Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 44.128
Filtrar
1.
Nitric Oxide ; 115: 55-61, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34364972

RESUMO

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide and has seriously threatened public health by causing significant morbidity and mortality. Patients with coronavirus disease (COVID-19) with preexisting endothelial dysfunction caused by aging, diabetes, hypertension, and obesity are at high risk for life-threatening thromboembolic complications. This suggests a possibility that reduced endothelial nitric oxide (NO) production and NO bioavailability could be a common underlying pathology for the progression of COVID-19. Increasingly, evidence from experimental and clinical studies of SARS-CoV-2 infection shows that NO inhibits the pathogenesis of COVID-19, including virus entry into host cells, viral replication, host immune response, and subsequent thromboembolic complications. Restoring NO bioavailability may have the potential to be a preventive or early-treatment option for COVID-19. This review aims to provide in-depth discussion of NO bioavailability to prevent SARS-CoV-2 infection, particularly by focusing on lifestyle factors such as nitrate-rich diets, physical exercise, and nasal breathing, which could be easily performed on a daily basis to boost NO bioavailability.


Assuntos
COVID-19/prevenção & controle , Estilo de Vida , Óxido Nítrico/metabolismo , COVID-19/metabolismo , Humanos
2.
Georgian Med News ; (315): 177-180, 2021 Jun.
Artigo em Russo | MEDLINE | ID: mdl-34365446

RESUMO

The aim of the research is to study the effect of L-arginine, the precursor of nitric oxide, and aminoguanidine, the inhibitor of inducible nitric oxide synthase, on morpho-functional changes in the liver of BALB/c mice with antiphospholipid syndrome. The study was carried out on 50 female BALB/c mice modelled with antiphospholipid syndrome. L-arginine (25 mg/kg) and aminoguanidine (10 mg/kg) were used for its correction. The material for microscopic study was taken by the method of Horalsky. The liver tissue samples were stained with hematoxylin and eosin. Significant hemodynamic disorders with manifestations of thrombosis in the liver in cases of antiphospholipid syndrome followed by destructive-degenerative changes of the stoma and parenchyma have been established. Administration of L-arginine in antiphospholipid syndrome caused restoration of the lobular and beam organization of the liver. The maximum effect on the morphological state of the liver was observed in using a combination of L-arginine and aminoguanidine. The protective effect of L-arginine and aminoguanidine on the microcirculation has been proved that evidences liver function restoration in mice with antiphospholipid syndrome.


Assuntos
Síndrome Antifosfolipídica , Óxido Nítrico , Animais , Síndrome Antifosfolipídica/tratamento farmacológico , Arginina , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo
3.
J Med Food ; 24(8): 852-859, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34382871

RESUMO

CYJ-27, a synthetic analog of decursin, prevents the generation of proinflammatory cytokines and oxidative stress. In this study, the effects of CYJ-27 on the regulation of inducible nitric oxide synthase (iNOS), heme oxygenase (HO)-1, and cyclooxygenase (COX-)2 were characterized in lipopolysaccharide (LPS)-treated human umbilical vein endothelial cells (HUVECs). In addition, the effects of CYJ-27 on the production of iNOS and representative proinflammatory cytokines, such as tumor necrosis factor (TNF)-α and interleukin (IL)-1ß, were tested in the lung tissues of LPS-treated mice. CYJ-27 promoted the expression of HO-1, suppressed NF-κB-luciferase activity, and reduced COX-2/PGE2 and iNOS/NO, resulting in a diminution in phosphorylated-STAT-1. Furthermore, CYJ-27 promoted the nuclear translocation of Nrf2, enhanced the combination of Nrf2 to antioxidant response elements, and diminished IL-1ß production in LPS-activated HUVECs. CYJ-27-downregulated iNOS/NO expression was rescued after the RNAi suppression of HO-1. In LPS-treated mice, CYJ-27 significantly diminished iNOS production in the lung tissues and TNF-α expression in the bronchoalveolar lavage fluid. These findings indicate that CYJ-27 exerts anti-inflammatory activities by regulating iNOS through downregulation of both NF-κB activation and phosphorylated-STAT-1. Hence, it can act as a template for the development of novel substances to treat inflammatory diseases.


Assuntos
Inflamação , NF-kappa B , Animais , Benzopiranos , Butiratos , Ciclo-Oxigenase 2/metabolismo , Regulação para Baixo , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Inflamação/tratamento farmacológico , Inflamação/genética , Lipopolissacarídeos , Camundongos , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo
4.
Biomolecules ; 11(7)2021 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-34356605

RESUMO

Cardiovascular diseases (CVDs) are the leading cause of death worldwide. The initial stage of CVDs is characterized by endothelial dysfunction, defined as the limited bioavailability of nitric oxide (NO). Thus, any factors that interfere with the synthesis or metabolism of NO in endothelial cells are involved in CVD pathogenesis. It is well established that hypoxia is both the triggering factor as well as the accompanying factor in cardiovascular disease, and diminished tissue oxygen levels have been reported to influence endothelial NO bioavailability. In endothelial cells, NO is produced by endothelial nitric oxide synthase (eNOS) from L-Arg, with tetrahydrobiopterin (BH4) as an essential cofactor. Here, we discuss the mechanisms by which hypoxia affects NO bioavailability, including regulation of eNOS expression and activity. What is particularly important is the fact that hypoxia contributes to the depletion of cofactor BH4 and deficiency of substrate L-Arg, and thus elicits eNOS uncoupling-a state in which the enzyme produces superoxide instead of NO. eNOS uncoupling and the resulting oxidative stress is the major driver of endothelial dysfunction and atherogenesis. Moreover, hypoxia induces impairment in mitochondrial respiration and endothelial cell activation; thus, oxidative stress and inflammation, along with the hypoxic response, contribute to the development of endothelial dysfunction.


Assuntos
Aterosclerose/metabolismo , Células Endoteliais/metabolismo , Endotélio Vascular/metabolismo , Hipóxia/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Óxido Nítrico/metabolismo , Oxigênio/metabolismo , Animais , Aterosclerose/patologia , Disponibilidade Biológica , Células Endoteliais/patologia , Endotélio Vascular/patologia , Humanos , Hipóxia/patologia , Estresse Oxidativo
5.
Biomolecules ; 11(7)2021 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-34356634

RESUMO

Nitric oxide (NO), a free radical, plays a critical role in a wide range of physiological and pathological processes. Due to its pleiotropic function, it has been widely investigated in various types of cancers and is strongly associated with cancer development. Mounting pieces of evidence show that NO regulates various cancer-related events, which mainly depends on phosphorylating the key proteins in several signaling pathways. However, phosphorylation of proteins modulated by NO signaling pathway may lead to different effects in different types of cancer, which is complex and remains unclear. Therefore, in this review, we focus on the effect of protein phosphorylation modulated by NO signaling pathway in different types of cancers including breast cancer, lung cancer, prostate cancer, colon cancer, gastric cancer, pancreatic cancer, ovarian cancer, and neuroblastoma. Phosphorylation of key proteins, including p38 MAPK, ERK, PI3K, STAT3, and p53, modified by NO in various signaling pathways affects different cancer-related processes including cell apoptosis, proliferation, angiogenesis, metastasis, and several cancer therapies. Our review links the NO signaling pathway to protein phosphorylation in cancer development and provides new insight into potential targets and cancer therapy.


Assuntos
Sistema de Sinalização das MAP Quinases , Proteínas de Neoplasias/metabolismo , Neoplasias/metabolismo , Óxido Nítrico/metabolismo , Humanos , Proteínas de Neoplasias/genética , Neoplasias/genética , Neoplasias/terapia , Fosforilação
6.
Int J Mol Sci ; 22(15)2021 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-34360769

RESUMO

Nitric oxide (NO) deficiency during pregnancy is a key reason for preeclampsia development. Besides its important vasomotor role, NO is shown to regulate the cell transcriptome. However, the role of NO in transcriptional regulation of developing smooth muscle has never been studied before. We hypothesized that in early ontogeny, NO is important for the regulation of arterial smooth muscle-specific genes expression. Pregnant rats consumed NO-synthase inhibitor L-NAME (500 mg/L in drinking water) from gestational day 10 till delivery, which led to an increase in blood pressure, a key manifestation of preeclampsia. L-NAME reduced blood concentrations of NO metabolites in dams and their newborn pups, as well as relaxations of pup aortic rings to acetylcholine. Using qPCR, we demonstrated reduced abundances of the smooth muscle-specific myosin heavy chain isoform, α-actin, SM22α, and L-type Ca2+-channel mRNAs in the aorta of newborn pups from the L-NAME group compared to control pups. To conclude, the intrauterine NO deficiency weakens gene expression specific for a contractile phenotype of arterial smooth muscle in newborn offspring.


Assuntos
Diferenciação Celular , Músculo Liso Vascular/metabolismo , Óxido Nítrico/deficiência , Complicações na Gravidez/metabolismo , Útero/metabolismo , Animais , Animais Recém-Nascidos , Feminino , Regulação da Expressão Gênica , Proteínas Musculares/biossíntese , Músculo Liso Vascular/patologia , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/metabolismo , Gravidez , Complicações na Gravidez/induzido quimicamente , Complicações na Gravidez/patologia , Ratos , Ratos Wistar , Útero/patologia
7.
Respir Res ; 22(1): 237, 2021 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-34446020

RESUMO

Follow-up studies of COVID-19 patients have found lung function impairment up to six months after initial infection, but small airway function has not previously been studied. Patients (n = 20) hospitalised for a severe SARS-CoV-2 infection underwent spirometry, impulse oscillometry, and multiple measurements of alveolar nitric oxide three to six months after acute infection. None of the patients had small airway obstruction, nor increased nitric oxide concentration in the alveolar level. None of the patients had a reduced FEV1/FVC or significant bronchodilator responses in IOS or spirometry. In conclusion, we found no evidence of inflammation or dysfunction in the small airways.


Assuntos
COVID-19/complicações , COVID-19/fisiopatologia , Doenças Respiratórias/fisiopatologia , Adulto , Idoso , Feminino , Finlândia , Seguimentos , Volume Expiratório Forçado , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Óxido Nítrico/metabolismo , Alvéolos Pulmonares/metabolismo , Testes de Função Respiratória , Doenças Respiratórias/etiologia , Espirometria , Sobreviventes , Capacidade Vital
8.
Int J Mol Sci ; 22(16)2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34445519

RESUMO

Cardiovascular disease is the leading cause of morbidity and mortality in diabetes. Recent clinical studies indicate that sodium-glucose co-transporter 2 (SGLT2) inhibitors improve cardiovascular outcomes in patients with diabetes. The mechanism underlying the beneficial effect of SGLT2 inhibitors is not completely clear but may involve direct actions on vascular cells. SGLT2 inhibitors increase the bioavailability of endothelium-derived nitric oxide and thereby restore endothelium-dependent vasodilation in diabetes. In addition, SGLT2 inhibitors favorably regulate the proliferation, migration, differentiation, survival, and senescence of endothelial cells (ECs). Moreover, they exert potent antioxidant and anti-inflammatory effects in ECs. SGLT2 inhibitors also inhibit the contraction of vascular smooth muscle cells and block the proliferation and migration of these cells. Furthermore, studies demonstrate that SGLT2 inhibitors prevent postangioplasty restenosis, maladaptive remodeling of the vasculature in pulmonary arterial hypertension, the formation of abdominal aortic aneurysms, and the acceleration of arterial stiffness in diabetes. However, the role of SGLT2 in mediating the vascular actions of these drugs remains to be established as important off-target effects of SGLT2 inhibitors have been identified. Future studies distinguishing drug- versus class-specific effects may optimize the selection of specific SGLT2 inhibitors in patients with distinct cardiovascular pathologies.


Assuntos
Complicações do Diabetes/prevenção & controle , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Remodelação Vascular/efeitos dos fármacos , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Complicações do Diabetes/metabolismo , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Humanos , Óxido Nítrico/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico
9.
Int J Mol Sci ; 22(15)2021 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-34360629

RESUMO

Macrophages play a critical role in the inflammatory response to environmental triggers, such as lipopolysaccharide (LPS). Inflammatory signaling through macrophages and the innate immune system are increasingly recognized as important contributors to multiple acute and chronic disease processes. Nitric oxide (NO) is a free radical that plays an important role in immune and inflammatory responses as an important intercellular messenger. In addition, NO has an important role in inflammatory responses in mucosal environments such as the ocular surface. Histatin peptides are well-established antimicrobial and wound healing agents. These peptides are important in multiple biological systems, playing roles in responses to the environment and immunomodulation. Given the importance of macrophages in responses to environmental triggers and pathogens, we investigated the effect of histatin-1 (Hst1) on LPS-induced inflammatory responses and the underlying molecular mechanisms in RAW264.7 (RAW) macrophages. LPS-induced inflammatory signaling, NO production and cytokine production in macrophages were tested in response to treatment with Hst1. Hst1 application significantly reduced LPS-induced NO production, inflammatory cytokine production, and inflammatory signaling through the JNK and NF-kB pathways in RAW cells. These results demonstrate that Hst1 can inhibit LPS-induced inflammatory mediator production and MAPK signaling pathways in macrophages.


Assuntos
Histatinas/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Animais , Citocinas/metabolismo , Avaliação Pré-Clínica de Medicamentos , Lipopolissacarídeos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Células RAW 264.7
10.
Int J Mol Sci ; 22(16)2021 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-34445767

RESUMO

The c-Jun N-terminal kinases (JNKs) are implicated in many neuropathological conditions, including neurodegenerative diseases. To explore potential JNK3 inhibitors from the U.S. Food and Drug Administration-approved drug library, we performed structure-based virtual screening and identified azelastine (Aze) as one of the candidates. NMR spectroscopy indicated its direct binding to the ATP-binding site of JNK3, validating our observations. Although the antihistamine effect of Aze is well documented, the involvement of the JNK pathway in its action remains to be elucidated. This study investigated the effects of Aze on lipopolysaccharide (LPS)-induced JNK phosphorylation, pro-inflammatory mediators, and cell migration in BV2 microglial cells. Aze was found to inhibit the LPS-induced phosphorylation of JNK and c-Jun. It also inhibited the LPS-induced production of pro-inflammatory mediators, including interleukin-6, tumor necrosis factor-α, and nitric oxide. Wound healing and transwell migration assays indicated that Aze attenuated LPS-induced BV2 cell migration. Furthermore, Aze inhibited LPS-induced IκB phosphorylation, thereby suppressing nuclear translocation of NF-κB. Collectively, our data demonstrate that Aze exerts anti-inflammatory and anti-migratory effects through inhibition of the JNK/NF-κB pathway in BV2 cells. Based on our findings, Aze may be a potential candidate for drug repurposing to mitigate neuroinflammation in various neurodegenerative disorders, including Alzheimer's and Parkinson's diseases.


Assuntos
Anti-Inflamatórios/farmacologia , Movimento Celular/efeitos dos fármacos , Inflamação/tratamento farmacológico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Microglia/efeitos dos fármacos , NF-kappa B/metabolismo , Ftalazinas/farmacologia , Animais , Linhagem Celular , Inflamação/induzido quimicamente , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Interleucina-6/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Lipopolissacarídeos/farmacologia , Camundongos , Microglia/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
11.
Molecules ; 26(16)2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34443451

RESUMO

Diabetes mellitus is characterized by tissue oxidative damage and impaired microcirculation, as well as worsened erythrocyte properties. Measurements of erythrocyte deformability together with determination of nitric oxide (NO) production and osmotic resistance were used for the characterization of erythrocyte functionality in lean (control) and obese Zucker diabetic fatty (ZDF) rats of two age categories. Obese ZDF rats correspond to prediabetic (younger) and diabetic (older) animals. As antioxidants were suggested to protect erythrocytes, we also investigated the potential effect of quercetin (20 mg/kg/day for 6 weeks). Erythrocyte deformability was determined by the filtration method and NO production using DAF-2DA fluorescence. For erythrocyte osmotic resistance, we used hemolytic assay. Erythrocyte deformability and NO production deteriorated during aging-both were lower in older ZDF rats than in younger ones. Three-way ANOVA indicates improved erythrocyte deformability after quercetin treatment in older obese ZDF rats only, as it was not modified or deteriorated in both (lean and obese) younger and older lean animals. NO production by erythrocytes increased post treatment in all experimental groups. Our study indicates the potential benefit of quercetin treatment on erythrocyte properties in condition of diabetes mellitus. In addition, our results suggest potential age-dependency of quercetin effects in diabetes that deserve additional research.


Assuntos
Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Eritrócitos/metabolismo , Quercetina/uso terapêutico , Animais , Antioxidantes , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Deformação Eritrocítica/efeitos dos fármacos , Eritrócitos/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Óxido Nítrico/metabolismo , Osmose , Estresse Oxidativo , Quercetina/farmacologia , Ratos Zucker
12.
Int J Mol Sci ; 22(16)2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34445374

RESUMO

Angiotensin II (Ang II) induces hypertension and endothelial dysfunction, but the involvement of thrombin in these responses is not clear. Here, we assessed the effects of the inhibition of thrombin activity by dabigatran on Ang II-induced hypertension and endothelial dysfunction in mice with a particular focus on NO- and 20-HETE-dependent pathways. As expected, dabigatran administration significantly delayed thrombin generation (CAT assay) in Ang II-treated hypertensive mice, and interestingly, it prevented endothelial dysfunction development, but it did not affect elevated blood pressure nor excessive aortic wall thickening. Dabigatran's effects on endothelial function in Ang II-treated mice were evidenced by improved NO-dependent relaxation in the aorta in response to acetylcholine in vivo (MRI measurements) and increased systemic NO bioavailability (NO2- quantification) with a concomitant increased ex vivo production of endothelium-derived NO (EPR analysis). Dabigatran treatment also contributed to the reduction in the endothelial expression of pro-inflammatory vWF and ICAM-1. Interestingly, the fall in systemic NO bioavailability in Ang II-treated mice was associated with increased 20-HETE concentration in plasma (UPLC-MS/MS analysis), which was normalised by dabigatran treatment. Taking together, the inhibition of thrombin activity in Ang II-induced hypertension in mice improves the NO-dependent function of vascular endothelium and normalises the 20-HETE-depedent pathway without affecting the blood pressure and vascular remodelling.


Assuntos
Angiotensina II/efeitos adversos , Antitrombinas/administração & dosagem , Dabigatrana/administração & dosagem , Ácidos Hidroxieicosatetraenoicos/sangue , Hipertensão/metabolismo , Remodelação Vascular/efeitos dos fármacos , Animais , Antitrombinas/farmacologia , Cromatografia Líquida , Dabigatrana/farmacologia , Modelos Animais de Doenças , Hipertensão/sangue , Hipertensão/induzido quimicamente , Molécula 1 de Adesão Intercelular/metabolismo , Masculino , Camundongos , Óxido Nítrico/metabolismo , Espectrometria de Massas em Tandem , Fator de von Willebrand/metabolismo
13.
J Agric Food Chem ; 69(31): 8747-8757, 2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34337939

RESUMO

High-purity Fab fragment and immunoglobulin Y (IgY) were prepared to evaluate their anti-inflammatory activity in the lipopolysaccharide (LPS)-induced Raw 264.7 macrophage system. Compared with IgY, the Fab fragment possessed a greater potency in inhibiting the inflammation by nitric oxide (NO)/inducible nitric oxide synthase (iNOS) and prostaglandin-E2 (PGE2)/cyclooxygenase-2 (COX-2) pathways. The Fab fragment attenuated the levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-10 (IL-10) to 38.07 ± 1.86-48.39 ± 11.33 pg/mL (63.1-71.0% inhibition), 31.59 ± 3.91-38.08 ± 4.44 pg/mL (72.4-77.1% inhibition), and 20.62 ± 0.46-21.91 ± 0.65 pg/mL (50-53% inhibition), respectively. Additionally, the Fab fragment significantly inhibited the translocation of nuclear transcription factor-κB (NF-κB) p65 and the phosphorylation of mitogen-activated protein kinase (MAPK) proteins, including ERK1/2 (41.5/33.2%), JNK1/2 (44.2/39.6%), and p38 (42.2%). The Fab fragment could be internalized into cells, and the pretreatment of RAW 264.7 macrophages with the Fab fragment reduced the mRNA expression of the Toll-like receptor (TLR4, 32.7-44.4% inhibition) and αVß3 integrin (76.1% inhibition). In conclusion, Fab fragments regulated the TLR4 and αVß3 integrin-mediated inflammatory processes by blocking the NF-κB and MAPKs pathways in the LPS-induced RAW 264.7 macrophage system.


Assuntos
Fragmentos Fab das Imunoglobulinas/imunologia , NF-kappa B , Receptor 4 Toll-Like , Animais , Ciclo-Oxigenase 2/metabolismo , Imunoglobulinas , Integrina alfa5 , Integrinas , Lipopolissacarídeos , Macrófagos/metabolismo , Camundongos , Proteínas Quinases Ativadas por Mitógeno/genética , NF-kappa B/genética , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Células RAW 264.7 , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo
14.
Int J Mol Sci ; 22(15)2021 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-34360585

RESUMO

New, tricyclic compounds containing a sulfonyl moiety in their structure, as potential safer COX inhibitors, were designed and synthesized. New derivatives have three conjugated rings and a sulfonyl group. A third ring, i.e., an oxazine, oxazepine or oxazocin, has been added to the 1,2-benzothiazine skeleton. Their anti-COX-1/COX-2 and cytotoxic effects in vitro on NHDF cells, together with the ability to interact with model membranes and the influence on reactive oxygen species and nitric oxide, were studied. Additionally, a molecular docking study was performed to understand the binding interaction of the compounds with the active site of cyclooxygenases. For the abovementioned biological evaluation of new tricyclic 1,2-benzothiazine derivatives, the following techniques and procedures were employed: the differential scanning calorimetry, the COX colorimetric inhibitor screening assay, the MTT, DCF-DA and Griess assays. All of the compounds studied demonstrated preferential inhibition of COX-2 compared to COX-1. Moreover, all the examined tricyclic 1,2-thiazine derivatives interacted with the phospholipid model membranes. Finally, they neither have cytotoxic potency, nor demonstrate significant influence on the level of reactive oxygen species or nitric oxide. Overall, the tricyclic 1,2-thiazine derivatives are good starting points for future pharmacological tests as a group of new anti-inflammatory agents.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Derme/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Óxido Nítrico/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Tiazinas/química , Anti-Inflamatórios não Esteroides/química , Células Cultivadas , Inibidores de Ciclo-Oxigenase/química , Derme/citologia , Fibroblastos/citologia , Humanos , Simulação de Acoplamento Molecular , Prostaglandina-Endoperóxido Sintases/química
15.
Theranostics ; 11(16): 7715-7734, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335960

RESUMO

Rationale: Emerging evidence indicates that the growth of blood vessels and osteogenesis is tightly coordinated during bone development. However, the molecular regulators of intercellular communication in the bone microenvironment are not well studied. Therefore, we aim to investigate whether BMMSC-Exo promotes osteogenesis and angiogenesis via transporting lnc-H19 in the CBS- heterozygous mouse model. Methods: Using RT2 lncRNA PCR array screening, we identify a bone-specific, long noncoding RNA-H19 (lncRNA-H19/lnc-H19) in exosomes derived from bone marrow mesenchymal stem cells (BMMSC-Exo) during osteogenesis. Using bioinformatics analysis, we further discovered the seed sequence of miR-106a that could bind to lnc-H19. A luciferase reporter assay was performed to demonstrate the direct binding of miR-106a to the target gene angiopoietin 1 (Angpt1). We employed an immunocompromised Nude mouse model, to evaluate the effects of BMMSC-Exo on angiogenesis in vivo. Using a micro-CT scan, we monitored microstructural changes of bone in the experimental mice. Results: BMMSC-Exo possessed exosomal characteristics including exosome size, and typical markers including CD63, CD9, and TSD101. In vitro, BMMSC-Exo significantly promoted endothelial angiogenesis and osteogenesis. Mechanistic studies have shown that exosomal lnc-H19 acts as "sponges" to absorb miR-106 and regulate the expression of angiogenic factor, Angpt1 that activates lnc-H19/Tie2-NO signaling in mesenchymal and endothelial cells. Both of these effects on osteogenesis and angiogenesis are inhibited by antagonizing Tie2 signaling. Treatment of BMMSC-Exo also restored the bone formation and mechanical quality in vivo. Conclusion: These findings provide a novel insight into how the extracellular role of exosomal lnc-H19 affects osteogenesis and angiogenesis through competing endogenous RNA networks.


Assuntos
MicroRNAs/genética , Osteogênese/genética , RNA Longo não Codificante/genética , Angiopoietina-1/genética , Angiopoietina-1/metabolismo , Angiopoietina-1/fisiologia , Animais , Osso e Ossos/metabolismo , Linhagem Celular Tumoral , Células Endoteliais/metabolismo , Exossomos/genética , Genes Supressores de Tumor , Células-Tronco Mesenquimais/metabolismo , Camundongos , Neovascularização Patológica/genética , Óxido Nítrico/metabolismo , RNA Longo não Codificante/metabolismo , Receptor TIE-2/metabolismo , Receptor TIE-2/fisiologia , Transdução de Sinais/genética
16.
Molecules ; 26(13)2021 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-34206838

RESUMO

Polyphenols, widely distributed in the genus Melastoma plants, possess extensive cellular protective effects such as anti-inflammatory, anti-tyrosinase, and anti-obesity, which makes it a potential anti-inflammatory drug or enzyme inhibitor. Therefore, the aim of this study is to screen for the anti-inflammatory and enzyme inhibitory activities of compounds from title plant. Using silica gel, MCI, ODS C18, and Sephadex LH-20 column chromatography, as well as semipreparative HPLC, the extract of Melastoma normale roots was separated. Four new ellagitannins, Whiskey tannin C (1), 1-O-(4-methoxygalloyl)-6-O-galloyl-2,3-O-(S)-hexahydroxydiphenoyl-ß-d-glucose (2), 1-O-galloyl-6-O-(3-methoxygalloyl)-2,3-O-(S)-hexahydroxydiphenoyl-ß-d-glucose (3), and 1-O-galloyl-6-O-vanilloyl-2,3-O-(S)-hexahydroxydiphenoyl-ß-d-glucose (4), along with eight known polyphenols were firstly obtained from this plant. The structures of all isolates were elucidated by HRMS, NMR, and CD analyses. Using lipopolysaccharide (LPS)-stimulated RAW2 64.7 cells, we investigated the anti-inflammatory activities of compounds 1-4, unfortunately, none of them exhibit inhibit nitric oxide (NO) production, their IC50 values are all > 50 µM. Anti-tyrosinase activity assays was done by tyrosinase inhibition activity screening model. Compound 1 showed weak tyrosinase inhibitory activity with IC50 values of 426.02 ± 11.31 µM. Compounds 2-4 displayed moderate tyrosinase inhibitory activities with IC50 values in the range of 124.74 ± 3.12-241.41 ± 6.23 µM. The structure-activity relationships indicate that hydroxylation at C-3', C-4', and C-3 in the flavones were key to their anti-tyrosinase activities. The successful isolation and structure identification of ellagitannin provide materials for the screening of anti-inflammatory drugs and enzyme inhibitors, and also contribute to the development and utilization of M. normale.


Assuntos
Anti-Inflamatórios/análise , Inibidores Enzimáticos/farmacologia , Taninos Hidrolisáveis/análise , Melastomataceae/química , Monofenol Mono-Oxigenase/antagonistas & inibidores , Extratos Vegetais/química , Polifenóis/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Concentração Inibidora 50 , Camundongos , Estrutura Molecular , Óxido Nítrico/metabolismo , Extratos Vegetais/análise , Polifenóis/química , Células RAW 264.7
17.
Chem Commun (Camb) ; 57(61): 7581-7584, 2021 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-34250986

RESUMO

A pharmacophore integration strategy was utilized to develop the first co-donor of formaldehyde and nitric oxide (FANO), composed of urotropine derived nitramine/nitrosamine. FANO simultaneously generated formaldehyde and nitric oxide on-demand, resulting in synergistic anticancer effects. Importantly, liposomal formulation of FANO effectively inhibited tumor growth with minimal side-effects, providing a potent combined nitric oxide therapy for malignancy.


Assuntos
Antineoplásicos/uso terapêutico , Formaldeído/metabolismo , Neoplasias/tratamento farmacológico , Doadores de Óxido Nítrico/uso terapêutico , Óxido Nítrico/metabolismo , Poliaminas/uso terapêutico , Animais , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Portadores de Fármacos/química , Lipossomos/química , Metenamina/química , Camundongos , Doadores de Óxido Nítrico/síntese química , Nitrosaminas/síntese química , Nitrosaminas/uso terapêutico , Poliaminas/síntese química
18.
Molecules ; 26(13)2021 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-34279415

RESUMO

Neurodegeneration is the consequence of harmful events affecting the nervous system that lead to neuronal death. Toxic substances, including air pollutants, are capable of inducing neurodegeneration. Ozone (O3) is the most oxidative toxic pollutant. O3 reacts with cellular components and forms reactive oxygen and nitrogen species, triggering nitro-oxidative damage during short-term exposure. Curcumin (CUR) is a natural phenolic molecule bearing well-documented antioxidant and anti-inflammatory biological activities in diverse experimental models. The aim of this work was to evaluate the effect of preventive dietary administration of CUR against hippocampal neurodegeneration and nitro-oxidative damage caused by short-term exposure to O3. Eighty Wistar male rats were distributed into four experimental groups, twenty rats each: intact control; CUR dietary supplementation without O3 exposure; exposure to 0.7 ppm of O3; and exposed to O3 with CUR dietary supplementation. Five rats from each group were sacrificed at 1, 2, 4, and 8 h of exposure. The CUR dose was 5.6 mg/kg and adjusted according to food consumption. CUR significantly decreased oxidative damage to plasma lipids and proteins, as well as neurodegeneration in CA1 and CA3 hippocampal regions. Concluding, CUR proved effective protection in decreasing neurodegeneration in the hippocampus and prevented systemic oxidative damage.


Assuntos
Proteínas Sanguíneas/metabolismo , Curcumina/farmacologia , Hipocampo/efeitos dos fármacos , Lipídeos/análise , Doenças Neurodegenerativas/tratamento farmacológico , Estresse Oxidativo , Ozônio/toxicidade , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/farmacologia , Hipocampo/metabolismo , Hipocampo/patologia , Masculino , Doenças Neurodegenerativas/induzido quimicamente , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Óxido Nítrico/metabolismo , Ratos , Ratos Wistar
19.
Molecules ; 26(13)2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34279442

RESUMO

Partially purified ginsenoside extract (PGE) and compound K enriched extract (CKE) were prepared from ginseng sprouts, and their antioxidant, anti-inflammatory and antithrombotic effects were investigated. Compared to the 6-year-old ginseng roots, ginseng sprouts were found to have a higher content of phenolic compounds, saponin and protopanaxadiol-type ginsenoside by about 56%, 36% and 43%, respectively. PGE was prepared using a macroporous adsorption resin, and compound K(CK) was converted and enriched from the PGE by enzymatic hydrolysis with a conversion rate of 75%. PGE showed higher effects than CKE on radical scavenging activity in antioxidant assays. On the other hand, CKE reduced nitric oxide levels more effectively than PGE in RAW 264.7 cells. CKE also reduced pro-inflammatory cytokines, such as tumor necrosis factor-α, interleukin (IL)-1ß and IL-6 than PGE. Tail bleeding time and volume were investigated after administration of CKE at 70-150 mg/kg/day to mice. CKE administered group showed a significant increase or increased tendency in bleeding time than the control group. Bleeding volume in the CKE group increased than the control group, but not as much as in the aspirin group. In conclusion, ginseng sprouts could be an efficient source of ginsenoside, and CKE converted from the ginsenosides showed antioxidant, anti-inflammatory and antithrombotic effects. However, it was estimated that the CKE might play an essential role in anti-inflammatory effects rather than antioxidant effects.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Fibrinolíticos/farmacologia , Ginsenosídeos/farmacologia , Panax/química , Extratos Vegetais/farmacologia , Animais , Citocinas/metabolismo , Hemorragia/tratamento farmacológico , Camundongos , Camundongos Endogâmicos ICR , Óxido Nítrico/metabolismo , Células RAW 264.7
20.
Molecules ; 26(14)2021 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-34299486

RESUMO

Coptisine is the major bioactive protoberberine alkaloid found in Rhizoma Coptidis. Coptisine reduces inflammatory responses and improves glucose tolerance; nevertheless, whether coptisine has vasoprotective effect in diabetes is not fully characterized. Conduit arteries including aortas and carotid arteries were obtained from male C57BL/6J mice for ex vivo treatment with risk factors (high glucose or tunicamycin) and coptisine. Some arterial rings were obtained from diabetic mice, which were induced by high-fat diet (45% kcal% fat) feeding for 6 weeks combined with a low-dose intraperitoneal injection of streptozotocin (120 mg/kg). Functional studies showed that coptisine protected endothelium-dependent relaxation in aortas against risk factors and from diabetic mice. Coptisine increased phosphorylations of AMPK and eNOS and downregulated the endoplasmic reticulum (ER) stress markers as determined by Western blotting. Coptisine elevates NO bioavailability and decreases reactive oxygen species level. The results indicate that coptisine improves vascular function in diabetes through suppression of ER stress and oxidative stress, implying the therapeutic potential of coptisine to treat diabetic vasculopathy.


Assuntos
Berberina/análogos & derivados , Diabetes Mellitus Experimental/complicações , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Doenças Vasculares/tratamento farmacológico , Doenças Vasculares/etiologia , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Berberina/farmacologia , Diabetes Mellitus Experimental/metabolismo , Dieta Hiperlipídica/efeitos adversos , Endotélio Vascular/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Doenças Vasculares/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...