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1.
BMC Pulm Med ; 20(1): 269, 2020 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-33066765

RESUMO

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19) has spread to almost 100 countries, infected over 31 M patients and resulted in 961 K deaths worldwide as of 21st September 2020. The major clinical feature of severe COVID-19 requiring ventilation is acute respiratory distress syndrome (ARDS) with multi-functional failure as a result of a cytokine storm with increased serum levels of cytokines. The pathogenesis of the respiratory failure in COVID-19 is yet unknown, but diffuse alveolar damage with interstitial thickening leading to compromised gas exchange is a plausible mechanism. Hypoxia is seen in the COVID-19 patients, however, patients present with a distinct phenotype. Intracellular levels of nitric oxide (NO) play an important role in the vasodilation of small vessels. To elucidate the intracellular levels of NO inside of RBCs in COVID-19 patients compared with that of healthy control subjects. METHODS: We recruited 14 COVID-19 infected cases who had pulmonary involvement of their disease, 4 non-COVID-19 healthy controls (without pulmonary involvement and were not hypoxic) and 2 hypoxic non-COVID-19 patients subjects who presented at the Masih Daneshvari Hospital of Tehran, Iran between March-May 2020. Whole blood samples were harvested from patients and intracellular NO levels in 1 × 106 red blood cells (RBC) was measured by DAF staining using flow cytometry (FACS Calibour, BD, CA, USA). RESULTS: The Mean florescent of intensity for NO was significantly enhanced in COVID-19 patients compared with healthy control subjects (P ≤ 0.05). As a further control for whether hypoxia induced this higher intracellular NO, we evaluated the levels of NO inside RBC of hypoxic patients. No significant differences in NO levels were seen between the hypoxic and non-hypoxic control group. CONCLUSIONS: This pilot study demonstrates increased levels of intracellular NO in RBCs from COVID-19 patients. Future multi-centre studies should examine whether this is seen in a larger number of COVID-19 patients and whether NO therapy may be of use in these severe COVID-19 patients.


Assuntos
Dióxido de Carbono/metabolismo , Infecções por Coronavirus/metabolismo , Eritrócitos/metabolismo , Hipóxia/metabolismo , Óxido Nítrico/metabolismo , Oxigênio/metabolismo , Pneumonia Viral/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Assintomáticas , Betacoronavirus , Gasometria , Estudos de Casos e Controles , Infecções por Coronavirus/sangue , Infecções por Coronavirus/complicações , Feminino , Citometria de Fluxo , Humanos , Hipóxia/sangue , Hipóxia/etiologia , Masculino , Pessoa de Meia-Idade , Pandemias , Pressão Parcial , Projetos Piloto , Pneumonia Viral/sangue , Pneumonia Viral/complicações , Doença Pulmonar Obstrutiva Crônica/sangue , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/metabolismo , Vasodilatação , Adulto Jovem
2.
PLoS Negl Trop Dis ; 14(8): e0008575, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32866156

RESUMO

BACKGROUND: Treatment failure and resistance to the commonly used drugs remains a major obstacle for successful chemotherapy against visceral leishmaniasis (VL). Since the development of novel therapeutics involves exorbitant costs, the effectiveness of the currently available antitrypanosomatid drug suramin has been investigated as an antileishmanial, specifically for VL,in vitro and in animal model experiments. METHODOLOGY/PRINCIPAL: Leishmania donovani promastigotes were treated with suramin and studies were performed to determine the extent and mode of cell mortality, cell cycle arrest and other in vitro parameters. In addition, L. donovani infected BALB/c mice were administered suramin and a host of immunological parameters determined to estimate the antileishmanial potency of the drug. Finally, isothermal titration calorimetry (ITC) and enzymatic assays were used to probe the interaction of the drug with one of its putative targets namely parasitic phosphoglycerate kinase (LmPGK). FINDINGS: The in vitro studies revealed the potential efficacy of suramin against the Leishmania parasite. This observation was further substantiated in the in vivo murine model, which demonstrated that upon suramin administration, the Leishmania infected BALB/c mice were able to reduce the parasitic burden and also generate the host protective immunological responses. ITC and enzyme assays confirmed the binding and consequent inhibition of LmPGK due to the drug. CONCLUSIONS/SIGNIFICANCE: All experiments affirmed the efficacy of suramin against L. donovani infection, which could possibly lead to its inclusion in the repertoire of drugs against VL.


Assuntos
Antiprotozoários/farmacologia , Antiprotozoários/uso terapêutico , Leishmaniose Visceral/tratamento farmacológico , Suramina/farmacologia , Suramina/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Concentração Inibidora 50 , Leishmania donovani/efeitos dos fármacos , Leishmaniose Visceral/parasitologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Óxido Nítrico/metabolismo , Fosfoglicerato Quinase/efeitos dos fármacos , Células RAW 264.7/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
3.
J Environ Pathol Toxicol Oncol ; 39(3): 235-245, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32865915

RESUMO

Ulcerative colitis (UC) is an intractable ailment, in which may chronic inflammations/ulcerations may develop in the mucosal lining of the colon with multiple recurrences. Various drugs such as steroids, immunosuppressants, and antibiotics are extensively used to treat UC. The patients suffer from adverse effects of these advanced drugs. So, they need a harmless therapeutic agent from natural sources. The therapeutic D-carvone has an anti-inflammatory action against the investigational colon cancer models. Therefore, we analyzed the effect of D-carvone on dextran sulfate sodium (DSS) provoked colitis model in mice as follows: Group I: noncolitis healthy control mice; Group II: ulcerative colitis mice models; Group III: D-carvone (40 mg/kg) + ulcerative colitis models; Group IV: sulfasalazine (50 mg/kg) + ulcerative colitis models. On the 8th day, the experimental study was terminated and serum samples and colon tissues were processed for further analysis. The effect of D-carvone at different concentration was studied on the LPS challenged RAW 264.7 cell lines. The D-carvone (40 mg/kg) treatment maintained the colon length and decreased disease activity index (DAI) score in UC animals. The increased antioxidant enzymes status and decreased oxidative stress and pro-inflammatory markers were noted in the D-carvone (40 mg/ kg) + UC mice. Histopathological study of colon tissue of D-carvone (40 mg/kg) treated UC mice displayed less mucosal damage and improved crypt integrity and goblet cells compared with DSS only provoked mice. The im-munohistochemical expression of iNOS and COX-2 was drastically diminished in the D-carvone treated UC mice. D-carvone (40 mg/kg) treatment appreciably diminished the LPS provoked NO production and pro-inflammatory modulators in the RAW 264.7 macrophage cell lines. These findings proved that D-carvone has a potential therapeutic effect to prevent LPS induced inflammation in in vitro cells and chemically induced ulcerative colitis in vivo models.


Assuntos
Anti-Inflamatórios/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Monoterpenos Cicloexânicos/uso terapêutico , Ciclo-Oxigenase 2/metabolismo , Macrófagos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fator de Necrose Tumoral alfa/sangue , Animais , Anti-Inflamatórios/administração & dosagem , Sobrevivência Celular/efeitos dos fármacos , Colite Ulcerativa/imunologia , Colite Ulcerativa/patologia , Colo/efeitos dos fármacos , Colo/imunologia , Colo/patologia , Monoterpenos Cicloexânicos/administração & dosagem , Sulfato de Dextrana , Modelos Animais de Doenças , Lipopolissacarídeos , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Células RAW 264.7
4.
Int J Nanomedicine ; 15: 6183-6200, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32922001

RESUMO

Purpose: Diethylaminoethyl-chitosan (DEAE-CH) is a derivative with excellent potential as a delivery vector for gene therapy applications. The aim of this study is to evaluate its toxicological profile for potential future clinical applications. Methods: An endotoxin-free chitosan (CH) modified with DEAE, folic acid (FA) and polyethylene glycol (PEG) was used to complex small interfering RNA (siRNA) and form nanoparticles (DEAE12-CH-PEG-FA2/siRNA). Based on the guidelines from the International Organization for Standardization (ISO), the American Society for Testing and Materials (ASTM), and the Nanotechnology Characterization Laboratory (NCL), we evaluated the effects of the interaction between these nanoparticles and blood components. In vitro screening assays such as hemolysis, hemagglutination, complement activation, platelet aggregation, coagulation times, cytokine production, and reactive species, such as nitric oxide (NO) and reactive oxygen species (ROS), were performed on erythrocytes, plasma, platelets, peripheral blood mononuclear cells (PBMC) and Raw 264.7 macrophages. Moreover, MTS and LDH assays on Raw 264.7 macrophages, PBMC and MG-63 cells were performed. Results: Our results show that a targeted theoretical plasma concentration (TPC) of DEAE12-CH-PEG-FA2/siRNA nanoparticles falls within the guidelines' thresholds: <1% hemolysis, 2.9% platelet aggregation, no complement activation, and no effect on coagulation times. ROS and NO production levels were comparable to controls. Cytokine secretion (TNF-α, IL-6, IL-4, and IL-10) was not affected by nanoparticles except for IL-1ß and IL-8. Nanoparticles showed a slight agglutination. Cell viability was >70% for TPC in all cell types, although LDH levels were statistically significant in Raw 264.7 macrophages and PBMC after 24 and 48 h of incubation. Conclusion: These DEAE12-CH-PEG-FA2/siRNA nanoparticles fulfill the existing ISO, ASTM and NCL guidelines' threshold criteria, and their low toxicity and blood biocompatibility warrant further investigation for potential clinical applications.


Assuntos
Quitosana/química , Terapia Genética , Nanopartículas/química , Polietilenoglicóis/química , Polímeros/química , Animais , Sobrevivência Celular/efeitos dos fármacos , Ácido Fólico/farmacologia , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Nanopartículas/administração & dosagem , Óxido Nítrico/metabolismo , Células RAW 264.7 , RNA Interferente Pequeno/genética , Espécies Reativas de Oxigênio/metabolismo , Testes de Toxicidade
5.
PLoS One ; 15(8): e0237604, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32790732

RESUMO

This study investigated the efficiency of a portable nitric oxide (NO) inhalation device through optimizing its design and structure. The portable rescue device could be used in clinical applications in outbreaks of viral pneumonia such as SARS. To reduce energy consumption for battery-powered portable usage, NO micro-channel plasma reactions induced by a continuous discharge arc were employed. A single-use airway tube could be combined with an intubation tube in clinical applications. In the experiment, a switching transistor controlled high frequency DC (12.5 kHz) was used to create a continuous discharge arc between two stainless steel electrodes (1-mm separation) after high-voltage breakthrough. A rotate instrument was employed to change the direction angle between the airflow and discharge arc, tube filled with Calcium hydroxide connected with gas outlet for reducing NO2, gas flow rate and input voltage were evaluated separately with concentration of NO and NO2/NO ratio. Results showed that a 2 L/min air flow direction from the cathode to the anode of electrodes (direction angle was zero) under 4 V input voltages produced 32.5±3.8 ppm NO, and the NO2/NO ratio reduced to less than 10%, stable output of nitric oxide might be convenient and effective for NO inhalation therapy. Modularization of the design produced a portable NO inhalation device that has potential for use in clinical applications as it is low cost, easy to disinfect, consumes low levels of energy and is ready to use.


Assuntos
Tratamento de Emergência/instrumentação , Desenho de Equipamento , Óxido Nítrico/metabolismo , Gases em Plasma/química , Pneumonia Viral/terapia , Terapia Respiratória/instrumentação , Ventiladores Mecânicos , Administração por Inalação , Tratamento de Emergência/métodos , Humanos , Óxido Nítrico/administração & dosagem , Terapia Respiratória/métodos
6.
Adv Exp Med Biol ; 1265: 39-56, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32761569

RESUMO

Cardiovascular disease is the major cause of global mortality and disability. Abundant evidence indicates that amino acids play a fundamental role in cardiovascular physiology and pathology. Decades of research established the importance of L-arginine in promoting vascular health through the generation of the gas nitric oxide. More recently, L-glutamine, L-tryptophan, and L-cysteine have also been shown to modulate vascular function via the formation of a myriad of metabolites, including a number of gases (ammonia, carbon monoxide, hydrogen sulfide, and sulfur dioxide). These amino acids and their metabolites preserve vascular homeostasis by regulating critical cellular processes including proliferation, migration, differentiation, apoptosis, contractility, and senescence. Furthermore, they exert potent anti-inflammatory and antioxidant effects in the circulation, and block the accumulation of lipids within the arterial wall. They also mitigate known risk factors for cardiovascular disease, including hypertension, hyperlipidemia, obesity, and diabetes. However, in some instances, the metabolism of these amino acids through discrete pathways yields compounds that fosters vascular disease. While supplementation with amino acid monotherapy targeting the deficiency has ameliorated arterial disease in many animal models, this approach has been less successful in the clinic. A more robust approach combining amino acid supplementation with antioxidants, anti-inflammatory agents, and/or specific amino acid enzymatic pathway inhibitors may prove more successful. Alternatively, supplementation with amino acid-derived metabolites rather than the parent molecule may elicit beneficial effects while bypassing potentially harmful pathways of metabolism. Finally, there is an emerging recognition that circulating levels of multiple amino acids are perturbed in vascular disease and that a more holistic approach that targets all these amino acid derangements is required to restore circulatory function in diseased blood vessels.


Assuntos
Aminoácidos/metabolismo , Sistema Cardiovascular/metabolismo , Saúde , Animais , Doenças Cardiovasculares/metabolismo , Endotélio Vascular/metabolismo , Humanos , Doenças Metabólicas/metabolismo , Óxido Nítrico/metabolismo
7.
Med Hypotheses ; 143: 110142, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32759013

RESUMO

BACKGROUND: Pulmonary hypertension is a significant complication for some patients with COVID-19 pneumonia, especially those requiring intensive care. Tachyphylaxis to the current therapy, inhaled nitric oxide (iNO), is also common. In vitro, folic acid directly increases nitric oxide (NO) production and extends its duration of action; effects which could be of benefit in reversing pulmonary hypertension and severe hypoxaemia. Our work has shown that, in the systemic circulation, folic acid in high dose rapidly improves nitric oxide mediated vasodilation, by activating endothelial nitric oxide synthase (eNOS). HYPOTHESIS: A similar effect of high dose folic acid on pulmonary endothelial function would be expected from the same mechanism and would lead to improvement in pulmonary perfusion. We therefore hypothesise that folic acid, 5 mg or greater, is a useful therapeutic option for pulmonary hypertension and/or refractory severe hypoxaemia, in patients with severe COVID-19 associated pneumonia in whom NO therapy is considered, with a very low risk of adverse effects.


Assuntos
Betacoronavirus , Infecções por Coronavirus/complicações , Ácido Fólico/uso terapêutico , Hipertensão Pulmonar/tratamento farmacológico , Óxido Nítrico/metabolismo , Pandemias , Pneumonia Viral/complicações , Administração por Inalação , Animais , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiologia , Ativação Enzimática/efeitos dos fármacos , Ácido Fólico/administração & dosagem , Ácido Fólico/farmacologia , Humanos , Hipertensão Pulmonar/complicações , Hipóxia/tratamento farmacológico , Hipóxia/etiologia , Camundongos , Óxido Nítrico/administração & dosagem , Óxido Nítrico/uso terapêutico , Óxido Nítrico Sintase Tipo III/efeitos dos fármacos , Taquifilaxia
8.
Chem Biol Interact ; 329: 109220, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32763245

RESUMO

The sepsis is considered as serious clinic-pathological condition related with high rate of morbidity and mortality in critical care settings. In the proposed study, the hydrazides derivatives N-(benzylidene)-2-((2-hydroxynaphthalen-1-yl)diazenyl)benzohydrazides (1-2) (NCHDH and NTHDH) were investigated against the LPS-induced sepsis in rodents. The NCHDH and NTHDH markedly improved the physiological sign and symptoms associated with the sepsis such as mortality, temperature, and clinical scoring compared to negative control group, which received only LPS (i.p.). The NCHDH and NTHDH also inhibited the production of the NO and MPO compared to the negative control. Furthermore, the treatment control improved the histological changes markedly of all the vital organs. Additionally, the Masson's trichrome and PAS (Periodic Acid Schiff) staining also showed improvement in the NCHDH and NTHDH treated group in contrast to LPS-induced group. The antioxidants were enhanced by the intervention of the NCHDH and NTHDH and the level of the MDA and POD were attenuated marginally compared to the LPS-induced group. The hematology study showed marked improvement and the reversal of the LPS-induced changes in blood composition compared to the negative control. The synthetic function of the liver and kidney were preserved in the NCHDH and NTHDH treated group compared to the LPS-induced group. The NCHDH and NTHDH markedly enhanced the Nrf2, HO-1 (Heme oxygenase-1), while attenuated the Keap1 and TRPV1 expression level as compared to LPS treated group. Furthermore, the NCHDH and NTHDH treatment showed marked increased in the mRNA expression level of the HSP70/90 proteins compared to the negative control.


Assuntos
Hidrazinas/farmacologia , Insuficiência de Múltiplos Órgãos/etiologia , Sepse/etiologia , Transdução de Sinais/efeitos dos fármacos , Animais , Sobrevivência Celular/efeitos dos fármacos , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Heme Oxigenase-1/metabolismo , Hidrazinas/química , Hidrazinas/uso terapêutico , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Lipopolissacarídeos/toxicidade , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Insuficiência de Múltiplos Órgãos/tratamento farmacológico , Insuficiência de Múltiplos Órgãos/mortalidade , Fator 2 Relacionado a NF-E2/metabolismo , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Peroxidase/metabolismo , Sepse/tratamento farmacológico , Sepse/mortalidade , Canais de Cátion TRPV/genética , Canais de Cátion TRPV/metabolismo
9.
PLoS One ; 15(8): e0237017, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32756588

RESUMO

Procyandin A2 (PCA2) is a polyphenolic compound which is isolated from grape seeds. It has been reported that PCA2 exhibits antioxidative and anti-inflammatory effects, but its molecular mechanism is still poorly understood. This study tests the hypothesis that PCA2 suppresses lipopolysaccharide (LPS)-induced inflammation and oxidative stress through targeting the nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), and NF-E2-related factor 2 (Nrf2) pathways in RAW264.7 cells. PCA2 (20, 40, 80 µM) exhibited no significant cytotoxicity in RAW264.7 cells and showed an inhibitory effect on an LPS-induced nitrite level. Pro-inflammatory cytokines like tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), prostaglandin E2 (PGE2), nitric oxide (NO), and reactive oxygen species (ROS) were suppressed by PCA2 with a concentration range of 0-80 µM. The mRNA levels of TNF-α and IL-6 were inhibited by PCA2 (80 µM). The hallmark-protein expression of the NF-κB (p-IKKα/ß, p-IκBα, and p-p65) and MAPK (p-p38, p-JNK, and p-ERK) pathways were decreased by PCA2 in LPS-stimulated RAW264.7 cells. In addition, immunofluorescence results indicated that PCA2 (80 µM) promoted the translocation of NF-κB/p65 from the cytoplasm into the nucleus. PCA2 upregulated the expressions of Nrf2 and HO-1 and downregulated the expression of Keap-1. Simultaneously, PCA2 (80 µM) reversed LPS-induced Nrf2 translocation from the nucleus into the cytoplasm. Collectively, PCA2 protect cells against the damage from inflammation and oxidative injury, which suggest a potential therapeutic strategy for inflammatory and oxidative stress through targeting NF-κB, MAPK, and Nrf2 pathways in RAW264.7 cells.


Assuntos
Catequina/metabolismo , Catequina/farmacologia , Inflamação/tratamento farmacológico , Proantocianidinas/metabolismo , Proantocianidinas/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Citocinas/metabolismo , Dinoprostona/metabolismo , Heme Oxigenase-1/metabolismo , Lipopolissacarídeos/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Proteína Quinase 1 Ativada por Mitógeno/efeitos dos fármacos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fator 2 Relacionado a NF-E2/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Inibidor de NF-kappaB alfa/metabolismo , NF-kappa B/efeitos dos fármacos , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos
10.
Life Sci ; 258: 118137, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32712299

RESUMO

AIMS: Chagas disease is a neglected tropical disease. The ability of Trypanosoma cruzi to survive within phagocytes is likely a critical factor for T. cruzi dissemination in the host. For control of the parasite load and host survival, macrophage action is required. Concanavalin-A (Con-A) presents properties that modulate immune functions and protect hosts from several experimental infectious diseases. Here, we evaluated the effects of Con-A on peritoneal macrophages as well as on the course of experimental infection by T. cruzi. MAIN METHODS: BALB/c mice, a susceptible model for T. cruzi infection, were treated with Con-A via the intraperitoneal route and 3 days later infected with T. cruzi. We quantified parasitemia, cytokines and nitric oxide (NO). Peritoneal exudate and macrophages were collected for macrophage phenotyping and cell viability, NO and cytokine detection, as well as for T. cruzi internalization and release index determination. KEY FINDINGS: Con-A treatment induced IL-17a and NO production by cells from the peritoneal cavity, and M1 marker expression predominated on peritoneal macrophages. These cells are also more prone to producing TNF-α, IL-6 and NO when infected by T. cruzi and show high trypanocidal capacity. Due to a hostile peritoneal microenvironment caused by Con-A, which induces macrophage cNOS and iNOS expression, infected BALB/c mice showed reduced parasitemia and an increased survival rate. SIGNIFICANCE: We conclude that Con-A can induce peritoneal M1 macrophage polarization to increase trypanocidal activity, resulting in ameliorated systemic infection in a susceptible experimental model.


Assuntos
Polaridade Celular , Doença de Chagas/patologia , Concanavalina A/farmacologia , Interleucina-17/metabolismo , Macrófagos Peritoneais/patologia , Macrófagos Peritoneais/parasitologia , Óxido Nítrico/metabolismo , Trypanosoma cruzi/fisiologia , Animais , Polaridade Celular/efeitos dos fármacos , Doença de Chagas/metabolismo , Feminino , Macrófagos Peritoneais/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Óxido Nítrico Sintase Tipo II/metabolismo , Parasitemia/metabolismo , Parasitemia/patologia , Trypanosoma cruzi/efeitos dos fármacos
11.
Artigo em Inglês | MEDLINE | ID: mdl-32656654

RESUMO

Nitric oxide (NO) being a signaling molecule inside the plant cells, play significant role in signaling cascades and protection against environmental stresses. However, the protective role of NO in alleviating As toxicity in rice plants is currently not available. In the present study, the level of NO, nitrogen (N), inorganic N (nitrate, ammonium), thiols {TT (Total thiols), NPT (Nonprotein thiol)} and AAs contents along with N assimilating enzymes (NR, GDH, GOGAT) were analyzed after exposure of AsIII/NO treatment alone, and in combination. NO supplementation enhanced the content of N, inorganic N & thiol contents, NR, GOGAT activities, when compared with AsIII exposure alone. In AsIII exposed rice seedlings, content of AAs (except His, Arg, Met) reduced over the control, while supplementation of SNP improved AAs contents, compared to AsIII treatment alone. In conclusion, rice seedlings supplemented with NO tolerate the AsIII toxicity by reducing the N related parameters, thiol contents, altering the AA profile and enhanced the nutritional quality by increasing EAAs (essential amino acids) and NEAAs (non-essential amino acids).


Assuntos
Aminoácidos/metabolismo , Arsênico/efeitos adversos , Óxido Nítrico/metabolismo , Nitrogênio/metabolismo , Oryza/metabolismo , Poluentes do Solo/efeitos adversos , Compostos de Sulfidrila/metabolismo , Relação Dose-Resposta a Droga , Glutationa/metabolismo , Óxido Nítrico/administração & dosagem , Oryza/efeitos dos fármacos , Estresse Fisiológico
12.
PLoS Comput Biol ; 16(7): e1008069, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32716940

RESUMO

Nitric oxide (NO) is a gaseous signaling molecule that plays an important role in neurovascular coupling. NO produced by neurons diffuses into the smooth muscle surrounding cerebral arterioles, driving vasodilation. However, the rate of NO degradation in hemoglobin is orders of magnitude higher than in brain tissue, though how this might impact NO signaling dynamics is not completely understood. We used simulations to investigate how the spatial and temporal patterns of NO generation and degradation impacted dilation of a penetrating arteriole in cortex. We found that the spatial location of NO production and the size of the vessel both played an important role in determining its responsiveness to NO. The much higher rate of NO degradation and scavenging of NO in the blood relative to the tissue drove emergent vascular dynamics. Large vasodilation events could be followed by post-stimulus constrictions driven by the increased degradation of NO by the blood, and vasomotion-like 0.1-0.3 Hz oscillations could also be generated. We found that these dynamics could be enhanced by elevation of free hemoglobin in the plasma, which occurs in diseases such as malaria and sickle cell anemia, or following blood transfusions. Finally, we show that changes in blood flow during hypoxia or hyperoxia could be explained by altered NO degradation in the parenchyma. Our simulations suggest that many common vascular dynamics may be emergent phenomena generated by NO degradation by the blood or parenchyma.


Assuntos
Encéfalo/fisiologia , Circulação Cerebrovascular , Óxido Nítrico/metabolismo , Anemia Falciforme/fisiopatologia , Arteríolas , Transfusão de Sangue , Sistema Livre de Células , Simulação por Computador , Difusão , Células Endoteliais/metabolismo , Eritrócitos/metabolismo , Hemodinâmica , Humanos , Processamento de Imagem Assistida por Computador , Imageamento Tridimensional , Malária/fisiopatologia , Mitocôndrias/metabolismo , Músculo Liso/metabolismo , Oscilometria , Distribuição de Poisson , Transdução de Sinais , Vasodilatação
13.
Medicine (Baltimore) ; 99(27): e21068, 2020 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-32629736

RESUMO

BACKGROUND: Alterations in the levels of arginine and its related catabolic products (ie, ornithine, citrulline, and argininosuccinate) in the urea and nitric oxide cycles were reported to play roles in the pathogenesis of major depressive disorder (MDD). The aim of this meta-analysis study is to explore the associations between arginine with its related catabolic products and MDD, and to discuss the possible role of arginine catabolism in the pathoetiology of MDD. METHODS: This study will be conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The English language literature published in the databases of PubMed, EMBASE, PsycINFO and Web of Science will be systematically searched. Forest plots will be used to estimate the associations between arginine and its related catabolic products with MDD. Subgroup analysis and meta-regression will also be performed to investigate the source of the potential heterogeneity. Sensitivity analysis will be performed to strengthen the results and to investigate whether any single study would have a significant effect on the results of meta-analysis. Publication bias will be tested for using the funnel plot with Begg test and Egger test. The Newcastle-Ottawa Scale will be applied to assess the risk of bias of observational studies. RESULTS: An integrated assessment of arginine with its related catabolic products may contribute to predict the risk of MDD. ETHICS AND DISSEMINATION: The results of associations between arginine with its related catabolic products and MDD will be reported in a peer-reviewed publication. With our findings from this meta-analysis, we hope to provide the most up-to-date evidence for the contributions of arginine and related catabolic products to predict the risk of MDD. SYSTEMATIC REVIEW REGISTRATION: The protocol of current meta-analysis has been registered at the Open Science Framework [Available at: https://doi.org/10.17605/osf.io/7fn59].


Assuntos
Arginina/metabolismo , Transtorno Depressivo Maior/metabolismo , Redes e Vias Metabólicas/fisiologia , Óxido Nítrico/metabolismo , Transtorno Depressivo Maior/fisiopatologia , Humanos , Medição de Risco , Sensibilidade e Especificidade
14.
Nitric Oxide ; 103: 29-30, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32712272

RESUMO

Most outcomes of COVID-19 are associated with dysfunction of the vascular system, particularly in the lung. Inhalation of nitric oxide (NO) gas is currently being investigated as a treatment for patients with moderate to severe COVID-19. In addition to the expected vasodilation effect, it has been also suggested that NO potentially prevents infection by SARS-CoV-2. Since NO is an unstable radical molecule that is easily oxidized by multiple mechanisms in the human body, it is practically difficult to control its concentration at lesions that need NO. Inorganic nitrate and/or nitrite are known as precursors of NO that can be produced through chemical as well enzymatic reduction. It appears that this NO synthase (NOS)-independent mechanism has been overlooked in the current developing of clinical treatments. Here, I suggest the missing link between nitrate and COVID-19 in terms of hypoxic NO generation.


Assuntos
Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Nitratos/metabolismo , Óxido Nítrico/metabolismo , Nitritos/metabolismo , Pneumonia Viral/tratamento farmacológico , Antivirais/metabolismo , Ácido Ascórbico/química , Ácido Ascórbico/uso terapêutico , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/prevenção & controle , Fatores Relaxantes Dependentes do Endotélio/metabolismo , Humanos , Nitratos/sangue , Nitritos/sangue , Nitritos/química , Pandemias/prevenção & controle , Pneumonia Viral/metabolismo , Pneumonia Viral/prevenção & controle , Vasodilatação/efeitos dos fármacos
15.
Exp Parasitol ; 217: 107934, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32698075

RESUMO

The inadequacy of available treatments for leishmaniasis has presented up to 40% therapeutic failure. This fact suggests an urgency in the discovery of new drugs or alternative approaches for treating this disease. The objective of this study was to evaluate the antileishmanial activity of combined therapy between crotamine (CTA) from Crotalus durissus terrificus and the pentavalent antimonial Glucantime® (GLU). The assays were in vitro performed measuring the inhibition of Leishmania amazonensis amastigotes, followed by the evaluation of cellular production of cytokines and nitrites. After that, analytical methods were performed in order to characterize the molecules involved in the study by Mass Spectrometry, molecular affinity through an in silico assay and Surface Plasmon Resonance. In vivo experiments with BALB/c mice were performed by analyzing parasitemia, lesion size and immunological mediators. In the in vitro experiments, the pharmacological association improved the inhibition of the amastigotes, modulated the production of cytokines and nitric oxide. The therapy improved the effectiveness of the GLU, demonstrating a decreased parasitemia in the infected tissues. Altogether, the results suggest that the combined approach with CTA and GLU may be a promising alternative for the treatment of cutaneous leishmaniasis.


Assuntos
Antiprotozoários/uso terapêutico , Venenos de Crotalídeos/uso terapêutico , Crotalus , Leishmania mexicana/efeitos dos fármacos , Leishmaniose Cutânea/tratamento farmacológico , Antimoniato de Meglumina/uso terapêutico , Animais , Antiprotozoários/farmacologia , Venenos de Crotalídeos/farmacologia , Combinação de Medicamentos , Interleucina-12/sangue , Interleucina-12/metabolismo , Leishmania mexicana/isolamento & purificação , Linfonodos/parasitologia , Macrófagos Peritoneais , Espectrometria de Massas , Antimoniato de Meglumina/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Óxido Nítrico/metabolismo , Nitritos/análise , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/metabolismo
16.
Med Hypotheses ; 143: 110129, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32721814

RESUMO

In trying to understand the biochemical mechanism involved in the recent pandemic COVID-19, there is currently growing interest in angiotensin-converting enzyme II (ACE2). Nevertheless, the attempts to counteract COVID-19 interference with this enzymatic cascade are frustrating, and the results have thus far been inconclusive. Let's start again by considering the involved factors in an alternative way: we could postulate that COVID-19 could be more aggressive/fatal due to a high level of "basal" inflammation with low Nitric Oxide (NO) levels in hypertensive, diabetic and obese patients. Interestingly, the "protective" effects of several factors (such as estrogens) may play a role by increasing the formation of endogenous NO. From a therapeutic point of view, phosphodiesterase type 5 inhibitors such as oral Tadalafil, could be used in order to increase the basal NO levels. In this way, we don't fight the virus, but we may be able to mitigate its effects.


Assuntos
Betacoronavirus/fisiologia , Infecções por Coronavirus/tratamento farmacológico , Óxido Nítrico/metabolismo , Pandemias , Pneumonia Viral/tratamento farmacológico , Animais , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/complicações , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/fisiopatologia , Estrogênios/fisiologia , Humanos , Hipertensão/complicações , Hipertensão/fisiopatologia , Inflamação , Interleucinas/fisiologia , Modelos Animais , Modelos Biológicos , Óxido Nítrico/uso terapêutico , Obesidade/complicações , Obesidade/fisiopatologia , Uso Off-Label , Peptidil Dipeptidase A/efeitos dos fármacos , Peptidil Dipeptidase A/fisiologia , Inibidores da Fosfodiesterase 5/farmacologia , Inibidores da Fosfodiesterase 5/uso terapêutico , Pneumonia Viral/complicações , Receptores Virais/efeitos dos fármacos , Receptores Virais/fisiologia , Citrato de Sildenafila/farmacologia , Citrato de Sildenafila/uso terapêutico , Tadalafila/farmacologia , Tadalafila/uso terapêutico
17.
PLoS One ; 15(7): e0236251, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32692754

RESUMO

This study investigated the effects of kaempferol and zinc gluconate on neurobehavioural and oxidative stress changes in Wistar rats exposed to noise. Thirty (30) rats were randomly divided into five groups: Groups I and II were administered with deionized water (DW); Group III, kaempferol (K); Group IV, zinc gluconate (Zn); Group V, kaempferol + zinc gluconate. Groups II, III, IV, and V were subjected to noise stress (N) induced by exposing rats to 100 dB (4 h/day) for 15 days, from day 33 to day 48 after starting the drug treatments. Neuromuscular coordination, motor coordination, motor strength, sensorimotor reflex, and learning and memory, were evaluated using standard laboratory methods. Levels of nitric oxide (NO), malondialdehyde (MDA) and activities of glutathione peroxidase (GPx), catalase and superoxide dismutase (SOD) were evaluated in the hippocampus. Exposure of rats to noise, induced significant neurobehavioural deficits and oxidative stress while the combined administration of kaempferol and zinc gluconate significantly (P < 0.05) improved open-field performance, motor coordination, motor strength, sensorimotor reflex, and learning and memory. Co-administration of kaempferol and zinc gluconate ameliorated noise-induced oxidative stress as demonstrated by the significantly increased activities of GPx, catalase, and SOD, and decreased levels of NO and MDA (P < 0.05 and P < 0.01 respectively), compared to the DW + N group. Our results suggest that oxidative stress, evidenced by increased NO and MDA concentration and decreased activities of GPx, catalase and SOD, were involved in the molecular mechanism underlying neurobehavioural impairment in Wistar rats, exposed to noise stress. Single treatment of kaempferol exerted a more potent mitigative effect than zinc gluconate, while their combination produced an improved outcome.


Assuntos
Comportamento Animal/efeitos dos fármacos , Encéfalo/patologia , Gluconatos/farmacologia , Quempferóis/farmacologia , Ruído/efeitos adversos , Animais , Encéfalo/efeitos dos fármacos , Masculino , Malondialdeído/metabolismo , Memória/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Junção Neuromuscular/efeitos dos fármacos , Junção Neuromuscular/fisiopatologia , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Reflexo/efeitos dos fármacos , Zinco/farmacologia
18.
Nat Commun ; 11(1): 3688, 2020 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-32703948

RESUMO

Zeta inhibitory peptide (ZIP), a PKMζ inhibitor, is widely used to interfere with the maintenance of acquired memories. ZIP is able to erase memory even in the absence of PKMζ, via an unknown mechanism. We found that ZIP induces redistribution of the AMPARGluA1 in HEK293 cells and primary cortical neurons, and decreases AMPAR-mediated currents in the nucleus accumbens (NAc). These effects were mimicked by free arginine or by a modified ZIP in which all but the arginine residues were replaced by alanine. Redistribution was blocked by a peptidase-resistant version of ZIP and by treatment with the nitric oxide (NO)-synthase inhibitor L-NAME. ZIP increased GluA1-S831 phosphorylation and ZIP-induced redistribution was blocked by nitrosyl-mutant GluA1-C875S or serine-mutant GluA1-S831A. Introducing the cleavable arginine-alanine peptide into the NAc attenuated expression of cocaine-conditioned reward. Together, these results suggest that ZIP may act as an arginine donor, facilitating NO-dependent downregulation of AMPARs, thereby attenuating learning and memory.


Assuntos
Peptídeos Penetradores de Células/farmacologia , Condicionamento Psicológico/efeitos dos fármacos , Lipopeptídeos/farmacologia , Memória de Longo Prazo/efeitos dos fármacos , Óxido Nítrico/metabolismo , Receptores de AMPA/metabolismo , Animais , Cocaína/administração & dosagem , Regulação para Baixo , Endocitose/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Células HEK293 , Humanos , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Camundongos , Modelos Animais , NG-Nitroarginina Metil Éster/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Óxido Nítrico/antagonistas & inibidores , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/fisiologia , Fosforilação , Cultura Primária de Células , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C/metabolismo , Ratos , Receptores de AMPA/genética , Recompensa , Técnicas Estereotáxicas
19.
PLoS One ; 15(7): e0235638, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32687499

RESUMO

IMPORTANCE: Sinonasal symptoms in patients suffering from cystic fibrosis can negatively influence the quality of life and sinuses can be a niche for pathogens causing infection and inflammation leading to a decrease of lung function. Ivacaftor, a potentiator of the Cystic Fibrosis Transmembrane Conductance Regulator protein, has shown improvement in pulmonary function in cystic fibrosis patients with different forms of class III gating mutations. However, the effects of ivacaftor on sinonasal pathology have hardly been studied. OBJECTIVE: To determine the impact of ivacaftor therapy on sinonasal pathology in patients with cystic fibrosis with an S1251N mutation. DESIGN: Prospective observational mono-center cohort study, between June 2015 and December 2016. SETTING: A tertiary referral center in Utrecht, The Netherlands. PARTICIPANTS: Eight patients with cystic fibrosis with an S1251N mutation, treated with the potentiator ivacaftor were investigated. EXPOSURES: Ivacaftor (Kalydeco, VX-770) therapy. Computed tomography imaging of paranasal sinuses. Nasal nitric oxide concentration measurements and nasal endoscopy. MAIN OUTCOMES AND MEASURES: Primary outcome is opacification of paranasal sinuses examined with computed tomography scan analysis and scaled by the modified Lund-Mackay score before and one year after treatment. Secondary outcomes are nasal nitric oxide concentration levels, sinonasal symptoms and nasal endoscopic findings before and approximately two months and in some cases one year after treatment. RESULTS: Computed tomography scan analysis showed a significant decrease in opacification of the majority of paranasal sinuses comparing the opacification score per paranasal sinus before and after one year of treatment with ivacaftor. Median nasal nitric oxide levels significantly improved from 220.00 (IQR:136.00-341.18) to 462.84 (IQR:233.17-636.25) (p = 0.017) parts per billion. Likewise, the majority of sinonasal symptoms and nasal endoscopic pathology decreased or resolved at two months after the use of ivacaftor. CONCLUSION AND RELEVANCE: Ivacaftor appears to improve sinonasal outcome parameters and thereby sinonasal health in patients with cystic fibrosis with an S1251N mutation.


Assuntos
Aminofenóis/uso terapêutico , Agonistas dos Canais de Cloreto/uso terapêutico , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/tratamento farmacológico , Seios Paranasais/patologia , Quinolonas/uso terapêutico , Adolescente , Adulto , Estudos de Coortes , Fibrose Cística/genética , Fibrose Cística/patologia , Feminino , Genótipo , Humanos , Masculino , Óxido Nítrico/metabolismo , Seios Paranasais/diagnóstico por imagem , Seios Paranasais/metabolismo , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Centros de Atenção Terciária , Tomografia Computadorizada por Raios X , Adulto Jovem
20.
PLoS Genet ; 16(6): e1008312, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32598344

RESUMO

Drosophila circadian behavior relies on the network of heterogeneous groups of clock neurons. Short- and long-range signaling within the pacemaker circuit coordinates molecular and neural rhythms of clock neurons to generate coherent behavioral output. The neurochemistry of circadian behavior is complex and remains incompletely understood. Here we demonstrate that the gaseous messenger nitric oxide (NO) is a signaling molecule linking circadian pacemaker to rhythmic locomotor activity. We show that mutants lacking nitric oxide synthase (NOS) have behavioral arrhythmia in constant darkness, although molecular clocks in the main pacemaker neurons are unaffected. Behavioral phenotypes of mutants are due in part to the malformation of neurites of the main pacemaker neurons, s-LNvs. Using cell-type selective and stage-specific gain- and loss-of-function of NOS, we also demonstrate that NO secreted from diverse cellular clusters affect behavioral rhythms. Furthermore, we identify the perineurial glia, one of the two glial subtypes that form the blood-brain barrier, as the major source of NO that regulates circadian locomotor output. These results reveal for the first time the critical role of NO signaling in the Drosophila circadian system and highlight the importance of neuro-glial interaction in the neural circuit output.


Assuntos
Relógios Circadianos , Proteínas de Drosophila/genética , Neuroglia/metabolismo , Neurônios/metabolismo , Óxido Nítrico/metabolismo , Proteínas de Ligação a RNA/genética , Animais , Drosophila , Mutação com Ganho de Função , Locomoção , Mutação com Perda de Função
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