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1.
Int J Mol Sci ; 22(19)2021 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-34639073

RESUMO

Our objective is to reveal the molecular mechanism of the anti-inflammatory action of low-molecular-weight heparin (LMWH) based on its influence on the activity of two key cytokines, IFNγ and IL-6. The mechanism of heparin binding to IFNγ and IL-6 and the resulting inhibition of their activity were studied by means of extensive molecular-dynamics simulations. The effect of LMWH on IFNγ signalling inside stimulated WISH cells was investigated by measuring its antiproliferative activity and the translocation of phosphorylated STAT1 in the nucleus. We found that LMWH binds with high affinity to IFNγ and is able to fully inhibit the interaction with its cellular receptor. It also influences the biological activity of IL-6 by binding to either IL-6 or IL-6/IL-6Rα, thus preventing the formation of the IL-6/IL-6Rα/gp130 signalling complex. These findings shed light on the molecular mechanism of the anti-inflammatory action of LMWH and underpin its ability to influence favourably conditions characterised by overexpression of these two cytokines. Such conditions are not only associated with autoimmune diseases, but also with inflammatory processes, in particular with COVID-19. Our results put forward heparin as a promising means for the prevention and suppression of severe CRS and encourage further investigations on its applicability as an anti-inflammatory agent.


Assuntos
Anti-Inflamatórios/farmacologia , Anticoagulantes/farmacologia , Heparina de Baixo Peso Molecular/farmacologia , Interferon gama/imunologia , Interleucina-6/imunologia , COVID-19/tratamento farmacológico , COVID-19/imunologia , Linhagem Celular , Humanos , Modelos Moleculares , Receptores de Interleucina-6/imunologia , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/imunologia
2.
Ann Palliat Med ; 10(8): 8939-8951, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34488381

RESUMO

BACKGROUND: A systematic review and meta-analysis were conducted to explore the clinical efficacy and coagulation function of regional citrate anticoagulation (RCA) in continuous renal replacement therapy (CRRT) in critically ill patients, to provide an effective treatment options for CRRT in severe patients. METHODS: The English databases Embase, Medline, PubMed, Ovid, Springer, and Web of Science were searched to screen for randomized controlled trials (RCTs) on RCA in the CRRT treatment of critically ill patients published before June 1, 2020. Meta analysis using the RevMan5.3 provided by the Cochrane collaboration network. The search terms included "citrate anticoagulation", "patient in severe condition", "CRRT", "clinical effect", and "coagulation function". RESULTS: ten articles meeting requirements were included, comprising 1,411 subjects. Meta-analysis results showed that after treatment, total calcium/ionized calcium (totCa/ionCa) [mean difference (MD) =0.05; 95% confidence interval (CI): (-0.02 to 0.12); Z=1.31; P=0.19], prothrombin time [MD =4.51; 95% CI: (2.77, 6.24); Z=5.10; P<0.00001], activated partial thromboplastin time [MD =2.56; 95% CI: (1.17, 3.95); Z=3.61; P=0.0003], and thrombin time [MD =4.22; 95% CI: (2.07, 6.36); Z=3.85; P=0.0001] all increased. However, platelet count [MD =-5.75; 95% CI: (-8.85, -2.64); Z=3.63; P=0.0003], cystatin [MD =-0.39; 95% CI: (-0.63, -0.15); Z=3.22; P=0.001], alanine aminotransferase [MD =-17.63; 95% CI: (-20.09, -15.16); Z=14.02; P<0.00001], aspartate aminotransferase [MD =-6.49; 95% CI: (-11.94, -1.04); Z=2.33; P=0.02], creatinine [MD =-3.70; 95% CI: (-5.08, -2.32); Z=5.24; P<0.00001], and total bilirubin [MD =-3.65; 95% CI: (-5.91, -1.40); Z=3.18; P=0.001] all decreased. Except for totCa/ionCa, the differences in other indicators were not statistically significant compared with the control group. DISCUSSION: RCA can significantly improve the clinical efficacy and blood coagulation indicators of CRRT for severely ill patients.


Assuntos
Terapia de Substituição Renal Contínua , Anticoagulantes/farmacologia , Anticoagulantes/uso terapêutico , Coagulação Sanguínea , Citratos/farmacologia , Ácido Cítrico/farmacologia , Ácido Cítrico/uso terapêutico , Humanos , Terapia de Substituição Renal , Resultado do Tratamento
4.
Mater Sci Eng C Mater Biol Appl ; 129: 112405, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34579917

RESUMO

Due to the uncontrollable anticoagulant activity and limited source, Heparin, which is commonly used in clinical anticoagulation therapies, faces the risk of spontaneous bleeding and thrombocytopenia. Herein, a series of anionic poly(amino acid) s poly (l-Serine-ran-L-Glutamic acid-ran-L-Cysteine-SO3) (PSEC-SO3) were prepared by the controlled Ring Opening Polymerization (ROP) of N-Carboxyanhydrides (NCAs). The anticoagulant activities of PSEC-SO3 can be regulated by simply adjusting the feeding ratio of monomers. In vitro tests show that these polypeptides can effectively prolong the Activated Partical Thromboplastin Time (APTT) and inhibit Factor IIa and Factor Xa, but has no significant effect on Prothrombin Time (PT) and Thrombin Time (TT), which indicates that PSEC-SO3 mainly act on the intrinsic pathway. In summary, the activity-tunable heparin-like polypeptides are expected to have good application prospects in the anticoagulant field.


Assuntos
Anticoagulantes , Heparina , Anticoagulantes/farmacologia , Heparina/farmacologia , Tempo de Tromboplastina Parcial , Peptídeos/farmacologia , Solubilidade
5.
Int J Mol Sci ; 22(17)2021 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-34502240

RESUMO

Blood platelets are considered as promising candidates as easily-accessible biomarkers of mitochondrial functioning. However, their high sensitivity to various stimulus types may potentially affect mitochondrial respiration and lead to artefactual outcomes. Therefore, it is crucial to identify the factors associated with platelet preparation that may lead to changes in mitochondrial respiration. A combination of flow cytometry and advanced respirometry was used to examine the effect of blood anticoagulants, the media used to suspend isolated platelets, respiration buffers, storage time and ADP stimulation on platelet activation and platelet mitochondria respiration. Our results clearly show that all the mentioned factors can affect platelet mitochondrial respiration. Briefly, (i) the use of EDTA as anticoagulant led to a significant increase in the dissipative component of respiration (LEAK), (ii) the use of plasma for the suspension of isolated platelets with MiR05 as a respiration buffer allows high electron transfer capacity and low platelet activation, and (iii) ADP stimulation increases physiological coupling respiration (ROUTINE). Significant associations were observed between platelet activation markers and mitochondrial respiration at different preparation steps; however, the fact that these relationships were not always apparent suggests that the method of platelet preparation may have a greater impact on mitochondrial respiration than the platelet activation itself.


Assuntos
Anticoagulantes/farmacologia , Plaquetas/fisiologia , Respiração Celular/fisiologia , Meios de Cultura/farmacologia , Mitocôndrias/fisiologia , Ativação Plaquetária , Plaquetas/efeitos dos fármacos , Citometria de Fluxo , Humanos , Mitocôndrias/efeitos dos fármacos
7.
Int J Mol Sci ; 22(15)2021 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-34360665

RESUMO

In this work we examined the properties of thrombin-binding aptamer (TBA) modified by the introduction of inversion of polarity sites (IPS) in order to assess the effect of modification on the activation of TBA to serve as DNAzyme with peroxidase-like activity. Two oligonucleotides were designed to possess one (IPS1) or three (IPS2) inversion sites. TBA typically forms antiparallel G-quadruplexes with two G-tetrads, which exhibits very low DNAzyme peroxidise activity. DNAzyme activity is generally attributed to parallel G-quadruplexes. Hence, inversion of polarity was introduced in the TBA molecule to force the change of G-quadruplex topology. All oligonucleotides were characterized using circular dichroism and UV-Vis melting profiles. Next, the activity of the DNAzymes formed by studied oligonucleotides and hemin was investigated. The enhancement of peroxidase activity was observed when inversion of polarity was introduced. DNAzyme based on IPS2 showed the highest peroxidase activity in the presence of K+ or NH4+ ions. This proves that inversion of polarity can be used to convert a low-activity DNAzyme into a DNAzyme with high activity. Since TBA is known for its anticoagulant properties, the relevant experiments with IPS1 and IPS2 oligonucleotides were performed. Both IPS1 and IPS2 retain some anticoagulant activity in comparison to TBA in the reaction with fibrinogen. Additionally, the introduction of inversion of polarity makes these oligonucleotides more resistant to nucleases.


Assuntos
Anticoagulantes/farmacologia , Aptâmeros de Nucleotídeos/farmacologia , DNA Catalítico/metabolismo , Fibrinogênio/metabolismo , Quadruplex G , Hemina/metabolismo , Aptâmeros de Nucleotídeos/química , Dicroísmo Circular , Humanos , Modelos Moleculares
8.
Medicine (Baltimore) ; 100(32): e26883, 2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34397907

RESUMO

BACKGROUND AND PURPOSE: This study aimed to evaluate the comparative efficacy and safety of 4 non-vitamin K antagonist oral anticoagulants (NOACs) and warfarin in Asians with non-valvular atrial fibrillation in real-world practice through a network meta-analysis of observational studies. METHODS: We searched multiple comprehensive databases (PubMed, Embase, and Cochrane library) for studies published until August 2020. Hazard ratios and 95% confidence intervals were used for the pooled estimates. Efficacy outcomes included ischemic stroke (IS), stroke/systemic embolism (SSE), myocardial infarction (MI), and all-cause mortality, and safety outcomes included major bleeding, gastrointestinal (GI) bleeding, and intracerebral hemorrhage (ICH). The P score was calculated for ranking probabilities. Subgroup analyses were separately performed in accordance with the dosage range of NOACs ("standard-" and "low-dose"). RESULTS: A total of 11, 6, and 8 studies were allocated to the total population, standard-dose group, and low-dose group, respectively. In the total study population, edoxaban ranked the best in terms of IS and ICH prevention and apixaban ranked the best for SSE, major bleeding, and GI bleeding. In the standard-dose regimen, apixaban ranked the best in terms of IS and SSE prevention. For major bleeding, GI bleeding, and ICH, edoxaban ranked the best. In the low-dose regimen, edoxaban ranked the best for IS, SSE, GI bleeding, and ICH prevention. For major bleeding prevention, apixaban ranked best. CONCLUSIONS: All 4 NOACs had different efficacy and safety outcomes according to their type and dosage. Apixaban and edoxaban might be relatively better and more well-balanced treatment for Asian patients with non-valvular atrial fibrillation.


Assuntos
Fibrilação Atrial , Inibidores do Fator Xa , Acidente Vascular Cerebral , Varfarina/farmacologia , Anticoagulantes/farmacologia , Grupo com Ancestrais do Continente Asiático/estatística & dados numéricos , Fibrilação Atrial/etiologia , Fibrilação Atrial/prevenção & controle , Inibidores do Fator Xa/classificação , Inibidores do Fator Xa/farmacologia , Humanos , Avaliação de Resultados em Cuidados de Saúde , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/tratamento farmacológico
9.
Molecules ; 26(16)2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34443462

RESUMO

Ajuga bracteosa Wall. ex Benth. is an endangered medicinal herb traditionally used against different ailments. The present study aimed to create new insight into the fundamental mechanisms of genetic transformation and the biological activities of this plant. We transformed the A. bracteosa plant with rol genes of Agrobacterium rhizogenes and raised the regenerants from the hairy roots. These transgenic regenerants were screened for in vitro antioxidant activities, a range of in vivo assays, elemental analysis, polyphenol content, and different phytochemicals found through HPLC. Among 18 polyphenolic standards, kaempferol was most abundant in all transgenic lines. Furthermore, transgenic line 3 (ABRL3) showed maximum phenolics and flavonoids content among all tested plant extracts. ABRL3 also demonstrated the highest total antioxidant capacity (8.16 ± 1 µg AAE/mg), total reducing power, (6.60 ± 1.17 µg AAE/mg), DPPH activity (IC50 = 59.5 ± 0.8 µg/mL), hydroxyl ion scavenging (IC50 = 122.5 ± 0.90 µg/mL), and iron-chelating power (IC50 = 154.8 ± 2 µg/mL). Moreover, transformed plant extracts produced significant analgesic, anti-inflammatory, anticoagulant, and antidepressant activities in BALB/c mice models. In conclusion, transgenic regenerants of A. bracteosa pose better antioxidant and pharmacological properties under the effect of rol genes as compared to wild-type plants.


Assuntos
Ajuga/química , Polifenóis/farmacologia , Regeneração , Analgésicos/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Anticoagulantes/farmacologia , Antidepressivos/farmacologia , Antioxidantes/análise , Bioensaio , Compostos de Bifenilo/química , Cromatografia Líquida de Alta Pressão , Elementos Químicos , Flavonoides/análise , Sequestradores de Radicais Livres/química , Hidróxidos/química , Concentração Inibidora 50 , Quelantes de Ferro/farmacologia , Masculino , Camundongos Endogâmicos BALB C , Fenóis/análise , Picratos/química , Plantas Geneticamente Modificadas , Regeneração/efeitos dos fármacos
10.
Int J Mol Sci ; 22(16)2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34445665

RESUMO

Mast cell disease is an epigenetically and genetically determined disease entity with very diverse clinical manifestations in potentially every system and tissue due to inap pro priate release of variable subsets of mast cell mediators together with accumulation of either morphologically normal or altered mast cells. Easy bruising, excessive bleeding, and aberrancies of erythropoiesis can frequently be observed in patients with mast cell disease. A thorough history, including a family history, will guide the appropriate work-up, and laboratory evaluations may provide clues to diagnosis. In recent years, our understanding of the involvement of coagulation and anticoagulant pathways, the fibrinolytic system, and erythropoiesis in the pathophysiology of mast cell disease has increased considerably. This review summarizes current knowledge of the impact of the disturbed hemostatic and erythropoietic balance in patients with mast cell disease and describes options of treatment.


Assuntos
Eritropoese/fisiologia , Hemostasia/fisiologia , Mastocitose/sangue , Anticoagulantes/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Eritropoese/efeitos dos fármacos , Fibrinólise/efeitos dos fármacos , Fibrinolíticos/farmacologia , Hemostasia/efeitos dos fármacos , Heparina/farmacologia , Humanos , Mastocitose/imunologia , Mastocitose/fisiopatologia
11.
Molecules ; 26(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34361773

RESUMO

The thrombin binding aptamer (TBA) is a promising nucleic acid-based anticoagulant. We studied the effects of chemical modifications, such as dendrimer Trebler and NHS carboxy group, on TBA with respect to its structures and thrombin binding affinity. The two dendrimer modifications were incorporated into the TBA at the 5' end and the NHS carboxy group was added into the thymine residues in the thrombin binding site of the TBA G-quadruplex (at T4, T13 and both T4/T13) using solid phase oligonucleotide synthesis. Circular dichroism (CD) spectroscopy confirmed that all of these modified TBA variants fold into a stable G-quadruplex. The binding affinity of TBA variants with thrombin was measured by surface plasmon resonance (SPR). The binding patterns and equilibrium dissociation constants (KD) of the modified TBAs are very similar to that of the native TBA. Molecular dynamics simulations studies indicate that the additional interactions or stability enhancement introduced by the modifications are minimized either by the disruption of TBA-thrombin interactions or destabilization elsewhere in the aptamer, providing a rational explanation for our experimental data. Overall, this study identifies potential positions on the TBA that can be modified without adversely affecting its structure and thrombin binding preference, which could be useful in the design and development of more functional TBA analogues.


Assuntos
Anticoagulantes/síntese química , Aptâmeros de Nucleotídeos/síntese química , Quadruplex G , Oligonucleotídeos/síntese química , Trombina/química , Anticoagulantes/metabolismo , Anticoagulantes/farmacologia , Aptâmeros de Nucleotídeos/metabolismo , Aptâmeros de Nucleotídeos/farmacologia , Sequência de Bases , Sítios de Ligação , Coagulação Sanguínea/efeitos dos fármacos , Dendrímeros/química , Humanos , Cinética , Simulação de Dinâmica Molecular , Conformação de Ácido Nucleico , Oligonucleotídeos/metabolismo , Ligação Proteica , Termodinâmica , Trombina/antagonistas & inibidores , Trombina/metabolismo
12.
Postgrad Med ; 133(sup1): 71-79, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34255597

RESUMO

Cancer is a leading cause of venous thromboembolism (VTE), which contributes to significant morbidity and mortality in these patients. Increased thrombotic risk in cancer patients is modified by tumor-specific biology, disease-directed interventions, and individual comorbidities. Risk stratification for prophylaxis and treatment requires regular reevaluation of these factors, which can be facilitated by validated prediction tools. This review also discusses large clinical trial data (SELECT-D, HOKUSAI-VTE, ADAM VTE, CARAVAGGIO) demonstrating that direct oral anticoagulants (DOACs) are effective in the treatment of cancer-associated VTE, with comparable efficacy to the traditional choice of low molecular weight heparin. In the prophylactic setting derived from patients with cancer with increased VTE risk, DOACs also reduced the incidence of VTE with only modest increases in bleeding risk. The ease of DOAC administration and acceptable risk profile in the carefully selected patient make them an appealing choice for anticoagulation. In instances where the risk of gastrointestinal bleeding is of concern, apixaban, in particular, may still be a suitable option in place of LMWH. These improvements in our anticoagulation approach to cancer-associated VTE are well-timed to accompany the recent advances in disease-directed therapies that are enabling patients to live longer with cancer and therefore at increased risk of complications such as VTE.


Assuntos
Anticoagulantes/farmacologia , Quimioprevenção , Neoplasias/complicações , Risco Ajustado/métodos , Medição de Risco/métodos , Tromboembolia Venosa , Quimioprevenção/métodos , Quimioprevenção/tendências , Humanos , Seleção de Pacientes , Resultado do Tratamento , Tromboembolia Venosa/etiologia , Tromboembolia Venosa/prevenção & controle
13.
Blood Coagul Fibrinolysis ; 32(5): 305-311, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34231501

RESUMO

Treatment of venous thromboembolism with concomitant thrombocytopenia is challenging. The platelet threshold for safe administration of anticoagulants is under debate, with minimum platelet count of 50 × 109/l being recommended as the safe cutoff. However, some evidence suggests administration of anticoagulants may still be safe at platelet levels of 30 × 109/l. Therefore, we developed an in-vitro thromboelastography (TEG) study to examine the effect of therapeutic or prophylactic levels of unfractionated heparin (UFH) and low molecular weight heparin (LMWH) on the clotting profile of platelet-reduced whole blood. Using magnetic bead-based antibody chromatography, platelets were removed to achieve platelet-depleted blood (<10 × 109/l of platelets). Platelet-depleted blood was then mixed with whole blood to produce blood samples with platelet counts of 30 × 109, 50 × 109 and 150 × 109/l. These blood samples were incubated with therapeutic or prophylactic levels of UFH or LMWH in disposable TEG cups. Clotting was initiated with 10 mmol/l calcium and optimized tissue factor levels for each anticoagulant used (2.25 pmol/l for UFH and 2.05 pmol/l for LMWH). Clotting was monitored by TEG at 37 °C for 180 min. The following TEG parameters were evaluated: R (time to clot), maximum amplitude (strength of clot) and area under the curve in 15 min (overall speed and strength of the clot at 15 min of clotting). No statistically significant differences were observed between platelet counts of 30 × 109 and 50 × 109/l for R, maximum amplitude or area under the curve in 15 min for most of the therapeutic and prophylactic doses of UFH and LMWH tested in this study. Use of anticoagulants compromised all of the TEG parameters relative to a normal platelet count of 150 × 109/l, in a dose dependent manner. The current study demonstrates that in-vitro clotting is impaired with use and increasing doses of anticoagulants. Despite this observation, we did not observe a significant difference in clotting between platelet levels of 30 × 109 and 50 × 109/l. Overall, this work provides further insight in the debated use of anticoagulants in patients with venous thromboembolism and concomitant thrombocytopenia, and provides support for possible use of anticoagulants at lower platelet thresholds.


Assuntos
Anticoagulantes/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Plaquetas , Heparina de Baixo Peso Molecular/farmacologia , Heparina/farmacologia , Plaquetas/efeitos dos fármacos , Humanos , Contagem de Plaquetas , Tromboelastografia , Trombocitopenia/sangue , Tromboembolia Venosa/sangue
15.
Forensic Sci Int ; 325: 110876, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34216943

RESUMO

The age estimation of blood traces provides important leads for the chronological assessment of criminal events and their reconstruction. To determine bloodstain age, experimental comparative data from a laboratory environment are used. Under these conditions the utilization of anticoagulants such as EDTA helps to suppress the blood clotting mechanism to allow the examination over a longer time period. This unnatural prevention of blood coagulation is highly questionable when estimating bloodstain age, since the blood's physical and chemical properties are altered. For this reason, the authors determined actual influence of EDTA on blood spectra over time in order to formulate a statement as to whether this effect can be measured. Human and porcine blood samples were aged under controlled conditions. The resulting UV/VIS spectra were separated into their individual components using signal separation techniques, allowing the changes in the ratios of the individual hemoglobin derivatives to be observed over time. The results show a significant influence of EDTA on the conversion of oxyhemoglobin to methemoglobin and a minor influence on the conversion of methemoglobin to hemichrome within the relevant time range of 5-100 h. The use of EDTA thus slows down the aging process of blood spots. To illustrate the great influence of EDTA, spectra of untreated pig blood samples were included as comparison data. These show that the difference between EDTA-treated and untreated blood samples is as great as the difference between human blood and pig blood. As a consequence of our findings experimental comparative data for the age estimation of bloodstains should never result from EDTA-treated blood.


Assuntos
Anticoagulantes/farmacologia , Manchas de Sangue , Ácido Edético/farmacologia , Animais , Feminino , Medicina Legal , Hemeproteínas/análise , Humanos , Masculino , Metemoglobina/análise , Oxiemoglobinas/análise , Espectrofotometria Ultravioleta , Suínos , Fatores de Tempo
16.
Nat Protoc ; 16(8): 3981-4003, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34215864

RESUMO

Thrombin generation (TG) assays are used widely to investigate both diseases and drugs that impact thrombosis and bleeding. TG assays were also instrumental in the identification of thrombogenic impurities in immune globulin products, which were associated with thrombotic adverse events in patients. TG assays are therefore now used by quality control laboratories of plasma derivative drug manufacturers and regulatory agencies responsible for the safety testing and release of immune globulin products. In this protocol, we describe a robust and sensitive version of the TG assay for quantitative measurement of thrombogenic activity in immune globulin products. Compared with the version of the assay commonly used in clinical laboratories that compares individual patient plasma samples with normal donor samples, our TG assay is suitable for quick (170-260 min) semiautomated analysis of multiple drug samples against the World Health Organization international standard for factor XIa. Commercially available reagents can be used for the assay, and it does not require specialized equipment. The protocol can be easily adapted for the measurement of the procoagulant activity of other biopharmaceuticals, e.g., coagulation factors.


Assuntos
Anticoagulantes/farmacologia , Fator XIa/metabolismo , Trombina/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos
17.
Adv Healthc Mater ; 10(19): e2100839, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34218526

RESUMO

Small-diameter vascular grafts (inner diameter < 6 mm) are useful in treating cardiovascular diseases. The off-the-shelf small-diameter vascular grafts for clinical applications remain a great limitation owing to their thrombogenicity or intimal hyperplasia. Herein, bilayer anticoagulant hydrogel tubes with poly(ε-caprolactone) (PCL) sheaths are prepared by freeze-thawing and electrospinning, which contain nanofibrillated cellulose (NFC)/poly(vinyl alcohol) (PVA)-heparin/poly-L-lysine nanoparticles tube as an inner layer and PCL sheath as an outer layer. The structure, anticoagulant property, and biocompatibility of the inner layer are studied. The effects of thickness of the outer layer on perfusion performance and mechanical property of hydrogel tubes with PCL sheaths (PCL-NFC/PVA-NPs tubes) are investigated. The effect of compliance of PCL-NFC/PVA-NPs tubes on their blood flow is studied by numerical simulation. The tissue compatibility and the patency of PCL-NFC/PVA-NPs tubes are evaluated by implantation in subcutaneous tissue of rats and carotid artery of rabbits. PCL-NFC/PVA-NPs tubes have prominent anticoagulation, sufficient burst pressure and good compliance similar to native arteries. PCL-NFC/PVA-NPs tubes facilitate infiltration of host cells and achieve active proliferation of recruited cells, which will be a promising candidate for small-diameter vascular grafts.


Assuntos
Anticoagulantes , Hidrogéis , Animais , Anticoagulantes/farmacologia , Prótese Vascular , Caproatos , Lactonas , Poliésteres , Coelhos , Ratos , Tecidos Suporte
18.
J Chem Inf Model ; 61(8): 4045-4057, 2021 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-34292735

RESUMO

The release of anticoagulant drugs such as warfarin from human serum albumin (HSA) has been important not only mechanistically but also clinically for patients who take multiple drugs simultaneously. In this study, the role of some commonly used drugs, including s-ibuprofen, ascorbic acid, and salicylic acid, was investigated in the release of warfarin bound to HSA in silico. The effects of the aforementioned drugs on the HSA-warfarin complex were investigated with molecular dynamics (MD) simulations using two approaches; in the first perspective, molecular docking was used to model the interaction of each drug with the HSA-warfarin complex, and in the second approach, drugs were positioned randomly and distant from the binary complex (HSA-warfarin) in a physiologically relevant concentration. The results obtained from both approaches indicated that s-ibuprofen and ascorbic acid both displayed allosteric effects on the release of warfarin from HSA. Although ascorbic acid aided in warfarin release, leading to destabilization of HSA, ibuprofen demonstrated a stabilizing effect on releasing the anticoagulant drug through several noncovalent interactions, including hydrophobic, electrostatic, and hydrogen-bonding interactions with the protein. The calculated binding free energy and energy contribution of involved residues using the molecular mechanics-Poisson Boltzmann surface area (MM-PBSA) method, along with root mean square deviation (RMSD) values, protein gyration, and free energy surface (FES) mapping of the protein, provided valuable details on the nature of the interactions of each drug on the release of warfarin from HSA. These results can provide important information on the mechanisms of anticoagulant release that has not been revealed in molecular details previously.


Assuntos
Ibuprofeno , Varfarina , Anticoagulantes/farmacologia , Sítios de Ligação , Humanos , Simulação de Acoplamento Molecular , Ligação Proteica , Salicilatos , Albumina Sérica/metabolismo , Albumina Sérica Humana
19.
Nutrients ; 13(5)2021 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-34063322

RESUMO

Preservation of vascular endothelium integrity and functionality represents an unmet medical need. Indeed, endothelial dysfunction leads to decreased nitric oxide biosynthesis, which is prodromic of hypertension and hypercoagulability. In this panorama, the nutraceutical supplement Taurisolo®, a polyphenolic extract from Aglianico cultivar grape, rich in catechin and procyanidins, was evaluated as a vasoprotective, vasorelaxing, anti-hypertensive and anti-coagulant agent in: cell lines, isolated vessels, in vivo models of chronic hypertension and hypercoagulability, and in clinical tests of endothelial reactivity. Taurisolo® demonstrated to fully protect vascular cell viability from oxidative stimulus at 100 µg/mL and evoke vasorelaxing effects (Emax = 80.6% ± 1.9 and pEC50 = 1.19 ± 0.03) by activation of the Sirtuins-AMPK-pathway. Moreover, Taurisolo®, chronically administered at 20 mg/Kg/die in in vivo experiments, inhibited the onset of cardiac hypertrophy (heart weight/rat weight = 3.96 ± 0.09 vs. 4.30 ± 0.03), hypercoagulability (decrease of fibrinogen vs. control: p < 0.01) and hypertension (mean of Psys: 200 ± 2 vs. control 234 ± 2 mmHg) and improved endothelial function (Emax = 88.9% ± 1.5 vs. control 59.6% ± 3.6; flow-mediated dilation in healthy volunteers after 400 mg twice daily for 8 weeks vs. baseline: p = 0.019). In conclusion, Taurisolo® preserves the vascular function against ox-inflamm-ageing process and the consequent cardiovascular accidents.


Assuntos
Suplementos Nutricionais , Endotélio Vascular/efeitos dos fármacos , Extratos Vegetais/farmacologia , Polifenóis/farmacologia , Vitis/química , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Anticoagulantes/farmacologia , Anti-Hipertensivos/farmacologia , Catequina/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Humanos , Hipertensão/tratamento farmacológico , Masculino , Estresse Oxidativo/efeitos dos fármacos , Proantocianidinas/farmacologia , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Sirtuínas/metabolismo , Trombofilia/tratamento farmacológico , Vasodilatadores/farmacologia
20.
In Vivo ; 35(4): 1999-2004, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34182474

RESUMO

BACKGROUND/AIM: We examined the mechanism of nitric oxide (NO) production in a tissue-factor (TF)-induced disseminated intravascular coagulation (DIC) model in rats, using inducible nitric oxide synthase (iNOS) inhibitor (L-NIL), endothelial nitric oxide synthase (eNOS) inhibitor (L-NAME), Factor Xa inhibitor (DX-9065a), and thrombin inhibitor argatroban. MATERIALS AND METHODS: Experimental DIC was induced by sustained infusion of 3.75 U/kg TF for 4 h via the tail vein. We then investigated the effect of these four agents on TF-induced DIC. RESULTS: Administration of L-NIL or L-NAME during induction of TF-induced DIC did not affect hemostatic markers, whereas elevated plasma levels of NO metabolites (NOX) were significantly suppressed by co-administration of L-NAME. A significant increase in eNOS-mRNA expression was observed in the TF-induced DIC model. Argatroban almost completely suppressed eNOS-mRNA expression. CONCLUSION: eNOS plays an important role in the NO production in the TF-induced DIC, and thrombin is a key stimulant of eNOS-mRNA expression in this model.


Assuntos
Coagulação Intravascular Disseminada , Óxido Nítrico , Animais , Anticoagulantes/farmacologia , Inibidores Enzimáticos , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Ratos , Ratos Wistar , Tromboplastina
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