance cannot do without the regulation of fatty acids and cholesterol. In normal cells and embryonic development, fatty acids and cholesterol metabolism are regulated by some important signalling pathways (such as Hedgehog, Notch, Wnt signalling pathways); these signalling pathways also play crucial roles in initiating and/or maintaining CSCs' properties, and such signalling is shown to be commonly modulated by the abnormal lipid metabolism in CSCs; on the other hand, the altered lipid metabolism in turn modifies the cell signalling and generates additional impacts on CSCs. Metabolic rewiring is considered as an ideal hallmark of CSCs, and metabolic alterations would be promising therapeutic targets of CSCs for aggressive tumors. In this review, we summarize the most updated findings of lipid metabolic abnormalities in CSCs and prospect the potential applications of targeting lipid metabolism for anticancer treatment.


Assuntos
Antineoplásicos/farmacologia , Metabolismo dos Lipídeos/fisiologia , Neoplasias/patologia , Células-Tronco Neoplásicas/metabolismo , Animais , Antineoplásicos/uso terapêutico , Diferenciação Celular , Autorrenovação Celular , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Invasividade Neoplásica/patologia , Neoplasias/tratamento farmacológico , Células-Tronco Neoplásicas/efeitos dos fármacos
11.
iScience ; 19: 715-727, 2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-31476618

RESUMO

Enterovirus A71 (EV-A71) infection causes hand-foot-and-mouth disease (HFMD) and fatal neurological diseases, and there are no effective treatments. Host factors play key roles in establishing viral infection and determining the disease progression and outcome of antiviral therapies. In this study, we found that the expression of Pim1 was significantly upregulated in EV-A71 infection. Ectopic expression or silencing of Pim1 promoted or inhibited EV-A71 replication through two distinct mechanisms. Pim1 enhanced viral IRES activity by increasing viral 2A protease-mediated eIF4G cleavage and blocked AUF1, a suppressor of IRES, translocation from the nucleus to cytosol. More importantly, we discovered that Pim1 inhibitors (SGI-1776, AZD-1208, and CX-6258) reduced EV-A71 reproduction. Particularly, CX-6258 remarkably reduced EV-A71 reproduction more than 1,000 times, providing a potential therapeutic agent for EV-A71 treatment.

12.
Cytokine ; 123: 154765, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31255913

RESUMO

OBJECTIVE: New clinical indicators are urgently needed for predicting the progression and complications of hand-foot-and-mouth disease (HFMD) caused by EV-A71 infections. MATERIALS AND METHODS: Serum specimens from 132 EV-A71 HFMD patients and 73 health children were collected during 2012-2014 in Shenzhen, China. The specific cytokines/chemokines were detected with a 274-human cytokine antibody array, followed by a 38-inflammation cytokine array, and further validated by ELISA. RESULTS: Cytokines varied in different severity of EV-A71 HFMD patients. The ROC curve analysis revealed 5 serum cytokines with high sensitivity and specificity in predicting the disease progression. Eotaxin, IL-8 and IP-10 have showed high AUC values (0.90-0.95) for discrimination between the health controls and the patient group. The three cytokines showed high sensitivity (80-91%) and specificity (88-95%). MMP-8 had a high sensitivity and specificity to predict mild HFMD (100%, 100%). IL-1b and leptin discriminated the severe/critical group from the mild group (79% and 69% in sensitivity, 73% and 63% in specificity). CONCLUSIONS: Eotaxin, IP-10 and IL-8 could be potential indicators for predicting HFMD progression with EV-A71 infection. MMP-8 is a specific indicator for mild infection, while IL-1b and leptin display potential for predicting the severity and criticality.


Assuntos
Quimiocinas/sangue , Enterovirus Humano A/metabolismo , Doença de Mão, Pé e Boca/sangue , Criança , Pré-Escolar , Progressão da Doença , Feminino , Humanos , Masculino , Valor Preditivo dos Testes , Análise Serial de Proteínas
13.
J Virol ; 93(9)2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30814282

RESUMO

Enterovirus 71 (EV-A71) is a human pathogen that causes hand, foot, and mouth disease (HFMD) and fatal neurological diseases, and no effective treatment is available. Characterization of key host factors is important for understanding its pathogenesis and developing antiviral drugs. Here we report that Hsp27 is one of the most upregulated proteins in response to EV-A71 infection, as revealed by two-dimensional gel electrophoresis-based proteomics studies. Depletion of Hsp27 by small interfering RNA or CRISPR/Cas9-mediated knockout significantly inhibited viral replication, protein expression, and reproduction, while restoration of Hsp27 restored such virus activities. Furthermore, we show that Hsp27 plays a crucial role in regulating viral internal ribosome entry site (IRES) activities by two different mechanisms. Hsp27 markedly promoted 2Apro-mediated eukaryotic initiation factor 4G cleavage, an important process for selecting and initiating IRES-mediated translation. hnRNP A1 is a key IRES trans-acting factor (ITAF) for enhancing IRES-mediated translation. Surprisingly, knockout of Hsp27 differentially blocked hnRNP A1 but not FBP1 translocation from the nucleus to the cytoplasm and therefore abolished the hnRNP A1 interaction with IRES. Most importantly, the Hsp27 inhibitor 1,3,5-trihydroxy-13,13-dimethyl-2H-pyran [7,6-b] xanthone (TDP), a compound isolated from a traditional Chinese herb, significantly protected against cytopathic effects and inhibited EV-A71 infection. Collectively, our results demonstrate new functions of Hsp27 in facilitating virus infection and provide novel options for combating EV-A71 infection by targeting Hsp27.IMPORTANCE Outbreaks of infections with EV-A71, which causes hand, foot, and mouth disease, severe neurological disorders, and even death, have been repeatedly reported worldwide in recent decades and are a great public health problem for which no approved treatments are available. We show that Hsp27, a heat shock protein, supports EV-A71 infection in two distinct ways to promote viral IRES-dependent translation. A small-molecule Hsp27 inhibitor isolated from a traditional Chinese medicinal herb effectively reduces virus yields. Together, our findings demonstrate that Hsp27 plays an important role in EV-A71 infection and may serve as an antiviral target.


Assuntos
Enterovirus Humano A/fisiologia , Infecções por Enterovirus/metabolismo , Regulação Viral da Expressão Gênica , Proteínas de Choque Térmico/metabolismo , Sítios Internos de Entrada Ribossomal , Chaperonas Moleculares/metabolismo , Biossíntese de Proteínas , Proteínas Virais/biossíntese , Replicação Viral/fisiologia , Linhagem Celular Tumoral , Núcleo Celular/genética , Núcleo Celular/metabolismo , Núcleo Celular/virologia , Citoplasma/genética , Citoplasma/metabolismo , Citoplasma/virologia , Fator de Iniciação 4G em Eucariotos/genética , Fator de Iniciação 4G em Eucariotos/metabolismo , Frutose-Bifosfatase/genética , Frutose-Bifosfatase/metabolismo , Técnicas de Inativação de Genes , Proteínas de Choque Térmico/genética , Ribonucleoproteína Nuclear Heterogênea A1/genética , Ribonucleoproteína Nuclear Heterogênea A1/metabolismo , Humanos , Chaperonas Moleculares/genética , Proteínas Virais/genética
14.
Artigo em Inglês | MEDLINE | ID: mdl-30820356

RESUMO

The dysregulation of autophagy, an evolutionarily conserved lysosomal degradation process, has been implicated in a wide variety of human diseases, and thus, small chemicals that modulate autophagy have therapeutic potential. Here, we assessed the ability of active components isolated from Bupleurum falcatum, a popular Chinese herb, to modulate autophagy. We found that saikosaponin D (SsD) and A (SsA) but not C (SsC) potently and reversibly inhibited the fusion of autophagosomes and lysosomes, resulting in the accumulation of autophagosomes, an increased lysosomal pH, and TFEB nuclear translocation. RAB5A knockdown or the expression of a dominant-negative RAB5 mutant significantly reduced the ability of SsD or SsA to block autophagy. Enterovirus A71 (EV-A71), the cause of hand-foot-mouth disease, has been shown to induce autophagy. We found that SsD potently inhibited EV-A71 RNA replication and subsequent viral protein synthesis, thereby preventing EV-A71-induced cell death. ATG5 knockdown inhibited EV-A71 viral protein synthesis, whereas autophagy induction by rapamycin promoted synthesis. Taken together, our data indicate that SsD and SsA are potent late-stage autophagy inhibitors that can be used to prevent EV-A71 infection.

15.
Semin Cancer Biol ; 57: 105-110, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30268432

RESUMO

The T-box factors belong to an ancient protein family, which comprises a cluster of evolutionarily-conserved transcription factors that regulate gene expression and that are crucial to embryonic development. T-box transcription factor 3 (Tbx3) is a member of this family, is expressed in some tissues, and is a key regulator in many critical organs, including the heart, mammary gland, and limbs. Overexpression of Tbx3 is associated with a number of cancers, including head and neck squamous cell carcinoma, gastric, breast, ovary, cervical, pancreatic, bladder and liver cancers, as well as melanoma. Tbx3 promotes tumor development by modulating cell proliferation, tumor formation, metastasis, cell survival and drug resistance. Moreover, there is strong evidence that Tbx3 regulates stem cell maintenance by controlling stem cell self-renewal and differentiation. Verification of the upstream regulatory factors and potential molecular mechanism of Tbx3, being able to explain the function of Tbx3 in carcinogenic effects and stem cell maintenance, will make a valuable contribution to stem cell and cancer research. This review provides an insight into the current research on Tbx3 and explores the significance of Tbx3 in stem cells and tumorigenesis.


Assuntos
Autorrenovação Celular/genética , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Neoplasias/etiologia , Neoplasias/metabolismo , Células-Tronco/metabolismo , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo , Animais , Regulação da Expressão Gênica , Humanos , Neoplasias/patologia , Transdução de Sinais , Células-Tronco/patologia
16.
Artigo em Inglês | MEDLINE | ID: mdl-30151243

RESUMO

Tbx3, a transcriptional repressor, is essential in the organogenesis of vertebrates, stem cell self-renewal and differentiation, and the carcinogenesis of multiple tumor types. However, the mechanism by which Tbx3 participates in the metastasis of hepatocellular carcinoma (HCC) remains largely unknown. In this study, we show that Tbx3 was dramatically upregulated in clinical HCC samples and that elevated expression of Tbx3 promoted cancer progression. To determine the underlying mechanism, systematic glycine scan mutagenesis and deletion assays were performed. We identified two critical motifs, 585LFSYPYT591 and 604HRH606, that contribute to the repression of transcriptional activity. These motifs are also essential for Tbx3 to promote cell migration and metastasis both in vitro and in vivo via the suppression of E-cadherin expression. More importantly, Tbx3 directly interacts with HDAC5 via these motifs, and an HDAC inhibitor blocks Tbx3-mediated cell migration and the downregulation of E-cadherin in HCC. As Tbx3 is involved in the carcinogenesis of multiple types of human cancers, our findings suggest an important target for anti-cancer drug development.

17.
Antiviral Res ; 150: 39-46, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29180285

RESUMO

Enterovirus A71 (EV-A71) is a small positive-stranded RNA virus that causes human hand, foot and mouth disease (HFMD) and fatal neurological disorders in some cases without effective treatment. Here we show that heat shock cognate protein 70 (Hsc70), a molecular chaperone, displays pivotal role in viral infections. Knockdown of Hsc70 significantly suppresses viral replication evidenced by reducing not only the level of both viral replication intermediates (negative stranded RNA) and viral genomic RNA (positive stranded RNA), but also the level of viral protein expression; whereas ectopic expression of Hsc70 markedly promotes viral replication. Interestingly, depletion of Hsc70 decreases the IRES activity of EV-A71, and the ectopic expression of Hsc70 enhances the IRES activity accordingly. Further study shows that Hsc70 binds viral genomic RNA but does not directly interact with IRES. Moreover, we reveal that Hsc70 interacts with 2A protease and promotes eIF4G cleavage. More importantly, Hsc70 inhibitor Ver-155008 significantly protects cytopathic effects from EV-A71 infection and inhibits both IRES activity and viral reproduction in a dose-dependent manner. The cell viability assay shows that the IC50 and CC50 are 2.01 µM and 47.67 µM, respectively. These results demonstrate not only an important mechanism of Hsc70 in facilitating EV-A71 replication, but also a target for antiviral drug development.


Assuntos
Enterovirus Humano A/fisiologia , Infecções por Enterovirus/metabolismo , Infecções por Enterovirus/virologia , Regulação Viral da Expressão Gênica , Proteínas de Choque Térmico HSC70/metabolismo , Sítios Internos de Entrada Ribossomal , Antivirais/farmacologia , Linhagem Celular , Enterovirus Humano A/efeitos dos fármacos , Regulação Viral da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Proteínas de Choque Térmico HSC70/antagonistas & inibidores , Humanos , Ligação Proteica , Replicação Viral
18.
Chem Sci ; 8(10): 6865-6870, 2017 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-29147511

RESUMO

Two novel series of (salen)ruthenium(iii) complexes bearing guanidine and amidine axial ligands were synthesized, characterized, and evaluated for anticancer activity. In vitro cytotoxicity tests demonstrate that these complexes are cytotoxic against various cancer cell lines and the leading complexes have remarkable cancer-cell selectivity. A detailed study of the guanidine complex 7 and the amidine complex 13 reveals two distinguished modes of action. Complex 7 weakly binds to DNA and induces DNA damage, cell cycle arrest, and typical apoptosis pathways in MCF-7 cells. In contrast, complex 13 induces paraptosis-like cell death hallmarked by massive vacuole formation, mitochondrial swelling, and ER stress, resulting in significant cytotoxicity against human breast cancer cells. Our results provide an extraordinary example of tuning the mechanism of action of (salen)ruthenium(iii) anticancer complexes by modifying the structure of the axial ligands.

19.
Sci Rep ; 6: 28019, 2016 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-27456431

RESUMO

5-fluorouracil (5-FU) is widely used to treat patients with gastric cancer (GC). However, the response rate is quite heterogeneous. The single nucleotide polymorphisms (SNPs) and their interactions of genes in the one-carbon metabolism (OCM) pathway, including Methylenetetrahydrofolate reductase (MTHFR), Methionine synthase reductase (MTRR), Methionine synthase (MTR), and Thymidylate synthase (TS), significantly affect 5-FU metabolism. In this study, 650 stage II-III patients were recruited from 1998 to 2006. Among them, 251 received 5-FU treatment and other 399 patients were untreated. The Cox regression analysis, log-rank tests and Kaplan-Meier plots were adopted. In the chemotherapy cohort, MTRR 66 GA + GG genotypes decreased death risk, however, the protect effect of MTRR 66 GA + GG disappeared when GC patients simultaneously had MTHFR 677TT + TC or MTR 2756GG + GA genotypes. TS 5'-UTR 2R3R + 3R3R genotypes also prolonged overall survival of patients treated with 5-FU. And this favorable prognosis obviously enhanced when GC patients simultaneously had TS 3'-UTR DD + DI and TS 5'-UTR 2R3R + 3R3R genotypes. Our findings showed that the polymorphisms of MTRR 66 A > G and TS 5'-UTR 3R > 2R may be potential prognostic factors for GC patients receiving 5-FU.


Assuntos
Fluoruracila/administração & dosagem , Genótipo , Proteínas de Neoplasias , Polimorfismo de Nucleotídeo Único , Neoplasias Gástricas , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/mortalidade , Taxa de Sobrevida
20.
J Infect ; 72(6): 731-737, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27038503

RESUMO

BACKGROUND: Human Enterovirus A71 (EV-A71) is one of the severest enteroviruses that causes hand, foot, and mouth disease (HFMD) among children. This study identified the mutations of EV-A71 VP1 amino acid residues over a number of years and explored the possible association of identified mutations and HFMD epidemic outbreaks in Shenzhen, China. METHODS: A total of 3760 stool specimens were collected from HFMD patients by Shenzhen Centers for Disease Control and Prevention (CDC) between 1998 and 2013. In total 289 VP1 strains were sequenced in this study, and amino acids mutation frequency was calculated. There were 2040 China nationwide sequences downloaded from Genebank as replication data. RESULTS: In our samples, 1036 subjects (27.6%) were EV-A71 infected. Three amino acid positions on VP1 protein were found to have high mutation prevalence. These are Q22H, S283T, and A289H. Site 22 showed a fast mutation fixation in the year 2008, at the time of the large scale epidemic outbreak in Shenzhen. Analysis of the nationwide data replicated the same trend of mutation prevalence of the three sites. CONCLUSION: The switching from Q to H on site 22 of the EV-A71 VP1 strain might be associated with the HFMD outbreak in Shenzhen in 2008. The identified amino acid sites 22, 283 and 289 provided information for developing anti-viral drugs against EV-A71 in the future.


Assuntos
Enterovirus Humano A/genética , Evolução Molecular , Doença de Mão, Pé e Boca/virologia , Substituição de Aminoácidos/genética , Proteínas do Capsídeo/genética , Criança , China/epidemiologia , Surtos de Doenças , Infecções por Enterovirus/epidemiologia , Infecções por Enterovirus/virologia , Epidemias , Fezes/virologia , Feminino , Genótipo , Doença de Mão, Pé e Boca/epidemiologia , Humanos , Masculino , Mutação , Filogenia , Análise de Sequência de DNA
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