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1.
Anticancer Res ; 41(9): 4313-4319, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34475051

RESUMO

BACKGROUND/AIM: In order to produce an animal model for oral mucositis induced by anticancer drugs, it is necessary to maintain an immunosuppressive state. We determined the optimal dose and frequency of 5-fluorouracil for a model mouse production. In addition, we used this model to investigate the effect of GGsTop® gelation on the therapeutic effect of oral mucositis. MATERIALS AND METHODS: Changes in body weight and white blood cell count were measured to determine the optimal dosing schedule. The therapeutic effect of GGsTop® gel using chitosan was evaluated by observing changes in the ulcer area for three weeks and measuring collagen and glutathione concentrations in oral mucosal tissue. RESULTS: The optimal dose and frequency of 5-fluorouracil were found to be 50 mg/kg every four days. It was revealed that the therapeutic effect of GGsTop® was enhanced by gelation. CONCLUSION: GGsTop® gel is suggested to be a promising formulation for the treatment of oral mucositis.


Assuntos
Aminobutiratos/administração & dosagem , Antimetabólitos Antineoplásicos/efeitos adversos , Fluoruracila/efeitos adversos , Leucócitos/efeitos dos fármacos , Organofosfonatos/administração & dosagem , Estomatite/tratamento farmacológico , Aminobutiratos/farmacologia , Animais , Antimetabólitos Antineoplásicos/administração & dosagem , Peso Corporal/efeitos dos fármacos , Colágeno/metabolismo , Modelos Animais de Doenças , Cálculos da Dosagem de Medicamento , Fluoruracila/administração & dosagem , Géis , Glutationa/metabolismo , Masculino , Camundongos , Organofosfonatos/farmacologia , Estomatite/induzido quimicamente , Estomatite/metabolismo
2.
Molecules ; 26(16)2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-34443591

RESUMO

The development and progression of heart failure (HF) due to myocardial infarction (MI) is a major concern even with current optimal therapy. Resveratrol is a plant polyphenol with cardioprotective properties. Sacubitril/valsartan is known to be beneficial in chronic HF patients. In this study, we investigated the comparative and combinatorial benefits of resveratrol with sacubitril/valsartan alongside an active comparator valsartan in MI-induced male Sprague Dawley rats. MI-induced and sham-operated animals received vehicle, resveratrol, sacubitril/valsartan, valsartan alone or sacubitril/valsartan + resveratrol for 8 weeks. Echocardiography was performed at the endpoint to assess cardiac structure and function. Cardiac oxidative stress, inflammation, fibrosis, brain natriuretic peptide (BNP), creatinine and neutrophil gelatinase associated lipocalin were measured. Treatment with resveratrol, sacubitril/valsartan, valsartan and sacubitril/valsartan + resveratrol significantly prevented left ventricular (LV) dilatation and improved LV ejection fraction in MI-induced rats. All treatments also significantly reduced myocardial tissue oxidative stress, inflammation and fibrosis, as well as BNP. Treatment with the combination of sacubitril/valsartan and resveratrol did not show additive effects. In conclusion, resveratrol, sacubitril/valsartan, and valsartan significantly prevented cardiac remodeling and dysfunction in MI-induced rats. The reduction in cardiac remodeling and dysfunction in MI-induced rats was mediated by a reduction in cardiac oxidative stress, inflammation and fibrosis.


Assuntos
Aminobutiratos/farmacologia , Compostos de Bifenilo/farmacologia , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Resveratrol/farmacologia , Valsartana/farmacologia , Remodelação Ventricular/efeitos dos fármacos , Animais , Combinação de Medicamentos , Interações Medicamentosas , Fibrose , Humanos , Masculino , Infarto do Miocárdio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Função Ventricular Esquerda/efeitos dos fármacos
3.
Int J Mol Sci ; 22(16)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34445301

RESUMO

Angiotensin receptor neprilysin inhibitor (ARNI) treatment reduces functional mitral regurgitation (MR) to a greater extent than angiotensin receptor blocker (ARB) treatment alone, but the mechanism is unclear. We evaluated the mechanisms of how ARNI has an effect on functional MR. After inducing functional MR by left circumflex coronary artery occlusion, male Sprague Dawley rats (n = 31) were randomly assigned to receive the ARNI LCZ696, the ARB valsartan, or corn oil only (MR control). Excised mitral leaflets and left ventricle (LV) were analyzed, and valvular endothelial cells were evaluated focusing on molecular changes. LCZ696 significantly attenuated LV dilatation after 6 weeks when compared with the control group (LV end-diastolic volume, 461.3 ± 13.8 µL versus 525.1 ± 23.6 µL; p < 0.05), while valsartan did not (471.2 ± 8.9 µL; p > 0.05 to control). Histopathological analysis of mitral leaflets showed that LCZ696 strongly reduced fibrotic thickness compared to the control group (28.2 ± 2.7 µm vs. 48.8 ± 7.5 µm; p < 0.05). Transforming growth factor-ß and downstream phosphorylated extracellular-signal regulated kinase were also significantly lower in the LCZ696 group. Consequently, excessive endothelial-to-mesenchymal transition (EndoMT) was mitigated in the LCZ696 group compared to the control group and leaflet area was higher (11%) in the LCZ696 group than in the valsartan group. Finally, the MR extent was significantly lower in the LCZ696 group and functional improvement was observed. In conclusion, neprilysin inhibitor has positive effects on LV reverse remodeling and also attenuates fibrosis in MV leaflets and restores adaptive growth by directly modulating EndoMT.


Assuntos
Aminobutiratos/uso terapêutico , Compostos de Bifenilo/uso terapêutico , Insuficiência da Valva Mitral/tratamento farmacológico , Infarto do Miocárdio/tratamento farmacológico , Valsartana/uso terapêutico , Aminobutiratos/farmacologia , Antagonistas de Receptores de Angiotensina/farmacologia , Antagonistas de Receptores de Angiotensina/uso terapêutico , Animais , Compostos de Bifenilo/farmacologia , Células Cultivadas , Combinação de Medicamentos , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/fisiologia , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Valva Mitral/efeitos dos fármacos , Valva Mitral/patologia , Valva Mitral/fisiologia , Insuficiência da Valva Mitral/diagnóstico , Insuficiência da Valva Mitral/etiologia , Insuficiência da Valva Mitral/fisiopatologia , Infarto do Miocárdio/complicações , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/complicações , Traumatismo por Reperfusão Miocárdica/diagnóstico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Neprilisina/antagonistas & inibidores , Ratos , Ratos Sprague-Dawley , Valsartana/farmacologia , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos
4.
Life Sci ; 280: 119692, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34102189

RESUMO

AIMS: This study investigated the renal protective effects and mechanisms of angiotensin receptor-neprilysin inhibitor LCZ696 in mice with cardiorenal syndrome. MATERIALS AND METHODS: Mice were divided into abdominal aortic ligation alone, or treatment with LCZ696 or valsartan, whilst those undergoing sham surgery served as controls. Rat proximal renal tubular epithelial cells from the NRK-52E line were treated with control solution, LCZ696 or valsartan, in the presence or absence of Ang II for 24 h. KEY FINDINGS: Compared to controls, abdominal aortic ligation significantly increased plasma NT-proBNP and urine neutrophil gelatinase-associated lipocalin (NGAL), which were associated with reduced renal length and velocity time integral on ultrasonography. Histology revealed wrinkling of the glomerular capillary wall and sclerosis of the glomerulus, dilatation of the Bowman's capsule, accompanied by diffuse renal tubular atrophy and fibrosis, accompanied by lower kidney index and higher percentage area of fibrosis. Increases in NGAL and decreased ANP protein and mRNA expression levels were observed. These abnormalities were significantly prevented by LCZ696 and to a lesser extent by valsartan. Cellular experiments demonstrated a central role of Ang II/transforming growth factor-ß1/Smad2/3/connective tissue growth factor-dependent signaling leading to type IV collagen deposition. This upregulation was reversed by LCZ696 in a greater extent than valsartan treatment alone, accompanied by a significant improvement in NGAL. SIGNIFICANCE: LCZ696 can reduce kidney injury to a level beyond valsartan therapy alone in mice with cardiorenal syndrome, which can be speculated by effects on epithelial-mesenchymal transition and fibrosis through downregulating the TGF-ß1/Smad2/3/CTGF/Collagen IV pathway.


Assuntos
Aminobutiratos/uso terapêutico , Antagonistas de Receptores de Angiotensina/uso terapêutico , Compostos de Bifenilo/uso terapêutico , Síndrome Cardiorrenal/tratamento farmacológico , Rim/efeitos dos fármacos , Substâncias Protetoras/uso terapêutico , Valsartana/uso terapêutico , Aminobutiratos/farmacologia , Antagonistas de Receptores de Angiotensina/farmacologia , Animais , Compostos de Bifenilo/farmacologia , Síndrome Cardiorrenal/patologia , Linhagem Celular , Combinação de Medicamentos , Rim/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Substâncias Protetoras/farmacologia , Ratos , Valsartana/farmacologia
5.
Arch Microbiol ; 203(6): 3623-3632, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33983489

RESUMO

Leaf spot (Pestalotiopsis microspora) is one of the major fungal diseases in blueberry (Vaccinium corymbosum L.) production and if not treated promptly that can eventually lead to plant death. To prevent and control leaf spot effectively, we selected BABA (beta-aminobutyric acid) as an inducer, "Canlan" in blueberries of rabbit eyes varieties as experimental material and then induced and inoculated leaf spot on blueberries as an experimental group and used uninduced blueberries inoculated with leaf spot as the control group. A transcriptome sequencing library was built, allowing identification of disease resistance and transcriptome analysis. The results showed that the resistance of blueberry to leaf spot was significantly increased after induction by BABA, which can increase the activity of the enzymes PPO, POD, PAL and and ß-1,3-glucanase in blueberry leaves, inducing disease resistance of blueberries to leaf spot. Transcriptome sequencing results showed that there are 3953 genes participating in the processing of disease in KEGG metabolic pathways. Among the transcripts annotated to diseases, 1115 were involved in plant-pathogen interactions and 35 were involved in anthocyanin synthesis. Differential expression results showed that there were 900 upregulated differential genes and 531 downregulated differential genes, there were 70 genes highly expressed in the library. The results of Blast2PHI database revealed that among the genes related to leaf spot disease in blueberry, there were 727 transcription factors, 200 involved in disease prevention, 45 associated with cell circulation, effector proteins and 7 pathogenic genes controlling the biosynthesis of a-(1,3)-glucan.


Assuntos
Aminobutiratos/farmacologia , Mirtilos Azuis (Planta)/genética , Perfilação da Expressão Gênica , Doenças das Plantas/genética , Animais , Regulação da Expressão Gênica de Plantas , Doenças das Plantas/prevenção & controle , Folhas de Planta/genética , Coelhos
6.
Aging (Albany NY) ; 13(7): 9582-9591, 2021 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-33839697

RESUMO

Lipopolysaccharide (LPS)-induced endothelial dysfunction plays an important role in the pathogenesis of cardiovascular diseases. LCZ696, the dual-acting angiotensin receptor blocker, and neprilysin inhibitor has been used for the treatment of heart failure with reduced ejection fraction. Recent work suggests that LCZ696 therapy might have an anti-inflammatory effect in cardiovascular tissue. In the current study, we show that LCZ696 attenuates LPS-induced oxidative stress by reducing the production of intracellular reactive oxygen species (ROS) and the measurements of malonyl dialdehyde (MDA) level in human umbilical vascular endothelial cells (HUVECs). LCZ696 inhibits LPS-induced expressions and secretions of the pro-inflammatory cytokines, interleukin-6 (IL-6), interleukin-1α (IL-1α), and tumor necrosis factor ß (TNF-ß) as well as the chemokines, monocyte chemotactic protein 1 (MCP-1), and chemokine (C-X-C motif) ligand 1 protein (CXCL1). Additionally, we found that LCZ696 reduces LPS-induced expressions of vascular cell adhesion molecule 1 (VCAM-1) and P-selectin and the attachment of U937 monocytes to HUVECs. Mechanistically, LCZ696 prevents LPS-induced activation of the TLR4/Myd88 pathway and nuclear translocation of nuclear factor kappa-B (NF-κB) p65 factor. Based on these findings, we conclude that LCZ696 is capable of ameliorating LPS-induced endothelial dysfunction via anti-inflammatory properties.


Assuntos
Aminobutiratos/farmacologia , Compostos de Bifenilo/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Valsartana/farmacologia , Citocinas/metabolismo , Combinação de Medicamentos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Lipopolissacarídeos/farmacologia , Malondialdeído/metabolismo , Transdução de Sinais/efeitos dos fármacos , Molécula 1 de Adesão de Célula Vascular/metabolismo
7.
Am J Physiol Renal Physiol ; 320(6): F1133-F1151, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33870733

RESUMO

Although renin-angiotensin blockade has shown beneficial outcomes in patients with diabetes, renal injury progresses in most of these patients. Therefore, there remains a need for new therapeutic targets in diabetic kidney disease. Enhancement of vasoactive peptides, such as natriuretic peptides, via neprilysin inhibition, has been a new approach. A first-in-class drug, sacubitril/valsartan (Sac/Val), a combination of the angiotensin II receptor blocker Val and neprilysin inhibitor prodrug Sac, has been shown to be more effective than renin-angiotensin blockade alone in the treatment of heart failure with reduced ejection fraction. In this study, we tested the effects of Sac/Val in diabetic kidney disease. We administered Sac/Val or Val to two type 2 diabetes mouse models, db/db mice or KKAy mice. After 3 mo of treatment, Sac/Val attenuated the progression of proteinuria, glomerulosclerosis, and podocyte loss in both models of diabetic mice. Val shared a similar improvement but to a lesser degree in some parameters compared with Sac/Val. Sac/Val but not Val decreased the blood glucose level in KKAy mice. Sac/Val exerted renal protection through coordinated effects on antioxidative stress and anti-inflammation. In both diabetic models, we revealed a new mechanism to cause inflammation, self-DNA-activated cGMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling, which was activated in diabetic kidneys and prevented by Sac/Val or Val treatment. The present data suggest that Sac/Val has sufficient therapeutical potential to counter the pathophysiological effects of diabetic kidney disease, and its effectiveness could be better than Val alone.NEW & NOTEWORTHY The first-in-class drug sacubitril/valsartan, a combination of the angiotensin II receptor blocker valsartan and neprilysin inhibitor sacubitril, was tested for its effects in diabetic kidney disease using db/db mice and KKAy mice. We found that Sac/Val has sufficient therapeutical potential to counter the pathophysiological effects of diabetic kidney disease. We further revealed a new mechanism to cause inflammation, self-DNA-activated cGAS-STING signaling, which was activated in diabetic kidneys and prevented by sacubitril/valsartan or valsartan treatment.


Assuntos
Aminobutiratos/farmacologia , Compostos de Bifenilo/farmacologia , Nefropatias Diabéticas/tratamento farmacológico , Valsartana/farmacologia , Albuminúria/tratamento farmacológico , Antagonistas de Receptores de Angiotensina/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Combinação de Medicamentos , Inflamação/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Estresse Oxidativo , Valsartana/administração & dosagem
8.
Int J Mol Sci ; 22(7)2021 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-33808232

RESUMO

The angiotensin receptor/neprilysin inhibitor Sacubitril/Valsartan (Sac/Val) has been shown to be beneficial in patients suffering from heart failure with reduced ejection fraction (HFrEF). However, the impact of Sac/Val in patients presenting with heart failure with preserved ejection fraction (HFpEF) is not yet clearly resolved. The present study aimed to reveal the influence of the drug on the functionality of the myocardium, the skeletal muscle, and the vasculature in a rat model of HFpEF. Female obese ZSF-1 rats received Sac/Val as a daily oral gavage for 12 weeks. Left ventricle (LV) function was assessed every four weeks using echocardiography. Prior to organ removal, invasive hemodynamic measurements were performed in both ventricles. Vascular function of the carotid artery and skeletal muscle function were monitored. Sac/Val treatment reduced E/é ratios, left ventricular end diastolic pressure (LVEDP) and myocardial stiffness as well as myocardial fibrosis and heart weight compared to the obese control group. Sac/Val slightly improved endothelial function in the carotid artery but had no impact on skeletal muscle function. Our results demonstrate striking effects of Sac/Val on the myocardial structure and function in a rat model of HFpEF. While vasodilation was slightly improved, functionality of the skeletal muscle remained unaffected.


Assuntos
Aminobutiratos/farmacologia , Compostos de Bifenilo/farmacologia , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Músculo Esquelético/efeitos dos fármacos , Valsartana/farmacologia , Antagonistas de Receptores de Angiotensina/farmacologia , Animais , Conectina/metabolismo , GMP Cíclico/sangue , Diástole/efeitos dos fármacos , Diástole/fisiologia , Modelos Animais de Doenças , Combinação de Medicamentos , Eletrocardiografia , Feminino , Fibrose , Hemoglobina A Glicada/análise , Músculo Esquelético/fisiologia , Atrofia Muscular/tratamento farmacológico , Atrofia Muscular/fisiopatologia , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Fosforilação/efeitos dos fármacos , Ratos Mutantes , Função Ventricular Esquerda/efeitos dos fármacos
9.
Mol Med Rep ; 23(6)2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33786624

RESUMO

The therapeutic effect of sacubitril/valsartan (S/V) on heart failure has been confirmed, while its role in atherosclerosis remains largely unexplored. The present study aimed to investigate the effects of S/V on the expression of metastasis­associated lung adenocarcinoma transcript 1 (MALAT1), inflammation and apoptosis in human umbilical vein endothelial cells (HUVECs) induced by oxidized low­density lipoprotein (ox­LDL) and to elucidate its possible mechanism. Cell Counting Kit­8 assay was used to detect cell viability. Reverse transcription­quantitative PCR was performed to detect the MALAT1 expression. ELISA was performed to detect the levels of IL­1ß, IL­6 and TNF­α. Flow cytometry was conducted to detect the apoptotic rate of cells. A nitric oxide (NO) detection kit was used to determine the concentration of NO. Western blotting analysis was performed to determine the levels of intercellular cell adhesion molecule (ICAM)­1, vascular cell adhesion molecule (VCAM)­1, endothelin­1, caspase­3, Bax, Bcl­2, Toll­like receptor 4 (TLR4), p65 and p­p65. Compared with the ox­LDL group, S/V treatment significantly increased the cell viability, NO concentration and Bcl­2 expression, decreased the levels of IL­1ß, IL­6 and TNF­α and reduced the expressions of MALAT1, ICAM­1, VCAM­1, cleaved­caspase­3, Bax, TLR4 and p­p65. Overall, the findings suggested that S/V could downregulate the expression of MALAT1, inhibit inflammation and apoptosis and improve endothelial function in ox­LDL­induced HUVECs via inactivating the TLR4/NF­κB signaling pathway. Therefore, S/V might be utilized as a promising therapeutic strategy for the prevention and treatment of atherosclerosis.


Assuntos
Aminobutiratos/farmacologia , Anti-Inflamatórios/farmacologia , Apoptose , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , RNA Longo não Codificante/genética , Tetrazóis/farmacologia , Valsartana/farmacologia , Combinação de Medicamentos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Lipoproteínas LDL/farmacologia , NF-kappa B/metabolismo , RNA Longo não Codificante/metabolismo , Transdução de Sinais , Receptor 4 Toll-Like/metabolismo
10.
Eur J Pharmacol ; 894: 173851, 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33422508

RESUMO

Sacubitril/valsartan (Entresto™; LCZ696) is the first angiotensin receptor-neprilysin inhibitor (ARNI) drug approved by the US and EU for heart failure (HF) and especially recommended for hypertensive HF (HHF). Sacubitril inhibits the enzyme neprilysin (NEP) which produces both beneficial and adverse effects in the human body. While LCZ696 causes beneficial cardiovascular effects, it may induce memory and cognitive dysfunction, or even exacerbate Alzheimer's disease (AD). This article reviewed data reported by experimental and clinical studies that examined NEP inhibitors and their dementia-related side effects. Based on the literature, LCZ696 increases the risk of memory and cognitive dysfunctions, and clinical trials failed to show compelling evidence for LCZ696 safety for the brain. Together, it was concluded that more experimental and clinical studies with particular focus on LCZ696 side effects on ß-amyloid (Aß) degradation are needed to assess LCZ696 safety for the cognitive function, especially in case of long-term administration.


Assuntos
Encefalopatias/induzido quimicamente , Insuficiência Cardíaca/tratamento farmacológico , Hipertensão/tratamento farmacológico , Neprilisina/antagonistas & inibidores , Aminobutiratos/efeitos adversos , Aminobutiratos/farmacologia , Antagonistas de Receptores de Angiotensina/efeitos adversos , Antagonistas de Receptores de Angiotensina/farmacologia , Animais , Compostos de Bifenilo/efeitos adversos , Compostos de Bifenilo/farmacologia , Comprometimento Cognitivo Relacionado à Quimioterapia/metabolismo , Combinação de Medicamentos , Humanos , Valsartana/efeitos adversos , Valsartana/farmacologia
11.
Clin Hemorheol Microcirc ; 77(4): 425-433, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33386797

RESUMO

OBJECTIVE: The aim of the present study was to observe the effect of sacubitril valsartan on cardiac function and vascular endothelial function in patients with chronic heart failure with reduced ejection fraction (HFrEF). METHODS: A total of 80 patients with HFrEF were randomly divided into an observation group and a control group, with 40 patients in each group. Sacubitril valsartan was added to the conventional treatment in the observation group, and perindopril was added to the conventional treatment in the control group. Both groups were treated continuously for 12 weeks. The left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVEDD), flow-mediated vasodilatory function (FMD) of the brachial artery, and levels of plasma Ang II, endothelin 1 (ET-1), and calcitonin gene-related peptide (CGRP), together with the serum nitric oxide (NO) and NO synthase (NOS) were compared before and after treatment in the groups. RESULTS: Before the treatment, the levels of LVEF, LVEDD, FMD, Ang II, ET-1, CGRP, NO, and NOS in the observation group were not significantly different from those in the control group (P > 0.05). However, the levels of LVEF, FMD, CGRP, NO, and NOS in both groups were significantly higher after the treatment than those before the treatment (P < 0.05) and significantly higher in the observation group than those in the control group. The difference was statistically significant (P < 0.05). Meanwhile, the levels of LVEDD, Ang II, and ET-1 in both groups decreased significantly after the treatment (P < 0.05) and were significantly lower in the observation group than those in the control group. The difference was statistically significant (P < 0.05). CONCLUSION: Sacubitril valsartan might improve endothelial function while increasing cardiac function in HFrEF patients.


Assuntos
Aminobutiratos/uso terapêutico , Compostos de Bifenilo/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Volume Sistólico/efeitos dos fármacos , Valsartana/uso terapêutico , Função Ventricular Esquerda/efeitos dos fármacos , Idoso , Aminobutiratos/farmacologia , Compostos de Bifenilo/farmacologia , Combinação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Valsartana/farmacologia
12.
Ann Pharmacother ; 55(3): 378-389, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32698597

RESUMO

OBJECTIVE: Systematically review the evidence of sacubitril/valsartan initiated in the hospital setting prior to discharge in patients with acute decompensated heart failure (HF). DATA SOURCES: A literature search using keywords related to sacubitril/valsartan, HF, and inpatient use was performed using MEDLINE, CINAHL, and Google Scholar from inception through May 8, 2020. STUDY SELECTION AND DATA EXTRACTION: Eligible studies included patients initiated on sacubitril/valsartan while inpatient and reported efficacy and safety outcomes. DATA SYNTHESIS: A total of 10 articles were included for study review, of which 9 were full text and 1 was a conference poster. Key outcomes of interest were related to tolerability, N-terminal proB-type natriuretic peptide (NT-proBNP), functional capacity, target dose attainment, or rehospitalization rates. NT-proBNP levels were improved in 4 trials, and the results of functional capacity were mixed based on 2 studies. Rehospitalization rates were reported as secondary outcomes, and only 1 large study showed numerical and statistical improvement. The most frequent dose initiated prior to discharge was sacubitril/valsartan 24/26 mg twice daily. Hypotension was the most commonly reported adverse drug reaction and was commonly cited as a reason for not tolerating inpatient initiation with sacubitril/valsartan therapy. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Inpatient initiation of sacubitril/valsartan may improve surrogate and clinical outcomes after hemodynamic stabilization. Clinicians should consider patient-specific factors to ensure that benefits outweigh the risks and monitor for hypotension when initiated prior to hospital discharge. CONCLUSION: Initiating inpatient treatment with sacubitril/valsartan after hemodynamic stabilization is reasonable based on available evidence.


Assuntos
Aminobutiratos/uso terapêutico , Antagonistas de Receptores de Angiotensina/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Tetrazóis/uso terapêutico , Aminobutiratos/farmacologia , Antagonistas de Receptores de Angiotensina/farmacologia , Combinação de Medicamentos , Feminino , Humanos , Masculino , Alta do Paciente , Ensaios Clínicos Controlados Aleatórios como Assunto , Tetrazóis/farmacologia
13.
Ann Pharmacother ; 55(4): 480-495, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-32741197

RESUMO

OBJECTIVE: Discuss the literature and describe strategies to overcome barriers of inpatient initiation of sacubitril/valsartan in patients with heart failure with reduced ejection fraction (HFrEF). DATA SOURCES: A PubMed, EMBASE, and Google Scholar literature search (January 2014 to June 2020) limited to English language articles was conducted with the following terms: sacubitril/valsartan, initiation, inpatient, hospitalized, B-type natriuretic peptide (BNP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), diuretic, cost, and cost-effectiveness. STUDY SELECTION AND DATA EXTRACTION: Included articles described inpatient initiation of sacubitril/valsartan or described its impact on BNP, NT-proBNP, diuretic dosing, or cost of care. DATA SYNTHESIS: A total of 20 studies were identified based on included search terms. CONCLUSIONS: Sacubitril/valsartan should be considered for hemodynamically stable patients with HFrEF (New York Heart Association class II or III), potassium <5.2 mmol/L, without a history of angioedema, and after a 36-hour washout from angiotensin-converting enzyme (ACE) inhibitor or aliskiren, if applicable. An appropriate dose can be determined based on the patient's previous ACE inhibitor or angiotensin receptor blocker dose and/or blood pressure along with patient-specific factors. To overcome barriers of use, the following are recommended: NT-proBNP or BNP with establishment of a new baseline 1 month after initiation may be used for prognosis or diagnosis; careful monitoring of diuretic requirements; utilization of multiple strategies to overcome cost barriers; and use of interdisciplinary care.


Assuntos
Aminobutiratos/uso terapêutico , Antagonistas de Receptores de Angiotensina/uso terapêutico , Compostos de Bifenilo/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Hospitalização/tendências , Valsartana/uso terapêutico , Aminobutiratos/farmacologia , Antagonistas de Receptores de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Compostos de Bifenilo/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Ensaios Clínicos como Assunto/métodos , Combinação de Medicamentos , Insuficiência Cardíaca/sangue , Humanos , Pacientes Internados , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Volume Sistólico/efeitos dos fármacos , Volume Sistólico/fisiologia , Valsartana/farmacologia
14.
Curr Opin Nephrol Hypertens ; 30(1): 123-130, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33148948

RESUMO

PURPOSE OF REVIEW: Chronic kidney disease (CKD) is associated with increased risk of progression to end-stage kidney disease and cardiovascular events. There is limited evidence that available treatments have beneficial effects on cardiorenal outcomes in all people with nondiabetic CKD. Neprilysin inhibition (NEPi) is a new therapeutic strategy with potential to improve outcomes for patients with CKD. RECENT FINDINGS: NEPi enhances the activity of the natriuretic peptide system producing natriuresis, diuresis and inhibition of the renin-angiotensin system and sympathetic nervous system. Sacubitril/valsartan is the first Angiotensin receptor-neprilysin inhibitor (ARNI) to be produced and has been shown to substantially improve cardiovascular outcomes in heart failure and delay progression of kidney disease in this population. Although ARNIs have not shown similar effects on kidney function in the short-to-medium term in people with CKD, they are associated with substantial reductions in cardiac biomarkers and blood pressure in CKD. SUMMARY: These data suggest that NEPi with an ARNI could benefit patients with CKD by reducing the risk of cardiovascular disease and have the possibility of retarding the progression of CKD (hence delaying the need for renal replacement therapy).


Assuntos
Aminobutiratos/uso terapêutico , Antagonistas de Receptores de Angiotensina/uso terapêutico , Compostos de Bifenilo/uso terapêutico , Doenças Cardiovasculares , Neprilisina , Insuficiência Renal Crônica/tratamento farmacológico , Valsartana/uso terapêutico , Aminobutiratos/farmacologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Compostos Benzidrílicos/uso terapêutico , Compostos de Bifenilo/farmacologia , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/prevenção & controle , Doença Crônica , Modelos Animais de Doenças , Progressão da Doença , Combinação de Medicamentos , Glucosídeos/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/etiologia , Humanos , Camundongos , Peptídeos Natriuréticos/fisiologia , Neprilisina/antagonistas & inibidores , Neprilisina/fisiologia , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/diagnóstico , Sistema Renina-Angiotensina/efeitos dos fármacos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Valsartana/farmacologia
15.
Life Sci ; 266: 118877, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33310048

RESUMO

AIMS: Pulmonary hypertension (PH) is a fatal disease identified by progressive elevated pulmonary arterial pressure, which neurohormonal activation is a notable contributor to its development. Sacubitril/valsartan is a complex of sacubitril [via enhancing the natriuretic peptide (NP) system] and valsartan [via blocking the renin-angiotensin-aldosterone system (RAAS)]. Regulation of the two neurohormonal system had been shown to attenuate PH. This study was to explore the role of sacubitril/valsartan in both monocrotaline (MCT)-induced and hypoxia-induced rat models and the underlying mechanism. MAIN METHODS: The rats were treated with MCT or hypoxic environment for 14 days, after that sacubitril/valsartan were given for another 14 days. Hemodynamic measurements and histological assessments were performed. The expression of NPs was measured using RT-PCR and ELISA, while the protein level of natriuretic peptide receptors (NPRs) and AT1 receptor were detected by western blot, the concentrations of cGMP, IL-1ß, IL-6, TNF-α and TGF-ß1 were tested by ELISA. KEY FINDINGS: We found that sacubitril/valsartan significantly improved the hemodynamic and histological data of two PH models. Sacubitril/valsartan suppressed the protein expression of AT1 receptor (P < 0.05). The intervention increased the expression of ANP and CNP (P< 0.05) and therefore upregulated the protein expression of NPRs (P < 0.05), raised the concentration of cGMP (P < 0.05). In addition, the treatment reduced the concentration of IL-1ß, IL-6 and TNF-α (P < 0.05) but have no effects on TGF-ß1. SIGNIFICANCE: Sacubitril/valsartan alleviated PH in MCT-induced and hypoxia-induced rat models by inhibiting the activated RAAS, promoting ANP/NPR-A/cGMP and CNP/NPR-B/cGMP pathway, restoring the NPR-C signaling and the anti-inflammatory effects.


Assuntos
Aminobutiratos/farmacologia , Antagonistas de Receptores de Angiotensina/farmacologia , Modelos Animais de Doenças , Hipertensão Pulmonar/prevenção & controle , Hipóxia/fisiopatologia , Monocrotalina/toxicidade , Tetrazóis/farmacologia , Animais , Peso Corporal , Progressão da Doença , Combinação de Medicamentos , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/patologia , Masculino , Ratos , Ratos Sprague-Dawley
16.
Biomed Pharmacother ; 133: 110824, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33378988

RESUMO

BACKGROUND: LCZ696, an angiotensin receptor-neprilysin inhibitor (ARNi), is reported to play a cardioprotective role after acute myocardial infarction (AMI). Angiotensin-converting enzyme inhibitors(ACEIs) have similar roles. However, it is unclear whether the combination of the two drugs has a better protective effect. The purpose of this study was to investigate the effect of this combination therapy after AMI. METHODS: Male C57BL/6 J mice subjected to ligation of left anterior descending artery were treated for 4 weeks with LCZ696, ACEI(benazepril), or both(combination therapy) after induction of MI. Cardiac function, hemodynamics, and inflammatory factors were evaluated at 1 st day, 14th day, and 28th day. Heart weight and myocardial fibrosis were measured at the end of the experiment. RESULTS: Blood pressure was lower in all treatment groups than in the control group. The combination therapy group had the strongest antihypertensive effect. Compared with LCZ696 or benazepril, treatment with combination therapy increased ejection fraction, fractional shortening, and cardiac output and decreased N-terminal pro-B-type natriuretic peptide(NT-proBNP). The ratios of heart weight to body weight in all treatment groups were less than that in the control group. Compared with the control and LCZ696 group, the fibrotic area in the combination therapy group was suppressed and had a lower level of TGF-ß1 in the left ventricle. The plasma concentration of bradykinin and renin in the combination therapy group were highest among groups at 14th and 28th day. CONCLUSIONS: LCZ696 in combination with benazepril showed better positive effects in modulating heart failure and myocardial fibrosis after acute AMI in mice and affect some inflammatory markers.


Assuntos
Aminobutiratos/farmacologia , Antagonistas de Receptores de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Benzazepinas/farmacologia , Insuficiência Cardíaca/tratamento farmacológico , Contração Miocárdica/efeitos dos fármacos , Infarto do Miocárdio/complicações , Miocárdio/patologia , Inibidores de Proteases/farmacologia , Tetrazóis/farmacologia , Função Ventricular Esquerda/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Combinação de Medicamentos , Quimioterapia Combinada , Fibrose , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Mediadores da Inflamação/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Miocárdio/metabolismo , Neprilisina/antagonistas & inibidores , Renina/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
17.
Oxid Med Cell Longev ; 2020: 9815039, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33014281

RESUMO

Aims: We aimed to investigate whether LCZ696 protects against pathological cardiac hypertrophy by regulating the Sirt3/MnSOD pathway. Methods: In vivo, we established a transverse aortic constriction animal model to establish pressure overload-induced heart failure. Subsequently, the mice were given LCZ696 by oral gavage for 4 weeks. After that, the mice underwent transthoracic echocardiography before they were sacrificed. In vitro, we introduced phenylephrine to prime neonatal rat cardiomyocytes and small-interfering RNA to knock down Sirt3 expression. Results: Pathological hypertrophic stimuli caused cardiac hypertrophy and fibrosis and reduced the expression levels of Sirt3 and MnSOD. LCZ696 alleviated the accumulation of oxidative reactive oxygen species (ROS) and cardiomyocyte apoptosis. Furthermore, Sirt3 deficiency abolished the protective effect of LCZ696 on cardiomyocyte hypertrophy, indicating that LCZ696 induced the upregulation of MnSOD and phosphorylation of AMPK through a Sirt3-dependent pathway. Conclusions: LCZ696 may mitigate myocardium oxidative stress and apoptosis in pressure overload-induced heart failure by regulating the Sirt3/MnSOD pathway.


Assuntos
Aminobutiratos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Sirtuína 3/metabolismo , Superóxido Dismutase/metabolismo , Tetrazóis/farmacologia , Remodelação Ventricular/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Aminobutiratos/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Cardiomegalia/prevenção & controle , Combinação de Medicamentos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miocárdio/patologia , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Sirtuína 3/antagonistas & inibidores , Sirtuína 3/genética , Tetrazóis/uso terapêutico , Regulação para Cima/efeitos dos fármacos
18.
Int J Mol Sci ; 21(21)2020 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-33114537

RESUMO

BACKGROUND: The overexpression of neurotensin subtype 1 receptors (NTS1Rs) in human tumors may be elegantly exploited for directing neurotensin (NT)-based radionuclide carriers specifically to cancer sites for theranostic purposes. We have recently shown that [99mTc]Tc-DT1 ([99mTc]Tc-[N4-Gly7]NT(7-13)) and [99mTc]Tc-DT5 ([99mTc]Tc-[N4-ßAla7,Dab9]NT(7-13)) show notably improved uptake in human colon adenocarcinoma WiDr xenografts in mice treated with neprilysin (NEP) inhibitors and/or angiotensin-converting enzyme (ACE) inhibitors compared with untreated controls. Aiming toward translation of this promising approach in NTS1R-positive pancreatic ductal adenocarcinoma (PDAC) patients, we now report on the impact of registered NEP/ACE inhibitors on the performance of [99mTc]Tc-DT1 and [99mTc]Tc-DT5 in pancreatic cancer models. METHODS: The cellular uptake of [99mTc]Tc-DT1 and [99mTc]Tc-DT5 was tested in a panel of pancreatic cell lines, and their stability was assessed in mice treated or not treated with Entresto, lisinopril, or their combinations. Biodistribution was conducted in severe combined immunodeficiency (SCID) mice bearing pancreatic AsPC-1 xenografts. RESULTS: The Entresto + lisinopril combination maximized the metabolic stability of the fast-internalizing [99mTc]Tc-DT1 in mice, resulting in notably enhanced tumor uptake (7.05 ± 0.80% injected activity (IA)/g vs. 1.25 ± 0.80% IA/g in non-treated controls at 4 h post-injection; p < 0.0001). CONCLUSIONS: This study has shown the feasibility of optimizing the uptake of [99mTc]Tc-DT1 in pancreatic cancer models with the aid of clinically established NEP/ACE inhibitors, in favor of clinical translation prospects.


Assuntos
Carcinoma Ductal Pancreático/metabolismo , Neurotensina/química , Compostos de Organotecnécio/química , Neoplasias Pancreáticas/metabolismo , Peptídeos/administração & dosagem , Inibidores de Proteases/administração & dosagem , Receptores de Neurotensina/metabolismo , Aminobutiratos/administração & dosagem , Aminobutiratos/farmacologia , Animais , Linhagem Celular Tumoral , Combinação de Medicamentos , Estabilidade de Medicamentos , Humanos , Lisinopril/administração & dosagem , Lisinopril/farmacologia , Masculino , Camundongos , Camundongos SCID , Transplante de Neoplasias , Peptídeos/química , Peptídeos/farmacocinética , Inibidores de Proteases/farmacologia , Tetrazóis/administração & dosagem , Tetrazóis/farmacologia , Distribuição Tecidual
19.
Plant Physiol Biochem ; 156: 552-565, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33059266

RESUMO

Either NPR1 or TGA1 serve as master redox-sensitive transcriptional regulators for the transcription of PR genes in plants. The redox modification of the two co-activators involved in BABA-induced priming resistance against Botrytis cinerea in grapes was examined in this study. The results showed that 10 mmol L-1 BABA could effectively trigger a priming defense in grapes as manifested by augmented expression levels of PR genes upon inoculation with B. cinerea. Moreover, transcriptome profiling analysis revealed that all of the sets of key genes in the enzymatic ROS scavenging system, the PPP and AsA-GSH cycle were in harmony and were transcriptionally induced in BABA-primed grapes with pathogenic infection; in addition, this enhanced expression caused the accelerated accumulation of reductive substances, namely, AsA, GSH and NADPH, resulting in reduced intercellular conditions. Under reduced conditions, the interaction of VvTGA1 and VvNPR1 in the Y2H assay implied that VvTGA1 can provide the DNA binding capacity required by VvNPR1 for activation of VvPR genes. Consequently, the transactivation of VvNPR1 by the promoters of VvPR1, VvPR2 and VvPR5 was determined via a DLR assay, and it induced the transcription of the VvPR genes. In parallel, the redox-modified reducing condition achieved with an abundant supply of reductive substances was closely associated with the translocation of NPR1 for interaction with TGA in the nucleus. Thus, the posttranslational modification and subsequent interaction of the two redox-sensitive co-activators of VvNPR1 and VvTGA1 under reduced conditions may be responsible for BABA-induced priming for effective disease resistance in grapes.


Assuntos
Aminobutiratos/farmacologia , Fatores de Transcrição de Zíper de Leucina Básica/fisiologia , Botrytis/patogenicidade , Citrus paradisi/microbiologia , Doenças das Plantas/prevenção & controle , Proteínas de Plantas/fisiologia , Resistência à Doença , Humanos , Oxirredução , Doenças das Plantas/microbiologia
20.
Biomolecules ; 10(9)2020 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-32938014

RESUMO

A library of novel phosphonic acid analogues of homophenylalanine and phenylalanine, containing fluorine and bromine atoms in the phenyl ring, have been synthesized. Their inhibitory properties against two important alanine aminopeptidases, of human (hAPN, CD13) and porcine (pAPN) origin, were evaluated. Enzymatic studies and comparison with literature data indicated the higher inhibitory potential of the homophenylalanine over phenylalanine derivatives towards both enzymes. Their inhibition constants were in the submicromolar range for hAPN and the micromolar range for pAPN, with 1-amino-3-(3-fluorophenyl) propylphosphonic acid (compound 15c) being one of the best low-molecular inhibitors of both enzymes. To the best of our knowledge, P1 homophenylalanine analogues are the most active inhibitors of the APN among phosphonic and phosphinic derivatives described in the literature. Therefore, they constitute interesting building blocks for the further design of chemically more complex inhibitors. Based on molecular modeling simulations and SAR (structure-activity relationship) analysis, the optimal architecture of enzyme-inhibitor complexes for hAPN and pAPN were determined.


Assuntos
Aminobutiratos/síntese química , Antígenos CD13/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Fenilalanina/síntese química , Ácidos Fosforosos/síntese química , Bibliotecas de Moléculas Pequenas/síntese química , Aminobutiratos/farmacologia , Animais , Sítios de Ligação , Bromo/química , Antígenos CD13/química , Antígenos CD13/metabolismo , Inibidores Enzimáticos/farmacologia , Flúor/química , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/química , Isoenzimas/metabolismo , Cinética , Modelos Moleculares , Fenilalanina/análogos & derivados , Fenilalanina/farmacologia , Ácidos Fosforosos/farmacologia , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Estrutura-Atividade , Especificidade por Substrato , Suínos , Termodinâmica
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