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1.
PLoS Genet ; 16(7): e1008917, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32628663

RESUMO

Mechanisms of transcriptional control in malaria parasites are still not fully understood. The positioning patterns of G-quadruplex (G4) DNA motifs in the parasite's AT-rich genome, especially within the var gene family which encodes virulence factors, and in the vicinity of recombination hotspots, points towards a possible regulatory role of G4 in gene expression and genome stability. Here, we carried out the most comprehensive genome-wide survey, to date, of G4s in the Plasmodium falciparum genome using G4Hunter, which identifies G4 forming sequences (G4FS) considering their G-richness and G-skewness. We show an enrichment of G4FS in nucleosome-depleted regions and in the first exon of var genes, a pattern that is conserved within the closely related Laverania Plasmodium parasites. Under G4-stabilizing conditions, i.e., following treatment with pyridostatin (a high affinity G4 ligand), we show that a bona fide G4 found in the non-coding strand of var promoters modulates reporter gene expression. Furthermore, transcriptional profiling of pyridostatin-treated parasites, shows large scale perturbations, with deregulation affecting for instance the ApiAP2 family of transcription factors and genes involved in ribosome biogenesis. Overall, our study highlights G4s as important DNA secondary structures with a role in Plasmodium gene expression regulation, sub-telomeric recombination and var gene biology.


Assuntos
Quadruplex G , Malária/genética , Motivos de Nucleotídeos/genética , Plasmodium falciparum/genética , Aminoquinolinas/farmacologia , Animais , Regulação da Expressão Gênica/efeitos dos fármacos , Genoma/efeitos dos fármacos , Humanos , Malária/tratamento farmacológico , Malária/parasitologia , Ácidos Picolínicos/farmacologia , Plasmodium falciparum/patogenicidade , Regiões Promotoras Genéticas/genética , Ribossomos/efeitos dos fármacos , Ribossomos/genética
2.
Medicine (Baltimore) ; 99(25): e20809, 2020 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-32569228

RESUMO

RATIONALE: Pyrotinib is a novel dual pan-ErbB receptor tyrosine kinase inhibitor, approved for the treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC). However, there was still limited information regarding specific effect of pyrotinib on HER2-positive MBC patients with phosphoinositol-3 kinase mutation. PATIENT CONCERNS: A 63-year-old woman accidentally discovered a left breast lesion. The breast cancer was diagnosed by biopsy of breast lesion and postoperative pathological examination in March, 2017. The patient was presented with HER2-positive (3+), invasive carcinoma of the left breast with lymph nodes and lung nodules metastasis, and the clinical stage was T4N2M1. However, the lesion continued to aggressive disease progression with the treatment of trastuzumab plus multiple chemotherapy regimens and traditional Chinese medicine. DIAGNOSES: The woman was diagnosed with invasive carcinoma of the left breast and lymph nodes and lung nodules metastasis. INTERVENTIONS: The patient received 6 cycles of pyrotinib in combination with capecitabine regularly. OUTCOMES: Progression free survival was more than 6 months, and the patient's efficacy evaluation was partial remission. LESSONS: Our clinical observations demonstrated that pyrotinib may be an effective treatment for patients with HER2-positive MBC.


Assuntos
Acrilamidas/uso terapêutico , Aminoquinolinas/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Carcinoma Ductal de Mama/tratamento farmacológico , Receptor ErbB-2/antagonistas & inibidores , Acrilamidas/administração & dosagem , Aminoquinolinas/administração & dosagem , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Capecitabina/administração & dosagem , Capecitabina/uso terapêutico , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Feminino , Humanos , Pessoa de Meia-Idade
3.
Life Sci ; 256: 117883, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32497632

RESUMO

The present pandemic of SARS-CoV-2 has been a tough task for the whole world to deal with. With the absence of specific drugs or vaccines against SARS-CoV-2, the situation is very difficult to control. Apart from the absence of specific therapies, the lack of knowledge about potential therapeutic targets and individual perception is adding to the complications. The present review describes the novel SARS-CoV-2 structure, surface proteins, asymptomatic and symptomatic transmission in addition to the genotype and phenotype of SARS-CoV-2 along with genetic strains and similarity between SARS, MERS and SARS-CoV-2. Therapeutic strategies such as inhibition of the endocytic pathway and suppressing RNA polymerase activity by metal ions, which could be quite beneficial for controlling COVID-19, are outlined. The drug repurposing for SARS-CoV-2 is discussed in detail along with therapeutic classes such as antivirals, antibiotics, and amino quinolones and their probable role in suppressing SARS-CoV-2 with reference to case studies. The ongoing clinical trials both with respect to drug repurposing and vaccines are summarized along with a brief description. The recent advancements and future perspective of ongoing research for therapy and detection of SARS-CoV-2 are provided. The review, in brief, summarizes epidemiology, therapy and the current scenario for combating SARS-CoV-2.


Assuntos
Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Aminoquinolinas/uso terapêutico , Antibacterianos/uso terapêutico , Antivirais/uso terapêutico , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/virologia , Reposicionamento de Medicamentos , Humanos , Pandemias , Pneumonia Viral/virologia , Vacinas Virais/administração & dosagem
4.
Life Sci ; 254: 117775, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: covidwho-322329

RESUMO

Recent global outbreak of the pandemic caused by coronavirus (COVID-19) emphasizes the urgent need for novel antiviral therapeutics. It can be supplemented by utilization of efficient and validated drug discovery approaches such as drug repurposing/repositioning. The well reported and clinically used anti-malarial aminoquinoline drugs (chloroquine and hydroxychloroquine) have shown potential to be repurposed to control the present pandemic by inhibition of COVID-19. The review elaborates the mechanism of action, safety (side effects, adverse effects, toxicity) and details of clinical trials for chloroquine and hydroxychloroquine to benefit the clinicians, medicinal chemist, pharmacologist actively involved in controlling the pandemic and to provide therapeutics for the treatment of COVID-19 infection.


Assuntos
Aminoquinolinas/efeitos adversos , Aminoquinolinas/uso terapêutico , Antivirais/efeitos adversos , Antivirais/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Betacoronavirus/efeitos dos fármacos , Cloroquina/efeitos adversos , Cloroquina/uso terapêutico , Ensaios Clínicos como Assunto , Reposicionamento de Medicamentos , Humanos , Hidroxicloroquina/efeitos adversos , Hidroxicloroquina/uso terapêutico , Pandemias , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
5.
Lakartidningen ; 1172020 04 23.
Artigo em Sueco | MEDLINE | ID: covidwho-178577

RESUMO

Hydroxychloroquine and chloroquine are currently being evaluated as treatment against COVID-19. These drugs are associated with some potential harms, including QTc-interval prolongation, hypoglycaemia, severe skin reactions and psychiatric effects. Use of hydroxychloroquine or chloroquine should be reserved to current indications or clinical trials, as recommended by several governmental medical products agencies.


Assuntos
Aminoquinolinas/efeitos adversos , Antivirais/efeitos adversos , Cloroquina/efeitos adversos , Infecções por Coronavirus/tratamento farmacológico , Hidroxicloroquina/efeitos adversos , Pneumonia Viral/tratamento farmacológico , Aminoquinolinas/uso terapêutico , Antimaláricos/efeitos adversos , Betacoronavirus , Humanos , Pandemias
6.
Am J Trop Med Hyg ; 103(1): 394-403, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32372747

RESUMO

Tafenoquine has been licensed for the single-dose radical cure of Plasmodium vivax in adults; however, it is only recommended in patients with > 70% of normal glucose-6-phosphate dehydrogenase (G6PD) activity. Because this may hinder widespread use, we investigated sex-based treatment strategies in which all adult patients are tested with a qualitative G6PD rapid diagnostic test (RDT). Glucose-6-phosphate dehydrogenase normal males are prescribed tafenoquine in all three strategies, whereas G6PD normal females are prescribed either a low-dose 14-day primaquine regimen (PQ14, total dose 3.5 mg/kg) or a high-dose 7-day primaquine regimen (PQ7, total dose 7 mg/kg), or referred to a healthcare facility for quantitative G6PD testing before prescribing tafenoquine. Patients testing G6PD deficient are prescribed a weekly course of primaquine for 8 weeks. We compared the cost-effectiveness of these three strategies to usual care in four countries using a decision tree model. Usual care in Ethiopia does not include radical cure, whereas Afghanistan, Indonesia, and Vietnam prescribe PQ14 without G6PD screening. The cost per disability-adjusted life-year (DALY) averted was expressed through incremental cost-effectiveness ratios (ICERs). Compared with usual care, the ICERs for a sex-based treatment strategy with PQ7 for females from a healthcare provider perspective were $127 per DALY averted in Vietnam, $466 in Ethiopia, $1,089 in Afghanistan, and $4,443 in Indonesia. The PQ14 and referral options cost more while averting fewer DALYs than PQ7. This study provides an alternative cost-effective mode of rolling out tafenoquine in areas where initial testing with only a G6PD RDT is feasible.


Assuntos
Aminoquinolinas/efeitos adversos , Anemia Hemolítica/induzido quimicamente , Antimaláricos/efeitos adversos , Deficiência de Glucosefosfato Desidrogenase/diagnóstico , Malária Vivax/tratamento farmacológico , Primaquina/efeitos adversos , Adulto , Afeganistão , Aminoquinolinas/administração & dosagem , Anemia Hemolítica/etiologia , Antimaláricos/administração & dosagem , Cloroquina/administração & dosagem , Análise Custo-Benefício , Etiópia , Feminino , Deficiência de Glucosefosfato Desidrogenase/complicações , Hemizigoto , Heterozigoto , Homozigoto , Humanos , Indonésia , Masculino , Programas de Rastreamento , Adesão à Medicação , Plasmodium vivax , Primaquina/administração & dosagem , Anos de Vida Ajustados por Qualidade de Vida , Recidiva , Fatores Sexuais , Vietnã
7.
Life Sci ; 254: 117775, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32418894

RESUMO

Recent global outbreak of the pandemic caused by coronavirus (COVID-19) emphasizes the urgent need for novel antiviral therapeutics. It can be supplemented by utilization of efficient and validated drug discovery approaches such as drug repurposing/repositioning. The well reported and clinically used anti-malarial aminoquinoline drugs (chloroquine and hydroxychloroquine) have shown potential to be repurposed to control the present pandemic by inhibition of COVID-19. The review elaborates the mechanism of action, safety (side effects, adverse effects, toxicity) and details of clinical trials for chloroquine and hydroxychloroquine to benefit the clinicians, medicinal chemist, pharmacologist actively involved in controlling the pandemic and to provide therapeutics for the treatment of COVID-19 infection.


Assuntos
Aminoquinolinas/efeitos adversos , Aminoquinolinas/uso terapêutico , Antivirais/efeitos adversos , Antivirais/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Betacoronavirus/efeitos dos fármacos , Cloroquina/efeitos adversos , Cloroquina/uso terapêutico , Ensaios Clínicos como Assunto , Reposicionamento de Medicamentos , Humanos , Hidroxicloroquina/efeitos adversos , Hidroxicloroquina/uso terapêutico , Pandemias , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
8.
Lakartidningen ; 1172020 04 23.
Artigo em Sueco | MEDLINE | ID: mdl-32365215

RESUMO

Hydroxychloroquine and chloroquine are currently being evaluated as treatment against COVID-19. These drugs are associated with some potential harms, including QTc-interval prolongation, hypoglycaemia, severe skin reactions and psychiatric effects. Use of hydroxychloroquine or chloroquine should be reserved to current indications or clinical trials, as recommended by several governmental medical products agencies.


Assuntos
Aminoquinolinas/efeitos adversos , Antivirais/efeitos adversos , Cloroquina/efeitos adversos , Infecções por Coronavirus/tratamento farmacológico , Hidroxicloroquina/efeitos adversos , Pneumonia Viral/tratamento farmacológico , Aminoquinolinas/uso terapêutico , Antimaláricos/efeitos adversos , Betacoronavirus , Humanos , Pandemias
9.
Nucleic Acids Res ; 48(9): 4960-4975, 2020 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-32232411

RESUMO

G-quadruplexes represent unique roadblocks to DNA replication, which tends to stall at these secondary structures. Although G-quadruplexes can be found throughout the genome, telomeres, due to their G-richness, are particularly predisposed to forming these structures and thus represent difficult-to-replicate regions. Here, we demonstrate that exonuclease 1 (EXO1) plays a key role in the resolution of, and replication through, telomeric G-quadruplexes. When replication forks encounter G-quadruplexes, EXO1 resects the nascent DNA proximal to these structures to facilitate fork progression and faithful replication. In the absence of EXO1, forks accumulate at stabilized G-quadruplexes and ultimately collapse. These collapsed forks are preferentially repaired via error-prone end joining as depletion of EXO1 diverts repair away from error-free homology-dependent repair. Such aberrant repair leads to increased genomic instability, which is exacerbated at chromosome termini in the form of dysfunction and telomere loss.


Assuntos
Enzimas Reparadoras do DNA/fisiologia , Replicação do DNA , Exodesoxirribonucleases/fisiologia , Quadruplex G , Telômero/química , Aminoquinolinas/farmacologia , Linhagem Celular , Reparo do DNA por Junção de Extremidades , Reparo do DNA , Enzimas Reparadoras do DNA/genética , Enzimas Reparadoras do DNA/metabolismo , Exodesoxirribonucleases/genética , Exodesoxirribonucleases/metabolismo , Quadruplex G/efeitos dos fármacos , Técnicas de Inativação de Genes , Células HeLa , Humanos , Neoplasias/metabolismo , Neoplasias/mortalidade , Ácidos Picolínicos/farmacologia , Prognóstico
10.
Beijing Da Xue Xue Bao Yi Xue Ban ; 52(2): 254-260, 2020 Apr 18.
Artigo em Chinês | MEDLINE | ID: mdl-32306007

RESUMO

OBJECTIVE: Pyrotinib, a novel irreversible pan-ErbB receptor tyrosine kinase inhibitor, showed promising antitumor activity and acceptable tolerability in phase II and phase III randomized clinical trials. We assessed the activity and safety of oral pyrotinib for human epidermal growth factor receptor 2 (HER2) positive metastatic breast cancer patients in the real world. METHODS: We retrospectively analyzed 72 HER2 positive metastatic breast cancer (MBC) patients who received oral pyrotinib based regimens at Beijing Cancer Hospital and other four hospitals (Peking University First Hospital, China-Japan Friendship Hospital, General Hospital of PLA, Peking University Third Hospital) from August 2018 to September 2019. Progression free survival (PFS), objective response rate (ORR), adverse events (AE) of pyrotinib were investigated. RESULTS: Seventy-two patients with HER2 positive MBC were enrolled. The median age of the patients was 55 years (range: 32-79 years). Sixty-nine (95.8%) patients had received anti-HER2 treatment in the metastatic and/or (neo) adjuvant settings; 61 (84.7%) patients had received anti-HER2 treatments in the metastatic setting in terms of trastuzumab 56 (77.8%) patients, lapatinib 36 (50.0%) patients, and T-DM1 4 (5.6%) patients. Among these 72 patients who received oral pyrotinib based regimens, 62 (86.1%) patients received pyrotinib (±trastuzumab) in combination with chemotherapy, 6 (8.3%) patients received pyrotinib (± trastuzumab) in combination with endocrine therapy and 4 (5.6%) patients received pyrotinib (±trastuzumab). Sixty-five (90.3%) patients received 400 mg pyrotinib once daily as initial dose, and 7 (9.7%) patients received 320 mg. OBJECTIVE response and safety to pyrotinib based therapy were evaluable in all the 72 patients. One (1.4%) patient achieved complete response (CR), 18 (25.0%) patients achieved partial response (PR), 41 (56.9%) patients had stable disease (SD), and 12 (16.7%) patients had progressive disease (PD). The ORR (CR+PR) was 26.4% and the median PFS was 7.6 months (95%CI: 5.5-9.7 months). Among the 36 patients with prior lapatinib therapy, the median PFS was 7.9 months (95%CI: 4.1-11.7 months). Among the 15 patients with brain metastasis, the median PFS was 6.0 months (95%CI: 2.2-9.8 months). The main toxicities related to pyrotinib were diarrhea in 57 (79.2%) cases, and 48 (66.7%) cases with grade 1-2 as well as 9 (12.5%) cases with grade 3. CONCLUSION: Pyrotinib based therapy is an effective treatment for patients with HER2 positive MBC, including patients with lapatinib treatment failure and brain metastasis, and the toxicities can be tolerated.


Assuntos
Acrilamidas/uso terapêutico , Aminoquinolinas/uso terapêutico , Neoplasias da Mama , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias da Mama/tratamento farmacológico , China , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Receptor ErbB-2 , Estudos Retrospectivos , Trastuzumab , Resultado do Tratamento
11.
Am J Trop Med Hyg ; 103(1): 378-393, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32314694

RESUMO

Malaria volunteer infection studies (VISs) accelerate new drug and vaccine development. In the induced blood-stage malaria (IBSM) model, volunteers are inoculated with erythrocytes infected with Plasmodium falciparum. Observations of elevated liver enzymes in the IBSM model with new chemical entities (NCEs) promoted an analysis of available data. Data were reviewed from eight IBSM studies of seven different NCEs, plus two studies with the registered antimalarial piperaquine conducted between June 2013 and January 2017 at QIMR Berghofer, Brisbane, Australia. Alanine aminotransferase (ALT) was elevated (> 2.5 times the upper limit of normal [×ULN]) in 20/114 (17.5%) participants. Of these, 8.9% (10/114) had moderate increases (> 2.5-5 × ULN), noted in seven studies of six different NCEs ± piperaquine or piperaquine alone, and 8.9% (10/114) had severe elevations (> 5 × ULN), occurring in six studies of six different NCEs ± piperaquine. Aspartate aminotransferase (AST) was elevated (> 2.5 × ULN) in 11.4% (13/114) of participants, across six of the 10 studies. Bilirubin was > 2 × ULN in one participant. Published data from other VIS models, using sporozoite inoculation by systemic administration or mosquito feeding, also showed moderate/severe liver enzyme elevations. In conclusion, liver enzyme elevations in IBSM studies are most likely multifactorial and could be caused by the model conditions, that is, malaria infection/parasite density and/or effective parasite clearance, or by participant-specific risk factors, acetaminophen administration, or direct hepatotoxicity of the test drug. We make recommendations that may mitigate the risk of liver enzyme elevations in future VISs and propose measures to assist their interpretation, should they occur.


Assuntos
Alanina Transaminase/metabolismo , Antimaláricos/efeitos adversos , Aspartato Aminotransferases/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Voluntários Saudáveis , Malária Falciparum/tratamento farmacológico , Parasitemia/tratamento farmacológico , Acrilamidas/efeitos adversos , Adamantano/efeitos adversos , Adamantano/análogos & derivados , Adulto , Aminopiridinas/efeitos adversos , Aminoquinolinas/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Transfusão de Eritrócitos , Eritrócitos/parasitologia , Feminino , Compostos Ferrosos/efeitos adversos , Compostos Heterocíclicos de 4 ou mais Anéis/efeitos adversos , Humanos , Indóis/efeitos adversos , Isoquinolinas/efeitos adversos , Masculino , Metalocenos/efeitos adversos , Peróxidos/efeitos adversos , Piperazinas/efeitos adversos , Plasmodium falciparum , Primaquina/efeitos adversos , Pirimidinas/efeitos adversos , Quinolinas/efeitos adversos , Compostos de Espiro/efeitos adversos , Sulfonas/efeitos adversos , Triazóis/efeitos adversos , Adulto Jovem
12.
J Chromatogr A ; 1620: 461012, 2020 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-32276856

RESUMO

Quantification of analysis results for the suspect and non-targeted screening is essential for obtaining meaningful insight from the measurements. Ionization efficiency predictions is a possible approach to enable quantitation without standard substances. This is, however, especially challenging for the analysis carried out by combining the full scan mode either with fragmentation experiments in data-dependent or data-independent acquisition mode. Here we investigate the correlation of ionization efficiency values measured in full scan mode with the response factors measured in multiple reaction monitoring (MRM) mode for derivatized amino acids. We observe good correlation (R2 of 0.80) for 6-Aminoquinolyl-N-hydroxysuccinimidyl carbamate (AQC) derivatized amino acids. This encourages the use of the measured ionization efficiency values to estimate amino acid concentrations in different beverages. We apply the measured ionization efficiency values for estimating the concentration of amino acids for measurements done both in full scan as well as in MRM mode in wines and beers. We show that the calculated concentrations are in very good correlation with measured values (R2 of 0.71 to 1.00). The method possesses average trueness of 70.5% and shows an insignificant matrix effect.


Assuntos
Aminoácidos/análise , Cromatografia Líquida/métodos , Espectrometria de Massas por Ionização por Electrospray/métodos , Vinho/análise , Aminas/análise , Aminoácidos/química , Aminoquinolinas/química , Cerveja/análise , Carbamatos/química , Indicadores e Reagentes , Malonatos/química , Reprodutibilidade dos Testes
14.
Malar J ; 19(1): 40, 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31969155

RESUMO

BACKGROUND: The Sustainable Development Goals (SDG) call for increased gender equity and reduction in malaria-related mortality and morbidity. Plasmodium vivax infections in pregnancy are associated with maternal anaemia and increased adverse perinatal outcomes. Providing radical cure for women with 8-aminoquinolines (e.g., primaquine) is hindered by gender-specific complexities. CASE PRESENTATION: A symptomatic episode of vivax malaria at 18 weeks of gestation in a primigravid woman was associated with maternal anaemia, a recurrent asymptomatic P. vivax episode, severe intra-uterine growth restriction with no other identifiable cause and induction to reduce the risk of stillbirth. At 5 months postpartum a qualitative glucose-6-phosphate dehydrogenase (G6PD) point-of-care test was normal and radical cure with primaquine was prescribed to the mother. A 33% fractional decrease in haematocrit on day 7 of primaquine led to further testing which showed intermediate phenotypic G6PD activity; the G6PD genotype could not be identified. Her infant daughter was well throughout maternal treatment and found to be heterozygous for Mahidol variant. CONCLUSION: Adverse effects of vivax malaria in pregnancy, ineligibility of radical cure for pregnant and postpartum women, and difficulties in diagnosing intermediate levels of G6PD activity multiplied morbidity in this woman. Steps towards meeting the SDG include prevention of malaria in pregnancy, reducing unnecessary exclusion of women from radical cure, and accessible quantitative G6PD screening in P. vivax-endemic settings.


Assuntos
Equidade em Saúde/estatística & dados numéricos , Malária Vivax/epidemiologia , Complicações Parasitárias na Gravidez/epidemiologia , Adolescente , Aminoquinolinas/uso terapêutico , Anemia/tratamento farmacológico , Anemia/etiologia , Antimaláricos/uso terapêutico , Combinação Arteméter e Lumefantrina/uso terapêutico , Feminino , Retardo do Crescimento Fetal/etiologia , Retardo do Crescimento Fetal/terapia , Deficiência de Glucosefosfato Desidrogenase/diagnóstico , Humanos , Recém-Nascido Pequeno para a Idade Gestacional , Transtornos da Lactação/etiologia , Transtornos da Lactação/parasitologia , Malária Vivax/tratamento farmacológico , Malária Vivax/mortalidade , Gravidez , Complicações Parasitárias na Gravidez/tratamento farmacológico , Complicações Parasitárias na Gravidez/mortalidade , Resultado da Gravidez , Primaquina/uso terapêutico
15.
Prostate ; 80(5): 412-423, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31995655

RESUMO

BACKGROUND: Mammalian target of rapamycin (mTOR) is a downstream substrate activated by PI3K/AKT pathway and it is essential for cell migration. It exists as two complexes: mTORC1 and mTORC2. mTORC1 is known to be regulated by active AKT, but the activation of mTORC2 is poorly understood. In this study, we investigated the roles and differential activation of the two mTOR complexes during cell migration in prostate cancer cells. METHODS: We used small interfering RNA to silence the expression of Rac1 and the main components of mTOR complexes (regulatory associated protein of mTOR [RAPTOR] and rapamycin-insensitive companion of mTOR [RICTOR]) in LNCaP, DU145, and PC3 prostate cancer cell lines. We performed transwell migration assay to evaluate the migratory capability of the cells, and Western blot analysis to study the activation levels of mTOR complexes. RESULTS: Specific knockdown of RAPTOR and RICTOR caused a decrease of cell migration, suggesting their essential role in prostate cancer cell movement. Furthermore, epidermal growth factor (EGF) treatments induced the activation of both the mTOR complexes. Lack of Rac1 activity in prostate cancer cells blocked EGF-induced activation of mTORC2, but had no effect on mTORC1 activation. Furthermore, the overexpression of constitutively active Rac1 resulted in significant increase in cell migration and activation of mTORC2 in PC3 cells, but had no effect on mTORC1 activation. Active Rac1 was localized in the plasma membrane and was found to be in a protein complex, with RICTOR, but not RAPTOR. CONCLUSION: We suggest that EGF-induced activation of Rac1 causes the activation of mTORC2 via RICTOR. This mechanism plays a critical role in prostate cancer cell migration.


Assuntos
Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Aminoquinolinas/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/fisiologia , Fator de Crescimento Epidérmico/farmacologia , Técnicas de Silenciamento de Genes , Humanos , Masculino , Células PC-3 , Pirimidinas/farmacologia , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/genética , Proteína Companheira de mTOR Insensível à Rapamicina/deficiência , Proteína Companheira de mTOR Insensível à Rapamicina/genética , Proteína Companheira de mTOR Insensível à Rapamicina/metabolismo , Proteína Regulatória Associada a mTOR/deficiência , Proteína Regulatória Associada a mTOR/genética , Proteína Regulatória Associada a mTOR/metabolismo , Sirolimo/farmacologia , Proteínas rac1 de Ligação ao GTP/antagonistas & inibidores , Proteínas rac1 de Ligação ao GTP/metabolismo
16.
Am J Physiol Regul Integr Comp Physiol ; 318(2): R369-R378, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31913689

RESUMO

Activation of Toll-like receptors (TLRs) after hypoxic-ischemic brain injury can exacerbate injury but also alleviate cell loss, as recently demonstrated with the TLR7 agonist Gardiquimod (GDQ). However, TLR agonists also modulate vascular function and neuronal excitability. Thus, we examined the effects of TLR7 activation with GDQ on cardiovascular function and seizures after asphyxia in preterm fetal sheep at 0.7 gestation (104 days, term ∼147 days). Fetuses received sham asphyxia or asphyxia induced by umbilical cord occlusion for 25 min or asphyxia followed by a continuous intracerebroventricular infusion of 3.34 mg of GDQ from 1 to 4 h after asphyxia. Fetuses were monitored continuously for 72 h postasphyxia. GDQ treatment was associated with sustained, moderate hypertension for 72 h (P < 0.05), with a transient increase in heart rate. Electroencephalographic (EEG) power was suppressed for the entire postasphyxial period in both groups, whereas EEG spectral edge transiently increased during the GDQ infusion compared with asphyxia alone (P < 0.05), with higher ß- and lower δ-EEG frequencies (P < 0.05). This increase in EEG frequency was not related to epileptiform activity. After the GDQ infusion, there was earlier onset of high-amplitude stereotypic evolving seizures, with increased numbers of seizures and seizure burden (P < 0.05). Hemodynamic function and seizure activity are important indices of preterm wellbeing. These data highlight the importance of physiological monitoring during preclinical testing of potential neuroprotective strategies.


Assuntos
Aminoquinolinas/toxicidade , Asfixia Neonatal/tratamento farmacológico , Hipertensão/induzido quimicamente , Imidazóis/toxicidade , Fármacos Neuroprotetores/toxicidade , Nascimento Prematuro , Convulsões/induzido quimicamente , Taquicardia/induzido quimicamente , Receptor 7 Toll-Like/agonistas , Animais , Animais Recém-Nascidos , Asfixia Neonatal/fisiopatologia , Pressão Sanguínea/efeitos dos fármacos , Ondas Encefálicas/efeitos dos fármacos , Modelos Animais de Doenças , Idade Gestacional , Frequência Cardíaca/efeitos dos fármacos , Hipertensão/fisiopatologia , Medição de Risco , Convulsões/fisiopatologia , Carneiro Doméstico , Transdução de Sinais , Taquicardia/fisiopatologia , Fatores de Tempo
17.
Int J Cancer ; 146(5): 1359-1368, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31241775

RESUMO

Tumor heterogeneity was associated with treatment outcome of metastatic cancers but few studies have examined whether tumor heterogeneity in circulating tumor DNA (ctDNA) can be used to predict treatment outcome. ctDNA analysis was performed in 37 HER2-positive metastatic breast cancer patients treated with pyrotinib. Patients with high tumor heterogeneity had significantly worse PFS outcomes, with a median PFS of 30.0 weeks vs. 60.0 weeks for patients with low tumor heterogeneity (hazard ratio [HR], 2.9; p = 0.02). Patients with trunk resistance mutations receiving pyrotinib monotherapy had worse outcomes (HR, 4.5; p = 0.03), with a median PFS of 7.8 weeks vs. 27.4 weeks for those with branch resistance mutations or without any resistance mutations in baseline ctDNA. Longitudinal monitoring of 21 patients during treatment showed that the molecular tumor burden index ([mTBI] a measure of the percentage of ctDNA in samples) was positively correlated with tumor size as evaluated by computed tomography (p < 0.0001, Pearson r = 0.52) and detected disease progression 8-16 weeks earlier. Our current findings suggested that ctDNA could be used to assess tumor heterogeneity and predict treatment outcomes. Furthermore, the mTBI is better for assessing therapeutic response than single gene mutations and might supplement the current therapeutic response evaluation system.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , DNA Tumoral Circulante/genética , Acrilamidas/farmacologia , Acrilamidas/uso terapêutico , Adulto , Aminoquinolinas/farmacologia , Aminoquinolinas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/sangue , Neoplasias da Mama/sangue , Neoplasias da Mama/tratamento farmacológico , Capecitabina/farmacologia , Capecitabina/uso terapêutico , DNA Tumoral Circulante/sangue , Estudos de Coortes , Progressão da Doença , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Mutação , Polimorfismo de Nucleotídeo Único , Prognóstico , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/metabolismo , Adulto Jovem
18.
Life Sci ; 240: 117105, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31786196

RESUMO

AIMS: To investigate whether Rac1 inhibition can alleviate radiation-induced intestinal injury (RIII), meanwhile exist no protection on tumors. MATERIALS AND METHODS: Rac1 inhibition was achieved by its specific inhibitor, NSC23766. Mice were pretreated with different intraperitoneal injections, which were normal saline for NS group (N = 9), and 2.5 mg/kg and 5 mg/kg of NSC23766 for Low-Dose group (N = 9) and High-Dose group (N = 9), respectively. After total body irritation (10Gy), small intestinal tissues were collected for Hematoxylin-Eosin (H&E) staining and Terminal-deoxynucleotidyl Transferase Mediated dUTP Nick End Labeling (TUNEL). Intestinal epithelial and tumor cell lines, namely MODE-k and CT-26, were used to further study the role of Rac1 inhibition on radiation damage. Flow cytometry was used to detect changes in reactive oxygen species production, cell cycles and mitochondrial membrane potential, the latter was also checked by fluorescence microscope. Changes of protein-expression associated with apoptosis and cell cycles were detected by Western blotting to explain the possible molecular mechanism. KEY FINDINGS: Height of intestine villi and depth of crypt were higher (P < 0.01) and apoptosis ratio lower (P < 0.01) in High-Dose group compared with those in NS group. After radiation, Rac1 inhibition pre-treatment improved the vitality (P < 0.01) and reduced the apoptosis (P < 0.01) in MODE-k while yielded opposite results in CT-26, and reduced ROS production of MODE-k (P < 0.01) while had little effect on that of CT-26. Rac1 inhibition differently affected the cell cycles of normal cells and that of tumor cells. SIGNIFICANCE: Inhibition of Rac1 could alleviate RIII, meanwhile assist the killing effect of radiation on tumor cells.


Assuntos
Aminoquinolinas/uso terapêutico , Neoplasias Intestinais/radioterapia , Intestinos/lesões , Neuropeptídeos/antagonistas & inibidores , Pirimidinas/uso terapêutico , Lesões Experimentais por Radiação/tratamento farmacológico , Protetores contra Radiação/uso terapêutico , Proteínas rac1 de Ligação ao GTP/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/efeitos da radiação , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Espécies Reativas de Oxigênio , Irradiação Corporal Total
20.
Org Biomol Chem ; 17(48): 10245-10250, 2019 12 28.
Artigo em Inglês | MEDLINE | ID: mdl-31793609

RESUMO

A general and simple metal-free protocol for expedient C-H functionalization leading to the regioselective generation of C-5 chalcogenated 8-aminoquinoline analogues in up to 90% yield at room temperature (25 °C) has been established. This methodology is an eco-friendly approach to the atom-economical utilization of diaryl/dialkyl chalcogenides for direct access to chalcogenated quinolines and is scalable to the gram scale without considerable decrease in the yield of the product. It represents a practical alternative to the existing metal-catalyzed functionalization of 8-aminoquinoline derivatives with broad functional group tolerance. The controlled experiments suggest that the reaction possibly proceeds through an ionic pathway at room temperature. Furthermore, the potentiality for the functionalization of free amines in chalcogenated-8-aminoquinolines provides an attractive perspective for further elaboration of the amine substituent through chemical manipulations. The applicability of the standardized method has been augmented through late-stage antimalarial drug diversification of primaquine analogues.


Assuntos
Aminoquinolinas/síntese química , Aminas/química , Catálise , Iodo/química , Estrutura Molecular , Oxirredução , Ácido Selênico/química , Solventes/química , Estereoisomerismo , Ácidos Sulfênicos/química
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