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1.
Nat Commun ; 11(1): 4387, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32873795

RESUMO

The role of neutrophils in solid tumor metastasis remains largely controversial. In preclinical models of solid tumors, both pro-metastatic and anti-metastatic effects of neutrophils have been reported. In this study, using mouse models of breast cancer, we demonstrate that the metastasis-modulating effects of neutrophils are dictated by the status of host natural killer (NK) cells. In NK cell-deficient mice, granulocyte colony-stimulating factor-expanded neutrophils show an inhibitory effect on the metastatic colonization of breast tumor cells in the lung. In contrast, in NK cell-competent mice, neutrophils facilitate metastatic colonization in the same tumor models. In an ex vivo neutrophil-NK cell-tumor cell tri-cell co-culture system, neutrophils are shown to potentially suppress the tumoricidal activity of NK cells, while neutrophils themselves are tumoricidal. Intriguingly, these two modulatory effects by neutrophils are both mediated by reactive oxygen species. Collectively, the absence or presence of NK cells, governs the net tumor-modulatory effects of neutrophils.


Assuntos
Células Matadoras Naturais/imunologia , Neoplasias Pulmonares/imunologia , Neoplasias Mamárias Animais/imunologia , Neutropenia/prevenção & controle , Neutrófilos/imunologia , Animais , Linhagem Celular Tumoral/transplante , Técnicas de Cocultura , Modelos Animais de Doenças , Feminino , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Humanos , Injeções Intravenosas , Pulmão/citologia , Pulmão/imunologia , Pulmão/patologia , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/secundário , Glândulas Mamárias Animais/citologia , Glândulas Mamárias Animais/imunologia , Glândulas Mamárias Animais/patologia , Neoplasias Mamárias Animais/sangue , Neoplasias Mamárias Animais/complicações , Neoplasias Mamárias Animais/patologia , Camundongos , Camundongos Endogâmicos NOD , Neutropenia/sangue , Neutropenia/etiologia , Neutropenia/imunologia , Neutrófilos/efeitos dos fármacos , Cultura Primária de Células
2.
Carbohydr Polym ; 247: 116740, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32829859

RESUMO

Pulmonary fibrosis (PF) is a lung disease with highly heterogeneous and mortality rate, but its therapeutic options are now still limited. Corona virus disease 2019 (COVID-19) has been characterized by WHO as a pandemic, and the global number of confirmed COVID-19 cases has been more than 8.0 million. It is strongly supported for that PF should be one of the major complications in COVID-19 patients by the evidences of epidemiology, viral immunology and current clinical researches. The anti-PF properties of naturally occurring polysaccharides have attracted increasing attention in last two decades, but is still lack of a comprehensively understanding. In present review, the resources, structural features, anti-PF activities, and underlying mechanisms of these polysaccharides are summarized and analyzed, which was expected to provide a scientific evidence supporting the application of polysaccharides for preventing or treating PF in COVID-19 patients.


Assuntos
Betacoronavirus , Produtos Biológicos/uso terapêutico , Infecções por Coronavirus/complicações , Pandemias , Pneumonia Viral/complicações , Polissacarídeos/uso terapêutico , Fibrose Pulmonar/tratamento farmacológico , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Bleomicina/toxicidade , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Proteína Forkhead Box O3/fisiologia , Fungos/química , Ribonucleoproteína Nuclear Heterogênea D0/fisiologia , Humanos , Macrófagos/efeitos dos fármacos , Medicina Tradicional Chinesa , Camundongos , Neutrófilos/efeitos dos fármacos , Fitoterapia , Plantas Medicinais/química , Polissacarídeos/farmacologia , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/etiologia , Fibrose Pulmonar/prevenção & controle , RNA Longo não Codificante/antagonistas & inibidores , Ratos , Alga Marinha/química , Transdução de Sinais/efeitos dos fármacos , Proteína Smad2/fisiologia , Proteína Smad3/fisiologia , Fator de Crescimento Transformador beta1/antagonistas & inibidores
3.
Adv Biol Regul ; 77: 100741, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32773102

RESUMO

Pandemic coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and poses an unprecedented challenge to healthcare systems due to the lack of a vaccine and specific treatment options. Accordingly, there is an urgent need to understand precisely the pathogenic mechanisms underlying this multifaceted disease. There is increasing evidence that the immune system reacts insufficiently to SARS-CoV-2 and thus contributes to organ damage and to lethality. In this review, we suggest that the overwhelming production of reactive oxygen species (ROS) resulting in oxidative stress is a major cause of local or systemic tissue damage that leads to severe COVID-19. It increases the formation of neutrophil extracellular traps (NETs) and suppresses the adaptive arm of the immune system, i.e. T cells that are necessary to kill virus-infected cells. This creates a vicious cycle that prevents a specific immune response against SARS-CoV-2. The key role of oxidative stress in the pathogenesis of severe COVID-19 implies that therapeutic counterbalancing of ROS by antioxidants such as vitamin C or NAC and/or by antagonizing ROS production by cells of the mononuclear phagocyte system (MPS) and neutrophil granulocytes and/or by blocking of TNF-α can prevent COVID-19 from becoming severe. Controlled clinical trials and preclinical models of COVID-19 are needed to evaluate this hypothesis.


Assuntos
Antioxidantes/uso terapêutico , Infecções por Coronavirus/epidemiologia , Armadilhas Extracelulares/imunologia , Linfopenia/epidemiologia , Neutrófilos/imunologia , Pandemias , Pneumonia Viral/epidemiologia , Acetilcisteína/uso terapêutico , Ácido Ascórbico/uso terapêutico , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Citocinas/genética , Citocinas/imunologia , Armadilhas Extracelulares/efeitos dos fármacos , Armadilhas Extracelulares/metabolismo , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Inata/efeitos dos fármacos , Linfopenia/tratamento farmacológico , Linfopenia/imunologia , Linfopenia/virologia , NF-kappa B/genética , NF-kappa B/imunologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/virologia , Estresse Oxidativo/efeitos dos fármacos , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/imunologia , Espécies Reativas de Oxigênio/metabolismo , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/virologia
4.
Am J Hum Genet ; 107(3): 539-543, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32758448

RESUMO

The identification of disease alleles underlying human autoinflammatory diseases can provide important insights into the mechanisms that maintain neutrophil homeostasis. Here, we focused our attention on generalized pustular psoriasis (GPP), a potentially life-threatening disorder presenting with cutaneous and systemic neutrophilia. Following the whole-exome sequencing of 19 unrelated affected individuals, we identified a subject harboring a homozygous splice-site mutation (c.2031-2A>C) in MPO. This encodes myeloperoxidase, an essential component of neutrophil azurophil granules. MPO screening in conditions phenotypically related to GPP uncovered further disease alleles in one subject with acral pustular psoriasis (c.2031-2A>C;c.2031-2A>C) and in two individuals with acute generalized exanthematous pustulosis (c.1705C>T;c.2031-2A>C and c.1552_1565del;c.1552_1565del). A subsequent analysis of UK Biobank data demonstrated that the c.2031-2A>C and c.1705C>T (p.Arg569Trp) disease alleles were also associated with increased neutrophil abundance in the general population (p = 5.1 × 10-6 and p = 3.6 × 10-5, respectively). The same applied to three further deleterious variants that had been genotyped in the cohort, with two alleles (c.995C>T [p.Ala332Val] and c.752T>C [p.Met251Thr]) yielding p values < 10-10. Finally, treatment of healthy neutrophils with an MPO inhibitor (4-Aminobenzoic acid hydrazide) increased cell viability and delayed apoptosis, highlighting a mechanism whereby MPO mutations affect granulocyte numbers. These findings identify MPO as a genetic determinant of pustular skin disease and neutrophil abundance. Given the recent interest in the development of MPO antagonists for the treatment of neurodegenerative disease, our results also suggest that the pro-inflammatory effects of these agents should be closely monitored.


Assuntos
Doenças Neurodegenerativas/genética , Peroxidase/genética , Psoríase/genética , Dermatopatias/genética , Ácido 4-Aminobenzoico/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular/efeitos dos fármacos , Feminino , Genótipo , Humanos , Mutação com Perda de Função/genética , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/patologia , Neutrófilos/efeitos dos fármacos , Peroxidase/antagonistas & inibidores , Fenótipo , Psoríase/tratamento farmacológico , Psoríase/patologia , Pele/efeitos dos fármacos , Pele/patologia , Dermatopatias/tratamento farmacológico , Dermatopatias/patologia
5.
Nat Commun ; 11(1): 4027, 2020 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-32788676

RESUMO

Programmed cell death or apoptosis is a central biological process that is dysregulated in many diseases, including inflammatory conditions and cancer. The detection and quantification of apoptotic cells in vivo is hampered by the need for fixatives or washing steps for non-fluorogenic reagents, and by the low levels of free calcium in diseased tissues that restrict the use of annexins. In this manuscript, we report the rational design of a highly stable fluorogenic peptide (termed Apo-15) that selectively stains apoptotic cells in vitro and in vivo in a calcium-independent manner and under wash-free conditions. Furthermore, using a combination of chemical and biophysical methods, we identify phosphatidylserine as a molecular target of Apo-15. We demonstrate that Apo-15 can be used for the quantification and imaging of drug-induced apoptosis in preclinical mouse models, thus creating opportunities for assessing the in vivo efficacy of anti-inflammatory and anti-cancer therapeutics.


Assuntos
Apoptose , Imageamento Tridimensional , Peptídeos Cíclicos/farmacologia , Sequência de Aminoácidos , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Feminino , Humanos , Camundongos Endogâmicos C57BL , Microscopia de Fluorescência , Neutrófilos/citologia , Neutrófilos/efeitos dos fármacos , Peptídeos Cíclicos/administração & dosagem , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/química , Fagocitose/efeitos dos fármacos , Fosfatidilserinas/metabolismo
6.
Anticancer Res ; 40(7): 4147-4156, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32620664

RESUMO

BACKGROUND/AIM: We investigated the efficacy of neutrophil-to-lymphocyte ratio (NLR), absolute lymphocyte count (ALC), and C-reactive protein (CRP) in predicting overall survival of metastatic breast cancer patients treated with eribulin. PATIENTS AND METHODS: Overall, 74 patients treated with eribulin were enrolled and their baseline levels of NLR, ALC, and CRP retrieved. Cutoff values of NLR, ALC, and CRP were set at 3.0, 1500/µl, and 0.3 mg/dl, respectively. Overall survival (OS) was compared according to marker levels. RESULTS: The OS of NLR-low, ALC-high, and CRP-low groups at baseline was significantly longer than that of NLR-high, ALC-low, and CRP-high groups (p=0.0027, p=0.0013, and p=0.0164, respectively). The combination of ALC and CRP was significantly associated with OS by multivariate analysis (p=0.048). CONCLUSION: Baseline levels of NLR, ALC, and CRP were significantly associated with OS in patients treated with eribulin. The combination of ALC and CRP improved the predictive efficacy compared to individual markers.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Furanos/uso terapêutico , Cetonas/uso terapêutico , Linfócitos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/sangue , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Proteína C-Reativa/análise , Feminino , Humanos , Contagem de Leucócitos , Pessoa de Meia-Idade
7.
Toxicol Lett ; 332: 140-145, 2020 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-32659472

RESUMO

Fumonisin B1 (FB1) is a congener of fumonisins produced by Fusarium species that may be found as corn contaminants threatening health of humans and animals. FB1 causes a variety of toxicity effects, including hepatotoxic, nephrotoxic and cytotoxic effects. However, detailed mechanisms associated with FB1 immunotoxicity in neutrophils are still unclear. To accomplish this, we utilized neutrophils to study the mechanisms of FB1 immunotoxicity. In the current study, we found that FB1 induced the formation of neutrophil extracellular traps (NETs), increased reactive oxygen species (ROS) levels, and decreased SOD and CAT activities. Concurrently, FB1 treatment led to the concentration-dependent phosphorylation of ERK-1/2 and p38 in neutrophils. Moreover, we demonstrated that FB1-induced NET formation was dependent of NADPH oxidase activity. Pretreatment of neutrophils with DPI, U0126 and SB202190 significantly reduced ROS generation, and prevented NET formation, further suggesting that ROS dependent activation of ERK 1/2 and p38 pathways, which possibly mediate FB1-induced NET release in neutrophils. Thus, NET formation and ROS production could be attributed to FB1 immunotoxicity, which might enrich the toxicological mechanisms of FB1.


Assuntos
Armadilhas Extracelulares/efeitos dos fármacos , Fumonisinas/toxicidade , Imunotoxinas/toxicidade , Micotoxinas/toxicidade , Neutrófilos/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Catalase/sangue , Bovinos , Armadilhas Extracelulares/imunologia , Técnicas In Vitro , L-Lactato Desidrogenase/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , NADPH Oxidases/metabolismo , Neutrófilos/imunologia , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/sangue , Proteínas Quinases p38 Ativadas por Mitógeno/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
8.
Medicine (Baltimore) ; 99(27): e20931, 2020 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-32629693

RESUMO

Various psychotropic drugs may affect the hematological and biochemical profiles of plasma and its metabolism. Carbamazepine, the most well-known psychotropic drug, can cause substantial hyponatremia. Methylphenidate, a piperidine derivative structurally related to amphetamines, acts as a central nervous system stimulant. The current study evaluated whether methylphenidate affects hematological and biochemical parameters of patients diagnosed with attention deficit hyperactivity disorder.Patients undergoing treatment for attention deficit hyperactivity disorder at our Adolescent Psychiatric Clinic were enrolled in the study. Blood samples for complete blood count and common biochemical analyses were collected before patients started methylphenidate and after 3 months of continuous treatment.Participants included 64 patients comprised the study cohort. There were 48 (75%) males and 16 (25%) females, with a median age of 16 years (range 11-31). The total median potassium level decreased by 0.6 mg/dL (P < .0001), while glucose rose by 15 mg/dL (P < .0001), sodium decreased in 0.7meq/L, (P = .006). The white blood count rose by 1350 cells/µL (P < .033) due to neutrophilia, lymphocytosis and eosinophilia. Hemoglobin rose slightly by 0.1 (P = .041). Changes in calcium, phosphorus, protein, albumin, and liver enzyme levels were not significant.The results indicate that methylphenidate may cause hypokalemia and elevated glucose, leukocyte, neutrophil, lymphocyte and eosinophil counts.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Estimulantes do Sistema Nervoso Central/uso terapêutico , Metilfenidato/uso terapêutico , Adolescente , Adulto , Transtorno do Deficit de Atenção com Hiperatividade/sangue , Estimulantes do Sistema Nervoso Central/farmacologia , Criança , Estudos de Coortes , Feminino , Humanos , Hipoglicemia/induzido quimicamente , Leucócitos/efeitos dos fármacos , Masculino , Metilfenidato/farmacologia , Neutrófilos/efeitos dos fármacos , Adulto Jovem
9.
Nat Rev Immunol ; 20(9): 515-516, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32728221

Assuntos
Antioxidantes/uso terapêutico , Betacoronavirus/patogenicidade , Infecções por Coronavirus/tratamento farmacológico , Pulmão/imunologia , Neutrófilos/efeitos dos fármacos , Pneumonia Viral/tratamento farmacológico , Acetilcisteína/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Citocinas/genética , Citocinas/imunologia , Quimioterapia Combinada , Armadilhas Extracelulares/efeitos dos fármacos , Armadilhas Extracelulares/imunologia , Armadilhas Extracelulares/metabolismo , Regulação da Expressão Gênica , Glicina/análogos & derivados , Glicina/uso terapêutico , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Imunidade Inata/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/virologia , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Linfócitos/virologia , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/imunologia , NF-kappa B/genética , NF-kappa B/imunologia , Neutrófilos/imunologia , Neutrófilos/virologia , Estresse Oxidativo/efeitos dos fármacos , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Proteínas Secretadas Inibidoras de Proteinases/uso terapêutico , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/imunologia , Espécies Reativas de Oxigênio/metabolismo , Índice de Gravidade de Doença , Sulfonamidas/uso terapêutico , Superóxido Dismutase/genética , Superóxido Dismutase/imunologia
10.
Drug Discov Ther ; 14(3): 117-121, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32595179

RESUMO

The advent of immune checkpoint inhibitors such as anti-PD-1 antibodies had a striking impact on the treatment for advanced malignant melanoma. However, less than half of the patients benefited from those antibodies, and biomarkers that could sensitively differentiate responders from non-responders are urgently needed. Herein, we explored such biomarkers by retrospectively analyzing clinical data from patients with advanced malignant melanoma treated with nivolumab and pembrolizumab. We found that anti-PD-1 antibody was especially effective for those with metastasis only to soft tissues. Although no significant difference was found in the baseline value of relative neutrophil count (RNC), relative lymphocyte count (RLC), neutrophil to lymphocyte ratio (NLR), and relative eosinophil count (REC) between responders and non-responders, responders after anti-PD-1 therapy revealed the increase of lymphocytes and eosinophils and the decrease of neutrophils within the first 6 weeks of the treatment. We also calculated the change of RNC and RLC 3 weeks and 6 weeks after the initiation of the therapy and designated as NΔ3-LΔ3 and NΔ6-LΔ6 respectively. NΔ3-LΔ3 was significantly decreased in responders, which suggest that the neutrophil decrease and lymphocyte increase after as early as 3 weeks of anti-PD-1 therapy might be a useful clinical indicator. In addition, the difference of NΔ6-LΔ6 between responders and non-responders was even more robust. These data suggest that change of RNC, RLC, and REC together with the combination of NΔ3-LΔ3 and NΔ6-LΔ6 might be a useful tool for early and sensitive biomarkers for anti-PD-1 therapy.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Melanoma/tratamento farmacológico , Nivolumabe/administração & dosagem , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Cutâneas/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Autoanticorpos/sangue , Autoanticorpos/efeitos dos fármacos , Eosinófilos/efeitos dos fármacos , Eosinófilos/metabolismo , Feminino , Humanos , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Masculino , Melanoma/sangue , Pessoa de Meia-Idade , Estadiamento de Neoplasias/métodos , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Receptor de Morte Celular Programada 1/sangue , Estudos Retrospectivos , Neoplasias Cutâneas/sangue , Resultado do Tratamento
11.
Nanotoxicology ; 14(7): 869-892, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32536294

RESUMO

Surface modification by different quaternary ammonium compounds (QAC) makes nanoclays more compatible with various polymeric matrices, thereby expanding their potential applications. The growing industrial use of nanoclays could potentially pose a health risk for workers. Here, we assessed how surface modification of nanoclays modulates their pulmonary toxicity. An in vitro screening of the unmodified nanoclay Bentonite (montmorillonite) and four organomodified nanoclays (ONC); coated with various QAC, including benzalkonium chloride (BAC), guided the selection of the materials for the in vivo study. Mice were exposed via a single intratracheal instillation to 18, 54, and 162 µg of unmodified Bentonite or dialkyldimethyl-ammonium-coated ONC (NanofilSE3000), or to 6, 18, and 54 µg of a BAC-coated ONC (Nanofil9), and followed for one, 3, or 28 days. All materials induced dose- and time-dependent responses in the exposed mice. However, all doses of Bentonite induced larger, but reversible, inflammation (BAL neutrophils) and acute phase response (Saa3 gene expression in lung) than the two ONC. Similarly, highest levels of DNA strand breaks were found in BAL cells of mice exposed to Bentonite 1 day post-exposure. A significant increase of DNA strand breaks was detected also for NanofilSE3000, 3 days post-exposure. Only mice exposed to Bentonite showed increased Tgf-ß gene expression in lung, biomarker of pro-fibrotic processes and hepatic extravasation, 3 days post-exposure. This study indicates that Bentonite treatment with some QAC changes main physical-chemical properties, including shape and surface area, and may decrease their pulmonary toxicity in exposed mice.


Assuntos
Reação de Fase Aguda/prevenção & controle , Bentonita/toxicidade , Dano ao DNA , Pulmão/efeitos dos fármacos , Nanopartículas/toxicidade , Compostos de Amônio Quaternário/química , Reação de Fase Aguda/imunologia , Animais , Bentonita/química , Líquido da Lavagem Broncoalveolar/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/imunologia , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Inflamação , Pulmão/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas/química , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Tamanho da Partícula , Propriedades de Superfície
12.
J Pineal Res ; 69(3): e12676, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32597503

RESUMO

Melatonin is a chronobiotic hormone, which can regulate human diseases like cancer, atherosclerosis, respiratory disorders, and microbial infections by regulating redox system. Melatonin exhibits innate immunomodulation by communicating with immune system and influencing neutrophils to fight infections and inflammation. However, sustaining redox homeostasis and reactive oxygen species (ROS) generation in neutrophils are critical during chemotaxis, oxidative burst, phagocytosis, and neutrophil extracellular trap (NET) formation. Therefore, endogenous antioxidant glutathione (GSH) redox cycle is highly vital in regulating neutrophil functions. Reduced intracellular GSH levels and glutathione reductase (GR) activity in the neutrophils during clinical conditions like autoimmune disorders, neurological disorders, diabetes, and microbial infections lead to dysfunctional neutrophils. Therefore, we hypothesized that redox modulators like melatonin can protect neutrophil health and functions under GSH and GR activity-deficient conditions. We demonstrate the dual role of melatonin, wherein it protects neutrophils from oxidative stress-induced apoptosis by reducing ROS generation; in contrast, it restores neutrophil functions like phagocytosis, degranulation, and NETosis in GSH and GR activity-deficient neutrophils by regulating ROS levels both in vitro and in vivo. Melatonin mitigates LPS-induced neutrophil dysfunctions by rejuvenating GSH redox system, specifically GR activity by acting as a parallel redox system. Our results indicate that melatonin could be a potential auxiliary therapy to treat immune dysfunction and microbial infections, including virus, under chronic disease conditions by restoring neutrophil functions. Further, melatonin could be a promising immune system booster to fight unprecedented pandemics like the current COVID-19. However, further studies are indispensable to address the clinical usage of melatonin.


Assuntos
Antioxidantes/uso terapêutico , Glutationa/metabolismo , Melatonina/uso terapêutico , Neutrófilos/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Avaliação Pré-Clínica de Medicamentos , Feminino , Glutationa Redutase/metabolismo , Humanos , Masculino , Melatonina/farmacologia , Camundongos , Mitocôndrias/metabolismo , NADPH Oxidases/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
13.
Parasitol Res ; 119(8): 2587-2595, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32524267

RESUMO

Lycorine is an Amaryllidaceae alkaloid that presents anti-Trichomonas vaginalis activity. T. vaginalis causes trichomoniasis, the most common non-viral sexually transmitted infection. The modulation of T. vaginalis purinergic signaling through the ectonucleotidases, nucleoside triphosphate diphosphohydrolase (NTPDase), and ecto-5'-nucleotidase represents new targets for combating the parasite. With this knowledge, the aim of this study was to investigate whether NTPDase and ecto-5'-nucleotidase inhibition by lycorine could lead to extracellular ATP accumulation. Moreover, the lycorine effect on the reactive oxygen species (ROS) production by neutrophils and parasites was evaluated as well as the alkaloid toxicity. The metabolism of purines was assessed by HPLC. ROS production was measured by flow cytometry. Cytotoxicity against epithelial vaginal cells and fibroblasts was tested, as well as the hemolytic effect of lycorine and its in vivo toxicity in Galleria mellonella larvae. Our findings showed that lycorine caused ATP accumulation due to NTPDase inhibition. The alkaloid did not affect the ROS production by T. vaginalis; however, it increased ROS levels in neutrophils incubated with lycorine-treated trophozoites. Lycorine was cytotoxic against vaginal epithelial cells and fibroblasts; conversely, it was not hemolytic neither exhibited toxicity against the in vivo model of G. mellonella larvae. Overall, besides having anti-T. vaginalis activity, lycorine modulates ectonucleotidases and stimulates neutrophils to secrete ROS. This mechanism of action exerted by the alkaloid could enhance the susceptibility of T. vaginalis to host immune cell, contributing to protozoan clearance.


Assuntos
Alcaloides de Amaryllidaceae/farmacologia , Amaryllidaceae/química , Antiprotozoários/farmacologia , Neutrófilos/metabolismo , Nucleosídeo-Trifosfatase/antagonistas & inibidores , Fenantridinas/farmacologia , Extratos Vegetais/farmacologia , Proteínas de Protozoários/antagonistas & inibidores , Tricomoníase/metabolismo , Trichomonas vaginalis/enzimologia , 5'-Nucleotidase/antagonistas & inibidores , 5'-Nucleotidase/metabolismo , Humanos , Neutrófilos/efeitos dos fármacos , Nucleosídeo-Trifosfatase/metabolismo , Proteínas de Protozoários/genética , Proteínas de Protozoários/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Tricomoníase/parasitologia , Trichomonas vaginalis/efeitos dos fármacos , Trichomonas vaginalis/crescimento & desenvolvimento , Trichomonas vaginalis/metabolismo , Trofozoítos/efeitos dos fármacos , Trofozoítos/enzimologia , Trofozoítos/crescimento & desenvolvimento , Trofozoítos/metabolismo
15.
Lung Cancer ; 145: 213-215, 2020 07.
Artigo em Inglês | MEDLINE | ID: covidwho-165217
16.
Cancer Immunol Immunother ; 69(9): 1813-1822, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32350592

RESUMO

BACKGROUND: Selected patients with advanced non-small cell lung cancer (NSCLC) benefit from immunotherapy, especially immune checkpoint inhibitors such as PD-1 (programmed cell death protein 1) inhibitor. Peripheral blood biomarkers would be most convenient to predict treatment outcome and immune-related adverse events (irAEs) in candidate patients. This study explored associations between inflammation-related peripheral blood markers and onset of irAEs and outcome in patients with advanced NSCLC receiving PD-1 inhibitors. METHODS: A retrospective analysis was conducted of 102 patients with advanced NSCLC receiving PD-1 inhibitors from January 2017 to May 2019. Cox regression models were employed to assess the prognostic effect of low/high neutrophil/lymphocyte ratio (NLR), lactate dehydrogenase (LDH), and prognostic nutrition index (PNI) on overall survival (OS) and progression-free survival (PFS). Logistic regression models were used to analyze the correlation between peripheral blood markers and the onset of irAEs. RESULT: NLR < 5, LDH < 240 U/L, or PNI ≥ 45 was favorably associated with significantly better outcomes compared with higher, higher, or lower values, respectively. The multivariate analysis determined that these parameters were independently associated with both better PFS (p = 0.049, 0.046, 0.014, respectively) and longer OS (p = 0.007, 0.031, < 0.001, respectively). Patients with three favorable factors among NLR, LDH, and PNI had better PFS and OS than did those with two, one, or none. PNI and NLR were associated with the onset of irAEs. CONCLUSION: In patients with advanced NSCLC treated with PD-1 inhibitors, pretreatment NLR, LDH, and PNI may be useful predictive markers of clinical outcome and irAEs.


Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/sangue , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/imunologia , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Antineoplásicos/imunologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Feminino , Humanos , Imunoterapia/métodos , Neoplasias Pulmonares/imunologia , Contagem de Linfócitos/métodos , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Masculino , Pessoa de Meia-Idade , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Prognóstico , Intervalo Livre de Progressão , Estudos Retrospectivos , Resultado do Tratamento
17.
Clin Chim Acta ; 508: 98-102, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32405079

RESUMO

BACKGROUND: Novel coronavirus infectious disease (COVID-19) has been spreading worldwide, and tracking laboratory indexes during the diagnosis and treatment of patients with severe COVID-19 can provide a reference for patients in other countries and regions. METHODS: We closely tracked the epidemiological history, diagnosis and treatment process, as well as dynamic changes in routine blood indicators, of a severe COVID-19 patient who was hospitalized for 26 days. RESULTS: Our study found that the patient's condition worsened in the first week after admission, white blood cells (WBCs), neutrophils, lymphocytes, monocytes, eosinophils, red blood cells (RBCs), hemoglobin, neutrophil lymphocyte ratio (NLR), platelets (PLT) and platelet lymphocyte ratio (PLR) decreased. On the 7th day of admission, the levels of these cells decreased to their lowest values, though the red blood cell distribution width (RDW) and C-reactive protein (CRP) level remained at high values. From 8 to 14 days of admission, the patient's condition improved, hypoxemia was corrected, and mechanical ventilation was discontinued. The number of WBCs, neutrophils, monocytes, eosinophils and lymphocytes increased gradually, and the erythrocyte parameters stopped declining and stabilized in a certain range; CRP decreased rapidly. On the 20th day of admission, the nucleic acid test was negative, WBC, neutrophil, CRP, NLR and PLR decreased gradually, and monocyte, lymphocyte, and eosinophil counts increased. Although RBCs and hemoglobin (Hb) levels continued to decrease, RDW gradually increased, indicating the recovery of hematopoiesis. In addition, it should be noted that monocytes and eosinophils were at extremely low levels within 10 days after admission; the recovery time of eosinophils was approximately 12 days after admission, which was earlier than other parameters, which might be of great value in judging the progress of the disease. CONCLUSIONS: Dynamic changes in routine blood parameters might be helpful for the prognosis of COVID-19 patients and evaluation of the treatment effect.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/sangue , Infecções por Coronavirus/diagnóstico , Pneumonia Viral/sangue , Pneumonia Viral/diagnóstico , Antibacterianos/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Biomarcadores/sangue , Plaquetas/efeitos dos fármacos , Plaquetas/patologia , Plaquetas/virologia , Proteína C-Reativa/metabolismo , Contagem de Células , Convalescença , Infecções por Coronavirus/fisiopatologia , Infecções por Coronavirus/terapia , Eritrócitos/efeitos dos fármacos , Eritrócitos/patologia , Eritrócitos/virologia , Feminino , Humanos , Pessoa de Meia-Idade , Monócitos/efeitos dos fármacos , Monócitos/patologia , Monócitos/virologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/patologia , Neutrófilos/virologia , Oseltamivir/uso terapêutico , Pandemias , Pneumonia Viral/fisiopatologia , Pneumonia Viral/terapia , Prognóstico , Respiração Artificial , Índice de Gravidade de Doença
18.
Clin Sci (Lond) ; 134(11): 1191-1218, 2020 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-32432676

RESUMO

Myocardial infarction (MI) is the leading cause of mortality worldwide. Interleukin (IL)-33 (IL-33) is a cytokine present in most cardiac cells and is secreted on necrosis where it acts as a functional ligand for the ST2 receptor. Although IL-33/ST2 axis is protective against various forms of cardiovascular diseases, some studies suggest potential detrimental roles for IL-33 signaling. The aim of the present study was to examine the effect of IL-33 administration on cardiac function post-MI in mice. MI was induced by coronary artery ligation. Mice were treated with IL-33 (1 µg/day) or vehicle for 4 and 7 days. Functional and molecular changes of the left ventricle (LV) were assessed. Single cell suspensions were obtained from bone marrow, heart, spleen, and peripheral blood to assess the immune cells using flow cytometry at 1, 3, and 7 days post-MI in IL-33 or vehicle-treated animals. The results of the present study suggest that IL-33 is effective in activating a type 2 cytokine milieu in the damaged heart, consistent with reduced early inflammatory and pro-fibrotic response. However, IL-33 administration was associated with worsened cardiac function and adverse cardiac remodeling in the MI mouse model. IL-33 administration increased infarct size, LV hypertrophy, cardiomyocyte death, and overall mortality rate due to cardiac rupture. Moreover, IL-33-treated MI mice displayed a significant myocardial eosinophil infiltration at 7 days post-MI when compared with vehicle-treated MI mice. The present study reveals that although IL-33 administration is associated with a reparative phenotype following MI, it worsens cardiac remodeling and promotes heart failure.


Assuntos
Eosinófilos/metabolismo , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Interleucina-33/farmacologia , Infarto do Miocárdio/fisiopatologia , Sístole/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Citocinas/sangue , Fragmentação do DNA/efeitos dos fármacos , Diástole/efeitos dos fármacos , Eosinofilia/patologia , Eosinófilos/efeitos dos fármacos , Fibrose , Ventrículos do Coração/efeitos dos fármacos , Hipertrofia Ventricular Esquerda/patologia , Mediadores da Inflamação/sangue , Interleucina-33/administração & dosagem , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/enzimologia , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Fenótipo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Esplenomegalia/patologia , Regulação para Cima/efeitos dos fármacos , Remodelação Ventricular/genética , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
19.
Nat Chem Biol ; 16(7): 731-739, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32393898

RESUMO

Glucose is catabolized by two fundamental pathways, glycolysis to make ATP and the oxidative pentose phosphate pathway to make reduced nicotinamide adenine dinucleotide phosphate (NADPH). The first step of the oxidative pentose phosphate pathway is catalyzed by the enzyme glucose-6-phosphate dehydrogenase (G6PD). Here we develop metabolite reporter and deuterium tracer assays to monitor cellular G6PD activity. Using these, we show that the most widely cited G6PD antagonist, dehydroepiandosterone, does not robustly inhibit G6PD in cells. We then identify a small molecule (G6PDi-1) that more effectively inhibits G6PD. Across a range of cultured cells, G6PDi-1 depletes NADPH most strongly in lymphocytes. In T cells but not macrophages, G6PDi-1 markedly decreases inflammatory cytokine production. In neutrophils, it suppresses respiratory burst. Thus, we provide a cell-active small molecule tool for oxidative pentose phosphate pathway inhibition, and use it to identify G6PD as a pharmacological target for modulating immune response.


Assuntos
Inibidores Enzimáticos/farmacologia , Glucosefosfato Desidrogenase/antagonistas & inibidores , Linfócitos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Via de Pentose Fosfato/efeitos dos fármacos , Animais , Linhagem Celular , Desidroepiandrosterona/farmacologia , Relação Dose-Resposta a Droga , Ensaios Enzimáticos , Glucose/metabolismo , Glucosefosfato Desidrogenase/imunologia , Glucosefosfato Desidrogenase/metabolismo , Glicólise/imunologia , Células HCT116 , Células Hep G2 , Humanos , Imunidade Inata , Ativação Linfocitária/efeitos dos fármacos , Linfócitos/citologia , Linfócitos/enzimologia , Linfócitos/imunologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/citologia , Macrófagos/enzimologia , Macrófagos/imunologia , NADP/antagonistas & inibidores , NADP/metabolismo , Neutrófilos/citologia , Neutrófilos/enzimologia , Neutrófilos/imunologia , Via de Pentose Fosfato/imunologia
20.
Lung Cancer ; 145: 213-215, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32389426
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