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1.
Biomed Res Int ; 2021: 7396580, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34532504

RESUMO

Endothelin is a chemical mediator that helps in maintaining balance within the blood-brain barrier by regulating the levels of toxicants and molecules which pass through the brain, suggesting that a rise in its production determines Alzheimer's disease. The inequity in the amyloid ß occurs due to a problem in its clearance from the brain initiating the production of reactive oxygen species and superoxide that activates a cascade wherein the release of inflammatory mediators and various enzymes like endothelin-converting enzymes take place. Furthermore, the cascade increases the levels of endothelin in the brain from endothelial cells. Endothelin levels are upregulated, which can be regulated by modulating the action of endothelin-converting enzymes and endothelin receptors. Hence, endothelin paves a pathway in the treatment of Alzheimer's disease. In this article, we have covered various mechanisms and preclinical studies that support and direct endothelin involvement in the progression of Alzheimer's disease by using various search tools such as PubMed, Science Direct, and Medline. Conclusive outcome data were extracted that all together defy contrivance pathways, potential drugs, endothelin receptors, and endothelin enzymes in our article giving profound importance to target endothelin for prevention and treatment of Alzheimer's disease.


Assuntos
Doença de Alzheimer/terapia , Endotelinas/efeitos dos fármacos , Endotelinas/metabolismo , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Encéfalo/metabolismo , Células Endoteliais/metabolismo , Enzimas Conversoras de Endotelina/metabolismo , Humanos , Neprilisina/genética
2.
Intern Med ; 60(17): 2807-2809, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34470986

RESUMO

Sacubitril/valsartan has demonstrated its prognostic advantageousness over enalapril in patients with heart failure with a reduced ejection fraction. However, the optimal therapeutic strategy using sacubitril/valsartan in real-world practice, particularly among a Japanee cohort, remains uncertain. A 75-year-old man with systolic heart failure and chronic kidney disease was administered sacubitril/valsartan. Plasma B-type natriuretic peptide transiently increased, accompanied by an increase in the urine volume, which allowed us to terminate loop diuretics. The estimated glomerular filtration rate as well as heart failure symptom improved at the one-month follow-up. Sacubitril/valsartan might be a promising option to preserve the renal function and improve clinical outcomes when the dose of concomitant diuretics can be decreased, although further large-scale studies are warranted to validate our hypothesis.


Assuntos
Insuficiência Cardíaca Sistólica , Insuficiência Cardíaca , Insuficiência Renal Crônica , Idoso , Aminobutiratos/uso terapêutico , Antagonistas de Receptores de Angiotensina/uso terapêutico , Compostos de Bifenilo , Combinação de Medicamentos , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca Sistólica/tratamento farmacológico , Humanos , Japão , Masculino , Neprilisina , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológico , Volume Sistólico , Tetrazóis/uso terapêutico , Resultado do Tratamento , Valsartana/uso terapêutico
3.
Int J Mol Sci ; 22(17)2021 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-34502327

RESUMO

Keloid is an aberrant scarring process of the skin, characterized by excessive extracellular matrix synthesis and deposition. The pathogenesis of this prevalent cutaneous disorder is not fully understood; however, a persistent inflammatory process is observed. To obtain more insight into this process, we analyzed lesional, perilesional and healthy tissue using multi-antigen-analysis (MAA) in conjunction with a data mining approach. Here, we demonstrate that monocyte-derived inflammatory dendritic cells (CD1a+, CD11c+, CD14+) and activated CD4+ T lymphocytes (CD45 RO+) dominated the immune infiltration in keloids while associating with fibroblasts. In perilesional tissue, precursor immune cells were dominant in the perivascular area, suggesting that they were attracted by an immune process, potentially in the lesional area. Supporting this hypothesis, only in keloid lesions, high levels of ADAM10/17 and Neprilysin (CD10) were observed in both fibroblasts and leukocytes. The spatial proximity of these two cell types, which could be confirmed by image analysis only in lesional tissue, could be a potential factor leading to the activation of fibroblasts. Our findings provide new insight into the pathogenesis of keloid formation and reveal metalloproteinases as a target for therapeutical intervention.


Assuntos
Proteína ADAM17/metabolismo , Células Dendríticas/imunologia , Fibroblastos/patologia , Inflamação/patologia , Queloide/patologia , Neprilisina/metabolismo , Adolescente , Adulto , Estudos de Casos e Controles , Células Cultivadas , Fibroblastos/imunologia , Fibroblastos/metabolismo , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Queloide/imunologia , Queloide/metabolismo , Pessoa de Meia-Idade , Adulto Jovem
4.
BMC Cancer ; 21(1): 1047, 2021 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-34556086

RESUMO

BACKGROUND: The differential diagnosis of endometrial stromal tumor (EST) and uterine cellular leiomyoma (CL) remains a challenge in clinical practice, especially low grade endometrial stromal sarcoma (ESS) and CL, suggesting the need for novel immunomarkers panels for differential diagnosis. Interferon-induced transmembrane protein 1 (IFITM1) is a novel immunomarker for endometrial stromal cells, h-caldesmon is an immunomarker for smooth muscle cells and has a higher specificity than smooth muscle actin (SMA). So this study aimed to evaluate whether IFITM1, cluster of differentiation 10(CD10), SMA, and h-caldesmon are useful biomarker combinations for the differential diagnosis of EST and CL. METHODS: Tissue microarrays were used to detect IFITM1, CD10, SMA, and h-caldesmon immunohistochemical staining in 30 EST and 33 CL cases. RESULTS: The expressions of IFITM1 and CD10 were high in EST (86.7 and 63.3%, respectively) but low in CL (18.2 and 21.2%), whereas those of h-caldesmon and SMA were high in CL (87.9 and 100%) and low in EST (6.9 and 40%). In diagnosing EST, IFITM1 shows better sensitivity and specificity (86.7 and 81.8%, respectively) than CD10 (63.3 and 78.8%). The specificity of h-caldesmon in diagnosing CL was significantly higher (93.1%) than that of SMA (60%). When all four antibodies were combined for the differential diagnosis, the area-under-the-curve (AUC) predictive value was 0.995. The best combination for diagnosing EST was IFITM1 (+) or CD10 (+) and h-caldesmon (-) (sensitivity 86.7%, specificity 93.9%). CONCLUSION: The best combination for diagnosing CL were h-caldesmon (+) and SMA (+) (sensitivity 87.9%, specificity 100%). IFITM1, CD10, SMA, and h-caldesmon are a good combination for the differential diagnosis of EST and CL.


Assuntos
Biomarcadores Tumorais/análise , Neoplasias do Endométrio/diagnóstico , Tumores do Estroma Endometrial/diagnóstico , Leiomioma/diagnóstico , Neoplasias Uterinas/diagnóstico , Actinas/análise , Adulto , Idoso , Antígenos de Diferenciação/análise , Antígenos de Neoplasias/análise , Área Sob a Curva , Proteínas de Ligação a Calmodulina/análise , Diagnóstico Diferencial , Neoplasias do Endométrio/química , Tumores do Estroma Endometrial/química , Feminino , Humanos , Imuno-Histoquímica , Leiomioma/química , Pessoa de Meia-Idade , Músculo Liso/química , Neprilisina/análise , Sensibilidade e Especificidade , Neoplasias Uterinas/química
5.
Rev Med Suisse ; 17(747): 1418-1422, 2021 Aug 25.
Artigo em Francês | MEDLINE | ID: mdl-34431635

RESUMO

Sacubitril/valsartan, a first-in-class angiotensin receptor-neprilysin inhibitor (ARNI), is indicated for the treatment of heart failure with reduced ejection fraction. It has demonstrated benefits in terms of cardiovascular morbidity and mortality reduction in this population. Recently, this drug association has also been shown to improve glycemic control and insulin sensitivity in patients with obesity and/or type 2 diabetes. Furthermore, some studies suggest a protective role of this new drug class in diabetic nephropathy. Altogether, these data raise the question about the potential place of ARNI in prevention and treatment of type 2 diabetes, a condition closely associated with heart failure.


Assuntos
Diabetes Mellitus Tipo 2 , Aminobutiratos , Antagonistas de Receptores de Angiotensina/uso terapêutico , Compostos de Bifenilo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Combinação de Medicamentos , Humanos , Neprilisina , Valsartana
6.
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
7.
Int J Mol Sci ; 22(16)2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34445698

RESUMO

The renin-angiotensin-aldosterone system (RAAS) plays a major role in cardiovascular health and disease. Short-term RAAS activation controls water and salt retention and causes vasoconstriction, which are beneficial for maintaining cardiac output in low blood pressure and early stage heart failure. However, prolonged RAAS activation is detrimental, leading to structural remodeling and cardiac dysfunction. Natriuretic peptides (NPs) are activated to counterbalance the effect of RAAS and sympathetic nervous system by facilitating water and salt excretion and causing vasodilation. Neprilysin is a major NP-degrading enzyme that degrades multiple vaso-modulatory substances. Although the inhibition of neprilysin alone is not sufficient to counterbalance RAAS activation in cardiovascular diseases (e.g., hypertension and heart failure), a combination of angiotensin receptor blocker and neprilysin inhibitor (ARNI) was highly effective in several clinical trials and may modulate the risk of atrial and ventricular arrhythmias. This review summarizes the possible link between ARNI and cardiac arrhythmias and discusses potential underlying mechanisms, providing novel insights about the therapeutic role and safety profile of ARNI in the cardiovascular system.


Assuntos
Antagonistas de Receptores de Angiotensina/uso terapêutico , Arritmias Cardíacas/fisiopatologia , Neprilisina/antagonistas & inibidores , Antagonistas de Receptores de Angiotensina/metabolismo , Anti-Hipertensivos/farmacologia , Arritmias Cardíacas/tratamento farmacológico , Arritmias Cardíacas/metabolismo , Doenças Cardiovasculares/tratamento farmacológico , Insuficiência Cardíaca/metabolismo , Humanos , Hipertensão/tratamento farmacológico , Peptídeos Natriuréticos/metabolismo , Peptídeos Natriuréticos/fisiologia , Receptores de Angiotensina/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia , Sistema Nervoso Simpático/fisiopatologia , Tetrazóis/farmacologia
8.
Comput Biol Med ; 136: 104691, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34343891

RESUMO

Alzheimer's disease (AD) is a progressive brain disorder. The accumulation of amyloid beta (Aß) peptides in the human brain leads to AD. The cleavage of Aß peptides by several enzymes is being considered as an essential aspect in the treatment of AD. Neprilysin (NEP) is an important enzyme that clears the Aß plaques in the human brain. The human NEP activity has been found reduced due to mutations in NEP and the presence of inhibitors. However, the role of NEP in the degradation of Aß peptides in detail at the molecular level is not yet clear. Hence, in the present study, we have investigated the structural significance of NEP from the bacterial source Streptococcus suis GZ1 using various bioinformatics approaches. The homology modelling technique was used to predict the three-dimensional structure of NEP. Further, molecular dynamic (MD) simulated model of NEP was docked with Aß peptide. Analysis of MD simulated docked complex showed that the wild-type NEP-Aß-peptide complex is more stable as compared to mutant complex. Hydrogen bonding interactions between NEP with Zn2+and Aß peptide confirm the degradation of the Aß peptide. The molecular docking and MD simulation results revealed that the active site residue Glu-538 of bacterial NEP along with Zn2+ interact with His-13 of Aß peptide. This stable interaction confirms the involvement of NEP with Glu-538 in the degradation of the Aß peptide. The other residues such as Glu203, Ser537, Gly140, Val587, and Val536 could also play an important role in the cleavage of Aß peptide in between Asp1-Ala2, Arg5-His6, Val18-Phe19, Gly9-Tyr10, and Arg5-His6. Hence, the predicted model of the NEP enzyme of Streptococcus suis GZ1could be useful to understand the Aß peptide degradation in detail at the molecular level. The information obtained from this study would be helpful in designing new lead molecules for the effective treatment of AD.


Assuntos
Doença de Alzheimer , Streptococcus suis , Doença de Alzheimer/genética , Peptídeos beta-Amiloides , Humanos , Simulação de Acoplamento Molecular , Neprilisina , Streptococcus suis/genética
9.
Int J Mol Sci ; 22(14)2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34299316

RESUMO

Redox-active metal ions, Cu(I/II) and Fe(II/III), are essential biological molecules for the normal functioning of the brain, including oxidative metabolism, synaptic plasticity, myelination, and generation of neurotransmitters. Dyshomeostasis of these redox-active metal ions in the brain could cause Alzheimer's disease (AD). Thus, regulating the levels of Cu(I/II) and Fe(II/III) is necessary for normal brain function. To control the amounts of metal ions in the brain and understand the involvement of Cu(I/II) and Fe(II/III) in the pathogenesis of AD, many chemical agents have been developed. In addition, since toxic aggregates of amyloid-ß (Aß) have been proposed as one of the major causes of the disease, the mechanism of clearing Aß is also required to be investigated to reveal the etiology of AD clearly. Multiple metalloenzymes (e.g., neprilysin, insulin-degrading enzyme, and ADAM10) have been reported to have an important role in the degradation of Aß in the brain. These amyloid degrading enzymes (ADE) could interact with redox-active metal ions and affect the pathogenesis of AD. In this review, we introduce and summarize the roles, distributions, and transportations of Cu(I/II) and Fe(II/III), along with previously invented chelators, and the structures and functions of ADE in the brain, as well as their interrelationships.


Assuntos
Doença de Alzheimer/metabolismo , Amiloide/metabolismo , Encéfalo/metabolismo , Proteína ADAM10/metabolismo , Doença de Alzheimer/etiologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Barreira Hematoencefálica/metabolismo , Quelantes/metabolismo , Cobre/metabolismo , Humanos , Insulisina/metabolismo , Ferro/metabolismo , Proteínas de Membrana/metabolismo , Metais/metabolismo , Neprilisina/metabolismo , Oxirredução , Proteólise
10.
Ann Hematol ; 100(10): 2487-2500, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34236495

RESUMO

Measurable residual disease (MRD) is an important parameter to predict outcome in B-cell acute lymphoblastic leukemia (B-ALL). Two different approaches have been used for the assessment of MRD by multiparametric flow cytometry that include the "Leukemia Associated Aberrant Immunophenotype (LAIP)" and "Difference from Normal (DFN)" approach. In this retrospective study, we analyzed 539 samples obtained from 281 patients of which 258 were paired samples and the remaining 23 samples were from post-induction time point only, to explore the utility of baseline immunophenotype (IPT) for MRD assessment. Single-tube 10-color panel was used both at diagnosis and MRD time points. Out of 281 patients, 31.67% (n = 89) were positive and 68.32% (n = 192) were negative for MRD. Among 258 paired diagnostic and follow-up samples, baseline IPT was required in only 9.31% (24/258) cases which included cases with hematogone pattern and isolated dim to negative CD10 expression patterns. Comparison of baseline IPT with post-induction MRD positive samples showed a change in expression of at least one antigen in 94.04% cases. Although the immunophenotypic change in expression of various antigens is frequent in post-induction samples of B-ALL, it does not adversely impact the MRD assessment. In conclusion, the baseline IPT is required in less than 10% of B-ALL, specifically those with hematogone pattern and/or dim to negative expression of CD10. Hence, a combination of DFN and LAIP approach is recommended for reliable MRD assessment.


Assuntos
Neoplasia Residual/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Antígenos CD/análise , Citometria de Fluxo , Humanos , Imunofenotipagem , Neoplasia Residual/terapia , Neprilisina/análise , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Estudos Retrospectivos
11.
Biochemistry (Mosc) ; 86(6): 680-692, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34225591

RESUMO

The incidence of Alzheimer's disease (AD) increases significantly following chronic stress and brain ischemia which, over the years, cause accumulation of toxic amyloid species and brain damage. The effects of global 15-min ischemia and 120-min reperfusion on the levels of expression of the amyloid precursor protein (APP) and its processing were investigated in the brain cortex (Cx) of male Wistar rats. Additionally, the levels of expression of the amyloid-degrading enzymes neprilysin (NEP), endothelin-converting enzyme-1 (ECE-1), and insulin-degrading enzyme (IDE), as well as of some markers of oxidative damage were assessed. It was shown that the APP mRNA and protein levels in the rat Cx were significantly increased after the ischemic insult. Protein levels of the soluble APP fragments, especially of sAPPß produced by ß-secretase, (BACE-1) and the levels of BACE-1 mRNA and protein expression itself were also increased after ischemia. The protein levels of APP and BACE-1 in the Cx returned to the control values after 120-min reperfusion. The levels of NEP and ECE-1 mRNA also decreased after ischemia, which correlated with the decreased protein levels of these enzymes. However, we have not observed any changes in the protein levels of insulin-degrading enzyme. Contents of the markers of oxidative damage (di-tyrosine and lysine conjugates with lipid peroxidation products) were also increased after ischemia. The obtained data suggest that ischemia shifts APP processing towards the amyloidogenic ß-secretase pathway and accumulation of the neurotoxic Aß peptide as well as triggers oxidative stress in the cells. These results are discussed in the context of the role of stress and ischemia in initiation and progression of AD.


Assuntos
Doença de Alzheimer/etiologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Isquemia Encefálica/metabolismo , Córtex Cerebral/metabolismo , Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/genética , Precursor de Proteína beta-Amiloide/genética , Animais , Isquemia Encefálica/complicações , Isquemia Encefálica/enzimologia , Córtex Cerebral/enzimologia , Enzimas Conversoras de Endotelina/genética , Enzimas Conversoras de Endotelina/metabolismo , Regulação da Expressão Gênica , Insulisina/genética , Insulisina/metabolismo , Masculino , Neprilisina/genética , Neprilisina/metabolismo , Estresse Oxidativo , Ratos , Ratos Wistar , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/enzimologia , Traumatismo por Reperfusão/metabolismo
13.
BMC Cardiovasc Disord ; 21(1): 324, 2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34215190

RESUMO

BACKGROUND: Treatment of heart failure with reduced ejection fraction (HFrEF) has been revolutionized by angiotensin receptor/neprilysin inhibitor (ARNI). ARNI has been shown to significantly reduce morbidity and mortality in a large, randomized controlled trial. However, real-world evaluation of ARNI with a diverse population is still limited. METHODS: HFrEF patients receiving angiotensin receptor/neprilysin inhibitor (ARNI) or standard HF treatment at a university hospital in Thailand were prospectively followed-up from January 2015 to December 2019. The primary outcome was a composite of all-cause mortality and heart failure hospitalization. Survival analysis and the Cox proportional hazard model were used to compare clinical outcomes between the two groups. RESULTS: During a follow-up period of 12 months, the primary outcome occurred in 10 patients in the ARNI group (11.5%) and 28 in the standard treatment group (28.0%) (hazard ratio 0.34; 95% CI: 0.15-0.80; p = 0.013). After adjustment for confounding factors, ARNI was significantly associated with a significant reduction in the primary outcome (HR 0.32, 95% CI: 0.13-0.82, p = 0.017). In addition, ARNI was also significantly associated with a decrease in the clinical signs and symptoms of HF, including dyspnea, orthopnea, and fatigue. Orthostatic hypotension was more frequently reported among the ARNI group than among the standard treatment group. The rates of target dose achievement were comparable between the two groups. CONCLUSION: In real-world practice, ARNI use was associated with a significant reduction in both clinical outcomes and symptom improvement, while orthostatic hypotension was more common in patients in the ARNI group than in patients in the standard treatment group.


Assuntos
Aminobutiratos/uso terapêutico , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Compostos de Bifenilo/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Neprilisina/antagonistas & inibidores , Padrões de Prática Médica/tendências , Inibidores de Proteases/uso terapêutico , Valsartana/uso terapêutico , Adulto , Idoso , Aminobutiratos/efeitos adversos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/efeitos adversos , Compostos de Bifenilo/efeitos adversos , Combinação de Medicamentos , Uso de Medicamentos/tendências , Feminino , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/fisiopatologia , Hospitalização/tendências , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Inibidores de Proteases/efeitos adversos , Recuperação de Função Fisiológica , Estudos Retrospectivos , Tailândia , Fatores de Tempo , Resultado do Tratamento , Valsartana/efeitos adversos
14.
Am J Trop Med Hyg ; 105(3): 638-642, 2021 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-34280134

RESUMO

Chagas disease (CD) mainly conveys stroke risk through structural cardiac disease. However, stroke and cognitive impairment are seen in CD independently of cardiac disease severity. Chronic inflammation may be an explanation for this association, because inflammation plays an important role in the pathogenesis of acute ischemic stroke and dementia. In the present study, we selected five candidate biomarkers for Chagas disease: interleukin-6, membrane metalloproteinase-9, tissue inhibitor of metalloproteinase-1 (TIMP1), orosomucoid, and neprilysin. We sought to determine if mean levels of proinflammatory biomarkers are higher in patients with heart failure (HF) associated with Chagas disease when compared with other etiologies of HF. Patients were consecutively enrolled from subspecialty HF outpatient clinics at two university-based hospitals. Serum biomarker levels from blood samples were analyzed by ELISA. Severity of HF on echocardiography was worse in non-CD when compared with CD patients. No significant difference was observed in the levels of candidate biomarkers between the CD and non-CD groups. We found a significantly 2.2 ng/mL higher level of TIMP1 in CD when compared with non-CD patients with HF after adjustment for age and gender (95% confidence interval = 0.1 to 4.5, P = 0.037). In patients with heart failure, serum TIMP1 is increased in Chagas patients despite a lower myocardial disease severity on echocardiography when compared with non-Chagas patients. TIMP1 is probably one of multiple mediators of inflammatory injury.


Assuntos
Cardiomiopatia Chagásica/metabolismo , Insuficiência Cardíaca/metabolismo , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Adulto , Idoso , Cardiomiopatia Chagásica/diagnóstico por imagem , Feminino , Insuficiência Cardíaca/diagnóstico por imagem , Humanos , Inflamação/metabolismo , Interleucina-6/metabolismo , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Pessoa de Meia-Idade , Neprilisina/metabolismo , Orosomucoide/metabolismo
15.
Iran J Kidney Dis ; 15(4): 288-299, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34279000

RESUMO

INTRODUCTION: Angiotensin receptor neprilysin inhibitor (ARNI) has been recommended by major guidelines as the leading therapy for heart failure with reduced ejection fraction (HFrEF). But little is known about its safety and effectiveness among maintenance hemodialysis patients with HFrEF in real-word practice. METHODS: An observational study was conducted among maintenance hemodialysis patients who received ARNI at our dialysis center. Enrollment commenced on June 1, 2018; and follow-up was completed on May 31, 2019. RESULTS: A total of 110 patients included in the study (age: 54.2 ± 14.8 y, 59% males). After 12 months of treatment, the average ARNI daily dose increased from 135 mg to 308 mg. The mean NT-pro- BNP concentration at baseline was 14455 pg/mL and 6435 pg/ mL after 12 months of treatment (P < .001). The left ventricular ejection fraction improved (35.1 vs. 49.8%, P < .001) over the 12 months, while left ventricular end-diastolic diameter, left ventricular mass index, left ventricular end-systolic diameter, and left atrial diameter also changed significantly (167.8 vs. 154.9 g/m, P < .001; 52.2 vs. 51.5 mm, P < .05; 35.9 vs. 36.9 mm, P < .001; 42.2 vs. 40.3 mm, P < .001). Furthermore, we found the quality of life and the NYHA symptom severity class improved significantly (P < .001). Kaplan-Meier analysis indicated that higher dose of ARNI and less vintage of HD were associated with best survival. CONCLUSION: In our study, ARNI appeared to be safe, relieved heart failure symptoms, and improved the scores of KCCQ physical and social activities in hemodialysis patients in real-world practice.


Assuntos
Insuficiência Cardíaca , Neprilisina , Adulto , Idoso , Aminobutiratos/efeitos adversos , Antagonistas de Receptores de Angiotensina/efeitos adversos , Combinação de Medicamentos , Feminino , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Receptores de Angiotensina , Diálise Renal/efeitos adversos , Volume Sistólico , Resultado do Tratamento , Função Ventricular Esquerda
16.
Kardiologiia ; 61(6): 4-10, 2021 Jul 01.
Artigo em Russo, Inglês | MEDLINE | ID: mdl-34311683

RESUMO

Major principles for treatment of chronic heart failure with reduced left ventricular ejection fraction <40% (HFrEF) include a "triple neurohormonal blockade" as a main approach. However, in recent 6 years, two new classes of drugs for the treatment of HFrEF have appeared, which beneficially influence the prognosis. These drugs are angiotensin receptor neprilysin inhibitors (ARNI) and type 2 sodium-glucose cotransporter 2 (SGLT2) inhibitors.Aim    To compare the net effect of simultaneous treatment with ARNI and SGLT2 inhibitors with the triple neurohormonal blockade in stable or decompensated patients with CHF based on Russian data.Material and methods    We analyzed the risk of death per 100 patient-years in patients with HFrEF. Stable patients were followed up at the A.L. Myasnikov Institute of Cardiology (presently, A.L. Myasnikov Research Institute of Clinical Cardiology of the National Medical Research Center of Cardiology) from 2006 through 2007; data from the EPOCH-Decompensation-CHF study were used for decompensated patients (12.2 % and 36.8 %, respectively).Results    When patients with stable HFrEF were successively switched from renin-angiotensin-aldosterone system (RAAS) inhibitors to ARNI (-16 %) and subsequently supplemented with SGLT2 (-13 %) the risk of death per 100 patient-years decreased from 12.2 % to 8.9 % (total risk decreased by 27 %; to save one patient the ARNI+ SGLT2 combination has to be prescribed to 30 patients). The estimated risk of death upon discharge from the hospital for the patients with decompensated CHF switched from RAAS inhibitors to ARNI (-16 %) and subsequently supplemented with SGLT2 (-13 %) was 26.9 deaths per 100 patient-years, whereas the number of patients to be treated for saving one life was only 10. Based on available data that demonstrate a greater effect of ARNI+ SGLT2 in patients immediately after CHF aggravation, the risk of death was recalculated. According to this analysis, the death rate per 1000 patient-years decreased from 36.8 to 19.9 % (relative risk decrease, 46 %), and to save one life only 6 patients had to be treated after they have achieved compensation of HFrEF.Conclusions    This analysis shows the importance of early initiation of the ARNI+ SGLT2 therapy in patients with both decompensated and with stable HFrEF.


Assuntos
Antagonistas de Receptores de Angiotensina/uso terapêutico , Insuficiência Cardíaca , Neprilisina , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Angiotensinas , Glucose , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Neprilisina/antagonistas & inibidores , Prognóstico , Federação Russa , Sódio , Volume Sistólico , Função Ventricular Esquerda
17.
OMICS ; 25(7): 408-416, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34191617

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus is anticipated to transition to an endemic state as vaccines are providing relief in some, but not all, countries. Drug discovery for COVID-19 can offer another tool in the fight against the pandemic. Additionally, COVID-19 impacts multiple organs that call for a systems medicine approach to planetary health and therapeutics innovation. In this context, innovation for drugs that prevent and treat COVID-19 is timely and much needed. As the virus variants emerge under different ecological conditions and contexts in the long haul, a broad array of vaccine and drug options will be necessary. This expert review article argues for a need to expand the COVID-19 interventions, including and beyond vaccines, to stimulate discovery and development of novel medicines against SARS-CoV-2 infection. The Renin-Angiotensin-Aldosterone System (RAAS) is known to play a major role in SARS-CoV-2 infection. Neprilysin (NEP) and angiotensin-converting enzyme (ACE) have emerged as the pharmaceutical targets of interest in the search for therapeutic interventions against COVID-19. While the NEP/ACE inhibitors offer promise for repurposing against COVID-19, they may display a multitude of effects in different organ systems, some beneficial, and others adverse, in modulating the inflammation responses in the course of COVID-19. This expert review offers an analysis and discussion to deepen our present understanding of the pathophysiological function of neprilysin in multiple organs, and the possible effects of NEP inhibitor-induced inflammatory responses in COVID-19-infected patients.


Assuntos
Neprilisina/química , Bradicinina/genética , Bradicinina/metabolismo , Sistema Renina-Angiotensina/genética , Sistema Renina-Angiotensina/fisiologia , SARS-CoV-2
18.
Cochrane Database Syst Rev ; 5: CD012721, 2021 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-34022072

RESUMO

BACKGROUND: Beta-blockers and inhibitors of the renin-angiotensin-aldosterone system improve survival and reduce morbidity in people with heart failure with reduced left ventricular ejection fraction (LVEF); a review of the evidence is required to determine whether these treatments are beneficial for people with heart failure with preserved ejection fraction (HFpEF). OBJECTIVES: To assess the effects of beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, angiotensin receptor neprilysin inhibitors, and mineralocorticoid receptor antagonists in people with HFpEF. SEARCH METHODS: We updated searches of CENTRAL, MEDLINE, Embase, and one clinical trial register on 14 May 2020 to identify eligible studies, with no language or date restrictions. We checked references from trial reports and review articles for additional studies.  SELECTION CRITERIA: We included randomised controlled trials with a parallel group design, enrolling adults with HFpEF, defined by LVEF greater than 40%. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included 41 randomised controlled trials (231 reports), totalling 23,492 participants across all comparisons. The risk of bias was frequently unclear and only five studies had a low risk of bias in all domains. Beta-blockers (BBs) We included 10 studies (3087 participants) investigating BBs. Five studies used a placebo comparator and in five the comparator was usual care. The mean age of participants ranged from 30 years to 81 years. A possible reduction in cardiovascular mortality was observed (risk ratio (RR) 0.78, 95% confidence interval (CI) 0.62 to 0.99; number needed to treat for an additional benefit (NNTB) 25; 1046 participants; three studies), however, the certainty of evidence was low. There may be little to no effect on all-cause mortality (RR 0.82, 95% CI 0.67 to 1.00; 1105 participants; four studies; low-certainty evidence). The effects on heart failure hospitalisation, hyperkalaemia, and quality of life remain uncertain. Mineralocorticoid receptor antagonists (MRAs) We included 13 studies (4459 participants) investigating MRA. Eight studies used a placebo comparator and in five the comparator was usual care. The mean age of participants ranged from 54.5 to 80 years. Pooled analysis indicated that MRA treatment probably reduces heart failure hospitalisation (RR 0.82, 95% CI 0.69 to 0.98; NNTB = 41; 3714 participants; three studies; moderate-certainty evidence). However, MRA treatment probably has little or no effect on all-cause mortality (RR 0.91, 95% CI 0.78 to 1.06; 4207 participants; five studies; moderate-certainty evidence) and cardiovascular mortality (RR 0.90, 95% CI 0.74 to 1.11; 4070 participants; three studies; moderate-certainty evidence). MRA treatment may have little or no effect on quality of life measures (mean difference (MD) 0.84, 95% CI -2.30 to 3.98; 511 participants; three studies; low-certainty evidence). MRA treatment was associated with a higher risk of hyperkalaemia (RR 2.11, 95% CI 1.77 to 2.51; number needed to treat for an additional harmful outcome (NNTH) = 11; 4291 participants; six studies; high-certainty evidence). Angiotensin-converting enzyme inhibitors (ACEIs) We included eight studies (2061 participants) investigating ACEIs. Three studies used a placebo comparator and in five the comparator was usual care. The mean age of participants ranged from 70 to 82 years. Pooled analyses with moderate-certainty evidence suggest that ACEI treatment likely has little or no effect on cardiovascular mortality (RR 0.93, 95% CI 0.61 to 1.42; 945 participants; two studies), all-cause mortality (RR 1.04, 95% CI 0.75 to 1.45; 1187 participants; five studies) and heart failure hospitalisation (RR 0.86, 95% CI 0.64 to 1.15; 1019 participants; three studies), and may result in little or no effect on the quality of life (MD -0.09, 95% CI -3.66 to 3.48; 154 participants; two studies; low-certainty evidence). The effects on hyperkalaemia remain uncertain. Angiotensin receptor blockers (ARBs) Eight studies (8755 participants) investigating ARBs were included. Five studies used a placebo comparator and in three the comparator was usual care. The mean age of participants ranged from 61 to 75 years. Pooled analyses with high certainty of evidence suggest that ARB treatment has little or no effect on cardiovascular mortality (RR 1.02, 95% 0.90 to 1.14; 7254 participants; three studies), all-cause mortality (RR 1.01, 95% CI 0.92 to 1.11; 7964 participants; four studies), heart failure hospitalisation (RR 0.92, 95% CI 0.83 to 1.02; 7254 participants; three studies), and quality of life (MD 0.41, 95% CI -0.86 to 1.67; 3117 participants; three studies). ARB was associated with a higher risk of hyperkalaemia (RR 1.88, 95% CI 1.07 to 3.33; 7148 participants; two studies; high-certainty evidence). Angiotensin receptor neprilysin inhibitors (ARNIs) Three studies (7702 participants) investigating ARNIs were included. Two studies used ARBs as the comparator and one used standardised medical therapy, based on participants' established treatments at enrolment. The mean age of participants ranged from 71 to 73 years. Results suggest that ARNIs may have little or no effect on cardiovascular mortality (RR 0.96, 95% CI 0.79 to 1.15; 4796 participants; one study; moderate-certainty evidence), all-cause mortality (RR 0.97, 95% CI 0.84 to 1.11; 7663 participants; three studies; high-certainty evidence), or quality of life (high-certainty evidence). However, ARNI treatment may result in a slight reduction in heart failure hospitalisation, compared to usual care (RR 0.89, 95% CI 0.80 to 1.00; 7362 participants; two studies; moderate-certainty evidence). ARNI treatment was associated with a reduced risk of hyperkalaemia compared with valsartan (RR 0.88, 95% CI 0.77 to 1.01; 5054 participants; two studies; moderate-certainty evidence). AUTHORS' CONCLUSIONS: There is evidence that MRA and ARNI treatment in HFpEF probably reduces heart failure hospitalisation but probably has little or no effect on cardiovascular mortality and quality of life. BB treatment may reduce the risk of cardiovascular mortality, however, further trials are needed. The current evidence for BBs, ACEIs, and ARBs is limited and does not support their use in HFpEF in the absence of an alternative indication. Although MRAs and ARNIs are probably effective at reducing the risk of heart failure hospitalisation, the treatment effect sizes are modest. There is a need for improved approaches to patient stratification to identify the subgroup of patients who are most likely to benefit from MRAs and ARNIs, as well as for an improved understanding of disease biology, and for new therapeutic approaches.


Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Sistema Renina-Angiotensina/efeitos dos fármacos , Volume Sistólico , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença Crônica , Insuficiência Cardíaca/mortalidade , Hospitalização , Humanos , Pessoa de Meia-Idade , Neprilisina/antagonistas & inibidores , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto
19.
PLoS One ; 16(5): e0249674, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33989294

RESUMO

BACKGROUND: Circulating Neprilysin (sNEP) has emerged as a potential prognostic biomarker in heart failure (HF). In PARAGON-HF benefit of sacubitril/valsartan was only observed in patients with left ventricular ejection fraction (LVEF) ≤57%. We aimed to assess the prognostic value of sNEP in outpatients with HF and LVEF >57%, in comparison with patients with LVEF ≤57%. METHODS: Consecutive HF outpatients were included from May-2006 to February-2016. The primary endpoint was the composite of all-cause death or HF hospitalization and the main secondary endpoint was the composite of cardiovascular death or HF hospitalization. For the later competing risk methods were used. RESULTS: sNEP was measured in 1428 patients (age 67.7±12.7, 70.3% men, LVEF 35.8% ±14), 144 of which had a LVEF >57%. sNEP levels did not significantly differ between LVEF groups (p = 0.31). During a mean follow-up of 6±3.9 years, the primary endpoint occurred in 979 patients and the secondary composite endpoint in 714 (in 111 and 84 of the 144 patients with LVEF >57%, respectively). sNEP was significantly associated with both composite endpoints. Age- and sex- adjusted Cox regression analyses showed higher hazard ratios for sNEP in patients with LVEF >57%, both for the primary (HR 1.37 [1.16-1.61] vs. 1.04 [0.97-1.11]) and the secondary (HR 1.38 [1.21-1.55] vs. 1.11 [1.04-1.18]) composite endpoints. CONCLUSIONS: sNEP prognostic value in patients with HF and LVEF >57% outperforms that observed in patients with lower LVEF. Precision medicine using sNEP may identify HF patients with preserved LVEF that may benefit from treatment with sacubitril/valsartan.


Assuntos
Insuficiência Cardíaca/tratamento farmacológico , Neprilisina/sangue , Idoso , Aminobutiratos/uso terapêutico , Biomarcadores , Compostos de Bifenilo/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Volume Sistólico/efeitos dos fármacos , Valsartana/uso terapêutico
20.
Toxins (Basel) ; 13(3)2021 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-33808971

RESUMO

Mammalian animal toxicity of ochratoxin A (OTA) has focused largely in the past half-century on pigs because of initial recognition of it as a principal cause of intermittent growth suppression and renal disease caused by mouldy feed. Subsequent classical toxicology has used laboratory rodents because renal pathology in pigs raised questions concerning possible involvement in the human idiopathic bilateral renal atrophy of Balkan endemic nephropathy for which OTA was a focus of attention for human nephropathy through 1980s and into 2000s. Emphasis on human nephropathy has more recently concerned the plant metabolite aristolochic acid. Recognition that agricultural management can often minimise food and feed-stuff spoilage by OTA-producing Aspergilli and Penicillia has moderated some of the risks for animals. Legislation for human food safety combined with sophisticated analysis generally provides safety in the developed world. Chronic experimental exposure of male rats, in the absence of clinical dis-ease, specifically causes renal cancer. The possibility of this as a unique model for the human has generated considerable experimental evidence which may be more directly relevant for carcinogenesis in the complex kidney than that obtained from biochemical toxicities in vitro. Nevertheless, there does not appear to be any case of human renal or urinary tract cancer for which there is verified etiological proof for causation by OTA, contrary to much claim in the literature. To contribute to such debate, histopathology review of OTA/rat renal cancers, augmented where appropriate by immune profiles, has been completed for all remaining tumours in our research archive. Overall consistency of positivity for vimentin, is matched with occasional positives either for CD10 or the cytokeratin MNF 116. The current situation is discussed. Suggestion that OTA could cause human testicular cancer has also been challenged as unsupported by any experimental findings in rats, where the Leydig cell tumour immune profile does not match that of human germ cell neoplasms.


Assuntos
Testes de Carcinogenicidade , Neoplasias Renais/induzido quimicamente , Ocratoxinas/toxicidade , Neoplasias Testiculares/induzido quimicamente , Animais , Exposição Dietética , Humanos , Queratinas/metabolismo , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Masculino , Neprilisina/metabolismo , Ratos Endogâmicos F344 , Medição de Risco , Fatores de Risco , Neoplasias Testiculares/metabolismo , Neoplasias Testiculares/patologia , Fatores de Tempo , Vimentina/metabolismo
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