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1.
Einstein (Sao Paulo) ; 18: eRC4582, 2020.
Artigo em Inglês, Português | MEDLINE | ID: mdl-31531557

RESUMO

The correct identification of erythrocyte antibodies is fundamental for the searching for compatible blood and haemolytic transfusion reactions prevention. Antibodies against antigens of high prevalence are difficult to identify because of the rarity of their occurrence and unavailability of negative red cells for confirmation. We report a case of 46-years-old woman, diagnosed with hemoglobinopathy, and who had symptomatic fall in hemoglobin levels (5.3g/dL) after blood transfusion suggestive of transfusion reaction. The patient's blood type was O RhD-positive. Irregular antibody screening was positive and demonstrated a panreaction against all erythrocytes tested, but this result was not reactive with dithiothreitol. Using negative red cells for antigens of high prevalence of our inventory we could identify in the serum of the same erythrocytes an anti-Holley antibody associated with anti-E. Molecular analysis confirmed that the patient was negative for E and Holley antigens. The crossmath with compatible units confirmed the results. Holley is a high prevalence antigen of the Dombrock blood system whose negative phenotype is extremely rare in all populations and is associated with hemolytic transfusion reactions. This is an antibody that is difficult to identify because laboratories need to have experience in solving complex cases, and have available a large stock of rare sera and erythrocytes, as well other tools such as enzymes, thiol reagents and molecular tests. The correct identification of a rare antibody is initial and mandatory for searching of compatible donors, and to guarantee a satisfactory transfusional support.


Assuntos
Anticorpos/imunologia , Antígenos de Grupos Sanguíneos/imunologia , Incompatibilidade de Grupos Sanguíneos/imunologia , Reação Transfusional/imunologia , Anticorpos/sangue , Eritrócitos/imunologia , Feminino , Testes Hematológicos/métodos , Humanos , Imunoglobulinas/sangue , Isoanticorpos/imunologia , Pessoa de Meia-Idade
2.
Adv Exp Med Biol ; 1131: 625-648, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31646528

RESUMO

Free Calcium (Ca2+) is an important and universal signalling entity in all cells, red blood cells included. Although mature mammalian red blood cells are believed to not contain organelles as Ca2+ stores such as the endoplasmic reticulum or mitochondria, a 20,000-fold gradient based on a intracellular Ca2+ concentration of approximately 60 nM vs. an extracellular concentration of 1.2 mM makes Ca2+-permeable channels a major signalling tool of red blood cells. However, the internal Ca2+ concentration is tightly controlled, regulated and maintained primarily by the Ca2+ pumps PMCA1 and PMCA4. Within the last two decades it became evident that an increased intracellular Ca2+ is associated with red blood cell clearance in the spleen and promotes red blood cell aggregability and clot formation. In contrast to this rather uncontrolled deadly Ca2+ signals only recently it became evident, that a temporal increase in intracellular Ca2+ can also have positive effects such as the modulation of the red blood cells O2 binding properties or even be vital for brief transient cellular volume adaptation when passing constrictions like small capillaries or slits in the spleen. Here we give an overview of Ca2+ channels and Ca2+-regulated channels in red blood cells, namely the Gárdos channel, the non-selective voltage dependent cation channel, Piezo1, the NMDA receptor, VDAC, TRPC channels, CaV2.1, a Ca2+-inhibited channel novel to red blood cells and i.a. relate these channels to the molecular unknown sickle cell disease conductance Psickle. Particular attention is given to correlation of functional measurements with molecular entities as well as the physiological and pathophysiological function of these channels. This view is in constant progress and in particular the understanding of the interaction of several ion channels in a physiological context just started. This includes on the one hand channelopathies, where a mutation of the ion channel is the direct cause of the disease, like Hereditary Xerocytosis and the Gárdos Channelopathy. On the other hand it applies to red blood cell related diseases where an altered channel activity is a secondary effect like in sickle cell disease or thalassemia. Also these secondary effects should receive medical and pharmacologic attention because they can be crucial when it comes to the life-threatening symptoms of the disease.


Assuntos
Canais de Cálcio , Animais , Cálcio/metabolismo , Canais de Cálcio/genética , Canais de Cálcio/metabolismo , Eritrócitos/fisiologia , Doenças Hematológicas/fisiopatologia , Humanos , Mutação
4.
Immunohematology ; 35(3): 95-101, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31621367

RESUMO

CONCLUSIONS: This report is part of a series reporting the proceedings from the International Society of Blood Transfusion (ISBT) Working Party on Immunohaematology Workshop on the Clinical Significance of Red Blood Cell Alloantibodies. The aim of the workshop was to review information regarding the clinical significance of alloantibodies to red blood cell antigens recognized by the ISBT. The first 12 systems will be covered in this report. It is understandable that many of the most clinically important antibodies are directed toward antigens found in the blood group systems discovered earlier in history. The ABO system was the first to be discovered and remains the most clinically important regarding transfusion.


Assuntos
Sistema do Grupo Sanguíneo ABO , Protestantismo , Antígenos de Grupos Sanguíneos , Transfusão de Sangue , Eritrócitos , Humanos , Isoanticorpos
5.
Immunohematology ; 35(3): 105-107, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31621369

RESUMO

CONCLUSIONS: A workshop on the clinical significance of red blood cell alloantibodies, organized by the Executive Committee of the Working Party on Immunohaematology of the International Society of Blood Transfusion (ISBT), took place in Dubai, United Arab Emirates, on 9 September 2016, in conjunction with the 34th International Congress of the ISBT. This event was funded by the ISBT Academy, founded in 2011, to support educational and knowledge activities. This report is a summary of that meeting.


Assuntos
Transfusão de Sangue , Eritrócitos , Humanos , Isoanticorpos
6.
Biochem Med (Zagreb) ; 29(3): 030801, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31624465

RESUMO

Introduction: It has already been reported that subinhibitory concentrations of ß-lactam antibiotics can cause abnormal changes of bacterial forms, such as spheroplasts. Herein we report a case of Croatian male patient with Escherichia coli spheroplasts present in urine after treatment with tazobactam, on the tenth day of hospitalization. The aim of this report is to emphasize the inability of imaging based automated urine analysers to recognize some relatively uncommon forms of bacterial presentation in urine sediment. Materials and methods: During routine urine analysis, unusual particles were observed in patient urine. Urine sediment was examined by two urine analysers: Atellica 1500 (Siemens, Germany) and Iris iQ200 (Beckman Coulter, USA). Additionally, urine was sent for culture testing to Microbiology department. Results: Both urine analysers didn't indicate presence of bacteria in urine sediment. Unusual particles observed on the tenth day were classified as erythrocytes by both instruments. Dipstick test showed blood trace and microscopic analysis revealed bacteria in urine. Urine culture was positive for Escherichia coli. Careful examination of urine sediment has confirmed that shapes present in urine were abnormal bacterial forms called spheroplasts. Conclusions: Imaging based automated urine analysers are not able to recognize bacterial spheroplasts in urine sediment misclassifying it as erythrocytes. Microscopic examination remains the gold standard for urines with blood trace or negative blood, in which erythrocytes are reported by urine analyser in urine sediment. Failure to identify and follow up such cases may lead to inaccurate treatment decisions and puts patient safety at risk.


Assuntos
Eritrócitos , Escherichia coli/isolamento & purificação , Esferoplastos/isolamento & purificação , Urinálise/métodos , Urinálise/normas , Croácia , Humanos , Masculino , Pessoa de Meia-Idade
7.
Klin Lab Diagn ; 64(9): 560-564, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31610109

RESUMO

Human babesiosis caused by parasitic protozoan Babesia spp. is sporadic zoonotic vector-borne infection. The course of babesiosis and prognosis depend on the type of pathogen and on the patient's immunological status. Significance this disease is a severe, often fatal course with immunocompromissed patients resembling complicated falciparum malaria. In Europe to date, more than 50 cases of confirmed human babesiosis have been reported in most cases caused by Babesia divergens. Possible there are unrecognized cases. Pathogen is an obligate intraerythrocyte parasite of vertebrate animals. The organism is transmitted from animal to man through bite of Ixodidae tick. Asexual reproduction of the parasite occurs in a vertebrate host. The pathogenesis of babesiosis is caused by the destruction of host cells. Intensive haemolysis of red blood cells leads to the development of haemolytic anemia, haematuria, jaundice, and polyorgan failure may develop. The clinical manifestations of the disease are nonspecific. Detection of intraerythrocyte parasites in blood smears stained Gimsa-Romanovsky confirms the proposed diagnosis. Blood smears and some laboratory signs from fatal cases were analyzed in the Reference-centre of E. I. Martsinovskii Institute. Original microphotographs B. divergens are shown. The main morphological forms of the parasite are shown. In addition to the well-known tetrades of parasites «Maltese Cross¼, for the first time, the parasites dividing into 6 interconnected trophozoites - "sextet" - were found. Originally, the invasion of Babesia in a normoblast is shown. An unusually high multiple invasion (14 parasites) of erythrocytes is noted. Because the patients, initially, were incorrectly diagnosed with malaria, the differential diagnosis of Babesia with Plasmodium is described step-by-step. It is important, since the treatment with antimalarial drugs is ineffective. Deviation laboratory signs are discussed. Complex morphological characteristics allowed us to speciated the parasites as B. divergens. DNA was detected in the sample with specific primers Bab di hsp70F/Bab di hsp70R and the probe Bab di hsp70P. The sequence demonstrated 99-100% and 98% similarity to the 18S rRNA gene fragment of B. divergence and Babesia venatorum, respectively. Molecular biological and serological methods of laboratory diagnosis of babesiosis are considered.


Assuntos
Babesia , Babesiose/diagnóstico , Animais , Técnicas de Laboratório Clínico , Primers do DNA , Diagnóstico Diferencial , Eritrócitos/parasitologia , Humanos , Malária Falciparum , Carrapatos/parasitologia
8.
Zhongguo Xue Xi Chong Bing Fang Zhi Za Zhi ; 31(4): 423-426, 2019 Sep 19.
Artigo em Chinês | MEDLINE | ID: mdl-31612680

RESUMO

OBJECTIVE: To evaluate the effects of intravenous injection of different blood components containing Babesia microti on B. microti infection in mice. METHODS: Healthy mice were infected with B. microti, and then blood samples were collected from the mouse orbit to prepare whole blood, serum-free blood components and pure red blood cells containing B. microti. Twenty seven BALB/c mice were divided into three groups, including the whole blood group, the serum-free blood component group and the pure red blood cell group, of 9 mice in each group, and then, each group was divided into three subgroups, of 3 mice in each subgroup, which were injected with 100 µL of blood components containing B. microti at concentrations of 9.00, 0.90, 0.09 B. microti parasites/µL (900, 90, 9 B. microti parasites) via the tail vein, respectively. Blood samples were collected from the mouse tail tip every other day since one day post-injection to prepare thin blood smears. Following Giemsa staining of blood smears, B. microti infection was identified in red blood cells using microscopy. RESULTS: Following injection of 900 B. microti parasites, B. microti was identified in the peripheral blood in the whole blood group and the serum-free blood component group 3 days post-injection, and the density of B. microti parasites started to increase 15 days post-injection and peaked 21 days post-injection, with 2.21% and 1.76% rates of B. microti infection in red blood cells, respectively. Subsequently, the density of B. microti parasites declined, and the percentage of B. microti infection in red blood cells tended to be 0 31 days post-injection. During the study period, no B. microti was found in the peripheral blood in the pure red blood cell group. Following injection of 90 B. microti parasites, B. microti was identified in the peripheral blood in the whole blood group 3 days post-injection, and the density of B. microti parasites increased 15 days post-injection and peaked 21 days post-injection, with a 1.35% rate of B. microti infection in red blood cells, while the percentage of B. microti infection in red blood cells tended to be 0 31 days post-injection. During the study period, no B. microti was detected in the peripheral blood in the serum-free blood component group or the pure red blood cell group. Following injection of 9 B. microti parasites, no B. microti was detected in the peripheral blood in the whole blood group, the serum-free blood component group or the pure red blood cell group. CONCLUSIONS: Blood components and dose of B. microti parasites may affect intravenous injection of B. microti injection in mice, and transfusion of blood components may case a risk of Babesia infection.


Assuntos
Babesia microti , Babesiose , Transfusão de Componentes Sanguíneos , Animais , Babesiose/sangue , Babesiose/transmissão , Transfusão de Componentes Sanguíneos/efeitos adversos , Eritrócitos/parasitologia , Camundongos , Camundongos Endogâmicos BALB C , Carga Parasitária , Fatores de Tempo
9.
Rinsho Ketsueki ; 60(9): 1046-1055, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31597826

RESUMO

Human iPS cells are somatic cells reprogrammed to the pluripotent state. Because of their pluripotent nature, iPS cells are now commonly used to model several developmental processes including hematopoiesis in vitro. The in vitro models can be used to study the mechanisms regulating not only normal hematopoiesis but also hematological diseases ranging from monogenic congenital disorders to genetically multifactorial malignancies. Those disease models can also be used to investigate novel treatments through procedures including high throughput drug screening. The possible clinical applications of iPS cell-derived hematopoietic cells include immunotherapy with T lymphocytes, NK cells and macrophages, and transfusion therapy with platelets and red blood cells. Platelets have now been produced from iPS cells in quantities sufficient for clinical use. By developing expandable immortalized megakaryocyte cell lines (imMKCLs), several novel drugs and turbulence-incorporated bioreactors, efficient and scalable generation of platelets was achieved. This review summarizes the current status of iPS cell research in hematopoiesis with details on iPS cell-derived platelets.


Assuntos
Plaquetas/citologia , Terapia Baseada em Transplante de Células e Tecidos , Células-Tronco Pluripotentes Induzidas/citologia , Diferenciação Celular , Eritrócitos , Hematopoese , Humanos , Imunoterapia , Células Matadoras Naturais , Macrófagos , Megacariócitos , Linfócitos T
10.
Rinsho Ketsueki ; 60(9): 1084-1091, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31597831

RESUMO

The blood supply system for transfusions in Japan functions well. However, in cases of sudden hemorrhagic shock, the swift supply of red blood cell (RBC) product might be difficult, particularly when medical care is required in remote regions and in obstetric medicine, where there is always a risk of hemorrhage. Blood pressure maintenance by infusion of volume expanders, such as crystalloids or colloids, may be insufficient to preserve the function of vital organs because they do not contain any oxygen-carrying molecules. If artificial RBCs were at hand, they could be used as a blood substitute until blood products are received from blood banks. This would save patients without degrading their quality of life. In the 1990s, we developed an artificial RBC in the form of a hemoglobin vesicle (Hb-V). Hb-V is a liposomal microparticle that encloses oxygen-carrying human Hb molecules. Different from RBCs, it has no blood type and is stable at room temperature, ensuring a long shelf-life. Its excellent biocompatibility and oxygen-carrying capacity have been proven in a number of animal experiments, and its production technique has also been established. Therefore, translational research is being designed with the aid of the Japan Agency of Medical Research and Development.


Assuntos
Substitutos Sanguíneos , Eritrócitos , Choque Hemorrágico/terapia , Pesquisa Médica Translacional , Animais , Hemoglobinas , Humanos , Japão , Oxigênio
11.
Exp Parasitol ; 206: 107771, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31585116

RESUMO

A PCR targeting mitochondrial cytochrome oxidase subunit III (cox3) for molecular detection of Babesia gibsoni infection in dogs has been developed in this study. Fifty blood samples from suspected clinical cases from dogs, brought to the veterinary college clinics, were examined for presence of B. gibsoni using conventional diagnosis by microscopic examination of Giemsa stained thin blood smears. In addition, species specific PCRs targeting ITS-1 region (BgITS-1 PCR) and nested PCR targeting 18S ribosomal RNA gene (Bg18SnPCR) were carried out. A 634 bp PCR fragment of B. gibsoni cox3 gene was amplified in positive samples from three geographical locations of Satara, Wai and Pune in Maharashtra state of India. From analysis of the sequence of the B. gibsoni cox3 gene, we found that the Indian isolate had 96-98% similarity to the isolate from Japan and China. Post sequencing, de-novo diagnostic primer pair for species specific amplification of 164 bp fragment of B. gibsonicox3 was designed and the PCR was standardized. The diagnostic results of de-novo Bgcox3 PCR were compared with BgITS-1 PCR and Bg18S nPCR. Thin blood smears detected 22% (11/50) samples positive for small form of Babesia species. The BgITS-1 PCR detected 25% samples (15/50) as positive and Bg18S nPCR detected 80% (40/50) B. gibsoni positive samples. The de-novo Bgcox3 PCR detected 66% (33/50) samples positive for B. gibsoni (at 95% CI). The analytical sensitivity of cox3 PCR was evaluated as 0.000003% parasitaemia or 09 parasites in 100  µl of blood. The de-novo diagnostic cox3 PCR did not cross react with control positive DNA from other haemoprotozoa and rickettsia like B. vogeli, Hepatozoon canis, Trypanosoma evansi, Ehrlichia canis and Anaplasma platys. Statistically, cox3 PCR had better diagnostic efficiency than ITS-1 PCR in terms of sensitivity (p = 0.0006). No statistically significant difference between results of cox3 PCR and 18S nPCR was observed (p = 0.1760). Kappa values estimated for each test pair showed fair to moderate agreement between the observations. Specificity of Bgcox3 PCR was 100% when compared with microscopy or BgITS-1 PCR. Sensitivity of Bgcox3 PCR was 100% when compared with that of Bg18S nPCR.


Assuntos
Babesia/isolamento & purificação , Babesiose/diagnóstico , Doenças do Cão/diagnóstico , Complexo IV da Cadeia de Transporte de Elétrons/genética , Mitocôndrias/enzimologia , Animais , Babesia/classificação , Babesia/genética , Babesiose/parasitologia , Sequência de Bases , Reações Cruzadas , DNA Espaçador Ribossômico/química , Doenças do Cão/parasitologia , Cães , Eritrócitos/parasitologia , Funções Verossimilhança , Filogenia , Reação em Cadeia da Polimerase/veterinária , Valor Preditivo dos Testes , RNA Ribossômico 18S/análise , Sensibilidade e Especificidade , Alinhamento de Sequência/veterinária
12.
Zhonghua Nei Ke Za Zhi ; 58(10): 777-781, 2019 Oct 01.
Artigo em Chinês | MEDLINE | ID: mdl-31594177

RESUMO

Objective: To detect the red blood cell lifespan in patients with polycythemia vera (PV), and explore the influencing factors. Methods: From February 2017 to December 2018, 27 patients with PV at Blood Diseases Hospital, Chinese Academy of Medical Science and 18 normal controls were recruited. Red blood cell lifespan was detected by endogenous carbon monoxide (CO) breath test. The related factors were analyzed. Results: The average red blood cell lifespan of 27 PV patients was 80 (range, 35-120) days (d), which was significantly shorter than that of the normal controls [110.5(69-166) d, P<0.05], namely 35.3 d shorter. The red blood cell lifespan of ten newly diagnosed patients and 17 patients who were treated with hydroxyurea and/or interferon were 98 (35-117) d and 69 (45-120) d, respectively, which were both shorter than that of the normal control (P=0.010, 0.000). Correlation analysis showed that red blood cell lifespan of patients with newly diagnosed PV was associated with JAK2 mutation allele burden (r=0.900, P=0.037), peripheral blood lymphocyte count (r=-0.742, P=0.014) and the level of serum vitamin B(12) (r=-0.821, P=0.023). Conclusion: The lifespan of red blood cells in patients with PV is about one-third shorter than normal, and is related to JAK2 mutation allele burden, absolute lymphocyte count, and serum vitamin B(12) level.


Assuntos
Testes Respiratórios/métodos , Monóxido de Carbono/análise , Monóxido de Carbono/metabolismo , Eritrócitos/patologia , Policitemia Vera/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Contagem de Eritrócitos , Feminino , Humanos , Janus Quinase 2 , Longevidade , Masculino , Pessoa de Meia-Idade
13.
Chem Biol Interact ; 313: 108821, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31525342

RESUMO

Decrease in the bioavailability of vasoactive nitric oxide (NO), derived from the endothelial nitric oxide synthase (NOS3), underlines vascular endothelial damage. Our expanding knowledge on mature red blood cells (RBCs) makes it supposable that RBCs might contribute to vascular function and integrity via their active NO synthetizing system (RBC-NOS3). This "rescue" mechanism of RBCs could be especially important during pregnancy with smoking habit, when smoking acts as an additional stressor and causes active change in the redox status. In this study RBC populations of 82 non-smoking (RBC-NS) and 75 smoking (RBC-S) pregnant women were examined. Morphological variants were followed by confocal microscopy and quantified by a microscopy based intelligent analysis software. Fluorescence activated cell sorting was used to examine the translational and posttranslational regulation of RBC-NOS, Arginase-1 and the formation of the major product of lipid peroxidation, 4-hydroxy-2-nonenal. To survey the rheological parameters of RBCs like elasticity and plasticity atomic force microscopy-based measurement was applied. Significant morphological and functional differences of RBCs were found between the non-smoking and smoking groups. The phenotypic variations in RBC-S population, even the characteristic biconcave disc-shaped cells, could be connected to impaired NOS3 activation and are compromised in their physiological properties. Membrane lipid studies reveal an elevated lipid oxidation state well paralleled with the changed elastic and plastic activities. These features can form a basic tool in the prenatal health screening conditions; hence the compensatory mechanism of RBC-S population completely fails to sense and rescue the acute oxidative stress conditions.


Assuntos
Arginase/metabolismo , Eritrócitos/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Óxido Nítrico/metabolismo , Fumar/efeitos adversos , Adulto , Aldeídos/metabolismo , Estudos de Casos e Controles , Morte Celular/efeitos dos fármacos , Eritrócitos/efeitos dos fármacos , Feminino , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Microscopia de Força Atômica , Gravidez
14.
Cell Physiol Biochem ; 53(3): 453-464, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31448885

RESUMO

BACKGROUND/AIMS: Eryptosis, the suicidal death of red blood cells (RBCs), is characterized by phosphatidylserine (PS) exposure at the cell surface. It can be catalysed by a variety of abnormal conditions and diseases. Until now, the many questions surrounding the physiology and pathophysiology of eryptosis have not been sufficiently answered. Recently, we demonstrated IgM and IgA autoantibodies (aab) to induce PS exposure on circulating RBCs of patients with autoimmune haemolytic anaemia (AIHA). However, it remained unclear how these aab lead to eryptosis. METHODS: Serum and plasma samples from patients with clinically relevant AIHA of cold type were used to induce eryptosis in O RBCs. Serum containing fresh complement from healthy donors, antibodies to complement component, and complement factor depleted sera were added to examine the influence of the complement on PS-exposure. RBC bound annexin V PE were analysed by flow cytometry. RESULTS: Eryptosis related to IgM aab was found to be dependent on complement activation and could be effectively inhibited by EDTA, serum heat inactivation and anti-C5. PS exposure increased with sequential activation of the sublytic terminal complement components C5b6, C5b-7 and was most significant at the C5b-8 stage. A decrease was observed following the formation of the lytic membrane attack complex C5b-9, either because of lysis of eryptotic RBCs or because of inhibition of eryptosis by C9. CONCLUSION: Our findings reflect new aspects on RBC destruction in AIHA as well the impact of the terminal complement complexes on the RBC membrane. The striking differences to nucleated cell apoptosis may even have physiological meaning of RBC acting as a buffer of the complement system.


Assuntos
Anemia Hemolítica Autoimune/patologia , Autoanticorpos/farmacologia , Proteínas do Sistema Complemento/metabolismo , Eriptose/efeitos dos fármacos , Imunoglobulina M/imunologia , Anemia Hemolítica Autoimune/sangue , Ativação do Complemento/efeitos dos fármacos , Complemento C5/metabolismo , Ácido Edético/farmacologia , Eritrócitos/citologia , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Humanos , Fosfatidilserinas/farmacologia
15.
16.
Chem Biodivers ; 16(10): e1900362, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31400187

RESUMO

A series of novel esters and amides was synthesized on the basis of para-coumaric acid containing isobornyl groups in ortho-positions relative to the phenolic hydroxy group. Antioxidant properties of the obtained compounds were evaluated and compared on in vitro models: radical-scavenging ability, antioxidant activity on a substrate containing the lipids of animal brain, cytotoxicity of red blood cells, antioxidant and membrane-protective properties on the model of oxidative red blood cells hemolysis. Statistically significant relationship was established between the antioxidant activity of the studied compounds in model system containing animal lipids and the parameters reflecting their antioxidant properties on the model of H2 O2 -induced hemolysis of red blood cells. It was determined that an amide with a morpholine fragment has the highest antioxidant activity. The specified derivative significantly surpassed the reference substances (parent acid, BHT) and was not inferior to the effective antioxidant 2,6-diisobornyl-4-methylphenol in terms of its properties.


Assuntos
Antioxidantes/farmacologia , Bornanos/farmacologia , Encéfalo/efeitos dos fármacos , Eritrócitos/efeitos dos fármacos , Propionatos/farmacologia , Animais , Antioxidantes/síntese química , Antioxidantes/química , Bornanos/química , Hidroxitolueno Butilado/química , Hemólise/efeitos dos fármacos , Peróxido de Hidrogênio/farmacologia , Camundongos , Estrutura Molecular , Propionatos/síntese química , Propionatos/química
17.
Nat Biotechnol ; 37(10): 1186-1197, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31427820

RESUMO

The clinical translation of cationic α-helical antimicrobial peptides (AMPs) has been hindered by structural instability, proteolytic degradation and in vivo toxicity from nonspecific membrane lysis. Although analyses of hydrophobic content and charge distribution have informed the design of synthetic AMPs with increased potency and reduced in vitro hemolysis, nonspecific membrane toxicity in vivo continues to impede AMP drug development. Here, we analyzed a 58-member library of stapled AMPs (StAMPs) based on magainin II and applied the insights from structure-function-toxicity measurements to devise an algorithm for the design of stable, protease-resistant, potent and nontoxic StAMP prototypes. We show that a lead double-stapled StAMP named Mag(i+4)1,15(A9K,B21A,N22K,S23K) can kill multidrug-resistant Gram-negative pathogens, such as colistin-resistant Acinetobacter baumannii in a mouse peritonitis-sepsis model, without observed hemolysis or renal injury in murine toxicity studies. Inputting the amino acid sequences alone, we further generated membrane-selective StAMPs of pleurocidin, CAP18 and esculentin, highlighting the generalizability of our design platform.


Assuntos
Peptídeos Catiônicos Antimicrobianos/síntese química , Bactérias/efeitos dos fármacos , Peritonite/tratamento farmacológico , Sepse/tratamento farmacológico , Animais , Antibacterianos , Linhagem Celular , Desenho de Drogas , Farmacorresistência Bacteriana , Eritrócitos/efeitos dos fármacos , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Peritonite/microbiologia , Sepse/microbiologia
18.
Int J Nanomedicine ; 14: 5323-5338, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31409990

RESUMO

Background: Candida albicans as an opportunistic fungus is one of the most important causes of late-onset morbidity and mortality in patients with major burns and severely impaired immune system. In recent years, the emergence of resistance to opportunistic fungi and toxicity of antimicrobial drugs make it necessary to develop new drugs. Methods: In the present study, we investigated anticandidal effects of indolicidin, as a representative of host defense peptide, conjugated with gold nanoparticles in fluconazole-resistant clinical isolates of C. albicans. After characterizing the conjugation of indolicidin using biophysical methodologies, the cytotoxicity and hemolytic activity of the nanocomplex were examined. In addition, the expression level of ERG11, responsible for antifungal resistance, and the immunomodulatory effect of peptide-nanomaterial conjugates were assessed. Results: Our data indicated that the nanocomplex was nontoxic for the fibroblast cells and erythrocytes. Treatment with the nanocomplex significantly reduced the expression levels of the ERG11 gene in fluconazole-resistant C. albicans isolates and the iNOS gene in macrophages. Conclusion: The study data provides a chance to develop innovative therapies for the treatment of C. albicans burn infections. However, further investigation is required to examine the efficiency of the nanocomplex.


Assuntos
Antifúngicos/farmacologia , Peptídeos Catiônicos Antimicrobianos/farmacologia , Queimaduras/microbiologia , Candida albicans/efeitos dos fármacos , Candida albicans/isolamento & purificação , Fluconazol/farmacologia , Ouro/farmacologia , Nanopartículas Metálicas/química , Animais , Peptídeos Catiônicos Antimicrobianos/química , Queimaduras/tratamento farmacológico , Candida albicans/genética , Morte Celular/efeitos dos fármacos , Farmacorresistência Fúngica/efeitos dos fármacos , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Fluconazol/química , Regulação Fúngica da Expressão Gênica/efeitos dos fármacos , Genes Fúngicos , Hemólise/efeitos dos fármacos , Humanos , Nanopartículas Metálicas/ultraestrutura , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Células NIH 3T3 , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo
20.
Int J Nanomedicine ; 14: 4817-4831, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31308660

RESUMO

Background: In vitro (1R,3S)-1-methyl-1,2,3,4-tetrahydro-ß-carboline-3-carboxyl-Lys(Pro-Ala-Lys)-Arg-Gly-Asp-Val (MTCA-KKV) adheres activated platelets, targets P-selectin and GPIIb/IIIa. This led to the development of MTCA-KKV as thrombus targeting nano-medicine. Methods: MTCA-KKV was characterized by nano-feature, anti-thrombotic activity, thrombolytic activity, thrombus target and targeting release. Results: In vivo 0.01 µmol/kg of MTCA-KKV formed nano-particles less than 100 nm in diameter, targeted thrombus, released anti-thrombotic and thrombolytic pharmacophores, prevented thrombosis and dissolved blood clots. Conclusion: Based on the profiles of targeting thrombus, targeting release, inhibiting thrombosis and dissolving blood clots MTCA-KKV is a promising nano-medicine.


Assuntos
Coagulação Sanguínea , Carbolinas/química , Carbolinas/uso terapêutico , Nanopartículas/química , Peptídeos/uso terapêutico , Trombose/sangue , Trombose/tratamento farmacológico , Administração Oral , Animais , Coagulação Sanguínea/efeitos dos fármacos , Plaquetas/efeitos dos fármacos , Carbolinas/administração & dosagem , Eritrócitos/efeitos dos fármacos , Humanos , Leucócitos/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Masculino , Nanopartículas/ultraestrutura , Selectina-P/metabolismo , Peptídeos/farmacologia , Adesividade Plaquetária/efeitos dos fármacos , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Ratos Sprague-Dawley , Espectroscopia de Infravermelho com Transformada de Fourier
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