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1.
Anticancer Res ; 40(10): 5539-5544, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988877

RESUMO

BACKGROUND/AIM: Endothelin-1 (ET-1) is overexpressed in many types of cancer, inhibiting the release of the microRNA 15a (miR-15a) and inducing the production of Mxi-2. Our aim was to identify a molecular complex regulating p53 activity in prostate cancer (PCa). MATERIALS AND METHODS: DU145 cells were treated with ET-1, MAPK p38 inhibitor, Endothelin A receptor inhibitor (ETAR inhibitor) and Endothelin B receptor inhibitor (ETBR inhibitor). Extracts were analysed using Western Blot, immunoprecipitation and qRT-PCR. Furthermore, prostate cancer patient samples were analysed using qRT-PCR and ELISA. RESULTS: The hypothesised molecular complex was identified, with miR-15a, microRNA 1285 (miR-1285) and Mxi-2 levels up-regulated in patients in relation to increasing aggressiveness of PCa. CONCLUSION: A complex composed of Argonaut 2 (Ago2)/Mxi-2/miR-1285 is involved in PCa. The expression of Mxi-2 correlates with increasing PCa aggressiveness and might be used as a non-invasive marker for the diagnosis and progression of PCa.


Assuntos
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteína Quinase 14 Ativada por Mitógeno/genética , Neoplasias da Próstata/genética , Proteína Supressora de Tumor p53/genética , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Argonauta/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Antagonistas do Receptor de Endotelina A/farmacologia , Antagonistas do Receptor de Endotelina B/farmacologia , Humanos , Masculino , MicroRNAs/genética , Neoplasias da Próstata/patologia , Receptor de Endotelina A/genética , Receptor de Endotelina B/genética , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores
2.
PLoS One ; 15(8): e0237442, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32790767

RESUMO

BACKGROUND: Prostate cancer (PCa) is the most commonly diagnosed cancer and the second leading cause of cancer-related deaths among adult males globally. The poor prognosis of PCa is largely due to late diagnosis of the disease when it has already progressed to an advanced stage marked by androgen-independence, thus necessitating new strategies for early detection and treatment. We construe that these direly needed advances are limited by our poor understanding of early events in the progression of PCa and that would thus represent ideal targets for early intervention. To begin to fill this void, we interrogated molecular "oncophenotypes" that embody the transition of PCa from an androgen-dependent (AD) to-independent (AI) state. METHODS: To accomplish this aim, we used our previously established AD and AI murine PCa cell lines, PLum-AD and PLum-AI, respectively, which recapitulate primary and progressive PCa morphologically and molecularly. We statistically surveyed global gene expressions in these cell lines by microarray analysis. Differential profiles were functionally interrogated by pathways, gene set enrichment and topological gene network analyses. RESULTS: Gene expression analysis of PLum-AD and PLum-AI transcriptomes (n = 3 each), revealed 723 differentially expressed genes (392 upregulated and 331 downregulated) in PLum-AI compared to PLum-AD cells. Gene set analysis demonstrated enrichment of biological functions and pathways in PLum-AI cells that are central to tumor aggressiveness including cell migration and invasion facilitated by epithelial-to-mesenchymal transition (EMT). Further analysis demonstrated that the p38 mitogen-activated protein kinase (MAPK) was predicted to be significantly activated in the PLum-AI cells, whereas gene sets previously associated with favorable response to the p38 inhibitor SB203580 were attenuated (i.e., inversely enriched) in the PLum-AI cells, suggesting that these aggressive cells may be therapeutically vulnerable to p38 inhibition. Gene set and gene-network analysis also alluded to activation of other signaling networks particularly those associated with enhanced EMT, inflammation and immune function/response including, but not limited to Tnf, IL-6, Mmp 2, Ctgf, and Ptges. Accordingly, we chose SB203580 and IL-6 to validate their effect on PLum-AD and PLum-AI. Some of the common genes identified in the gene-network analysis were validated at the molecular and functional level. Additionally, the vulnerability to SB203580 and the effect of IL-6 were also validated on the stem/progenitor cell population using the sphere formation assay. CONCLUSIONS: In summary, our study highlights pathways associated with an augmented malignant phenotype in AI cells and presents new high-potential targets to constrain the aggressive malignancy seen in the castration-resistant PCa.


Assuntos
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Imidazóis/farmacologia , Interleucina-6/farmacologia , Neoplasias da Próstata/patologia , Piridinas/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Androgênios/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Progressão da Doença , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Redes Reguladoras de Genes/genética , Imidazóis/uso terapêutico , Interleucina-6/uso terapêutico , Masculino , Camundongos , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Piridinas/uso terapêutico , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
3.
Cell ; 182(3): 685-712.e19, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32645325

RESUMO

The causative agent of the coronavirus disease 2019 (COVID-19) pandemic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected millions and killed hundreds of thousands of people worldwide, highlighting an urgent need to develop antiviral therapies. Here we present a quantitative mass spectrometry-based phosphoproteomics survey of SARS-CoV-2 infection in Vero E6 cells, revealing dramatic rewiring of phosphorylation on host and viral proteins. SARS-CoV-2 infection promoted casein kinase II (CK2) and p38 MAPK activation, production of diverse cytokines, and shutdown of mitotic kinases, resulting in cell cycle arrest. Infection also stimulated a marked induction of CK2-containing filopodial protrusions possessing budding viral particles. Eighty-seven drugs and compounds were identified by mapping global phosphorylation profiles to dysregulated kinases and pathways. We found pharmacologic inhibition of the p38, CK2, CDK, AXL, and PIKFYVE kinases to possess antiviral efficacy, representing potential COVID-19 therapies.


Assuntos
Betacoronavirus/metabolismo , Infecções por Coronavirus/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Pneumonia Viral/metabolismo , Proteômica/métodos , Células A549 , Animais , Antivirais/farmacologia , Células CACO-2 , Caseína Quinase II/antagonistas & inibidores , Caseína Quinase II/metabolismo , Chlorocebus aethiops , Infecções por Coronavirus/virologia , Quinases Ciclina-Dependentes/antagonistas & inibidores , Quinases Ciclina-Dependentes/metabolismo , Células HEK293 , Interações Hospedeiro-Patógeno , Humanos , Pandemias , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Fosforilação , Pneumonia Viral/virologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Células Vero , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
4.
Cell ; 182(3): 685-712.e19, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: covidwho-624826

RESUMO

The causative agent of the coronavirus disease 2019 (COVID-19) pandemic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected millions and killed hundreds of thousands of people worldwide, highlighting an urgent need to develop antiviral therapies. Here we present a quantitative mass spectrometry-based phosphoproteomics survey of SARS-CoV-2 infection in Vero E6 cells, revealing dramatic rewiring of phosphorylation on host and viral proteins. SARS-CoV-2 infection promoted casein kinase II (CK2) and p38 MAPK activation, production of diverse cytokines, and shutdown of mitotic kinases, resulting in cell cycle arrest. Infection also stimulated a marked induction of CK2-containing filopodial protrusions possessing budding viral particles. Eighty-seven drugs and compounds were identified by mapping global phosphorylation profiles to dysregulated kinases and pathways. We found pharmacologic inhibition of the p38, CK2, CDK, AXL, and PIKFYVE kinases to possess antiviral efficacy, representing potential COVID-19 therapies.


Assuntos
Betacoronavirus/metabolismo , Infecções por Coronavirus/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Pneumonia Viral/metabolismo , Proteômica/métodos , Células A549 , Animais , Antivirais/farmacologia , Células CACO-2 , Caseína Quinase II/antagonistas & inibidores , Caseína Quinase II/metabolismo , Chlorocebus aethiops , Infecções por Coronavirus/virologia , Quinases Ciclina-Dependentes/antagonistas & inibidores , Quinases Ciclina-Dependentes/metabolismo , Células HEK293 , Interações Hospedeiro-Patógeno , Humanos , Pandemias , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Fosforilação , Pneumonia Viral/virologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Células Vero , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
5.
Life Sci ; 256: 117885, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32485175

RESUMO

Inflammatory and neuropathic pain is initiated by tissue inflammation and nerve injury, respectively. Both are characterized by increased activity in the peripheral and central nervous system, where multiple inflammatory cytokines and other active molecules activate different signaling pathways that involve in the development and/or maintenance of pain. P38 mitogen-activated protein kinase (MAPK) is one member of the MAPK family, which is activated in neurons and glia and contributes importantly to inflammatory and neuropathic pain. The aim of this review is to summarize the latest advances made about the implication of p38 MAPK signaling cascade in pain. It can deepen our understanding of the molecular mechanisms of pain and may help to offer new targets for pain treatment.


Assuntos
Dor/enzimologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Ensaios Clínicos como Assunto , Ativação Enzimática , Humanos , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores
6.
J Mol Cell Cardiol ; 144: 63-65, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32422320

RESUMO

COVID-19, caused by the SARS-CoV-2 virus, is a major source of morbidity and mortality due to its inflammatory effects in the lungs and heart. The p38 MAPK pathway plays a crucial role in the release of pro-inflammatory cytokines such as IL-6 and has been implicated in acute lung injury and myocardial dysfunction. The overwhelming inflammatory response in COVID-19 infection may be caused by disproportionately upregulated p38 activity, explained by two mechanisms. First, angiotensin-converting enzyme 2 (ACE2) activity is lost during SARS-CoV-2 viral entry. ACE2 is highly expressed in the lungs and heart and converts Angiotensin II into Angiotensin 1-7. Angiotensin II signals proinflammatory, pro-vasoconstrictive, pro-thrombotic activity through p38 MAPK activation, which is countered by Angiotensin 1-7 downregulation of p38 activity. Loss of ACE2 upon viral entry may tip the balance towards destructive p38 signaling through Angiotensin II. Second, SARS-CoV was previously shown to directly upregulate p38 activity via a viral protein, similar to other RNA respiratory viruses that may hijack p38 activity to promote replication. Given the homology between SARS-CoV and SARS-CoV-2, the latter may employ a similar mechanism. Thus, SARS-CoV-2 may induce overwhelming inflammation by directly activating p38 and downregulating a key inhibitory pathway, while simultaneously taking advantage of p38 activity to replicate. Therapeutic inhibition of p38 could therefore attenuate COVID-19 infection. Interestingly, a prior preclinical study showed protective effects of p38 inhibition in a SARS-CoV mouse model. A number of p38 inhibitors are in the clinical stage and should be considered for clinical trials in serious COVID-19 infection.


Assuntos
Antivirais/farmacologia , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Animais , Betacoronavirus/patogenicidade , Infecções por Coronavirus/enzimologia , Ativação Enzimática , Interações Hospedeiro-Patógeno/fisiologia , Humanos , Inflamação/tratamento farmacológico , Inflamação/virologia , Pulmão/metabolismo , Pulmão/fisiopatologia , Pulmão/virologia , Pandemias , Pneumonia Viral/enzimologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
7.
J Mol Cell Cardiol ; 144: 63-65, 2020 07.
Artigo em Inglês | MEDLINE | ID: covidwho-276660

RESUMO

COVID-19, caused by the SARS-CoV-2 virus, is a major source of morbidity and mortality due to its inflammatory effects in the lungs and heart. The p38 MAPK pathway plays a crucial role in the release of pro-inflammatory cytokines such as IL-6 and has been implicated in acute lung injury and myocardial dysfunction. The overwhelming inflammatory response in COVID-19 infection may be caused by disproportionately upregulated p38 activity, explained by two mechanisms. First, angiotensin-converting enzyme 2 (ACE2) activity is lost during SARS-CoV-2 viral entry. ACE2 is highly expressed in the lungs and heart and converts Angiotensin II into Angiotensin 1-7. Angiotensin II signals proinflammatory, pro-vasoconstrictive, pro-thrombotic activity through p38 MAPK activation, which is countered by Angiotensin 1-7 downregulation of p38 activity. Loss of ACE2 upon viral entry may tip the balance towards destructive p38 signaling through Angiotensin II. Second, SARS-CoV was previously shown to directly upregulate p38 activity via a viral protein, similar to other RNA respiratory viruses that may hijack p38 activity to promote replication. Given the homology between SARS-CoV and SARS-CoV-2, the latter may employ a similar mechanism. Thus, SARS-CoV-2 may induce overwhelming inflammation by directly activating p38 and downregulating a key inhibitory pathway, while simultaneously taking advantage of p38 activity to replicate. Therapeutic inhibition of p38 could therefore attenuate COVID-19 infection. Interestingly, a prior preclinical study showed protective effects of p38 inhibition in a SARS-CoV mouse model. A number of p38 inhibitors are in the clinical stage and should be considered for clinical trials in serious COVID-19 infection.


Assuntos
Antivirais/farmacologia , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Animais , Betacoronavirus/patogenicidade , Infecções por Coronavirus/enzimologia , Ativação Enzimática , Interações Hospedeiro-Patógeno/fisiologia , Humanos , Inflamação/tratamento farmacológico , Inflamação/virologia , Pulmão/metabolismo , Pulmão/fisiopatologia , Pulmão/virologia , Pandemias , Pneumonia Viral/enzimologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
8.
Nat Commun ; 11(1): 1711, 2020 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-32249764

RESUMO

Recently, organoid technology has been used to generate a large repository of breast cancer organoids. Here we present an extensive evaluation of the ability of organoid culture technology to preserve complex stem/progenitor and differentiated cell types via long-term propagation of normal human mammary tissues. Basal/stem and luminal progenitor cells can differentiate in culture to generate mature basal and luminal cell types, including ER+ cells that have been challenging to maintain in culture. Cells associated with increased cancer risk can also be propagated. Single-cell analyses of matched organoid cultures and native tissues by mass cytometry for 38 markers provide a higher resolution representation of the multiple mammary epithelial cell types in the organoids, and demonstrate that protein expression patterns of the tissue of origin can be preserved in culture. These studies indicate that organoid cultures provide a valuable platform for studies of mammary differentiation, transformation, and breast cancer risk.


Assuntos
Técnicas de Cultura de Células/métodos , Linhagem da Célula , Glândulas Mamárias Humanas/citologia , Organoides/citologia , Organoides/metabolismo , Células-Tronco/citologia , Adulto , Proteína BRCA1/genética , Neoplasias da Mama , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Linhagem da Célula/genética , Fator de Crescimento Epidérmico/farmacologia , Receptores ErbB/metabolismo , Feminino , Humanos , Glândulas Mamárias Humanas/química , Glândulas Mamárias Humanas/metabolismo , Pessoa de Meia-Idade , Organoides/química , Análise de Célula Única , Células-Tronco/química , Células-Tronco/metabolismo , Fator de Crescimento Transformador beta/antagonistas & inibidores , Adulto Jovem , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores
9.
Toxicol Appl Pharmacol ; 395: 114981, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32240662

RESUMO

What factors and underlying mechanisms influence the occurrence of the atopic march remain unclear. Recent studies suggest that exposure to diisononyl phthalate (DINP) might be associated with the occurrence of atopic dermatitis (AD) and asthma. However, little is known about the role of DINP exposure in the atopic march. In this study, we investigated the effect of DINP exposure on the progression from AD to asthma, and explored the potential mechanisms. We built an atopic march mouse model from AD to asthma, by exposure to DINP and sensitization with OVA. Pyrrolidine dithiocarbamate and SB203580 were used to block NF-κB and p38 MAPK respectively, to explore the possible molecular mechanisms. The data showed that DINP aggravated airway remodeling and airway hyperresponsiveness (AhR) in the progression from AD to asthma, induced a sharp increase in IL-33, IgE, Th2 and Th17 cytokines, and resulted in an increase in the expression of thymic stromal lymphopoietin (TSLP) and in the number of inflammatory cells. Blocking NF-κB inhibited AD-like lesions, and the production of IL-33 and TSLP in the progression of AD, while alleviating airway remodeling, AhR, and the expression of Th2 and Th17 cytokines in both the progression of AD and the asthmatic phenotype. Blocking p38 MAPK in the progression of asthma, inhibited airway remodeling, AhR, and the expression of Th2 and Th17 cytokines. The results demonstrated that exposure to DINP enhanced the immune response to memory CD4+ T helper cells through the NF-κB and p38 MAPK signaling pathways, leading to an aggravation of the atopic march.


Assuntos
Hipersensibilidade Imediata/induzido quimicamente , NF-kappa B/fisiologia , Ácidos Ftálicos/toxicidade , Proteínas Quinases p38 Ativadas por Mitógeno/fisiologia , Remodelação das Vias Aéreas/efeitos dos fármacos , Animais , Asma/induzido quimicamente , Citocinas/biossíntese , Dermatite Atópica/induzido quimicamente , Modelos Animais de Doenças , Progressão da Doença , Ativação Enzimática/efeitos dos fármacos , Hipersensibilidade Imediata/imunologia , Hipersensibilidade Imediata/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/antagonistas & inibidores , Ovalbumina/imunologia , Hipersensibilidade Respiratória/induzido quimicamente , Transdução de Sinais/efeitos dos fármacos , Organismos Livres de Patógenos Específicos , Células Th17/imunologia , Células Th2/imunologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores
10.
Nat Commun ; 11(1): 1943, 2020 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-32327648

RESUMO

Kidney fibrosis is a highly deleterious process and a final manifestation of chronic kidney disease. Alpha-(α)-synuclein (SNCA) is an actin-binding neuronal protein with various functions within the brain; however, its role in other tissues is unknown. Here, we describe the expression of SNCA in renal epithelial cells and demonstrate its decrease in renal tubules of murine and human fibrotic kidneys, as well as its downregulation in renal proximal tubular epithelial cells (RPTECs) after TGF-ß1 treatment. shRNA-mediated knockdown of SNCA in RPTECs results in de novo expression of vimentin and α-SMA, while SNCA overexpression represses TGF-ß1-induced mesenchymal markers. Conditional gene silencing of SNCA in RPTECs leads to an exacerbated tubulointerstitial fibrosis (TIF) in two unrelated in vivo fibrotic models, which is associated with an increased activation of MAPK-p38 and PI3K-Akt pathways. Our study provides an evidence that disruption of SNCA signaling in RPTECs contributes to the pathogenesis of renal TIF by facilitating partial epithelial-to-mesenchymal transition and extracellular matrix accumulation.


Assuntos
Nefropatias/patologia , Rim/patologia , alfa-Sinucleína/metabolismo , Actinas/genética , Actinas/metabolismo , Animais , Linhagem Celular , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Fibrose , Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Rim/metabolismo , Nefropatias/genética , Nefropatias/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Fenótipo , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta1/farmacologia , Obstrução Ureteral/genética , Obstrução Ureteral/metabolismo , Obstrução Ureteral/patologia , Vimentina/genética , Vimentina/metabolismo , alfa-Sinucleína/genética , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
11.
Nat Immunol ; 21(6): 615-625, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32251403

RESUMO

Increasing age alters innate immune-mediated responses; however, the mechanisms underpinning these changes in humans are not fully understood. Using a human dermal model of acute inflammation, we found that, although inflammatory onset is similar between young and elderly individuals, the resolution phase was substantially impaired in elderly individuals. This arose from a reduction in T cell immunoglobulin mucin receptor-4 (TIM-4), a phosphatidylserine receptor expressed on macrophages that enables the engulfment of apoptotic bodies, so-called efferocytosis. Reduced TIM-4 in elderly individuals was caused by an elevation in macrophage p38 mitogen-activated protein kinase (MAPK) activity. Administering an orally active p38 inhibitor to elderly individuals rescued TIM-4 expression, cleared apoptotic bodies and restored a macrophage resolution phenotype. Thus, inhibiting p38 in elderly individuals rejuvenated their resolution response to be more similar to that of younger people. This is the first resolution defect identified in humans that has been successfully reversed, thereby highlighting the tractability of targeting pro-resolution biology to treat diseases driven by chronic inflammation.


Assuntos
Inflamação/etiologia , Inflamação/metabolismo , Fagocitose/imunologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Fatores Etários , Idoso , Animais , Apoptose , Vesícula/imunologia , Vesícula/metabolismo , Vesícula/patologia , Cantaridina , Expressão Gênica , Humanos , Imunidade Inata , Inflamação/patologia , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Neutrófilos/imunologia , Neutrófilos/metabolismo , Neutrófilos/patologia , Receptores de Superfície Celular/metabolismo , Transdução de Sinais
12.
Mol Immunol ; 120: 13-22, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32045770

RESUMO

OBJECTIVE: To investigate the impact of death-associated protein kinase 1 (Dapk1) on lipopolysaccharide (LPS)-induced acute lung injury (ALI) via p38MAPK/NF-κB pathway. METHODS: Dapk1+/+ and Dapk1-/- mice were randomized into Control, LPS, SB203580 (a p38MAPK pathway inhibitor) + LPS, and PDTC (a NF-κB pathway inhibitor) + LPS groups. Cell counts, lung wet to dry weight ratio (W/D weight ratio), as well as indicators of oxidative stress were determined followed by the detection with HE staining, ELISA, qRT-PCR, Western blotting and Immunofluorescence. Besides, to explore whether the effect of Dapk1 on ALI directly mediated via p38MAPK/NF-κB pathway, mice were injected with TC-DAPK 6 (a Dapk1 inhibitor) with or without SB203580/PDTC before LPS administration. RESULTS: LPS induced lung injury with increased lung W/D weight ratio, which could be partly reversed by SB203580 and PDTC in LPS-induced mice with activated p38MAPK/NF-κB pathway in lung tissues, especially in Dapk1-/- mice. SB203580 and PDTC reduced total cells and neutrophils in BALF in LPS-induced mice, accompanying with decreased levels of TNF-α, IL-6, MPO, LPO and MDA and the expressions of beclin-1, Atg5 and LC3II, but with the up-regulated activities of SOD and GSH-Px, as well as p62 protein expression. Besides, TC-DAPK 6 aggravated the pathologic injury in LPS-induced ALI with more serious inflammatory response, oxidative stress and autophagy as well as the activated p38MAPK/NF-κB pathway, which were reversed by SB203580 or PDTC. CONCLUSION: Dapk1 improved oxidative stress, inhibited autophagy, and reduce inflammatory response of LPS-induced ALI mice by inhibiting p38MAPK/NF-κB pathway.


Assuntos
Lesão Pulmonar Aguda/metabolismo , Proteínas Quinases Associadas com Morte Celular/metabolismo , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/patologia , Animais , Autofagia , Proteínas Quinases Associadas com Morte Celular/deficiência , Proteínas Quinases Associadas com Morte Celular/genética , Imidazóis/farmacologia , Inflamação/metabolismo , Inflamação/patologia , Lipopolissacarídeos/toxicidade , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Estresse Oxidativo , Piridinas/farmacologia , Pirrolidinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Tiocarbamatos/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
13.
J Leukoc Biol ; 107(4): 663-671, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32017227

RESUMO

This study tests the hypothesis that activation of MAPK by physiologically relevant concentrations of IL-33 contributes to enhanced cytokine expression by IL-12 stimulated human NK cells. While IL-33 canonically triggers type 2 cytokine responses, this cytokine can also synergize with type 1 cytokines like IL-12 to provoke IFN-γ. We show that picogram concentrations of IL-12 and IL-33 are sufficient to promote robust secretion of IFN-γ by human NK cells that greatly exceeds resposes to either cytokine alone. Nanogram doses of IL-33, potentially consistent with levels in tissue microenvironments, synergize with IL-12 to induce secretion of additional cytokines, including TNF and GM-CSF. IL-33-induced activation of the p38 MAPK pathway in human NK cells is crucial for enhanced release of IFN-γ and TNF in response to IL-12. Mechanistically, IL-33-induced p38 MAPK signaling enhances stability of IFNG transcripts and triggers A disintegrin and metalloproteinase domain 17 (ADAM17) mediated cleavage of TNF from the cell surface. These data support our hypothesis and suggest that altered sensitivity of NK cells to IL-12 in the presence of IL-33 may have important consequences in diseases associated with mixed cytokine milieus, like asthma and chronic obstructive pulmonary disease.


Assuntos
Citocinas/metabolismo , Interleucina-33/metabolismo , Células Matadoras Naturais/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Proteína ADAM17/metabolismo , Linhagem Celular , Humanos , Interferon gama/genética , Interferon gama/metabolismo , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Interleucina-12/metabolismo , Fosforilação , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fator de Transcrição STAT4/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores
14.
DNA Cell Biol ; 39(4): 513-521, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31999475

RESUMO

The apoptosis of human lens epithelial cells (HLECs) is a characteristic change that occurs during the development of cataracts. Ultraviolet B (UVB) is known to induce the generation of reactive oxygen species (ROS) and apoptosis in HLECs, and thus cause cataracts. Previously, we reported the functions of cartilage acidic protein 1 (CRTAC1) in UVB-treated HLECs. However, the underlying mechanism was not known. In this study, we found that CRTAC1 expression and nuclear factor-kappa B (NF-κB) p65 nuclear translocation were elevated in capsule tissues of cataract patients in comparison with normal controls. The NF-κB inhibitor, pyrrolidine dithiocarbamate (PDTC), alleviated UVB-induced apoptosis in HLECs; while activation of NF-κB suppressed the effects of the ROS inhibitor, N-acetyl-L-cysteine (NAC), on UVB-treated HLECs. The expression and promoter activity of CRTAC1 was inhibited by PDTC and NAC. Moreover, the suppressed effects of CRTAC1 knockdown on UVB-induced ROS generation, cell apoptosis, nuclear translocation of NF-κB p65, and p38 phosphorylation were attenuated by a p38 agonist. In contrast, the p38 inhibitor abolished the promotional effects of CRTAC1 overexpression on HLECs. Taken together, our results for the first time show that NF-κB is a potential transcription factor for CRTAC1. The regulatory network involving NF-κB, CRTAC1, and p38 may therefore play an important role in cataract formation.


Assuntos
Apoptose/fisiologia , Proteínas de Ligação ao Cálcio/metabolismo , Catarata/patologia , Cristalino/patologia , Fator de Transcrição RelA/metabolismo , Acetilcisteína/farmacologia , Proteínas de Ligação ao Cálcio/genética , Células Cultivadas , Células Epiteliais/patologia , Humanos , Cristalino/citologia , Pirrolidinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Tiocarbamatos/farmacologia , Raios Ultravioleta , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
15.
Biochem Pharmacol ; 174: 113825, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31987854

RESUMO

We have previously reported that the spinal angiotensin (Ang) system is involved in the modulation of streptozotocin (STZ)-induced diabetic neuropathic pain in mice. An important drawback of this model however is the fact that the neuropathic pain is independent of hyperglycemia and produced by the direct stimulation of peripheral nerves. Here, using the leptin deficient ob/ob mouse as a type 2 diabetic model, we examined whether the spinal Ang system was involved in naturally occuring diabetic neuropathic pain. Blood glucose levels were increased in ob/ob mice at 5-15 weeks of age. Following the hyperglycemia, persistent tactile and thermal hyperalgesia were observed at 11-14 and 9-15 weeks of age, respectively, which was ameliorated by insulin treatment. At 12 weeks of age, the expression of Ang-converting enzyme (ACE) 2 in the spinal plasma membrane fraction was decreased in ob/ob mice. Spinal ACE2 was expressed in neurons and microglia but the number of NeuN-positive neurons was decreased in ob/ob mice. In addition, the intrathecal administration of Ang (1-7) and SB203580, a p38 MAPK inhibitor, attenuated hyperalgesia in ob/ob mice. The phosphorylation of spinal p38 MAPK was also attenuated by Ang (1-7) in ob/ob mice. These inhibitory effects of Ang (1-7) were prevented by A779, a Mas receptor antagonist. In conclusion, we revealed that the Ang (1-7)-generating system is downregulated in ob/ob mice and is accompanied by a loss of ACE2-positive neurons. Furthermore, Ang (1-7) decreased the diabetic neuropathic pain through inhibition of p38 MAPK phosphorylation via spinal Mas receptors.


Assuntos
Diabetes Mellitus Experimental/enzimologia , Diabetes Mellitus Tipo 2/enzimologia , Regulação para Baixo/fisiologia , Neuralgia/enzimologia , Peptidil Dipeptidase A/deficiência , Medula Espinal/enzimologia , Angiotensina I/metabolismo , Angiotensina I/farmacologia , Animais , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Regulação para Baixo/efeitos dos fármacos , Masculino , Camundongos , Camundongos Knockout , Camundongos Obesos , Camundongos Transgênicos , Neuralgia/genética , Neuralgia/patologia , Fragmentos de Peptídeos/metabolismo , Fragmentos de Peptídeos/farmacologia , Peptidil Dipeptidase A/genética , Medula Espinal/efeitos dos fármacos , Medula Espinal/patologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
16.
J Biol Chem ; 295(7): 2057-2067, 2020 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-31915244

RESUMO

Macrolide antibiotics, such as erythromycin and josamycin, are natural polyketide products harboring 14- to 16-membered macrocyclic lactone rings to which various sugars are attached. These antibiotics are used extensively in the clinic because of their ability to inhibit bacterial protein synthesis. More recently, some macrolides have been shown to also possess anti-inflammatory and other therapeutic activities in mammalian cells. To better understand the targets and effects of this drug class in mammalian cells, we used a genome-wide shRNA screen in K562 cancer cells to identify genes that modulate cellular sensitivity to josamycin. Among the most sensitizing hits were proteins involved in mitochondrial translation and the mitochondrial unfolded protein response, glycolysis, and the mitogen-activated protein kinase signaling cascade. Further analysis revealed that cells treated with josamycin or other antibacterial agents exhibited impaired oxidative phosphorylation and metabolic shifts to glycolysis. Interestingly, we observed that knockdown of the mitogen-activated protein kinase kinase kinase 4 (MAP3K4) gene, which contributes to p38 mitogen-activated protein kinase signaling, sensitized cells only to josamycin but not to other antibacterial agents. There is a growing interest in better characterizing the therapeutic effects and toxicities of antibiotics in mammalian cells to guide new applications in both cellular and clinical studies. To our knowledge, this is the first report of an unbiased genome-wide screen to investigate the effects of a clinically used antibiotic on human cells.


Assuntos
Antibacterianos/farmacologia , MAP Quinase Quinase Quinase 4/genética , Biossíntese de Proteínas/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Animais , Antibacterianos/efeitos adversos , Resistência Microbiana a Medicamentos/efeitos dos fármacos , Eritromicina/efeitos adversos , Eritromicina/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Glicólise/efeitos dos fármacos , Humanos , Josamicina/efeitos adversos , Josamicina/farmacologia , Células K562 , MAP Quinase Quinase Quinase 4/antagonistas & inibidores , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Macrolídeos/efeitos adversos , Macrolídeos/farmacologia , Proteínas Quinases Ativadas por Mitógeno/genética , Fosforilação Oxidativa/efeitos dos fármacos , Inibidores da Síntese de Proteínas/efeitos adversos , Inibidores da Síntese de Proteínas/farmacologia , Resposta a Proteínas não Dobradas/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores
17.
Gynecol Oncol ; 156(1): 23-31, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31791552

RESUMO

OBJECTIVE: This phase 1b/2 clinical trial (NCT01663857) evaluated the efficacy of ralimetinib in combination with gemcitabine (G) and carboplatin (C), followed by maintenance ralimetinib, for patients with recurrent platinum-sensitive epithelial ovarian cancer. METHODS: Phase 1b was to determine the recommended phase 2 dose (RP2D) of ralimetinib administered Q12H on Days 1-10 (q21d) in combination with G (1000 mg/m2, Days 3 and 10) and C (AUC 4, Day 3) for six cycles. In phase 2, patients were randomized double-blind 1:1 to ralimetinib (R)+GC or placebo (P)+GC, for six cycles, followed by ralimetinib 300 mg Q12H or placebo on Days 1-14, q28d. RESULTS: 118 patients received at least one dose of ralimetinib or placebo; eight in phase 1b and 110 in phase 2 (R+GC, N = 58; P+GC, N = 52). The RP2D for R+GC was 200 mg Q12H. The study met its primary objective of a statistically significant difference in PFS (median: R+GC, 10.3 mo vs. P+GC, 7.9 mo; hazard ratio [HR] = 0.773, P = 0.2464, against a two-sided false positive rate of 0.4). Secondary objectives were not statistically significant for median overall survival (R+GC, 29.2 mo vs. P+GC, 25.1 mo; HR = 0.827, P = 0.4686) or overall response rate (R+GC 46.6% vs. P+GC, 46.2%; P = 0.9667). The safety profile of R+GC therapy was mainly consistent with safety of the chemotherapy backbone alone. Grade 3/4 elevated alanine aminotransferase was more common in the ralimetinib arm. CONCLUSIONS: Addition of ralimetinib to GC resulted in a modest improvement in PFS.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Epitelial do Ovário/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Método Duplo-Cego , Feminino , Humanos , Imidazóis/administração & dosagem , Imidazóis/efeitos adversos , Quimioterapia de Manutenção , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Adulto Jovem , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores
18.
Gut ; 69(2): 365-379, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31076403

RESUMO

OBJECTIVE: Hepatocellular carcinoma (HCC), mostly developed in fibrotic/cirrhotic liver, exhibits relatively low responsiveness to immune checkpoint blockade (ICB) therapy. As myeloid-derived suppressor cell (MDSC) is pivotal for immunosuppression, we investigated its role and regulation in the fibrotic microenvironment with an aim of developing mechanism-based combination immunotherapy. DESIGN: Functional significance of MDSCs was evaluated by flow cytometry using two orthotopic HCC models in fibrotic liver setting via carbon tetrachloride or high-fat high-carbohydrate diet and verified by clinical specimens. Mechanistic studies were conducted in human hepatic stellate cell (HSC)-peripheral blood mononuclear cell culture systems and fibrotic-HCC patient-derived MDSCs. The efficacy of single or combined therapy with anti-programmed death-1-ligand-1 (anti-PD-L1) and a clinically trialled BET bromodomain inhibitor i-BET762 was determined. RESULTS: Accumulation of monocytic MDSCs (M-MDSCs), but not polymorphonuclear MDSCs, in fibrotic livers significantly correlated with reduced tumour-infiltrating lymphocytes (TILs) and increased tumorigenicity in both mouse models. In human HCCs, the tumour-surrounding fibrotic livers were markedly enriched with M-MDSC, with its surrogate marker CD33 significantly associated with aggressive tumour phenotypes and poor survival rates. Mechanistically, activated HSCs induced monocyte-intrinsic p38 MAPK signalling to trigger enhancer reprogramming for M-MDSC development and immunosuppression. Treatment with p38 MAPK inhibitor abrogated HSC-M-MDSC crosstalk to prevent HCC growth. Concomitant with patient-derived M-MDSC suppression by i-BET762, combined treatment with anti-PD-L1 synergistically enhanced TILs, resulting in tumour eradication and prolonged survival in the fibrotic-HCC mouse model. CONCLUSION: Our results signify how non-tumour-intrinsic properties in the desmoplastic microenvironment can be exploited to reinstate immunosurveillance, providing readily translatable combination strategies to empower HCC immunotherapy.


Assuntos
Carcinoma Hepatocelular/terapia , Imunoterapia/métodos , Neoplasias Hepáticas/terapia , Animais , Antígeno B7-H1/antagonistas & inibidores , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/imunologia , Reprogramação Celular/imunologia , Ciclopropanos/farmacologia , Ciclopropanos/uso terapêutico , Células Estreladas do Fígado/imunologia , Humanos , Tolerância Imunológica , Cirrose Hepática/complicações , Cirrose Hepática/patologia , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas Experimentais/etiologia , Neoplasias Hepáticas Experimentais/imunologia , Neoplasias Hepáticas Experimentais/patologia , Neoplasias Hepáticas Experimentais/terapia , Masculino , Camundongos Endogâmicos C57BL , Monócitos/imunologia , Células Supressoras Mieloides/imunologia , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/farmacologia , Piridinas/uso terapêutico , Transdução de Sinais/fisiologia , Células Tumorais Cultivadas , Microambiente Tumoral , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/fisiologia
19.
J Surg Res ; 246: 170-181, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31590030

RESUMO

BACKGROUND: Electroacupuncture has been reported to protect the body from organ damages, but its mechanisms remain to be explored. This research was designed to investigate the function of electroacupuncture in lung injury resulted from hind limb ischemia-reperfusion (LIR) and whether p38 mitogen-activated protein kinase (p38 MAPK)-mediated nuclear factor erythroid-2-related factor-2 (Nrf2)/heme oxygenase (HO)-1 pathway contributes to the protective effect of electroacupuncture on LIR-originated lung damage. MATERIALS AND METHODS: Rabbits were subjected to occluding femoral artery for 2 h. Then they received reperfusion for 4 h to establish lung injury model. Electroacupuncture stimulation was performed bilaterally at Feishu and Zusanli acupoints for 15 min once a day for 5 d before the experiment and throughout the hind LIR model performing in the experimental day. Blood samples and lung tissues were collected to examine the role of electroacupuncture treatment in inflammatory response, oxidative stress, and lung injury. Both the protein expression and the messenger RNA level of Nrf2 and HO-1 were detected. RESULTS: The results showed that electroacupuncture treatment remarkably alleviated lung injury, decreased inflammatory cytokines secretion, attenuated lung oxidative stress, increased the amount of Nrf2 and HO-1, and increased the ratio of phospho-p38 MAPK to p38 MAPK after LIR. However, the protective effects exerted by electroacupuncture were reversed to some extent by the preconditioning with SB203580, a p38 MAPK-specific inhibitor. CONCLUSIONS: These results suggested that electroacupuncture could attenuate lung injury in rabbits subjected to LIR by inhibition of proinflammatory cytokine response and oxidative stress through activating p38 MAPK-mediated Nrf2/HO-1 pathway.


Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Eletroacupuntura , Extremidades/irrigação sanguínea , Sistema de Sinalização das MAP Quinases/imunologia , Traumatismo por Reperfusão/complicações , Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/patologia , Animais , Modelos Animais de Doenças , Artéria Femoral/cirurgia , Heme Oxigenase-1/metabolismo , Humanos , Imidazóis/farmacologia , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/imunologia , Piridinas/farmacologia , Coelhos , Traumatismo por Reperfusão/imunologia , Traumatismo por Reperfusão/terapia , Resultado do Tratamento , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
20.
Mol Cell Biochem ; 464(1-2): 1-9, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31673920

RESUMO

Glioblastoma is the most common and deadly type of brain cancer. The poor prognosis may be largely attributed to inadequate disease response to current chemotherapeutic agents. Activation of p38 is associated with deleterious outcomes in glioblastoma patients, as its signaling mediates chemoresistance mechanisms. Antimicrobial peptide tilapia piscidin (TP) 4 was identified from Nile tilapia (Oreochromis niloticus) and exhibits strong bactericidal effects on Gram-positive and Gram-negative bacteria. TP4 also has anticancer activity toward human triple-negative breast cancer cells and glioblastoma cells. In the present study, we tested the cytotoxic effects of combined TP4 and p38 inhibitors on glioblastoma U251 cells. We found that the combination of TP4 and p38 inhibitors (SB202190 and VX-745) enhanced cytotoxicity in U251 glioblastoma cells but not noncancerous neural cells. Cytotoxicity from the combination treatments proceeded via necrosis and not apoptosis. Mechanistically, SB202190 potentiated TP4-induced mitochondrial dysfunction, reactive oxygen species generation and unbalanced antioxidant status, which resulted in necrotic cell death. Thus, we demonstrated for the first time that combinations of TP4 and p38 inhibitors have the potential to preferentially target glioblastoma cells, while sparing noncancerous neural cells.


Assuntos
Peptídeos Catiônicos Antimicrobianos/farmacologia , Glioblastoma/tratamento farmacológico , Imidazóis/farmacologia , Proteínas de Neoplasias/antagonistas & inibidores , Fragmentos de Peptídeos/farmacologia , Piridazinas/farmacologia , Piridinas/farmacologia , Pirimidinas/farmacologia , Timopoietinas/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Animais , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Glioblastoma/enzimologia , Glioblastoma/patologia , Humanos , Proteínas de Neoplasias/metabolismo , Tilápia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/enzimologia , Neoplasias de Mama Triplo Negativas/patologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
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