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1.
Front Immunol ; 12: 695972, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34341659

RESUMO

COVID-19 ranges from asymptomatic in 35% of cases to severe in 20% of patients. Differences in the type and degree of inflammation appear to determine the severity of the disease. Recent reports show an increase in circulating monocytic-myeloid-derived suppressor cells (M-MDSC) in severe COVID 19 that deplete arginine but are not associated with respiratory complications. Our data shows that differences in the type, function and transcriptome of granulocytic-MDSC (G-MDSC) may in part explain the severity COVID-19, in particular the association with pulmonary complications. Large infiltrates by Arginase 1+ G-MDSC (Arg+G-MDSC), expressing NOX-1 and NOX-2 (important for production of reactive oxygen species) were found in the lungs of patients who died from COVID-19 complications. Increased circulating Arg+G-MDSC depleted arginine, which impaired T cell receptor and endothelial cell function. Transcriptomic signatures of G-MDSC from patients with different stages of COVID-19, revealed that asymptomatic patients had increased expression of pathways and genes associated with type I interferon (IFN), while patients with severe COVID-19 had increased expression of genes associated with arginase production, and granulocyte degranulation and function. These results suggest that asymptomatic patients develop a protective type I IFN response, while patients with severe COVID-19 have an increased inflammatory response that depletes arginine, impairs T cell and endothelial cell function, and causes extensive pulmonary damage. Therefore, inhibition of arginase-1 and/or replenishment of arginine may be important in preventing/treating severe COVID-19.


Assuntos
COVID-19/imunologia , Granulócitos/imunologia , Células Supressoras Mieloides/imunologia , SARS-CoV-2/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antivirais/administração & dosagem , Arginase/antagonistas & inibidores , Arginase/metabolismo , Arginina/administração & dosagem , Arginina/sangue , Arginina/metabolismo , Infecções Assintomáticas , COVID-19/sangue , COVID-19/diagnóstico , COVID-19/tratamento farmacológico , Estudos de Casos e Controles , Quimioterapia Combinada/métodos , Inibidores Enzimáticos/administração & dosagem , Feminino , Granulócitos/metabolismo , Voluntários Saudáveis , Humanos , Interferon Tipo I/metabolismo , Masculino , Pessoa de Meia-Idade , Células Supressoras Mieloides/metabolismo , Índice de Gravidade de Doença , Transdução de Sinais/imunologia , Linfócitos T/imunologia
2.
Cancer Sci ; 112(8): 3218-3232, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34080260

RESUMO

Skp2 is overexpressed in multiple cancers and plays a critical role in tumor development through ubiquitin/proteasome-dependent degradation of its substrate proteins. Drugs targeting Skp2 have exhibited promising anticancer activity. Here, we identified a plant-derived Skp2 inhibitor, betulinic acid (BA), via high-throughput structure-based virtual screening of a phytochemical library. BA significantly inhibited the proliferation and migration of non-small cell lung cancer (NSCLC) through targeting Skp2-SCF E3 ligase both in vitro and in vivo. Mechanistically, BA binding to Skp2, especially forming H-bonds with residue Lys145, decreases its stability by disrupting Skp1-Skp2 interactions, thereby inhibiting the Skp2-SCF E3 ligase and promoting the accumulation of its substrates; that is, E-cadherin and p27. In both subcutaneous and orthotopic xenografts, BA significantly inhibited the proliferation and metastasis of NSCLC through targeting Skp2-SCF E3 ligase and upregulating p27 and E-cadherin protein levels. Taken together, BA can be considered a valuable therapeutic candidate to inhibit metastasis of NSCLC.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Inibidores Enzimáticos/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Triterpenos Pentacíclicos/administração & dosagem , Proteínas Quinases Associadas a Fase S/metabolismo , Células A549 , Animais , Antineoplásicos Fitogênicos/farmacologia , Sítios de Ligação , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Detecção Precoce de Câncer , Inibidores Enzimáticos/farmacologia , Ensaios de Triagem em Larga Escala , Humanos , Neoplasias Pulmonares/metabolismo , Masculino , Camundongos , Triterpenos Pentacíclicos/farmacologia , Ligação Proteica/efeitos dos fármacos , Proteínas Quinases Associadas a Fase S/química , Ensaios Antitumorais Modelo de Xenoenxerto
3.
AAPS PharmSciTech ; 22(5): 168, 2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34080070

RESUMO

Formulation development of KO-947-K mesylate injectable drug products was described. Solution formulations were initially attempted, and key parameters such as drug concentration, buffer, pH, complexing agent, and tonicity modifying agent were carefully evaluated in the lab setting, mainly focusing on solubility and chemical stability. A lead solution formulation was advanced to a scaleup campaign. An unexpected stability issue was encountered, and the root cause was attributed to the heterogeneous liquid freezing process of the formulated solution at -20°C, which had not been captured in the lab setting. A lyophilized product was then designed to overcome the issue and supplied to the phase I clinical trial.


Assuntos
Química Farmacêutica/métodos , Composição de Medicamentos/métodos , Desenvolvimento de Medicamentos/métodos , Inibidores Enzimáticos/síntese química , Estabilidade de Medicamentos , Inibidores Enzimáticos/administração & dosagem , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Liofilização , Congelamento , Injeções , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/síntese química , Solubilidade
4.
Medicine (Baltimore) ; 100(26): e26449, 2021 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-34190169

RESUMO

RATIONALE: Anaplastic lymphoma kinase (ALK) inhibitors have been approved for patients with ALK-rearrangement lung cancer. The effect is superior to the standard first-line therapy of pemetrexed plus platinum-based chemotherapy. However, ALK inhibitors are associated with rare and sometimes fatal adverse events. Organizing pneumonitis (OP) is a rare and serious adverse event usually caused by ceritinib, and it is easily misdiagnosed as infectious pneumonia, metastasis, or cancer progression. PATIENT CONCERNS: A 56-year-old female presented with chest tightness and dyspnea for more than 10 days. She was previously healthy with no significant medical history. Workup including chest computed tomography (CT), pathological examination of a biopsy specimen, and next-generation sequencing was consistent with a diagnosis of IVA ALK-rearrangement lung adenocarcinoma. She was treated with pemetrexed plus platinum-based chemotherapy and crizotinib concurrently, followed by maintenance therapy with crizotinib alone and she had an almost complete response. However, about 26 months after beginning treatment she developed multiple brain metastases. Crizotinib was discontinued and she was begun on ceritinib. After about 3 months the brain metastases had almost complete response. After 5 months of ceritinib, however, multiple patchy lesions appeared in the bilateral upper lungs. DIAGNOSES: Treatment with antibiotics had no effect and blood and sputum cultures are negative. A CT-guided biopsy of the upper lung was performed, and pathological hematoxylin-eosin staining and immunohistochemical studies were consistent with OP. INTERVENTIONS: Ceritinib was discontinued, she was begun on prednisone 0.5 mg/kg orally every day, and regular follow-up is necessary. OUTCOMES: CT of the chest 2 and 4 weeks after beginning prednisone showed the lung lesions to be gradually resolving, and she was continued on prednisone for 2 months and gradually reduced the dose of prednisone every 2 weeks. No related adverse events were occurred in patient. LESSONS: OP must be differentiated from infectious pneumonia, metastasis, or cancer progression. The mechanism of OP is still unknown and needs further research. Biopsy plays a role in making a diagnosis of OP. In our patient, discontinuing ceritinib and treating her with prednisone resulted in a good outcome.


Assuntos
Adenocarcinoma de Pulmão , Quinase do Linfoma Anaplásico , Pneumonia em Organização Criptogênica , Neoplasias Pulmonares , Prednisona/administração & dosagem , Pirimidinas , Sulfonas , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/fisiopatologia , Quinase do Linfoma Anaplásico/antagonistas & inibidores , Quinase do Linfoma Anaplásico/genética , Antineoplásicos/uso terapêutico , Biópsia/métodos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/secundário , Crizotinibe/uso terapêutico , Pneumonia em Organização Criptogênica/induzido quimicamente , Pneumonia em Organização Criptogênica/patologia , Pneumonia em Organização Criptogênica/terapia , Substituição de Medicamentos , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/efeitos adversos , Feminino , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Pulmão/diagnóstico por imagem , Pulmão/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/fisiopatologia , Pessoa de Meia-Idade , Pemetrexede/uso terapêutico , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Sulfonas/administração & dosagem , Sulfonas/efeitos adversos , Tomografia Computadorizada por Raios X/métodos , Resultado do Tratamento
5.
Curr Hematol Malig Rep ; 16(2): 207-217, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33939107

RESUMO

PURPOSE OF REVIEW: Mutations in isocitrate dehydrogenase genes (IDH1 and IDH2) are common in acute myeloid leukemia (AML), occurring in up to 30% of AML cases. Mutations in IDH leads to abnormal epigenetic regulation in AML cells and blocks differentiation. Inhibitors of mutated IDH1 and IDH2, ivosidenib and enasidenib, respectively, were recently approved by the FDA for relapsed/refractory AML; ivosidenib is also approved for newly diagnosed AML patients not fit for standard chemotherapy. Here, we discuss the clinical development of IDH inhibitors, their unique side effects, and outline future combination approaches in AML. RECENT FINDINGS: IDH inhibitors are well-tolerated but can induce differentiation of AML cells, which leads to the on-target side effect of differentiation syndrome in up to 20% of patients. Although IDH inhibitors demonstrate efficacy as monotherapy, recent trials have shown that they have higher response rates in combination with hypomethylating agents (HMAs). Current trials of IDH inhibitors include combination with standard induction chemotherapy, as maintenance therapy, and in combination with venetoclax-based regimens. IDH inhibitors are active and have a favorable toxicity profile in AML therapy. Current clinical trials are evaluating how to best incorporate IDH inhibitors into combination therapy to optimize outcomes and duration of response for AML patients with IDH mutations.


Assuntos
Antineoplásicos/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Isocitrato Desidrogenase/antagonistas & inibidores , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ensaios Clínicos como Assunto , Desenvolvimento de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/efeitos adversos , Humanos , Quimioterapia de Indução , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/metabolismo , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/etiologia , Quimioterapia de Manutenção , Mutação , Resultado do Tratamento
6.
Nat Commun ; 12(1): 2814, 2021 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-33990561

RESUMO

Determining divergent metabolic requirements of T cells, and the viruses and tumours they fail to combat, could provide new therapeutic checkpoints. Inhibition of acyl-CoA:cholesterol acyltransferase (ACAT) has direct anti-carcinogenic activity. Here, we show that ACAT inhibition has antiviral activity against hepatitis B (HBV), as well as boosting protective anti-HBV and anti-hepatocellular carcinoma (HCC) T cells. ACAT inhibition reduces CD8+ T cell neutral lipid droplets and promotes lipid microdomains, enhancing TCR signalling and TCR-independent bioenergetics. Dysfunctional HBV- and HCC-specific T cells are rescued by ACAT inhibitors directly ex vivo from human liver and tumour tissue respectively, including tissue-resident responses. ACAT inhibition enhances in vitro responsiveness of HBV-specific CD8+ T cells to PD-1 blockade and increases the functional avidity of TCR-gene-modified T cells. Finally, ACAT regulates HBV particle genesis in vitro, with inhibitors reducing both virions and subviral particles. Thus, ACAT inhibition provides a paradigm of a metabolic checkpoint able to constrain tumours and viruses but rescue exhausted T cells, rendering it an attractive therapeutic target for the functional cure of HBV and HBV-related HCC.


Assuntos
Inibidores Enzimáticos/farmacologia , Vírus da Hepatite B/efeitos dos fármacos , Esterol O-Aciltransferase/antagonistas & inibidores , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/virologia , Quimioterapia Combinada , Inibidores Enzimáticos/administração & dosagem , Vírus da Hepatite B/imunologia , Vírus da Hepatite B/patogenicidade , Hepatite B Crônica/tratamento farmacológico , Humanos , Inibidores de Checkpoint Imunológico/administração & dosagem , Inibidores de Checkpoint Imunológico/farmacologia , Técnicas In Vitro , Fígado/efeitos dos fármacos , Fígado/imunologia , Fígado/virologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/virologia , Linfócitos T/imunologia
7.
Expert Rev Clin Pharmacol ; 14(7): 901-918, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33861168

RESUMO

BACKGROUND: Scarce evidence verifying the clinical impact of baloxavir on influenza complications is found. METHODS: PubMed, Cochrane Library, and Web of Science databases were searched through December 2020. Randomized-controlled trials (RCT) that enrolled patients with laboratory-confirmed influenza receiving neuraminidase inhibitors (NAI) or baloxavir comparing to placebo were assessed. PROSPERO Registration-number: CRD42021226854. RESULTS: Twenty-one RCTs (11,697 patients) were included. Antiviral administration significantly reduced time to clinical resolution (mean difference: -21.3 hours) and total influenza-related complications (OR:0.55, 95%CI: 0.42-0.73). Specifically, antivirals significantly decreased bronchitis (OR:0.54, 95%CI: 0.38-0.75), sinusitis (OR:0.51, 95%CI: 0.33-0.78), acute otitis media (OR:0.48, 95%CI: 0.30-0.77), and antibiotic prescription (OR:0.62; 95%CI: 0.48-0.80). A positive trend favored antivirals administration to reduce pneumonia (OR:0.47, 95%CI: 0.16-1.33), or hospitalization rates (OR:0.65; 95%CI: 0.34-1.24) compared to placebo, but did not reach statistical significance. Adverse events (AE) were reported in 11%, 8.9%, and 5.1% of NAIs, placebo and baloxavir recipients, respectively. Compared with NAIs, administration of baloxavir showed non-significantly reduced AEs (OR:0.74, 95%CI: 0.53-1.04). CONCLUSIONS: Single-dose baloxavir and NAIs were superior to placebo to reduce complications in uncomplicated influenza, with 40% significant reduction in antibiotic prescription. Safety and efficacy of single-dose baloxavir were non-inferior to NAIs.


Assuntos
Dibenzotiepinas/farmacologia , Influenza Humana/tratamento farmacológico , Morfolinas/farmacologia , Neuraminidase/antagonistas & inibidores , Piridonas/farmacologia , Triazinas/farmacologia , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Antivirais/farmacologia , Dibenzotiepinas/administração & dosagem , Dibenzotiepinas/efeitos adversos , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/farmacologia , Humanos , Influenza Humana/virologia , Morfolinas/administração & dosagem , Morfolinas/efeitos adversos , Piridonas/administração & dosagem , Piridonas/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Triazinas/administração & dosagem , Triazinas/efeitos adversos
8.
Yakugaku Zasshi ; 141(4): 527-540, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-33790120

RESUMO

The biological properties of elastase and Aspergillus flavus elastase inhibitor (AFLEI) from A. flavus were examined. Pathogenicity of elastase was investigated in mice immunocompromised with cyclophosphamide, cyclosporine, prednisolone and carrageenan. Compared to cyclophosphamide immunocompromised mice treated with the spores of elastase nonproducing strain, cyclophosphamide immunocompromised mice treated with the spores of elastase producing strain had a significantly shorter survival rate. Molecular mass of AFLEI was determined to be 7525.8 Da. The elastolytic activity of elastases from A. flavus, and human leukocytes were inhibited by AFLEI. The primary structure of AFLEI was determined by the Edman sequencing procedure. The search for amino acid homology with other proteins demonstrated that amino acid residues 1 to 68 of AFLEI are 100% identical to residues 20 to 87 of the hypothetical protein AFUA_3G14940 of A. fumigatus. When immunocompromised mice administered of cyclophosphamide were infected by inhalation of A. flavus then administered amphotericin B (AMPH) alone or in combination with AFLEI, survival rate tended to be higher with combination treatment than with AMPH alone. Moreover, although extensive bleeding was seen in pathology sections taken from rat lung resected 24 h after elastase was administered to the lung via the bronchus, this bleeding was inhibited by AFLEI. The X-ray analysis has revealed that the structure of this inhibitor was wedge shaped and composed of a binding loop and a scaffold protein core. As synthetic-inhibitor strongly inhibited cytotoxicity induced by elastase in human-derived cells, it could prove beneficial for the treatment of pulmonary aspergillosis.


Assuntos
Aspergillus flavus/química , Aspergillus flavus/patogenicidade , Inibidores Enzimáticos/farmacologia , Elastase Pancreática/efeitos adversos , Anfotericina B/administração & dosagem , Animais , Aspergillus flavus/enzimologia , Aspergillus flavus/genética , Modelos Animais de Doenças , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Hemorragia/tratamento farmacológico , Hemorragia/etiologia , Humanos , Hospedeiro Imunocomprometido , Pneumopatias/tratamento farmacológico , Pneumopatias/etiologia , Camundongos , Elastase Pancreática/química , Elastase Pancreática/isolamento & purificação , Aspergilose Pulmonar/tratamento farmacológico , Ratos
9.
FASEB J ; 35(5): e21374, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33835493

RESUMO

Inhibition of insulin-degrading enzyme (IDE) is a possible target for treating diabetes. However, it has not yet evolved into a medical intervention, mainly because most developed inhibitors target the zinc in IDE's catalytic site, potentially causing toxicity to other essential metalloproteases. Since IDE is a cellular receptor for the varicella-zoster virus (VZV), we constructed a VZV-based inhibitor. We computationally characterized its interaction site with IDE showing that the peptide specifically binds inside IDE's central cavity, however, not in close proximity to the zinc ion. We confirmed the peptide's effective inhibition on IDE activity in vitro and showed its efficacy in ameliorating insulin-related defects in types 1 and 2 diabetes mouse models. In addition, we suggest that inhibition of IDE may ameliorate the pro-inflammatory profile of CD4+ T-cells toward insulin. Together, we propose a potential role of a designed VZV-derived peptide to serve as a selectively-targeted and as an efficient diabetes therapy.


Assuntos
Diabetes Mellitus Experimental/terapia , Diabetes Mellitus Tipo 1/terapia , Diabetes Mellitus Tipo 2/terapia , Insulina/metabolismo , Insulisina/antagonistas & inibidores , Fragmentos de Peptídeos/administração & dosagem , Proteínas do Envelope Viral/metabolismo , Animais , Linfócitos T CD4-Positivos/imunologia , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 1/etiologia , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/patologia , Inibidores Enzimáticos/administração & dosagem , Feminino , Herpesvirus Humano 3/fisiologia , Insulisina/genética , Insulisina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Knockout
10.
Front Immunol ; 12: 613070, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33815368

RESUMO

Lack of specific antiviral treatment for COVID-19 has resulted in long hospitalizations and high mortality rate. By harnessing the regulatory effects of adenosine on inflammatory mediators, we have instituted a new therapeutic treatment with inhaled adenosine in COVID-19 patients, with the aim of reducing inflammation, the onset of cytokine storm, and therefore to improve prognosis. The use of inhaled adenosine in COVID19 patients has allowed reduction of length of stay, on average 6 days. This result is strengthened by the decrease in SARS-CoV-2 positive days. In treated patients compared to control, a clear improvement in PaO2/FiO2 was observed together with a reduction in inflammation parameters, such as the decrease of CRP level. Furthermore, the efficacy of inhaled exogenous adenosine led to an improvement of the prognosis indices, NLR and PLR. The treatment seems to be safe and modulates the immune system, allowing an effective response against the viral infection progression, reducing length of stay and inflammation parameters.


Assuntos
Adenosina/farmacologia , COVID-19/tratamento farmacológico , Adenosina/uso terapêutico , Adulto , Idoso , Antibacterianos/administração & dosagem , Azitromicina/administração & dosagem , COVID-19/diagnóstico por imagem , COVID-19/fisiopatologia , Estudos de Casos e Controles , Inibidores do Citocromo P-450 CYP3A/administração & dosagem , Síndrome da Liberação de Citocina/fisiopatologia , Inibidores Enzimáticos/administração & dosagem , Feminino , Heparina/administração & dosagem , Hospitalização , Humanos , Hidroxicloroquina/administração & dosagem , Inflamação/tratamento farmacológico , Lopinavir/administração & dosagem , Masculino , Pessoa de Meia-Idade , Prognóstico , Tomografia Computadorizada por Raios X
11.
Theranostics ; 11(8): 3540-3551, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33664846

RESUMO

Rationale: Aldehyde dehydrogenase (ALDH) enzymes are often upregulated in cancer cells and associated with therapeutic resistance. ALDH enzymes protect cells by metabolizing toxic aldehydes which can induce DNA double stand breaks (DSB). We recently identified a novel ALDH1A family inhibitor (ALDHi), 673A. We hypothesized that 673A, via inhibition of ALDH1A family members, could induce intracellular accumulation of genotoxic aldehydes to cause DSB and that ALDHi could synergize with inhibitors of the ATM and ATR, proteins which direct DSB repair. Methods: We used immunofluorescence to directly assess levels of the aldehyde 4-hydroxynonenal and comet assays to evaluate DSB. Western blot was used to evaluate activation of the DNA damage response pathways. Cell counts were performed in the presence of 673A and additional aldehydes or aldehyde scavengers. ALDH inhibition results were confirmed using ALDH1A3 CRISPR knockout. Synergy between 673A and ATM or ATR inhibitors was evaluated using the Chou-Talalay method and confirmed in vivo using cell line xenograft tumor studies. Results: The ALDHi 673A cellular accumulation of toxic aldehydes which induce DNA double strand breaks. This is exacerbated by addition of exogenous aldehydes such as vitamin-A (retinaldehyde) and ameliorated by aldehyde scavengers such as metformin and hydralazine. Importantly, ALDH1A3 knockout cells demonstrated increased sensitivity to ATM/ATR inhibitors. And, ALDHi synergized with inhibitors of ATM and ATR, master regulators of the DSB DNA damage response, both in vitro and in vivo. This synergy was evident in homologous recombination (HR) proficient cell lines. Conclusions: ALDHi can be used to induce DNA DSB in cancer cells and synergize with inhibitors the ATM/ATR pathway. Our data suggest a novel therapeutic approach to target HR proficient ovarian cancer cells.


Assuntos
Família Aldeído Desidrogenase 1/antagonistas & inibidores , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Dano ao DNA , Inibidores Enzimáticos/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Aldeído Oxirredutases/deficiência , Aldeído Oxirredutases/genética , Aldeídos/metabolismo , Aldeídos/toxicidade , Animais , Linhagem Celular Tumoral , Quebras de DNA de Cadeia Dupla , Sinergismo Farmacológico , Inibidores Enzimáticos/administração & dosagem , Feminino , Técnicas de Inativação de Genes , Humanos , Camundongos , Medicina de Precisão , Inibidores de Proteínas Quinases/administração & dosagem , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Meat Sci ; 176: 108486, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33711679

RESUMO

The purpose of this study was to develop an in situ model for dark cutting beef. Iodoacetic acid (IAA) was injected at different concentrations (0, 0.625, 1.25, 2.5, 3.75, 5, or 10 µmol/g of muscle) into pre-rigor bovine longissimus thoracis et lumborum (LTL) muscle samples, and pH and color were evaluated over a 48 h period. Injection of IAA blunted muscle pH decline and lowered lightness (L*), redness (a*), and yellowness (b*) values (P ≤ 0.05) in a concentration dependent fashion. In a follow-up study, LTL muscle samples were injected with 5 µmol IAA/g of muscle to test whether IAA maintains its effect over a 336 h post-mortem storage period. In addition to inhibiting pH decline and decreasing color values, IAA increased LTL muscle water holding capacity (WHC) and firmness (P ≤ 0.05) throughout the 336 h post-mortem storage period. Collectively, these data suggest that pre-rigor injection of IAA generates beef with dark cutting-like characteristics.


Assuntos
Ácido Iodoacético/administração & dosagem , Carne Vermelha/análise , Animais , Bovinos , Cor , Inibidores Enzimáticos/administração & dosagem , Concentração de Íons de Hidrogênio , Masculino , Músculo Esquelético/química
13.
Lancet Haematol ; 8(4): e289-e298, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33770484

RESUMO

BACKGROUND: Primary immune thrombocytopenia is an autoimmune bleeding disorder. Preclinical reports suggest that the sialidase inhibitor oseltamivir induces a platelet response in the treatment of immune thrombocytopenia. This study investigated the activity and safety of dexamethasone plus oseltamivir versus dexamethasone alone as initial treatment in adult patients with primary immune thrombocytopenia. METHODS: This multicentre, randomised, open-label, parallel group, phase 2 trial was done in five tertiary medical hospitals in China. Eligible patients were aged 18 years or older with newly diagnosed, treatment-naive primary immune thrombocytopenia. Participants were randomly assigned (1:1), using block randomisation, to receive either dexamethasone (orally at 40 mg per day for 4 days) plus oseltamivir (orally at 75 mg twice a day for 10 days) or dexamethasone monotherapy (orally at 40 mg a day for 4 days). Patients who did not respond to treatment (platelet counts remained <30 × 109 cells per L or showed bleeding symptoms by day 10) were given an additional cycle of dexamethasone for 4 days in each group. Patients in the dexamethasone plus oseltamivir group who relapsed (platelet counts reduced again to <30 × 109 cells per L) after an initial response were allowed a supplemental course of oseltamivir (75 mg twice a day for 10 days). The coprimary endpoints were 14-day initial overall response and 6-month overall response. Complete response was defined as a platelet count at or above 100 × 109 cells per L and an absence of bleeding. Partial response was defined as a platelet count at or above 30 × 109 cells per L but less than 100 × 109 cells per L and at least a doubling of the baseline platelet count and an absence of bleeding. A response lasting for at least 6 months without any additional primary immune thrombocytopenia-specific intervention was defined as sustained response. All patients who were randomly assigned and received the allocated intervention were included in the modified intention-to-treat population analysis. This study has been completed and is registered with ClinicalTrials.gov, number NCT01965626. FINDINGS: From Feb 1, 2016, to May 1, 2019, 120 patients were screened for eligibility, of whom 24 were ineligible and excluded, 96 were enrolled and randomly assigned to receive dexamethasone plus oseltamivir (n=47) or dexamethasone (n=49), and 90 were included in the modified intention-to-treat analysis. Six patients did not receive the allocated intervention. Patients in the dexamethasone plus oseltamivir group had a significantly higher initial response rate (37 [86%] of 43 patients) than did those in the dexamethasone group (31 [66%] of 47 patients; odds ratio [OR] 3·18; 95 CI% 1·13-9·23; p=0·030) at day 14. The 6-month sustained response rate in the dexamethasone plus oseltamivir group was also significantly higher than that in the dexamethasone group (23 [53%] vs 14 [30%]; OR 2·17; 95 CI% 1·16-6·13; p=0·032). During the median follow-up of 8 months (IQR 5-14), two of 90 patients discontinued treatment due to serious adverse events (grade 3); one (2%) patient with general oedema in the dexamethasone plus oseltamivir group and one (2%) patient with fever in the dexamethasone group. The most frequently observed adverse events of any grade were fatigue (five [12%] of 43 in the dexamethasone plus oseltamivir group vs eight [17%] of 47 in the dexamethasone group), gastrointestinal reactions (eight [19%] vs three [6%]), insomnia (seven [16%] vs four [9%]), and anxiety (five [12%] vs three [6%]). There were no grade 4 or 5 adverse events and no treatment-related deaths. INTERPRETATION: Dexamethasone plus oseltamivir offers a readily available combination therapy in the management of newly diagnosed primary immune thrombocytopenia. The preliminary activity of this combination warrants further investigation. Multiple cycles of oseltamivir, as a modification of current first-line treatment, might be more effective in maintaining the platelet response. FUNDING: National Natural Science Foundation of China.


Assuntos
Dexametasona/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Glucocorticoides/uso terapêutico , Oseltamivir/uso terapêutico , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Administração Oral , Adulto , China/epidemiologia , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Quimioterapia Combinada/efeitos adversos , Quimioterapia Combinada/métodos , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/efeitos adversos , Feminino , Seguimentos , Glucocorticoides/administração & dosagem , Glucocorticoides/efeitos adversos , Hemorragia/epidemiologia , Humanos , Análise de Intenção de Tratamento/métodos , Masculino , Pessoa de Meia-Idade , Oseltamivir/administração & dosagem , Oseltamivir/efeitos adversos , Contagem de Plaquetas/estatística & dados numéricos , Contagem de Plaquetas/tendências , Púrpura Trombocitopênica Idiopática/imunologia , Segurança , Resultado do Tratamento
14.
Expert Opin Ther Pat ; 31(6): 453-472, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33783295

RESUMO

Introduction: Steroid sulfatase (STS) enzyme is responsible for transforming the inactive sulfate metabolites of steroid sex hormones into the active free steroids. Both the deficiency and the over-expression of STS are associated with the pathophysiology of certain diseases. This article provides the readership with a comprehensive review about STS enzyme and its recently reported inhibitors.Areas covered: In the present article, we reviewed the structure, location, and substrates of STS enzyme, physiological functions of STS, and disease states related to over-expression or deficiency of STS enzyme. STS inhibitors reported during the last five years (2016-present) have been reviewed as well.Expert opinion: Irosustat is the most successful STS inhibitor drug candidate so far. It is currently under investigation in clinical trials for treatment of estrogen-dependent breast cancer. Non-steroidal sulfamate is the most favorable scaffold for STS inhibitor design. They can be beneficial for the treatment of hormone-dependent cancers and neurodegenerative disorders without significant estrogenic side effects. Moreover, dual-acting molecules (inhibitors of STS + another synergistic mechanism) can be therapeutically efficient.


Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Esteril-Sulfatase/antagonistas & inibidores , Animais , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Inibidores Enzimáticos/administração & dosagem , Feminino , Humanos , Patentes como Assunto , Esteril-Sulfatase/metabolismo , Ácidos Sulfônicos/administração & dosagem , Ácidos Sulfônicos/farmacologia
15.
Bioorg Med Chem Lett ; 39: 127854, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33631370

RESUMO

p300 and CREB-binding protein (CBP) are essential for a multitude of cellular processes. Dysregulation of p300/CBP histone acetyltransferase activity is linked to a broad spectrum of human diseases including cancers. A novel drug-like spirohydantoin (21) has been discovered as a selective orally bioavailable inhibitor of p300/CBP histone acetyltransferase. Lead compound 21 is more potent than the first-in-class lead A-485 in both enzymatic and cellular assays and lacks the off-target inhibition of dopamine and serotonin transporters, that was observed with A-485.


Assuntos
Proteína de Ligação a CREB/antagonistas & inibidores , Descoberta de Drogas , Proteína p300 Associada a E1A/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Hidantoínas/farmacologia , Compostos de Espiro/farmacologia , Administração Oral , Disponibilidade Biológica , Proteína de Ligação a CREB/metabolismo , Relação Dose-Resposta a Droga , Proteína p300 Associada a E1A/metabolismo , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/metabolismo , Humanos , Hidantoínas/administração & dosagem , Hidantoínas/metabolismo , Estrutura Molecular , Compostos de Espiro/administração & dosagem , Compostos de Espiro/metabolismo , Relação Estrutura-Atividade
16.
Biomed Res Int ; 2021: 8630596, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33564682

RESUMO

Objectives: Mycophenolate mofetil (MMF) is the standard treatment for lupus nephritis. In Japan, it was approved for lupus nephritis in 2015. We investigated its real-world safety and effectiveness in Japanese patients with systemic lupus erythematosus (SLE). Methods: We analyzed the continuation rate, adverse events, and reasons for discontinuation of MMF in Japanese patients with SLE in a retrospective single-center study. We included 119 patients who received MMF from 31 July 2015 to 31 May 2019. To compare demographic and clinical characteristics between groups, the Mann-Whitney U-test was used for nonnormally distributed variables. Categorical variables were compared using Fisher's exact test. Kaplan-Meier curves were plotted for the discontinuation rate of MMF. Results: Patients consisted of 18 males and 101 females. Thirty-five patients discontinued MMF. The cumulative discontinuation rate was 42.4%. Twenty-nine patients discontinued MMF due to adverse events, and six patients discontinued MMF due to remission of SLE or desire for childbearing. At the time of the last observation, the lupus low disease activity state achievement rate was significantly lower in patients who experienced adverse events than those who did not (64% vs. 35%, P = 0.009). We examined the concentration of mycophenolate acid (trough level) in stored frozen serum in 11 patients. Two patients had irreversible complications due to viral meningitis; their trough mycophenolate acid concentrations were 8.3 and 6.3 µg/mL, respectively. Conclusions: Although MMF may be effective in Japanese patients with SLE, physicians should pay attention to infections in patients with high mycophenolate acid concentrations.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Nefrite Lúpica/tratamento farmacológico , Ácido Micofenólico/uso terapêutico , Adulto , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/classificação , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Inibidores Enzimáticos/administração & dosagem , Feminino , Humanos , Imunossupressores/uso terapêutico , Japão/epidemiologia , Estimativa de Kaplan-Meier , Lúpus Eritematoso Sistêmico/epidemiologia , Lúpus Eritematoso Sistêmico/patologia , Nefrite Lúpica/epidemiologia , Nefrite Lúpica/patologia , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/efeitos adversos , Estudos Retrospectivos , Resultado do Tratamento
17.
Expert Opin Ther Pat ; 31(7): 645-661, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33567917

RESUMO

INTRODUCTION: Tankyrase inhibitors gained significant attention as therapeutic targets in oncology because of their potency. Their primary role in inhibiting the Wnt signaling pathway makes them an important class of compounds with the potential to be used as a combination therapy in future treatments of colorectal cancer. AREAS COVERED: This review describes pertinent work in the development of tankyrase inhibitors with a great emphasis on the recently patented TNKS inhibitors published from 2013 to 2020. This article also highlights a couple of promising candidates having tankyrase inhibitory effects and are currently undergoing clinical trials. EXPERT OPINION: Following the successful clinical applications of PARP inhibitors, tankyrase inhibition has gained significant attention in the research community as a target with high therapeutic potential. The ubiquitous role of tankyrase in cellular homeostasis and Wnt-dependent tumor proliferation brought difficulties for researchers to strike the right balance between potency and on-target toxicity. The need for novel tankyrase inhibitors with a better ADMET profile can introduce an additional regimen in treating various malignancies in monotherapy or adjuvant therapy. The development of combination therapies, including tankyrase inhibitors with or without PARP inhibitory properties, can potentially benefit the larger population of patients with unmet medical needs.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Tanquirases/antagonistas & inibidores , Animais , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Desenvolvimento de Medicamentos , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacologia , Humanos , Patentes como Assunto , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Tanquirases/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos
18.
Biochem Pharmacol ; 186: 114450, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33571504

RESUMO

Werner (WRN) expression is epigenetically downregulated in various tumors. It is imperative to understand differential repair process in WRN-proficient and WRN-deficient cancers to find pharmacological targets for radio-sensitization of WRN-deficient cancer. In the current investigation, we showed that pharmacological inhibition of CHK1 mediated homologous recombination repair (HRR), but not non-homologous end joining (NHEJ) repair, can causes hyper-radiosensitization of WRN-deficient cancers. This was confirmed in cancer cell lines of different tissue origin (osteosarcoma, colon adenocarcinoma and melanoma) with WRN silencing and overexpression. We established that WRN-depleted cells are dependent on a critical but compromised CHK1-mediated HRR-pathway for repairing ionizing radiation (IR) induced DSBs for their survival. Mechanistically, we unraveled a new finding that the MRE11, CTIP and WRN proteins are largely responsible for resections of late and persistent DSBs. In response to IR-treatment, MRE11 and CTIP-positively and WRN-negatively regulate p38-MAPK reactivation in a CHK1-dependent manner. A degradation resistant WRN protein, mutated at serine 1141, abrogates p38-MAPK activation. We also showed that CHK1-p38-MAPK axis plays important role in RAD51 mediated HRR in WRN-silenced cells. Like CHK1 inhibition, pharmacological-inhibition of p38-MAPK also hyper-radiosensitizes WRN-depleted cells by targeting HR-pathway. Combination treatment of CHK1-inhibitor (currently under various clinical trials) and IR exhibited a strong synergy against WRN-deficient melanoma tumor in vivo. Taken together, our findings suggest that pharmacological targeting of CHK1-p38-MAPK mediated HRR is an attractive strategy for enhancing therapeutic response of radiation treatment of cancer.


Assuntos
Reparo do DNA/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodos , Radiossensibilizantes/administração & dosagem , Helicase da Síndrome de Werner/antagonistas & inibidores , Helicase da Síndrome de Werner/deficiência , Animais , Linhagem Celular Tumoral , Quinase 1 do Ponto de Checagem/antagonistas & inibidores , Quinase 1 do Ponto de Checagem/metabolismo , Reparo do DNA/fisiologia , Inibidores Enzimáticos/administração & dosagem , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Melanoma Experimental , Camundongos , Camundongos Endogâmicos C57BL , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
19.
Int J Mol Sci ; 22(3)2021 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-33572654

RESUMO

Altered sialylation patterns play a role in chronic autoimmune diseases such as rheumatoid arthritis (RA). Recent studies have shown the pro-inflammatory activities of immunoglobulins (Igs) with desialylated sugar moieties. The role of neuraminidases (NEUs), enzymes which are responsible for the cleavage of terminal sialic acids (SA) from sialoglycoconjugates, is not fully understood in RA. We investigated the impact of zanamivir, an inhibitor of the influenza virus neuraminidase, and mammalian NEU2/3 on clinical outcomes in experimental arthritides studies. The severity of arthritis was monitored and IgG titers were measured by ELISA. (2,6)-linked SA was determined on IgG by ELISA and on cell surfaces by flow cytometry. Zanamivir at a dose of 100 mg/kg (zana-100) significantly ameliorated collagen-induced arthritis (CIA), whereas zana-100 was ineffective in serum transfer-induced arthritis. Systemic zana-100 treatment reduced the number of splenic CD138+/TACI+ plasma cells and CD19+ B cells, which was associated with lower IgG levels and an increased sialylation status of IgG compared to controls. Our data reveal the contribution of NEU2/3 in CIA. Zanamivir down-modulated the T and B cell-dependent humoral immune response and induced an anti-inflammatory milieu by inhibiting sialic acid degradation. We suggest that neuraminidases might represent a promising therapeutic target for RA and possibly also for other antibody-mediated autoimmune diseases.


Assuntos
Anti-Inflamatórios/administração & dosagem , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Inibidores Enzimáticos/administração & dosagem , Neuraminidase/antagonistas & inibidores , Zanamivir/administração & dosagem , Animais , Artrite Experimental/induzido quimicamente , Colágeno/efeitos adversos , Imunoglobulina G/sangue , Camundongos , Camundongos Endogâmicos C57BL , Orthomyxoviridae/enzimologia , Ácidos Siálicos/metabolismo
20.
Life Sci ; 271: 119154, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33539910

RESUMO

Ulcerative colitis (UC) is a chronic inflammatory bowel disease that increases the risk of colorectal cancer. UC is highly associated with the disturbance of the immune system leading to oxidative stress and chronic inflammation of intestine. Therefore, the current study was conducted to investigate the potential anti-oxidant and anti-inflammatory effects of MMF against acetic acid-induced UC that might be associated with the regulation of Nrf-2 and NLRP3 inflammasome signaling. UC was induced in Sprague-Dawley rats by intracolonic instillation of acetic acid. Forty-eight hours post UC induction, MMF (50 mg/kg/day, orally) was given for 8 consecutive days. Then, colon tissues and blood samples were collected. Results showed that MMF significantly attenuated the acetic acid-induced functional, biochemical, and inflammatory injuries in colon. MMF significantly decreased oxidative stress as indicated by the decreased malondialdehyde concentration and the increased total antioxidant capacity, glutathione, catalase, and superoxide dismutase concentrations in colon tissues. MMF also significantly increased Nrf-2 and decreased NLRP3 inflammasome expressions. Moreover, MMF decreased expression of interferon-gamma and increased expression of interferon-alpha. MMF also significantly decreased expression of pro-inflammatory cytokines, interleukin (IL)-1ß and IL-18. These results suggest that MMF has antioxidant and anti-inflammatory effects against acetic acid-induced UC through the upregulation of Nrf-2, and INF-α expression in addition to the suppression of NLRP3 inflammasome and subsequent release of IL1ß, IL-18 and INF-γ.


Assuntos
Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Ácido Micofenólico/administração & dosagem , Fator 2 Relacionado a NF-E2/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Ácido Acético/toxicidade , Animais , Colite Ulcerativa/induzido quimicamente , Inibidores Enzimáticos/administração & dosagem , Inflamassomos/antagonistas & inibidores , Inflamassomos/metabolismo , Masculino , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
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