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1.
Lancet ; 394(10216): 2263-2270, 2020 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-31836196

RESUMO

BACKGROUND: Irbesartan, a long acting selective angiotensin-1 receptor inhibitor, in Marfan syndrome might reduce aortic dilatation, which is associated with dissection and rupture. We aimed to determine the effects of irbesartan on the rate of aortic dilatation in children and adults with Marfan syndrome. METHODS: We did a placebo-controlled, double-blind randomised trial at 22 centres in the UK. Individuals aged 6-40 years with clinically confirmed Marfan syndrome were eligible for inclusion. Study participants were all given 75 mg open label irbesartan once daily, then randomly assigned to 150 mg of irbesartan (increased to 300 mg as tolerated) or matching placebo. Aortic diameter was measured by echocardiography at baseline and then annually. All images were analysed by a core laboratory blinded to treatment allocation. The primary endpoint was the rate of aortic root dilatation. This trial is registered with ISRCTN, number ISRCTN90011794. FINDINGS: Between March 14, 2012, and May 1, 2015, 192 participants were recruited and randomly assigned to irbesartan (n=104) or placebo (n=88), and all were followed for up to 5 years. Median age at recruitment was 18 years (IQR 12-28), 99 (52%) were female, mean blood pressure was 110/65 mm Hg (SDs 16 and 12), and 108 (56%) were taking ß blockers. Mean baseline aortic root diameter was 34·4 mm in the irbesartan group (SD 5·8) and placebo group (5·5). The mean rate of aortic root dilatation was 0·53 mm per year (95% CI 0·39 to 0·67) in the irbesartan group compared with 0·74 mm per year (0·60 to 0·89) in the placebo group, with a difference in means of -0·22 mm per year (-0·41 to -0·02, p=0·030). The rate of change in aortic Z score was also reduced by irbesartan (difference in means -0·10 per year, 95% CI -0·19 to -0·01, p=0·035). Irbesartan was well tolerated with no observed differences in rates of serious adverse events. INTERPRETATION: Irbesartan is associated with a reduction in the rate of aortic dilatation in children and young adults with Marfan syndrome and could reduce the incidence of aortic complications. FUNDING: British Heart Foundation, the UK Marfan Trust, the UK Marfan Association.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Aorta/diagnóstico por imagem , Irbesartana/administração & dosagem , Síndrome de Marfan/tratamento farmacológico , Adolescente , Adulto , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Aorta/efeitos dos fármacos , Criança , Método Duplo-Cego , Esquema de Medicação , Ecocardiografia , Feminino , Humanos , Irbesartana/farmacologia , Masculino , Síndrome de Marfan/diagnóstico por imagem , Resultado do Tratamento , Reino Unido , Adulto Jovem
2.
Acta Biochim Biophys Sin (Shanghai) ; 52(1): 38-48, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31836883

RESUMO

Obstructive sleep apnea is characterized by chronic intermittent hypoxia (CIH), which is a risk factor for renal peritubular capillary (PTC) loss, and angiotensin II receptor blockers can alleviate PTC loss. However, the mechanism by which losartan (an angiotensin II receptor blocker) reduces CIH-induced PTC loss and attenuates kidney damage is still unknown. Thus, in this study, we examined the protective effects of losartan against CIH-induced PTC loss and explored the underlying mechanisms in rat CIH model. The immunohistochemical staining of CD34 and morphological examination showed that CIH reduced PTC density and damaged tubular epithelial cells. Immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), real-time quantitative PCR, and western blot analysis results revealed that CIH increased the expression of hypoxia inducible factor-1α (HIF-1α), angiotensin II (Ang II), angiotensin II type 1 receptor (AT1R), pro-angiogenesis factor vascular endothelial growth factor (VEGF), and anti-angiogenesis factor thrombospondin-1 (TSP-1) in the renal cortex of rats. CIH may up-regulate VEGF expression and simultaneously increase TSP-1 production. By histopathological, immunohistochemistry, ELISA, RT-qPCR, and western blot analysis, we found that the expressions of renal renin-angiotensin system (RAS), HIF-1α, VEGF, and TSP-1 were decreased, and PTC loss and tubular epithelial cell injury were attenuated with losartan treatment. Losartan ameliorated CIH-induced PTC loss by modulating renal RAS to improve the crosstalk between endothelial cells and tubular epithelial cells and subsequently regulate the balance of angiogenesis factors. Our study provided novel insights into the mechanisms of CIH-induced kidney damage and indicated that losartan could be a potential therapeutic agent for renal protection by alleviating CIH-induced PTC loss.


Assuntos
Indutores da Angiogênese/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Capilares/patologia , Hipóxia/complicações , Losartan/farmacologia , Substâncias Protetoras/farmacologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Angiotensina II/sangue , Animais , Peso Corporal/efeitos dos fármacos , Creatinina/sangue , Células Epiteliais/efeitos dos fármacos , Hipóxia/etiologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Córtex Renal/irrigação sanguínea , Córtex Renal/metabolismo , Masculino , Ratos , Ratos Wistar , Receptor Tipo 1 de Angiotensina/metabolismo , Apneia Obstrutiva do Sono/complicações , Trombospondina 1/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
3.
Int Heart J ; 61(1): 1-6, 2020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-31875616

RESUMO

Chronic heart failure (CHF) seriously affects the quality of patients' lives. Sacrubitril/valsartan is a combination angiotensin receptor-neprilysin inhibitor, a new therapeutic drugs to treat CHF.This study aims to observe the impact of sacrubitril/valsartan on clinical treatment and high-sensitivity cardiac troponin T (hs-cTnT), N-terminal pro-brain natriuretic peptide (NT-ProBNP) serum levels, the improvement of the left atrial diameter (LAD) and left ventricular end diastolic dimension (LVEDD), and the left ventricular ejection fraction (LVEF) in patients with CHF.120 patients were randomly divided into a sacrubitil/valsartan group and a valsantan group, with 60 cases in each. Patients in the sacrubitil/valsartan group were administered sacrubitril/valsartan; while in the valsantan group, they were administered valsartan. The clinical effects, adverse reactions, and rehospitalization were observed eight weeks later, and hs-cTnT and NT-ProBNP serum levels and LAD, LVEDD, and LVEF were assayed.There were 53 cases of positive effect in the sacrubitil/valsartan group and 42 in the valsartan group (P < 0.05). Eight participants demonstrated adverse reactions in the sacrubitil/valsartan group, while 17 in the control group (P < 0.05). Hs-cTnT and NT-ProBNP serum levels, the measurements of LAD, LVEDD, and LVEF in the sacrubitil/valsartan group before the treatments were (24.47 ± 7.54) pg/mL, (10,356.94 ± 5,447.68) pg/mL, (49.41 ± 5.22) mm, (68.06 ± 6.20) mm and (31.12 ±6.65) %; in the valsartan group were (29.752 ± 10.03) pg/mL, (9,518.17 ± 5,905.17) pg/mL, (49.65 ± 4.91) mm, (67.06 ± 3.97) mm, and (30.41 ± 6.11) % (P > 0.05), while in the sacrubitil/valsartan group, the values decreased after the treatments to (17.92 ± 4.74) pg/mL, (3,881.59 ± 2,087.79) pg/mL, (42.18 ± 4.87) mm, (60.35 ± 7.12) mm and (45.35 ± 4.49) %; in the valsartan group to (25.81 ± 7.36) pg/mL, (6,278.35 ± 2,643.11) pg/mL, (46.53 ± 4.80) mm, (64.51 ± 4.34) mm, and (36.47 ± 5.21) % (P < 0.05). There were significant differences within the same group, before and after treatments (P < 0.05).Sacrubitril/valsartan treatment of patients with CHF improves their symptoms and is deserving of clinical application. This is also evident from significantly improved levels of serum hs-cTnT and NT-ProBNP and the left ventricular function.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Troponina T/sangue , Valsartana/uso terapêutico , Função Ventricular Esquerda/efeitos dos fármacos , Idoso , Idoso de 80 Anos ou mais , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Biomarcadores/sangue , Doença Crônica , Combinação de Medicamentos , Quimioterapia Combinada , Feminino , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Valsartana/farmacologia
4.
Biochemistry (Mosc) ; 84(12): 1442-1450, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31870248

RESUMO

The theories interpreting senescence as a phenomenon favored by natural selection require the existence of specific, genetically determined and regulated mechanisms that cause a progressive age-related increase in mortality. The mechanisms defined in the subtelomere-telomere theory suggest that progressive slackening of cell turnover and decline in cellular functions are determined by the subtelomere-telomere-telomerase system, which causes a progressive "atrophic syndrome" in all organs and tissues. If the mechanisms underlying aging-related dysfunctions are similar and having the same origin, it could be hypothesized that equal interventions could produce similar effects. This article reviews the consequences of some factors (diabetes, obesity/dyslipidemia, hypertension, smoking, moderate use and abuse of alcohol) and classes of drugs [statins, angiotensin-converting enzyme (ACE) inhibitors, sartans] in accelerating and anticipating or in counteracting the process of aging. The evidence is compatible with the programmed aging paradigm and the mechanisms defined by the subtelomere-telomere theory but it has no obvious discriminating value against the theories of non-programmed aging paradigm. However, the existence of mechanisms, determined by the subtelomere-telomere-telomerase system and causing a progressive age-related decline in fitness through gradual cell senescence and cell senescence, is not justifiable without an evolutionary motivation. Their existence is expected by the programmed aging paradigm, while is incompatible with the opposite paradigm.


Assuntos
Envelhecimento/patologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Modelos Teóricos , Fatores de Risco , Telômero/efeitos dos fármacos
5.
Life Sci ; 237: 116890, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31606379

RESUMO

AIMS: Telmisartan (TEL), an angiotensin II type I receptor blocker and PPARγ partial agonist, has been used for to treat hypertension. It is known that PPARγ activation induces bone loss. Therefore, we evaluate the effects of telmisartan on PPARγ protein expression, biomechanics, density and bone microarchitecture of femurs and lumbar vertebrae in SHR ovariectomized animals, a model of hypertension in which preexisting bone impairment has been demonstrated. MAIN METHODS: SHR females (3 months old) were distributed into four groups: sham (S), sham + TEL (ST), OVX (C) and OVX + TEL (CT). TEL (5 mg/kg/day) or vehicle were administered according to the groups. After the protocol, blood pressure was measured and density, microarchitecture and biomechanics of bone were analyzed. Western blotting analysis was performed to evaluate PPARγ protein expression in the bones. KEY FINDINGS: Castration induced a deleterious effect on mineral density and trabecular parameters, with telmisartan enhancing such effects. Telmisartan increased PPARγ levels, which were at their highest when the treatment was combined with castration. As to biomechanical properties, telmisartan reduced the stiffness in the castration group (CT vs. S or C group), as well as resilience and failure load in ST group (vs. all others groups). SIGNIFICANCE: These results demonstrated that telmisartan compromised bone density and microarchitecture in animals that shows preexisting osteoporotic bone disorders, probably via mechanisms associated with increased PPARγ. If this translates to humans, a need for greater caution in the use of telmisartan by patients that have preexisting bone problems, as in the postmenopausal period, may be in order.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Doenças Ósseas/tratamento farmacológico , Osso Esponjoso/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Osteoporose/tratamento farmacológico , PPAR gama/metabolismo , Telmisartan/farmacologia , Animais , Densidade Óssea/efeitos dos fármacos , Doenças Ósseas/metabolismo , Doenças Ósseas/fisiopatologia , Osso Esponjoso/diagnóstico por imagem , Osso Esponjoso/patologia , Feminino , Osteoporose/metabolismo , Osteoporose/fisiopatologia , PPAR gama/genética , Ratos , Ratos Endogâmicos SHR , Tomografia Computadorizada por Raios X
6.
Pharmacol Rev ; 71(4): 539-570, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31537750

RESUMO

Despite the success of renin-angiotensin system (RAS) blockade by angiotensin-converting enzyme (ACE) inhibitors and angiotensin II type 1 receptor (AT1R) blockers, current therapies for hypertension and related cardiovascular diseases are still inadequate. Identification of additional components of the RAS and associated vasoactive pathways, as well as new structural and functional insights into established targets, have led to novel therapeutic approaches with the potential to provide improved cardiovascular protection and better blood pressure control and/or reduced adverse side effects. The simultaneous modulation of several neurohumoral mediators in key interconnected blood pressure-regulating pathways has been an attractive approach to improve treatment efficacy, and several novel approaches involve combination therapy or dual-acting agents. In addition, increased understanding of the complexity of the RAS has led to novel approaches aimed at upregulating the ACE2/angiotensin-(1-7)/Mas axis to counter-regulate the harmful effects of the ACE/angiotensin II/angiotensin III/AT1R axis. These advances have opened new avenues for the development of novel drugs targeting the RAS to better treat hypertension and heart failure. Here we focus on new therapies in preclinical and early clinical stages of development, including novel small molecule inhibitors and receptor agonists/antagonists, less conventional strategies such as gene therapy to suppress angiotensinogen at the RNA level, recombinant ACE2 protein, and novel bispecific designer peptides.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Insuficiência Cardíaca/tratamento farmacológico , Hipertensão/tratamento farmacológico , Sistema Renina-Angiotensina/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Hipertensão/fisiopatologia , Terapia de Alvo Molecular
7.
Neuropeptides ; 77: 101960, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31474309

RESUMO

To assess the effects of central administration of losartan, an antagonist of angiotensin II AT1 receptors, on cardiovascular function during aerobic exercise, heart rate, systolic and diastolic arterial pressures and rate pressure product of Wistar rats were measured as cardiac workload indexes. The animals ran on a treadmill until fatigue after an intracerebroventricular injection of losartan or saline. Pulsatile arterial pressure was recorded by a catheter implanted into the ascending aorta, from which were derived cardiovascular parameters to estimate the cardiac workload. Total exercise time and exercise workload were determined as performance indexes. The rats showed a more intense increase in heart rate after 8 min of exercise and sustained until fatigue (P < .05). Furthermore, the rats injected with losartan had a higher increase of both systolic and diastolic arterial pressures as well as rate pressure product from approximately 6 min of exercise until fatigued (P < .05). In addition, a 22% reduction in exercise time was found in losartan-rats (P < .01). This ergolytic effect induced by losartan was strongly inversely correlated with rate-pressure product during aerobic exercise (r = 0.78, P ≤ .01). The data shows that central administration of losartan augments the cardiac workload during aerobic exercise, which courses in parallel with the reduced exercise performance.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Losartan/administração & dosagem , Condicionamento Físico Animal/fisiologia , Animais , Pressão Sanguínea/fisiologia , Frequência Cardíaca/fisiologia , Masculino , Ratos , Ratos Wistar
8.
Anticancer Res ; 39(9): 4597-4602, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519556

RESUMO

Our previous review of the literature assessed the existing knowledge (until 2000) about the possible link between angiotensin-converting enzyme inhibitors (ACEIs) and factors influencing the development of malignancies. We reviewed the literature for reports of statistical associations (or lack thereof) between ACEi treatment and incidence of specific cancers (e.g. breast, gastrointestinal, and skin). We concluded then that results from the epidemiological studies are conflicting, even taking the different methodology and endpoints into consideration, and thus inconclusive. Further investigation is needed beyond the observation period of most of these studies, and additional experimental studies are needed also to study the mechanisms by which agents blocking the renin-angiotensin system may obtain their inhibitory effect on tumor growth and metastasis. The present review elaborates further with more recent evidence from numerous human clinical studies from the past two decades (including large epidemiological studies, and long-term prospective and retrospective studies) on a protective association between ACEi treatment and the prognosis of patients with specific cancer types, malignancy characteristics or stage. Moreover, treatment with ACEI/angiotensin receptor blockers represents an adjuvant therapy with synergistic effects to chemotherapy and may improve patient outcomes (i.e. progression-free survival, and prolonged overall survival) in different types of cancers.


Assuntos
Neoplasias/metabolismo , Neoplasias/mortalidade , Sistema Renina-Angiotensina/efeitos dos fármacos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estudos Clínicos como Assunto , Modelos Animais de Doenças , Progressão da Doença , Humanos , Estadiamento de Neoplasias , Neoplasias/diagnóstico , Neoplasias/etiologia , Prognóstico , Resultado do Tratamento
9.
Eur J Med Chem ; 181: 111553, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31369932

RESUMO

A series of new 6-substituted aminocarbonyl benzimidazole derivatives with 1, 4-disubsituted or 1, 5-disubsituted indole moiety and benzoic acid moiety were designed, synthesized and pharmacologically evaluated. Most of the synthesized compounds could bind to the AT1 receptor and decrease blood pressure significantly. Notably, 2e and 1h could obviously decrease MBP in a dose dependent manner. The maximal response lowered 57.9 ±â€¯2.3 mmHg (2e) and 57.6 ±â€¯1.9 mmHg (1h) of MBP at 10 mg/kg after oral administration, and the antihypertensive effect lasted beyond 24 h, which performed better than Losartan (Fig. 1). These results indicate that 2e and 1h are effective and long-lasting anti-hypertension drug candidates and deserve further investigation for therapeutic application.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Benzimidazóis/farmacologia , Desenho de Drogas , Receptor Tipo 1 de Angiotensina/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II/síntese química , Bloqueadores do Receptor Tipo 1 de Angiotensina II/química , Animais , Benzimidazóis/síntese química , Benzimidazóis/química , Relação Dose-Resposta a Droga , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
10.
Eur J Pharmacol ; 860: 172585, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31376367

RESUMO

We previously reported that neonatal blockade of angiotensin II AT1 receptor prevents cardiac changes in 4 weeks rats with neonatal hyperoxia-induced cardiomyopathy, a recognized model of prematurity-related deleterious conditions. Considering the importance of AT1 receptor and the renin angiotensin system (RAS) in normal development, the present study aimed to investigate the adult effects of neonatal AT1 blockade on left ventricle (LV) in rats exposed to neonatal hyperoxia. Sprague-Dawley pups were exposed to 80% O2 or room air from days 3-10. AT1 blocker (losartan) or H2O were given by gavage from day 8-10. LV function (echo and intraventricular pressure), histology and expression of RAS components were examined in 15-16 weeks old adult males. Losartan treatment prevented myocardial fibrosis, LV wall thickening and stroke volume reduction in rats exposed to high O2 in the neonatal period. However, Losartan treatment of O2-exposed pups led to reduced ejection fraction (EF) and fractional shortening (FS), and did not prevent changes in diastolic function. Losartan also did not prevent increased LV AT2 and decreased angiotensin-(1-7) Mas receptors expression observed in high O2-exposed rats. Neonatal Losartan attenuated long-term impact of neonatal hyperoxia but also led to decreased EF and FS. Increased AT2 and decreased Mas receptor expression observed in O2-exposed group were unaffected by Losartan treatment. Our results show that early life Losartan treatment aimed at preventing cardiac consequences of neonatal deleterious conditions may also comprise detrimental effects that require further investigation prior to clinical translation in developing children.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Cardiomiopatias/patologia , Cardiomiopatias/fisiopatologia , Coração/efeitos dos fármacos , Oxigênio/efeitos adversos , Receptor Tipo 1 de Angiotensina/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Biomarcadores/metabolismo , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/metabolismo , Diástole/efeitos dos fármacos , Modelos Animais de Doenças , Fibrose , Coração/fisiopatologia , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/metabolismo , Losartan/farmacologia , Miocárdio/patologia , Ratos , Ratos Sprague-Dawley , Sístole/efeitos dos fármacos , Fatores de Tempo
11.
Hypertension ; 74(4): 1014-1020, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31378099

RESUMO

Obesity-related hypertension is a major public health concern. We recently demonstrated that plasma levels of the soluble form of the prorenin receptor (sPRR) were elevated in obesity-associated hypertension. Therefore, in the present study, we investigated the contribution of sPRR to blood pressure (BP) elevation in the context of obesity. High fat-fed C57BL/6 male mice were infused with vehicle or sPRR (30 µg/kg per day) via subcutaneously implanted osmotic minipump for 4 weeks. BP parameters were recorded using radiotelemetry devices. Male mice infused with sPRR exhibited higher systolic BP and mean arterial pressure and lower spontaneous baroreflex sensitivity than mice infused with vehicle. To define mechanisms involved in systolic BP elevation, mice were injected with an AT1R (Ang II [angiotensin II] type 1 receptor) antagonist (losartan), a muscarinic receptor antagonist (atropine), a ß-adrenergic antagonist (propranolol), and a ganglionic blocker (chlorisondamine). Losartan did not blunt sPRR-induced elevation in systolic BP. Chlorisondamine treatment exacerbated the decrease in mean arterial pressure in male mice infused with sPRR. These results demonstrated that sPRR induced autonomic nervous dysfunction. Interestingly, plasma leptin levels were increased in high fat-fed C57BL/6 male mice infused with sPRR. Overall, our results indicated that sPRR increased systolic BP through an impairment of the baroreflex sensitivity and an increase in the sympathetic tone potentially mediated by leptin in high fat-fed C57BL/6 male mice.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Dieta Hiperlipídica , Receptores de Superfície Celular/administração & dosagem , Antagonistas Adrenérgicos beta/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Atropina/farmacologia , Barorreflexo/efeitos dos fármacos , Clorisondamina/farmacologia , Bloqueadores Ganglionares/farmacologia , Infusões Subcutâneas , Leptina/sangue , Losartan/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Antagonistas Muscarínicos/farmacologia , Propranolol/farmacologia
12.
Life Sci ; 234: 116792, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31465733

RESUMO

AIMS: Assisted reproductive technologies (ART) have been widely used to treat infertility, which may impact on fetuses and offspring. This study investigated the effects of in vitro fertilization-embryo transfer (IVF-ET) on angiotensin II (AII)-mediated vasoconstrictions in umbilical cord vein, and explored possible reprogrammed methylation mechanism. MATERIALS AND METHODS: Human umbilical cords were randomly divided into ordinary pregnancy and IVF-ET pregnancy. Vascular studies with AII as well as its specific receptor antagonists losartan and PD123,319 were conducted. Real-time quantitative PCR, Western blotting, and methylation analysis by bisulfite sequencing were performed with the cord vessel samples. KEY FINDINGS: In IVF-ET group, the maximal response to AII in umbilical vessels was significantly greater than that in the ordinary pregnancy. Using losartan and PD123,319, angiotensin receptor subtype 1 (AT1R) was found mainly responsible for the enhanced contraction in the umbilical vein of IVF-ET pregnancy. Decreased mRNA expression of DNMT3A was found in umbilical vein of IVF-ET group. Hypomethylation of the AGTR1 gene (gene encoding AT1R) in the umbilical veins of the IVF group was found. The data suggested that the IVF-ET treatments altered AII-mediated vasoconstrictions in umbilical veins, which could be partially attributed to the increased expression of AT1R. SIGNIFICANCE: The hypo-methylation of the AGTR1 gene caused by IVF-ET might play important roles in altered vasoconstrictions, impacting on cardiovascular systems in the long run.


Assuntos
Angiotensina II/metabolismo , Metilação de DNA , Transferência Embrionária/métodos , Fertilização In Vitro/métodos , Receptor Tipo 1 de Angiotensina/genética , Cordão Umbilical/irrigação sanguínea , Vasoconstrição , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 2 de Angiotensina II/farmacologia , Anti-Hipertensivos/farmacologia , Transferência Embrionária/efeitos adversos , Feminino , Fertilização In Vitro/efeitos adversos , Humanos , Imidazóis/farmacologia , Losartan/farmacologia , Gravidez , Piridinas/farmacologia , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologia
13.
Plast Reconstr Surg ; 144(5): 803e-813e, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31385893

RESUMO

BACKGROUND: Angiotensin II engagement of angiotensin II type 1 receptor (AT1R) is implicated in fibrogenesis, with AT1R blockers used clinically to attenuate cardiac and renal fibrosis. The authors tested the hypothesis that the AT1R blocker losartan could reduce postsurgical cutaneous scarring in rats. METHODS: Human dermal fibroblasts were treated with losartan and assessed for viability, contractile activity, migration, and profibrotic gene transcription by means of calcein, collagen gel, scratch, and quantitative reverse transcriptase polymerase chain reaction assays, respectively. Monocyte migration and adhesion to losartan-treated and control fibroblasts were examined. Losartan effects in vivo were assessed using a mechanical distraction hypertrophic scar model. Three days after incisions were made and closed on their backs, rats were assigned randomly to receive drinking water with or without losartan (1 mg/kg per day; n = 6 per group). Distraction devices were applied and activated up to day 14. On day 28, scars underwent cross-sectional area and elevation index analyses, and α-SMA (alpha-smooth muscle actin) and CD68 (monocyte/macrophage marker) immunostaining. RESULTS: Losartan-treated human dermal fibroblasts displayed decreased contractile activity, migration, and gene expression of transforming growth factor-ß1, collagen I, and monocyte chemoattractant protein-1 relative to controls (p < 0.05). Monocyte migration and adhesion to losartan-treated fibroblasts were reduced (p < 0.01). Compared to controls, scars from losartan-treated rats demonstrated decreased cross-sectional area (19.4 ± 3.1 mm versus 45.0 ± 5.2 mm; p = 0.002), elevation index (1.5 ± 0.1 versus 2.6 ± 0.3; p = 0.003), and α-SMA and CD68 immunostaining (p < 0.001). CONCLUSIONS: Losartan decreases myofibroblast activity and reduces monocyte trafficking to cutaneous scar. These findings support losartan as a potential novel therapy for the prevention of hypertrophic scars.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Cicatriz Hipertrófica/prevenção & controle , Fibroblastos/efeitos dos fármacos , Losartan/farmacologia , Miofibroblastos/efeitos dos fármacos , Receptor Tipo 1 de Angiotensina/efeitos dos fármacos , Animais , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Fibroblastos/fisiologia , Humanos , Miofibroblastos/citologia , Distribuição Aleatória , Ratos , Receptor Tipo 1 de Angiotensina/metabolismo , Valores de Referência , Sensibilidade e Especificidade
14.
Int J Mol Sci ; 20(13)2019 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-31261874

RESUMO

Esophageal squamous cell carcinoma (ESCC) is the most common primary esophageal malignancy. Telmisartan, an angiotensin II type 1 (AT1) receptor blocker (ARB) and a widely used antihypertensive, has been shown to inhibit proliferation of various cancer types. This study evaluated the effects of telmisartan on human ESCC cell proliferation in vitro and in vivo and sought to identify the microRNAs (miRNAs) involved in these antitumor effects. We examined the effects of telmisartan on three human ESCC cell lines (KYSE150, KYSE180, and KYSE850). Telmisartan inhibited proliferation of these three cell lines by inducing S-phase arrest, which was accompanied by decreased expression of cyclin A2, cyclin-dependent kinase 2, and other cell cycle-related proteins. Additionally, telmisartan reduced levels of phosphorylated ErbB3 and thrombospondin-1 in KYSE180 cells. Furthermore, expression of miRNAs was remarkably altered by telmisartan in vitro. Telmisartan also inhibited tumor growth in vivo in a xenograft mouse model. In conclusion, telmisartan inhibited cell proliferation and tumor growth in ESCC cells by inducing cell-cycle arrest.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Neoplasias Esofágicas/tratamento farmacológico , Fase S/efeitos dos fármacos , Telmisartan/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Animais , Linhagem Celular Tumoral , Ciclina A2/genética , Ciclina A2/metabolismo , Quinase 2 Dependente de Ciclina/genética , Quinase 2 Dependente de Ciclina/metabolismo , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Receptor ErbB-3/genética , Receptor ErbB-3/metabolismo , Telmisartan/uso terapêutico , Trombospondina 1/genética , Trombospondina 1/metabolismo
15.
Int Immunopharmacol ; 75: 105750, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31330445

RESUMO

Telmisartan, widely prescribed for the treatment of hypertension, has an anti-inflammatory property in addition to being an angiotensin II type 1 receptor antagonist. This study was carried out to explore the influence of telmisartan upon the elaboration of inflammatory mediators in murine macrophages stimulated with lipopolysaccharide (LPS) prepared from Prevotella intermedia, a periodontal pathogen, as well as its molecular mechanisms. Telmisartan significantly inhibited LPS-induced generation of inducible nitric oxide (NO) synthase-derived NO and interleukin-1ß (IL-1ß) as well as their gene expressions in RAW264.7 cells. Telmisartan treatment of LPS-activated cells significantly up-regulated arginase 1 (Arg-1) and chitinase-like 3 (Ym-1), which are specific markers of M2 macrophages. Telmisartan caused a significant increase in heme oxygenase-1 (HO-1) expression in cells stimulated with LPS, and its inhibitory action against NO production was reversed by treatment with SnPP, an HO-1 inhibitor. Phosphorylation of STAT1 and STAT3 induced by LPS was attenuated by telmisartan. Telmisartan inhibited LPS-induced generation of NO and IL-1ß independently of PPAR-γ activation. In addition, activation of NF-κB as well as JNK and p38 signaling induced by LPS was not modulated by telmisartan. In summary, telmisartan is a potent inhibitor of P. intermedia LPS-induced generation of NO and IL-1ß in RAW264.7 cells and promotes macrophage phenotype switching toward the M2 phenotype. Telmisartan may have potential to be developed into host modulatory agent for inflammatory periodontal disease, although additional studies are needed to confirm the therapeutic effect.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Anti-Inflamatórios/farmacologia , Interleucina-1beta/imunologia , Óxido Nítrico/imunologia , Prevotella intermedia , Telmisartan/farmacologia , Animais , Heme Oxigenase-1/genética , Heme Oxigenase-1/imunologia , Interleucina-1beta/genética , Lipopolissacarídeos , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Camundongos , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/imunologia , Células RAW 264.7
16.
Eur J Med Chem ; 179: 623-633, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31279295

RESUMO

Fibrosis is a final pathological feature of many chronic diseases, but few interventions are available that specifically target the pathogenesis of fibrosis. The highlights of common cellular and molecular mechanisms of fibrosis facilitate the discovery of effective antifibrotic drugs. The renin-angiotensin system (RAS) plays a central physiological role in the control of blood pressure and fluid homeostasis. Emerging evidence has revealed that activation of RAS was consistently found in fibrotic tissue. At the same time, as more components of the RAS are described, other pot Potential therapeutic targets emerge, so it seems sensible to revisit the contribution of RAS in anti-fibrotic therapy. So far, angiotensin converting enzyme inhibitors (ACEI) and angiotensin II type 1 receptor blockers (ARB) are the main commercial available drugs for intervening RAS. However, RAS inhibitors had lots of limitations in long-term application owing to occurring AngII and aldosterone escape. Over the past decades, natural products have aroused growing attention as potential RAS inhibitors due to their high efficacy and low risk of side effects. In this review, we revisit the contribution of RAS and its new members to anti-fibrotic therapy. Ultimately, we summarize and evaluate the use of natural products including isolated compounds, crude extracts and traditional Chinese herbal formulas to regulate RAS. These natural products can retard tissue fibrosis by targeting different RAS components, which provide us new therapeutic strategies to discover anti-fibrotic drugs.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Produtos Biológicos/farmacologia , Fibrose/tratamento farmacológico , Sistema Renina-Angiotensina/efeitos dos fármacos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/química , Inibidores da Enzima Conversora de Angiotensina/química , Produtos Biológicos/química , Relação Dose-Resposta a Droga , Estrutura Molecular , Relação Estrutura-Atividade
17.
Cardiology ; 143(1): 1-10, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31307032

RESUMO

The aberrant proliferation and migration of vascular smooth muscle cells (VSMCs) in the vascular wall are crucial pathological events involved in cardiovascular impairments including hypertension, heart failure, and atherosclerosis. At the molecular level, the mammalian target of rapamycin (mTOR)-ribosomal protein S6 kinase beta-1 (p70S6K) signaling pathway is essential to potentiate VSMC proliferation and migration. Although angiotensin II receptor type 1 -(AT1-R) antagonists such as valsartan and telmisartan have a significant cardiovascular protective effect, the molecular basis of this class of drugs in VSMC proliferation and migration remains elusive. By using cultured VSMCs, adenosine monophosphate-activated protein kinase (AMPK) α2 knockout mice, and hypertensive rat models, this study investigated whether AT1-R antagonists can inhibit the mTOR-p70S6K signaling pathway in VSMCs and the vascular wall. Valsartan activated AMPK, which in turn suppressed reactive oxygen species production and consequently attenuated VSMC proliferation and migration. In vivo, a clinical dose of telmisartan significantly inhibited the mTOR-p70S6K signaling pathway in the vascular wall of wild-type but not AMPKα2-/- mice. Furthermore, spontaneously hypertensive rats had significantly elevated phosphorylation of mTOR and p70S6K in the aorta compared to Wistar-Kyoto rats, which were reduced by telmisartan administration. These data suggest that AT1-R antagonists inhibit VSMC proliferation and migration via their regulation of AMPK, mTOR, and p70S6K, which contribute to the cardioprotective effects of these drugs.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Músculo Liso Vascular/citologia , Serina-Treonina Quinases TOR/metabolismo , Animais , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Camundongos Knockout , Músculo Liso Vascular/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fosforilação , Ratos Endogâmicos SHR , Ratos Wistar , Proteínas Quinases S6 Ribossômicas 70-kDa , Transdução de Sinais/efeitos dos fármacos , Telmisartan/farmacologia , Valsartana/farmacologia
18.
Eur J Pharmacol ; 859: 172519, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31271743

RESUMO

Juvenile Paget disease (JPD1), an autosomal-recessive disorder, is characterized by extremely rapid bone turnover due to osteoprotegerin deficiency. Its extra-skeletal manifestations, such as hypertension and heart failure, suggest a pathogenesis with shared skeletal and cardiovascular system components. In spite of this, the effects of anti-hypertensive drugs on bone morphometry remain unknown. We administered an angiotensin II type 1 receptor blocker, olmesartan (5 mg/kg/day) to 8-week-old male mice lacking the osteoprotegerin gene, with and without 1 µg/kg/min of angiotensin II infusion for 14 days. Olmesartan treatment decreased systolic blood pressure, and echocardiography showed increased left ventricular systolic contractility. Three-dimensional micro-computed tomography scans demonstrated that olmesartan treatment increased trabecular bone volume (sham, +176%; angiotensin II infusion, +335%), mineral density (sham, +150%; angiotensin II infusion, +313%), and trabecular number (sham, +407%; angiotensin II infusion, +622%) in the tibia. Olmesartan increased cortical mineral density (sham, +19%; angiotensin II infusion, +24%), decreased the cortical bone section area (sham, -16%; angiotensin II infusion, -18%), decreased thickness (sham, -18%; angiotensin II infusion, -31%), and decreased the lacunar area (sham, -41%; angiotensin II infusion, -27%) in the tibia. Similar trend was observed in the femur. Moreover, olmesartan decreased angiotensin II-induced increases in tartrate-resistant acid phosphatase concentrations in plasma, but it affected neither type I procollagen N-terminal propeptides, nor the receptor activator of nuclear factor kappa-B ligand. Our data suggest that blockade of the angiotensin II type 1 receptor improves bone vulnerability, and helps to maintain the heart's structural integrity in osteoprotegerin-deficient mice.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Densidade Óssea/efeitos dos fármacos , Contração Miocárdica/efeitos dos fármacos , Osteíte Deformante/tratamento farmacológico , Osteíte Deformante/fisiopatologia , Disfunção Ventricular Esquerda/tratamento farmacológico , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Animais , Pressão Sanguínea/efeitos dos fármacos , Modelos Animais de Doenças , Fêmur/efeitos dos fármacos , Fêmur/patologia , Fêmur/fisiopatologia , Hipertrofia/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miocárdio/metabolismo , Miocárdio/patologia , Osteíte Deformante/metabolismo , Osteíte Deformante/patologia , Fragmentos de Peptídeos/sangue , Pró-Colágeno/sangue , Ligante RANK/sangue , Sístole/efeitos dos fármacos , Sístole/fisiologia , Fosfatase Ácida Resistente a Tartarato/sangue
19.
Environ Pollut ; 252(Pt A): 317-329, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31158660

RESUMO

Fine dust (FD) is a form of air pollution and is responsible for a wide range of diseases. Specially, FD is associated with several cardiovascular diseases (CVDs); long-term exposure to FD was shown to decrease endothelial function, but the underlying mechanism remains unclear. We investigated whether exposure to FD causes premature senescence-associated endothelial dysfunction in endothelial cells (ECs) isolated from porcine coronary arteries. The cells were treated with different concentrations of FD and senescence associated-beta galactosidase (SA-ß-gal) activity, cell cycle progression, expression of endothelial nitric oxide synthase (eNOS), oxidative stress level, and vascular function were evaluated. We found that FD increased SA-ß-gal activity, caused cell cycle arrest, and increased oxidative stress, suggesting the premature induction of senescence; on the other hand, eNOS expression was downregulated and platelet aggregation was enhanced. FD exposure impaired vasorelaxation in response to bradykinin and activated the local angiotensin system (LAS), which was inhibited by treatment with the antioxidant N-acetyl cysteine (NAC) and angiotensin II receptor type 1 (AT1) antagonist losartan (LOS). NAC and LOS also suppressed FD-induced SA-ß-gal activity, increased EC proliferation and eNOS expression, and improved endothelial function. These results demonstrate that FD induces premature senescence of ECs and is associated with increased oxidative stress and activation of LAS. This study can serve as a pharmacological target for prevention and/or treatment of air pollution-associated CVD.


Assuntos
Poluição do Ar/efeitos adversos , Angiotensinas/metabolismo , Senescência Celular/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/fisiologia , Material Particulado/farmacologia , Receptor Tipo 1 de Angiotensina/metabolismo , Acetilcisteína/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Antioxidantes/metabolismo , Plaquetas/citologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Vasos Coronários/citologia , Endotélio Vascular/citologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Losartan/farmacologia , Óxido Nítrico Sintase Tipo III/biossíntese , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Suínos , beta-Galactosidase/antagonistas & inibidores , beta-Galactosidase/metabolismo
20.
Int. j. morphol ; 37(2): 515-521, June 2019. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1002253

RESUMO

SUMMARY: Reproductive dysfunction is a complication for many diseases and toxins. Its early diagnosis and treatment are immensely important. Here the morphological histoarchitecture changes in early testicular and cauda toxicity before and after treatment with angiotensin receptor blockers were evaluated. Low-grade testicular damage was induced using thioacetamide (TAA, 50 mg/kg/day) intraperitoneally for two weeks in rats. The rats were randomly divided into four groups (n = 8) treated daily orally for three weeks as follows: Normal control (distilled water), TAA (positive control), TAA+candesartan (0.2 mg/kg) and TAA+losartan (7.5 mg/kg). Serum testosterone and testicular malondialdehyde and glutathione were measured. The changes in histoarchitecture of testis and cauda epididymis were evaluated by hematoxylin and eosin for general structure, Masson's trichrome for collagen, periodic acid Schiff for basement membrane, and caspase-3 and proliferating cell nuclear antigen (PCNA) for immunohistochemical analysis. The TAA-rats showed decreases of serum testosterone and testicular glutathione, increases in testicular malondialdehyde, degenerative changes and apoptosis in germ cells, thickening of tubular basal lamina and increases in expression of caspase 3, and decreases in expression of PCNA. The ARBs (candesartan and losartan) significantly reversed these changes with non-significant differences in-between. Treatment with ARBs (candesartan and losartan) significantly reversed TAA-induced low-grade testicular and cauda toxicity in rats. This could be potentially useful for early treatment of male patients with occupational toxicant-induced reproductive dysfunction especially if they are using ARBs for other comorbidities.


RESUMEN: La disfunción reproductiva es una complicación por muchas enfermedades y toxinas. Su diagnóstico y tratamiento tempranos son inmensamente importantes. Aquí se evaluaron los cambios morfológicos en la histoarquitectura en la toxicidad precoz testicular y cauda antes y después del tratamiento con bloqueadores de receptores de angiotensina. Se indujo daño testicular de bajo grado usando tioacetamida (TAA, 50 mg / kg / día) por vía intraperitoneal durante dos semanas en ratas. Las ratas se dividieron aleatoriamente en cuatro grupos (n = 8) tratados diariamente por vía oral durante tres semanas de la siguiente manera: control normal (agua destilada), TAA (control positivo), TAA + candesartan (0,2 mg / kg) y TAA + losartán (7,5 mg / kg). Se midieron la testosterona sérica, el malondialdehído testicular y el glutatión. Los cambios en la histoarquitectura de los testículos y la epidermis de la cauda se evaluaron mediante Hematoxilina y Eosina para determinar la estructura general, con tricrómicro de Masson para el colágeno, ácido periódico de Schiff para la membrana basal y la caspasa-3 y el antígeno nuclear de células proliferantes (PCNA) para análisis inmunohistoquímico. Las ratas TAA mostraron disminución de la testosterona sérica y glutatión testicular, aumentos en el malondialdehído testicular, cambios degenerativos y apoptosis en células germinales, engrosamiento de la lámina basal tubular y aumentos en la expresión de la caspasa 3, y disminución en la expresión de PCNA. Los ARB (candesartán y losartán) revirtieron significativamente estos cambios con diferencias no significativas en el medio. El tratamiento con BRA (candesartán y losartán) revirtió significativamente la toxicidad testicular y cauda inducida por TAA en ratas. Esto podría ser potencialmente útil para el tratamiento temprano de pacientes con disfunción reproductiva inducida por tóxicos ocupacionales, especialmente si están usando BRA para otras comorbilidades.


Assuntos
Animais , Masculino , Ratos , Testículo/efeitos dos fármacos , Tioacetamida/toxicidade , Benzimidazóis/farmacologia , Losartan/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Testículo/patologia , Testosterona/análise , Tetrazóis/farmacologia , Imuno-Histoquímica , Ratos Sprague-Dawley , Antígeno Nuclear de Célula em Proliferação/metabolismo , Caspase 3/metabolismo , Glutationa/análise , Malondialdeído/análise
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