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1.
Nutrients ; 13(10)2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34684491

RESUMO

Vitamin K dependent proteins (VKDP), such as hepatic coagulation factors and vascular matrix Gla protein (MGP), play key roles in maintaining physiological functions. Vitamin K deficiency results in inactive VKDP and is strongly linked to vascular calcification (VC), one of the major risk factors for cardiovascular morbidity and mortality. In this study we investigated how two vitamin K surrogate markers, dephosphorylated-undercarboxylated MGP (dp-ucMGP) and protein induced by vitamin K absence II (PIVKA-II), reflect vitamin K status in patients on hemodialysis or with calcific uremic arteriolopathy (CUA) and patients with atrial fibrillation or aortic valve stenosis. Through inter- and intra-cohort comparisons, we assessed the influence of vitamin K antagonist (VKA) use, vitamin K supplementation and disease etiology on vitamin K status, as well as the correlation between both markers. Overall, VKA therapy was associated with 8.5-fold higher PIVKA-II (0.25 to 2.03 AU/mL) and 3-fold higher dp-ucMGP (843 to 2642 pM) levels. In the absence of VKA use, non-renal patients with established VC have dp-ucMGP levels similar to controls (460 vs. 380 pM), while in HD and CUA patients, levels were strongly elevated (977 pM). Vitamin K supplementation significantly reduced dp-ucMGP levels within 12 months (440 to 221 pM). Overall, PIVKA-II and dp-ucMGP showed only weak correlation (r2 ≤ 0.26) and distinct distribution pattern in renal and non-renal patients. In conclusion, VKA use exacerbated vitamin K deficiency across all etiologies, while vitamin K supplementation resulted in a vascular VKDP status better than that of the general population. Weak correlation of vitamin K biomarkers calls for thoughtful selection lead by the research question. Vitamin K status in non-renal deficient patients was not anomalous and may question the role of vitamin K deficiency in the pathogenesis of VC in these patients.


Assuntos
Biomarcadores/sangue , Proteínas de Ligação ao Cálcio/sangue , Proteínas da Matriz Extracelular/sangue , Precursores de Proteínas/sangue , Calcificação Vascular/sangue , Deficiência de Vitamina K/sangue , Vitamina K/sangue , 4-Hidroxicumarinas/uso terapêutico , Estenose da Valva Aórtica/sangue , Estenose da Valva Aórtica/complicações , Fibrilação Atrial/sangue , Fibrilação Atrial/complicações , Doenças Cardiovasculares/etiologia , Estudos de Coortes , Suplementos Nutricionais , Feminino , Fatores de Risco de Doenças Cardíacas , Humanos , Indenos/uso terapêutico , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Estado Nutricional , Protrombina , Diálise Renal/efeitos adversos , Uremia/sangue , Uremia/complicações , Calcificação Vascular/complicações , Vitamina K/antagonistas & inibidores , Vitamina K/uso terapêutico , Deficiência de Vitamina K/complicações , Proteína de Matriz Gla
2.
J Pharm Pharmacol ; 67(4): 573-82, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25556550

RESUMO

OBJECTIVES: Due to the increasing prevalence of drug-resistant Staphylococcus aureus infection, we develop novel 4-hydroxycoumarin derivatives as antimicrobials. METHODS: The antibacterial activity of 4-hydroxycoumarin derivatives against drug-susceptive S. aureus (ATCC 29213) and methicillin-resistant S. aureus (MRSA) were evaluated using minimal inhibitory concentration (MIC) assay; the activity of favourable compound was further observed using bacterial growth curves assay and in the MRSA infection mice. KEY FINDINGS: Compared with dihydropyran derivatives, compound 1 as one of biscoumarins showed most potent activity with MIC values of 4-8 µg/ml and apparently inhibited the growth rate of S. aureus ATCC 29213 and USA300 strain in concentrations of both 16 and 32 mg/ml. In the mice infected with MRSA USA300, administration of 5 mg/kg compound 1 improved the animal survival rate to 66.7%, and improved the pathological change in lung tissue compared with the infection model animals. No significant cytotoxicity of compound 1 was observed on the umbilical vein endothelial cells (HUVECs) under the concentration of 800 µg/ml. CONCLUSION: Compared with the dihydropyran derivatives, biscoumarins exhibited more promising activity against both drug-sensitive and drug-resistant S. aureus, and it is efficacious in treating MRSA infections in mouse models with a favourable safety in human cells.


Assuntos
4-Hidroxicumarinas/uso terapêutico , Antibacterianos/uso terapêutico , Pneumopatias/tratamento farmacológico , Pulmão/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Infecções Estafilocócicas/tratamento farmacológico , 4-Hidroxicumarinas/biossíntese , 4-Hidroxicumarinas/farmacologia , Animais , Antibacterianos/farmacologia , Células Endoteliais da Veia Umbilical Humana , Pulmão/microbiologia , Pulmão/patologia , Pneumopatias/microbiologia , Pneumopatias/patologia , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus
3.
Cancer Chemother Pharmacol ; 65(5): 931-40, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19690859

RESUMO

PURPOSE: We have previously reported that in vitro treatment of B16-F10 melanoma cells with 4-hydroxycoumarin (4-HC) decreases their metastatic potential. However, the antimetastatic efficacy of 4-HC in vivo is unknown; therefore, we investigated the antimetastatic and antineoplastic effects of 4-HC in a mouse melanoma model. Based on the findings, the immunomodulatory and toxic effects of 4-HC were also studied. METHODS: Experimental metastasis assay was performed in C57BL/6 mice that received 4-HC before intravenous injection of B16-F10 cells. Antitumor and antimetastatic efficacy of 4-HC was assessed in mice implanted subcutaneously with melanoma cells. Possible immunostimulant and toxic effects of 4-HC were studied in healthy mice. RESULTS: 4-HC reduced the number of experimental lung metastases. Moreover, 4-HC diminished primary tumor growth and increased survival time in mice bearing melanoma tumors. Treatments also decrease spontaneous lung metastases in the same animals. Different to other coumarins, the antitumor effect of 4-HC seems to be unrelated to immunostimulation, since plasma concentrations of cytokines remained unchanged. In contrast, toxic histological changes in nephrons and bronchiolar epithelium and a pronounced anticoagulant effect were found in 4-HC treated animals. CONCLUSIONS: These results show that 4-HC not only exhibit antimetastatic effect in vivo, but also effectively reduces tumor growth and improves survival, even when it produce toxic effects. Although the molecular mechanism of 4-HC actions needs to be further defined, our data suggest that 4-HC may lead to the development of agents that could be used as adjuvants in the therapy of melanoma.


Assuntos
4-Hidroxicumarinas/uso terapêutico , Antineoplásicos/uso terapêutico , Melanoma Experimental/tratamento farmacológico , 4-Hidroxicumarinas/efeitos adversos , Animais , Anticoagulantes/efeitos adversos , Anticoagulantes/uso terapêutico , Antineoplásicos/efeitos adversos , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Rim/efeitos dos fármacos , Rim/patologia , Rim/ultraestrutura , Fígado/efeitos dos fármacos , Fígado/patologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/ultraestrutura , Masculino , Melanoma Experimental/patologia , Melanoma Experimental/ultraestrutura , Camundongos , Camundongos Endogâmicos C57BL , Metástase Neoplásica
4.
Farmakol Toksikol ; 48(3): 74-7, 1985.
Artigo em Russo | MEDLINE | ID: mdl-2411594

RESUMO

A study was made of the effects of heparin and sodium fepromaron on prekallikrein (PK); kallikrein inhibitors (KI), initial esterase activity (IEA) of rat blood in health and pituitrin hypertension. Pituitrin hypertension was associated with IEA increase and KI decrease. A single administration of heparin raised IEA; if administered for 3 days, heparin reduced IEA. After pituitrin administration heparin decreased IEA if administered once or for 3 days. Administration of fepromaron in courses following pituitrin also reduced. IEA, with that reduction being preserved for not less than 4 days after drug discontinuation. Similarity of the effects of heparin and fepromaron on hemocoagulation and the tone of blood vessels suggests the common mechanisms of their action on the blood kinin system.


Assuntos
4-Hidroxicumarinas/uso terapêutico , Anticoagulantes/uso terapêutico , Heparina/uso terapêutico , Hipertensão/tratamento farmacológico , Calicreínas/sangue , Cininas/sangue , Hormônios Neuro-Hipofisários/toxicidade , Animais , Avaliação Pré-Clínica de Medicamentos , Hipertensão/sangue , Hipertensão/induzido quimicamente , Masculino , Ratos , Fatores de Tempo
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