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1.
PLoS One ; 15(8): e0238052, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32866163

RESUMO

The integrase inhibitor dolutegravir was included in initial antiretroviral therapy in Brazil in January 2017. Studies have demonstrated that the efficacy and safety of antiretrovirals have improved with the introduction of new classes of antiretrovirals, such as integrase inhibitors. This study aimed to estimate the frequency of individuals with a virologic response by week 24 of antiretroviral treatment and to describe the adverse events of the regimen containing dolutegravir. This was a cohort of people living with HIV followed up at a referral hospital. Patients were included who had initiated their first treatment between January and August 2017. Data were obtained from medical records, the Drug Logistics Management System and from the Laboratory Tests Control System. Two hundred and twenty-two patients were included for the tolerability analysis and one hundred and thirty-seven for the virologic response analysis. The mean age was 34 years, the median time between diagnosis and initiating treatment was 1.9 months and the median time on antiretroviral therapy was 13.2 months. The frequency of adverse events was 10% (95% CI: 7% to 15.2%), of these, amongst the most frequent events, 91% presented gastrointestinal effects, and 47.8% neuropsychiatric. By week 24 the estimated incidence of virologic response was 89.1% (95% CI: 83% to 93.5%), with an increase during the first 6 months in the number of T-CD4 lymphocytes of 50.7 cells/mm 3 (95% CI: 42 to 59.3). Initial antiretroviral regimens containing dolutegravir were well tolerated and effective in viral suppression during the first 24 weeks after initiating treatment. The occurrence of adverse events was low, either mild or moderate.


Assuntos
Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/farmacologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Compostos Heterocíclicos com 3 Anéis/farmacologia , Segurança , Adolescente , Adulto , Idoso , Fármacos Anti-HIV/uso terapêutico , Feminino , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Virologia
3.
J Cancer Res Clin Oncol ; 146(10): 2559-2574, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32681294

RESUMO

PURPOSE: Canonical Wnt/ ß-catenin pathway is one mechanism being activated in platinum-resistant epithelial ovarian cancer (EOC). Detecting potential targets for Wnt pathway modulation as a putative future therapeutic approach was the aim of this study. METHODS: Biological effects of different Wnt modulators (SB216763, XAV939 and triptolide) on the EOC cell lines A2780 and its platinum-resistant clone A2780cis were investigated via multiple functional tests. Immunohistochemistry (IHC) was carried out to compare the expression levels of Wnt marker proteins (ß-catenin, snail/ slug, E-cadherin) in patient specimens and to correlate them with lifetime data. RESULTS: We could show that activated Wnt signaling of the platinum-resistant EOC cell line A2780cis can be reversed by Wnt manipulators through SB216763 or XAV939. All Wnt manipulators tested consecutively decreased cell proliferation and cell viability. Apoptosis of A2780 and A2780cis was enhanced by triptolide in a dose-dependent manner, whereas cell migration was inhibited by SB216763 and triptolide. IHC analyses elucidated significantly different expression patterns for Wnt markers in the serous subtype. Herein, higher plasmatic snail/ slug expression is associated with improved progression-free (PFS) and overall survival (OS). CONCLUSION: According to the described effects on EOC biology, all three Wnt manipulators seem to have the potential to augment the impact of a platinum-based chemotherapy in EOC. This is promising as a dominance of this pathway was confirmed in serous histology.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/metabolismo , Compostos Organoplatínicos/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , Antígenos CD/biossíntese , Antígenos CD/metabolismo , Caderinas/biossíntese , Caderinas/metabolismo , Carcinoma Epitelial do Ovário/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Diterpenos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Compostos de Epóxi/farmacologia , Feminino , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Indóis/farmacologia , Maleimidas/farmacologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Compostos Organoplatínicos/administração & dosagem , Neoplasias Ovarianas/patologia , Fenantrenos/farmacologia , beta Catenina/biossíntese , beta Catenina/metabolismo
4.
J Vis Exp ; (160)2020 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-32597864

RESUMO

Studying myelination in vitro and in vivo poses numerous challenges. The differentiation of oligodendrocyte precursor cells (OPCs) in vitro, although scalable, does not recapitulate axonal myelination. OPC-neuron cocultures and OPC-fiber cultures allow for the examination of in vitro myelination, but they lack additional cell types that are present in vivo, such as astrocytes and microglia. In vivo mouse models, however, are less amenable to chemical, environmental, and genetic manipulation and are much more labor intensive. Here, we describe an ex vivo mouse cerebellar slice culture (CSC) quantitative system that is useful for: 1) studying developmental myelination, 2) modeling demyelination and remyelination, and 3) conducting translational research. Sagittal sections of the cerebellum and hindbrain are isolated from postnatal day (P) 0-2 mice, after which they myelinate ex vivo for 12 days. During this period, slices can be manipulated in various ways, including the addition of compounds to test for an effect on developmental myelination. In addition, tissue can be fixed for electron microscopy to assess myelin ultrastructure and compaction. To model disease, CSC can be subjected to acute hypoxia to induce hypomyelination. Demyelination in these explants can also be induced by lysolecithin, which allows for the identification of factors that promote remyelination. Aside from chemical and environmental modifications, CSC can be isolated from transgenic mice and are responsive to genetic manipulation induced with Ad-Cre adenoviruses and tamoxifen. Thus, cerebellar slice cultures are a fast, reproducible, and quantifiable model for recapitulating myelination.


Assuntos
Cerebelo/crescimento & desenvolvimento , Cerebelo/patologia , Bainha de Mielina/metabolismo , Remielinização/fisiologia , Ativinas/metabolismo , Animais , Diferenciação Celular , Meios de Cultura , Modelos Animais de Doenças , Compostos Heterocíclicos com 3 Anéis/farmacologia , Camundongos Transgênicos , Oligodendroglia/citologia
5.
Proc Natl Acad Sci U S A ; 117(24): 13457-13467, 2020 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-32482868

RESUMO

The protooncogene MYC regulates a variety of cellular processes, including proliferation and metabolism. Maintaining MYC at homeostatic levels is critical to normal cell function; overexpression drives many cancers. MYC stability is regulated through phosphorylation: phosphorylation at Thr58 signals degradation while Ser62 phosphorylation leads to its stabilization and functional activation. The bromodomain protein 4 (BRD4) is a transcriptional and epigenetic regulator with intrinsic kinase and histone acetyltransferase (HAT) activities that activates transcription of key protooncogenes, including MYC We report that BRD4 phosphorylates MYC at Thr58, leading to MYC ubiquitination and degradation, thereby regulating MYC target genes. Importantly, BRD4 degradation, but not inhibition, results in increased levels of MYC protein. Conversely, MYC inhibits BRD4's HAT activity, suggesting that MYC regulates its own transcription by limiting BRD4-mediated chromatin remodeling of its locus. The MYC stabilizing kinase, ERK1, regulates MYC levels directly and indirectly by inhibiting BRD4 kinase activity. These findings demonstrate that BRD4 negatively regulates MYC levels, which is counteracted by ERK1 activation.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Fatores de Transcrição/metabolismo , Acetilação , Núcleo Celular/metabolismo , Cromatina/metabolismo , Dipeptídeos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Células HeLa , Compostos Heterocíclicos com 3 Anéis/farmacologia , Histonas/metabolismo , Humanos , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Fosforilação , Ligação Proteica , Estabilidade Proteica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-myc/genética , Ubiquitinação
6.
PLoS One ; 15(5): e0233180, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32437392

RESUMO

Lipoprotein lipase (LPL) is upregulated in atherosclerotic lesions and it may promote the progression of atherosclerosis, but the mechanisms behind this process are not completely understood. We previously showed that the phosphorylation of Akt within THP-1 macrophages is increased in response to the lipid hydrolysis products generated by LPL from total lipoproteins. Notably, the free fatty acid (FFA) component was responsible for this effect. In the present study, we aimed to reveal more detail as to how the FFA component may affect Akt signalling. We show that the phosphorylation of Akt within THP-1 macrophages increases with total FFA concentration and that phosphorylation is elevated up to 18 hours. We further show that specifically the palmitoleate component of the total FFA affects Akt phosphorylation. This is tied with changes to the levels of select molecular species of phosphoinositides. We further show that the total FFA component, and specifically palmitoleate, reduces apolipoprotein A-I-mediated cholesterol efflux, and that the reduction can be reversed in the presence of the Akt inhibitor MK-2206. Overall, our data support a negative role for the FFA component of lipoprotein hydrolysis products generated by LPL, by impairing macrophage cholesterol efflux via Akt activation.


Assuntos
Colesterol/metabolismo , Macrófagos/metabolismo , Ácido Palmítico/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Apolipoproteína A-I/metabolismo , Ativação Enzimática/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Lipase Lipoproteica/metabolismo , Macrófagos/citologia , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Células THP-1
7.
Mol Immunol ; 121: 186-194, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32244067

RESUMO

NLRP3 (NOD-, LRR- and pyrin domain- containing protein 3) inflammasome is involved in diverse inflammatory diseases, so the activation of NLRP3 inflammasome needs to be tightly regulated to prevent excessive inflammation. However, the endogenous regulatory mechanisms of NLRP3 inflammasome are still less defined. Here, we report that ß-catenin, which is the central mediator of the canonical Wnt/ß-catenin signaling, promotes NLRP3 inflammasome activation. When we suppressed the expression of ß-catenin by siRNA or pharmacological inhibitor, the NLRP3 inflammasome activation was impaired. Accordingly, ß-catenin inhibitor attenuated LPS-induced systemic inflammation in vivo. Mechanistically, we found ß-catenin interacted with NLRP3 and promoted the association between NLRP3 and ASC. Thus, our study revealed a novel role of ß-catenin in NLRP3 inflammasome activation and suggest an endogenous crosstalk between Wnt/ß-catenin signal and NLRP3 inflammasome.


Assuntos
Proteínas Adaptadoras de Sinalização CARD/metabolismo , Compostos Heterocíclicos com 3 Anéis/farmacologia , Inflamassomos/imunologia , Inflamação/prevenção & controle , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , beta Catenina/metabolismo , Animais , Proteínas Adaptadoras de Sinalização CARD/imunologia , Modelos Animais de Doenças , Células HEK293 , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Humanos , Inflamassomos/efeitos dos fármacos , Inflamação/imunologia , Injeções Intraperitoneais , Lipopolissacarídeos/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Cultura Primária de Células , RNA Interferente Pequeno/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , Via de Sinalização Wnt/imunologia , beta Catenina/antagonistas & inibidores , beta Catenina/genética
8.
J Med Chem ; 63(8): 3956-3975, 2020 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-32208600

RESUMO

The bromodomain and extra-terminal (BET) family proteins have recently emerged as promising drug targets for cancer therapy. In this study, identification of an 8-methyl-pyrrolo[1,2-a]pyrazin-1(2H)-one fragment (47) as a new binder to the BET bromodomains and the subsequent incorporation of fragment 47 to the scaffold of ABBV-075, which recently entered Phase I clinical trials, enabled the generation of a series of highly potent BET bromodomain inhibitors. Further druggability optimization led to the discovery of compound 38 as a potential preclinical candidate. Significantly, compared with ABBV-075, which exhibits a 63-fold selectivity for BRD4(1) over EP300, compound 38 demonstrates an excellent selectivity for the BET bromodomain family over other bromodomains, with an ∼1500-fold selectivity for BRD4(1) over EP300. Orally administered 38 achieves a complete inhibition of tumor growth with a tumor growth inhibition (TGI) of 99.7% accompanied by good tolerability.


Assuntos
Acetanilidas/química , Acetanilidas/farmacologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Descoberta de Drogas/métodos , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/farmacologia , Piridonas/química , Piridonas/farmacologia , Sulfonamidas/química , Sulfonamidas/farmacologia , Fatores de Transcrição/antagonistas & inibidores , Animais , Proteínas de Ciclo Celular/metabolismo , Cães , Relação Dose-Resposta a Droga , Proteína p300 Associada a E1A/antagonistas & inibidores , Proteína p300 Associada a E1A/metabolismo , Haplorrinos , Humanos , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Domínios Proteicos/efeitos dos fármacos , Domínios Proteicos/fisiologia , Estrutura Secundária de Proteína , Ratos , Relação Estrutura-Atividade , Fatores de Transcrição/metabolismo
9.
Science ; 367(6479): 806-810, 2020 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-32001525

RESUMO

Although second-generation HIV integrase strand-transfer inhibitors (INSTIs) are prescribed throughout the world, the mechanistic basis for the superiority of these drugs is poorly understood. We used single-particle cryo-electron microscopy to visualize the mode of action of the advanced INSTIs dolutegravir and bictegravir at near-atomic resolution. Glutamine-148→histidine (Q148H) and glycine-140→serine (G140S) amino acid substitutions in integrase that result in clinical INSTI failure perturb optimal magnesium ion coordination in the enzyme active site. The expanded chemical scaffolds of second-generation compounds mediate interactions with the protein backbone that are critical for antagonizing viruses containing the Q148H and G140S mutations. Our results reveal that binding to magnesium ions underpins a fundamental weakness of the INSTI pharmacophore that is exploited by the virus to engender resistance and provide a structural framework for the development of this class of anti-HIV/AIDS therapeutics.


Assuntos
Farmacorresistência Viral , Inibidores de Integrase de HIV/química , Integrase de HIV/química , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos de 4 ou mais Anéis/química , Substituição de Aminoácidos/genética , Domínio Catalítico , Microscopia Crioeletrônica/métodos , Glutamina/genética , Glicina/genética , Integrase de HIV/genética , Inibidores de Integrase de HIV/farmacologia , Compostos Heterocíclicos com 3 Anéis/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Histidina/genética , Humanos , Magnésio/química , Mutação , Serina/genética , Imagem Individual de Molécula/métodos
10.
Nat Commun ; 11(1): 929, 2020 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-32066735

RESUMO

Current treatments for clear cell renal cell cancer (ccRCC) are insufficient because two-thirds of patients with metastases progress within two years. Here we report the identification and characterization of a cancer stem cell (CSC) population in ccRCC. CSCs are quantitatively correlated with tumor aggressiveness and metastasis. Transcriptional profiling and single cell sequencing reveal that these CSCs exhibit an activation of WNT and NOTCH signaling. A significant obstacle to the development of rational treatments has been the discrepancy between model systems and the in vivo situation of patients. To address this, we use CSCs to establish non-adherent sphere cultures, 3D tumor organoids, and xenografts. Treatment with WNT and NOTCH inhibitors blocks the proliferation and self-renewal of CSCs in sphere cultures and organoids, and impairs tumor growth in patient-derived xenografts in mice. These findings suggest that our approach is a promising route towards the development of personalized treatments for individual patients.


Assuntos
Antineoplásicos/farmacologia , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Células-Tronco Neoplásicas/efeitos dos fármacos , Receptores Notch/antagonistas & inibidores , Proteínas Wnt/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Antineoplásicos/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Rim/patologia , Neoplasias Renais/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Células-Tronco Neoplásicas/patologia , Cultura Primária de Células , Pirimidinonas/farmacologia , RNA Interferente Pequeno/metabolismo , Receptores Notch/metabolismo , Transdução de Sinais/efeitos dos fármacos , Análise de Célula Única , Esferoides Celulares , Proteínas Wnt/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Int Immunopharmacol ; 80: 106121, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31972426

RESUMO

The research plans to make sure how Geniposide (GEN) functions in osteoblast proliferation and differentiation. The MC3T3-E1 and ATDC5 cells were treated with the GEN, XAV-939 and/or transfected with microRNA (miR)-214 mimic or corresponding control. Cell viability was detected with the CCK-8. The CyclinD1, Runx2, Osx, Ocn, Wnt3a and ß-catenin were individually quantified via western blot. The cell cycle was tested by cell cycle analysis assay. The ALP activity was tested by ALP assay. qRT-PCR was used to examine the miR-214 expression level. The cell viability and the expressions of the CyclinD1, Runx2, Osx, Ocn Wnt3a and ß-catenin, as well as the ALP activity were individually and significantly promoted by the GEN. Besides, miR-214 was down-regulated by the GEN. The XAV-939 or the miR-214 mimic destroyed the promotional effect of GEN on these elements above. In conclusion, GEN induced the proliferation and differentiation of the MC3T3-E1 and ATDC5 cells by targeting the miR-214 through Wnt/ß-catenin activation.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Iridoides/farmacologia , MicroRNAs/antagonistas & inibidores , Osteoblastos/efeitos dos fármacos , Células 3T3 , Animais , Diferenciação Celular/genética , Proliferação de Células/genética , Regulação para Baixo/efeitos dos fármacos , Fraturas Ósseas/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Camundongos , MicroRNAs/agonistas , MicroRNAs/metabolismo , Osteoblastos/fisiologia , Osteogênese/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacos , Via de Sinalização Wnt/genética
12.
Artif Cells Nanomed Biotechnol ; 48(1): 479-487, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31975621

RESUMO

Cervical cancer is the second most common malignant tumour threatening women's health. In recent years, heavy-ion beam therapy is becoming a newly emerging therapeutic mean of cancer; however, radio-resistance and radiation-induced damage constitute the main obstacles for curative treatment of cervical cancer. Therefore, to identify the radiosensitizers is essential. Here, we investigated the effects of Wnt signalling pathway on the response of 12C6+ radiation in HeLa cells. XAV939, an inhibitor of Wnt signalling pathway, was added two hours before 12C6+ radiation.12C6+ radiation inhibited the viability of HeLa cells in a time-dependent manner, and inhibiting Wnt signalling using XAV939 significantly intensified this stress. Meanwhile, 12C6+ radiation induced a significant increased cell apoptosis, G2/M phase arrest, and the number of γ-H2AX foci. Supplementation with XAV939 significantly increased the effects induced by 12C6+ radiation alone. Combining XAV939 with 12C6+ irradiation, the expression of apoptotic genes (p53, Bax, Bcl-2) was significantly increased, while the expression of Wnt-related genes (Wnt3a, Wnt5a, ß-catenin, cyclin D1 and c-Myc) was significantly decreased. Overall, these findings suggested that blockage of the Wnt/ß-catenin pathway effectively sensitizes HeLa cells to 12C6+ irradiation, and it may be a potential therapeutic approach in terms of increasing the clinical efficacy of 12C6+ beams.


Assuntos
Apoptose , Compostos Heterocíclicos com 3 Anéis/farmacologia , Tolerância a Radiação , Neoplasias do Colo do Útero , Via de Sinalização Wnt , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Proteínas Reguladoras de Apoptose/metabolismo , Feminino , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos da radiação , Células HeLa , Humanos , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem da Fase M do Ciclo Celular/efeitos da radiação , Proteínas de Neoplasias/metabolismo , Tolerância a Radiação/efeitos dos fármacos , Tolerância a Radiação/efeitos da radiação , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/radioterapia , Via de Sinalização Wnt/efeitos dos fármacos , Via de Sinalização Wnt/efeitos da radiação
13.
Oncol Rep ; 43(2): 395-404, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31894338

RESUMO

Lung cancer, which is a leading cause of cancer­related deaths, is diagnosed at a male to female ratio of 2.1:1. Serine­threonine kinase 31 (STK31) is a novel cancer/testis (CT)­related gene that is highly expressed in several types of cancers, such as lung and colorectal cancer, and plays crucial roles in cancer. In the present study, increased expression of STK31 and ß­catenin was observed in lung cancer tissues and cell lines. Downregulation of STK31 expression in lung cancer cells significantly inhibited their proliferation by arresting the cell cycle in the G1 phase concurrent with decreased ß­catenin, c­myc and cyclin D1 protein levels, while upregulation of STK31 had the opposite effects. In addition, STK31­induced lung cancer cell viability, proliferation, cell cycle progression, and expression of related genes were completely attenuated by a Wnt/ß­catenin inhibitor (XAV939). Similar to XAV939, a c­myc inhibitor (10058­F4) also significantly attenuated STK31­induced proliferation and cell cycle progression in lung cancer cells. Inhibiting c­myc and TRRAP significantly decreased the expression of STK31, and a chromatin immunoprecipitation (ChIP) assay confirmed that c­myc directly bound to the STK31 promoter. These results indicated that STK31 may act as an oncogene in lung cancer and that c­myc may be the transcription factor that promotes STK31 expression. Moreover, the results suggested that c­myc can also regulate STK31 expression in a positive feedback loop, and the downregulation of STK31 in lung cancer cells had an inhibitory effect on cell viability, cell proliferation and cell cycle progression, likely by inactivating the Wnt/ß­catenin pathway and positive feedback regulation by c­myc.


Assuntos
Neoplasias Pulmonares/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas c-myc/genética , beta Catenina/genética , Células A549 , Idoso , Idoso de 80 Anos ou mais , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Retroalimentação Fisiológica , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Masculino , Pessoa de Meia-Idade , Tiazóis/farmacologia , Regulação para Cima , Via de Sinalização Wnt
14.
J Agric Food Chem ; 68(4): 982-988, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31909997

RESUMO

Cycloxaprid (CYC) is effective in the control of hemipteran pests, but its bioactivity against lepidopteran pests is still unclear. Here, the bioactivity of CYC against lepidopteran pests was found to be much worse than that against hemipteran insects. To reveal the mechanism, the transcriptomes of CYC-treated and untreated Ostrinia furnacalis larvae were compared. Among the top 20 differentially expressed genes, 11 encode proteins involved in cuticle formation, while only one encodes a detoxifying enzyme. Thus, the cuticle appears to be important for the insensitivity of O. furnacalis to CYC. A pretreatment of O. furnacalis larvae with methoprene enhanced the bioactivity of CYC by 1.12-fold. Moreover, mixtures of CYC with graphene oxide increased the bioactivity of CYC by 1.88-fold. Because lepidopteran and hemipteran insects often harm crops at the same time, the work can help make full use of CYC and reduce the environmental impacts of using multiple pesticides.


Assuntos
Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/farmacologia , Inseticidas/química , Inseticidas/farmacologia , Mariposas/efeitos dos fármacos , Piridinas/química , Piridinas/farmacologia , Sequência de Aminoácidos , Animais , Proteínas de Insetos/química , Proteínas de Insetos/genética , Proteínas de Insetos/metabolismo , Larva/efeitos dos fármacos , Larva/crescimento & desenvolvimento , Estrutura Molecular , Mariposas/química , Mariposas/genética , Mariposas/crescimento & desenvolvimento , Alinhamento de Sequência
15.
Food Chem Toxicol ; 136: 110963, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31715308

RESUMO

Excessive exposure to ultraviolet (UV) irradiation from the sun is the primary environmental factor that causes aging of the skin. Most skin diseases caused by UV are attributed to UVB (280-320 nm). The purpose of this study is to investigate the protective effect of diphlorethohydroxycarmalol (DPHC), isolated from the marine brown alga, Ishige okamurae, against UVB-induced photodamage using both in vitro and in vivo models. Results indicate that DPHC remarkably inhibited commercial collagenase and elastase activities. It also reduced intracellular levels of ROS, improved cell viability and collagen content in UVB-irradiated human dermal fibroblasts (HDF cells). In addition, DPHC significantly inhibited activities of intracellular collagenase and elastase and reduced the expression of matrix metalloproteinases (MMPs) and pro-inflammatory cytokines. These events occurred through regulation of nuclear factor kappa B (NF-κB), activator protein 1 (AP-1), and mitogen-activated protein kinases (MAPKs) signaling pathways in UVB-irradiated HDF cells. Furthermore, DPHC also protected against in vivo photodamage by decreasing cell death through reducing lipid peroxidation and inflammatory response via decreasing ROS levels in UVB-irradiated zebrafish. In conclusion, DPHC has strong in vitro and in vivo photoprotective effects and has the potential to be used as an ingredient in pharmaceutical and cosmeceutical industries.


Assuntos
Fibroblastos/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Feófitas/química , Protetores contra Radiação/uso terapêutico , Envelhecimento da Pele/efeitos dos fármacos , Animais , Sobrevivência Celular/efeitos dos fármacos , Colágeno/metabolismo , Colagenases/metabolismo , Fibroblastos/efeitos da radiação , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Metaloproteinases da Matriz/metabolismo , Elastase Pancreática/metabolismo , Protetores contra Radiação/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Envelhecimento da Pele/efeitos da radiação , Raios Ultravioleta , Peixe-Zebra
16.
Genes Genomics ; 42(3): 317-324, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31872384

RESUMO

BACKGROUND: Procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2) was induced in hypoxia and participated in cancer development. However, the role of PLOD2 in endometrial carcinoma remains unclear. OBJECTIVE: To explore the influences and regulation mechanism of PLOD2 in endometrial carcinoma under hypoxic condition. METHODS: The small interfering RNA (siRNA) targeting to PLOD2 and pcDNA3.1-PLPD2 were transfected to endometrial carcinoma cells to alter PLOD2 expression. Cell proliferation ability was determined by colony formation assay. Wound healing assay used to detect cell migration ability. Transwell invasion assay was used to detect cell invasion ability. RESULTS: PLOD2 and Hypoxia-inducible factor-1α (HIF-1α) were induced by hypoxia. Down-regulation of PLOD2 did not affect endometrial carcinoma cell proliferation ability, while inhibited cell migration, invasion under hypoxic condition. Besides, down-regulation of PLOD2 increased the levels of γ-catenin and E-cadherin and decreased levels of Fibronectin and Snail under hypoxic condition. Down-regulation of PLOD2 also inactivated Src and phosphoinositide 3-kinase (PI3K)/ protein kinase B (Akt) signaling under hypoxic condition. The promoting effects of PLOD2 overexpression on migration, invasion and epithelial-mesenchymal transition (EMT) of endometrial carcinoma cells were reversed by Akt inhibitor (MK2206) under hypoxic condition. CONCLUSION: PLOD2 expression was increased in endometrial carcinoma cells under hypoxic condition. PLOD2 modulated migration, invasion, and EMT of endometrial carcinoma cells via PI3K/Akt signaling. PLOD2 may be a potential therapeutic target for endometrial carcinoma.


Assuntos
Movimento Celular/genética , Neoplasias do Endométrio/metabolismo , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica/genética , Pró-Colágeno-Lisina 2-Oxoglutarato 5-Dioxigenase/metabolismo , Caderinas/metabolismo , Hipóxia Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação para Baixo , Neoplasias do Endométrio/enzimologia , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/secundário , Feminino , Fibronectinas/metabolismo , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Pró-Colágeno-Lisina 2-Oxoglutarato 5-Dioxigenase/genética , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Interferente Pequeno , Transdução de Sinais/genética , Fatores de Transcrição da Família Snail/metabolismo , gama Catenina/metabolismo , Quinases da Família src/metabolismo
17.
Mater Sci Eng C Mater Biol Appl ; 107: 110352, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31761165

RESUMO

In this study, we fabricated polyvinyl alcohol hydrogels containing diphlorethohydroxycarmalol (DPHC) from Ishige okamurae for its anti-bacterial effect in wound-dressing applications. First, the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of DPHC against Staphylococcus aureus and Pseudomonas aeruginosa were investigated, and these were found to be about 128 µg/mL and 512 µg/mL, respectively. Polyvinyl alcohol hydrogels loaded with different concentrations of DPHC were then produced for the dressing of wounds to assist in the healing process and to provide an antibacterial effect. To investigate the characteristics of the proposed PVA/DPHC hydrogels, we conducted SEM analysis, rheological analysis, thermogravimetric analysis, water swelling analysis, drug release testing, and gel fraction assessment. The antibacterial activity of the PVA/DPHC hydrogels was also tested against the gram-positive bacterium S. aureus and the gram-negative bacterium P. aeruginosa using ASTM E2149 tests. The biocompatibility of the PVA/DPHC hydrogels was assessed using in vitro indirect and direct contact tests and in vivo tests on ICR mice. The PVA/DPHC hydrogels exhibited the ability to reduce the viability of S. aureus and P. aeruginosa by about 99% in ASTM E2149 testing, while not producing any toxic effect on NHDF-Neo or HaCaT cells as shown in MTT assays and in vitro FDA fluorescence analysis. In addition, the PVA/DPHC hydrogels had a strong wound healing effect when compared to non-treated groups of ICR mice in vivo. Based on the characterization of the PVA/DPHC hydrogels in vitro and in vivo, this study suggests that the proposed hydrogel has significant potential for use in wound dressing.


Assuntos
Antibacterianos/farmacologia , Bandagens , Compostos Heterocíclicos com 3 Anéis/isolamento & purificação , Compostos Heterocíclicos com 3 Anéis/farmacologia , Hidrogéis/farmacologia , Cicatrização/efeitos dos fármacos , Animais , Antibacterianos/química , Células Cultivadas , Liberação Controlada de Fármacos , Humanos , Hidrogéis/química , Masculino , Camundongos Endogâmicos ICR , Testes de Sensibilidade Microbiana , Feófitas/química , Álcool de Polivinil/química , Pseudomonas aeruginosa/efeitos dos fármacos , Reologia , Staphylococcus aureus/efeitos dos fármacos , Termogravimetria
18.
Drugs ; 80(1): 61-72, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31865558

RESUMO

The oral once-daily, fixed-dose single-tablet regimen (STR) of dolutegravir/lamivudine (Dovato®), combining a second generation integrase single-strand transfer inhibitor (INSTI) and a nucleoside reverse transcriptase inhibitor (NRTI), is indicated as a complete regimen for the treatment of HIV-1 infection in adults and adolescents (> 12 years of age weighing at least 40 kg) with no known or suspected resistance to the INSTI class or lamivudine. In GEMINI trials in antiretroviral therapy (ART)-naïve HIV-1-infected adults, treatment with dolutegravir plus lamivudine provided rapid and sustained virological suppression and was noninferior to dolutegravir plus tenofovir disoproxil fumarate/emtricitabine at 48 weeks, irrespective of baseline patient or disease characteristics. Virological suppression was sustained at 96 weeks in these ongoing trials. In patients with HIV-1 with sustained virological suppression on their current tenofovir alafenamide (AF)-based ART regimen (≥ 3 drugs), switching to treatment with dolutegravir/lamivudine was noninferior to continuing on a tenofovir AF-based regimen at 48 weeks in the ongoing TANGO trial. No resistance mutations to dolutegravir or lamivudine were detected in patients who met criteria for confirmed virological withdrawal in GEMINI and TANGO trials. Hence, the dolutegravir/lamivudine STR is an effective, generally well tolerated and convenient initial and subsequent ART option for adolescents and adults with HIV-1 infection with no known or suspected resistance to the INSTI class or lamivudine.


Assuntos
Infecções por HIV/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Lamivudina/administração & dosagem , Adolescente , Adulto , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/farmacologia , Criança , Combinação de Medicamentos , Farmacorresistência Viral , HIV-1/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Lamivudina/efeitos adversos , Lamivudina/farmacologia , Comprimidos
19.
Biomed Pharmacother ; 121: 109572, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31704613

RESUMO

Colorectal Cancer (CRC) is highly heterogeneous for which prognosis is dependent mainly on clinical staging. There is a need to stratify subpopulations of CRC on molecular basis to better predict outcome and therapy response. Truncating mutations in adenomatous polyposis coli (APC) are well-described events in CRC carcinogenesis. Clinical and genotypic characterization of Middle Eastern CRC based on presence and type of APC was determined in 412 CRC tumors using modern next generation sequencing. APC truncating mutations were identified in 58.2% (240/412) of CRCs. Overall, mutation was significant predictor of superior overall survival. Further, the type of APC mutations (short or long) did not have impact on clinical outcome. However, in vitro analysis showed difference between CRC cell lines carrying short truncating APC vs CRC cells that carry long truncating APC mutation in response to 5-flourouracil (5-FU). Importantly, we were able to overcome the resistance to 5-FU seen in CRC cells carrying short APC by tankyrase inhibitor, XAV939, thereby inhibiting Wnt/ß-catenin signaling cascade. Overall, our results showed that APC mutation status plays an important role in predicting overall survival in Middle Eastern population. Furthermore, in vitro data showed that selective targeting of APC mutated CRC by tankyrase inhibitor can be an effective strategy to overcome 5-FU resistance in CRC cells.


Assuntos
Polipose Adenomatosa do Colo/genética , Antimetabólitos Antineoplásicos/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Fluoruracila/farmacologia , Idoso , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Resistencia a Medicamentos Antineoplásicos , Feminino , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Arábia Saudita , Sobrevida , Tanquirases/antagonistas & inibidores , Tanquirases/metabolismo , Via de Sinalização Wnt/genética
20.
Can Respir J ; 2019: 9107806, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31885751

RESUMO

Background: The small molecule inhibitor XAV939 could inhibit the proliferation and promote the apoptosis of non-small cell lung cancer (NSCLC) cells. This study was conducted to identify the key circular RNAs (circRNAs) and microRNAs (miRNAs) in XAV939-treated NSCLC cells. Methods: After grouping, the NCL-H1299 cells in the treatment group were treated by 10 µM XAV939 for 12 h. RNA-sequencing was performed, and then the differentially expressed circRNAs (DE-circRNAs) were analyzed by the edgeR package. Using the clusterprofiler package, enrichment analysis for the hosting genes of the DE-circRNAs was performed. Using Cytoscape software, the miRNA-circRNA regulatory network was built for the disease-associated miRNAs and the DE-circRNAs. The DE-circRNAs that could translate into proteins were predicted using circBank database and IRESfinder tool. Finally, the transcription factor (TF)-circRNA regulatory network was built by Cytoscape software. In addition, A549 and HCC-827 cell treatment with XAV939 were used to verify the relative expression levels of key DE-circRNAs. Results: There were 106 DE-circRNAs (including 61 upregulated circRNAs and 45 downregulated circRNAs) between treatment and control groups. Enrichment analysis for the hosting genes of the DE-circRNAs showed that ATF2 was enriched in the TNF signaling pathway. Disease association analysis indicated that 8 circRNAs (including circ_MDM2_000139, circ_ATF2_001418, circ_CDC25C_002079, and circ_BIRC6_001271) were correlated with NSCLC. In the miRNA-circRNA regulatory network, let-7 family members⟶circ_MDM2_000139, miR-16-5p/miR-134-5p⟶circ_ATF2_001418, miR-133b⟶circ_BIRC6_001271, and miR-221-3p/miR-222-3p⟶circ_CDC25C_002079 regulatory pairs were involved. A total of 47 DE-circRNAs could translate into proteins. Additionally, circ_MDM2_000139 was targeted by the TF POLR2A. The verification test showed that the relative expression levels of circ_MDM2_000139, circ_CDC25C_002079, circ_ATF2_001418, and circ_DICER1_000834 in A549 and HCC-827 cell treatment with XAV939 were downregulated comparing with the control. Conclusions: Let-7 family members and POLR2A targeting circ_MDM2_000139, miR-16-5p/miR-134-5p targeting circ_ATF2_001418, miR-133b targeting circ_BIRC6_001271, and miR-221-3p/miR-222-3p targeting circ_CDC25C_002079 might be related to the mechanism in the treatment of NSCLC by XAV939.


Assuntos
Compostos Heterocíclicos com 3 Anéis/farmacologia , MicroRNAs/efeitos dos fármacos , RNA Circular/efeitos dos fármacos , Transcriptoma/efeitos dos fármacos , Fator 2 Ativador da Transcrição/genética , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Proteínas Inibidoras de Apoptose/genética , Proteínas Proto-Oncogênicas c-mdm2/genética , Análise de Sequência de RNA , Fosfatases cdc25/genética
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