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1.
Sci Total Environ ; 737: 140304, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32783869

RESUMO

Despite the damaging effects of pesticides glyphosate (Gly), atrazine (Atra) and fipronil (Fip) on different organisms, the mutagenic, genotoxic and morphotoxic potential of testudine erythrocytes in freshwater remains unknown. Thus, the aim of the present study is to assess the toxicological potential of these compounds in Podocnemis expansa (Amazonian turtles) neonates from eggs artificially incubated in substrate at different concentrations of herbicides Gly and Atra and insecticide Fip. Micronucleus test and other nuclear abnormalities, as well as comet assay and morphometric measurements taken of models' circulating erythrocytes were used as toxicity biomarkers. Pups exposed to Gly (groups Gly-65 ppb and Gly-6500 ppb) were the ones recording the largest amount of nuclear abnormalities; erythrocytes with multilobulated, notched and displaced nucleus were mostly frequent in groups Atra-2 ppb and Gly -65 ppb. All treatments (Gly-6500 ppb, Atra-2 ppb, Atra-200 ppb, Fip-4 ppb and Fip-400 ppb), except for group Gly-65 ppb, led to decreased erythrocyte area, increased "nuclear area: erythrocyte area" ratio, as well as to decreased erythrocyte and erythrocyte nuclei circularity, which highlights the clear effect on the size and shape of these cells. On the other hand, the comet assay did not evidence any genotoxic effect caused by the assessed pesticides. This is a pioneer study on the mutagenic and morphotoxic potential of pesticides in P. expansa eclodides exposed in ovo to Gly, Atra and Fip; therefore, it is an insight on how these compounds can affect the health of these animals.


Assuntos
Atrazina , Praguicidas , Animais , Dano ao DNA , Eritrócitos/efeitos dos fármacos , Humanos , Recém-Nascido , Testes para Micronúcleos , Mutagênicos
4.
Ann Biol Clin (Paris) ; 78(3): 319-322, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32540818

RESUMO

The purpose of this work was to compare the measured red-cell volume (RCV) using sodium pertechnétate [RCV-99mTc] compared to the reference technique using sodium radiochromate [RCV-51Cr] and to assess the influence of technetium-99 elution on the RCV-99mTc value. Ten patients had simultaneous measurements of RCV-99mTc and RCV-51Cr. Elution of Tc-99m from red blood cells was 2.9% and led to an average overestimation of RCV-99mTc of 3.7%. The introduction of individual tracer elution rates in the RCV-99mTc calculation corrects this overestimation.


Assuntos
Radioisótopos de Cromo/farmacologia , Volume de Eritrócitos/efeitos dos fármacos , Eritrócitos/citologia , Eritrócitos/efeitos dos fármacos , Marcação por Isótopo/métodos , Tecnécio/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Relação Dose-Resposta a Droga , Contagem de Eritrócitos/métodos , Feminino , Hematócrito/métodos , Humanos , Marcação por Isótopo/efeitos adversos , Masculino , Pessoa de Meia-Idade , Técnica de Diluição de Radioisótopos
5.
Int J Nanomedicine ; 15: 3433-3445, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32523342

RESUMO

Background: Reconstituted lipoproteins (rLips) based on endogenous lipid nanostructures has been increasingly regarded as an excellent and promising antitumor drug delivery. However, some problems relating to the main component, apolipoprotein, for instance, rare source, unaffordable price, and low specificity of relevant receptor expression, become chief obstacles to its broad development and application. Purpose: The primary aim of this study is to develop biomimetic rLips by utilizing folic acid (FA)-modified bovine serum albumin (BSA) as a replacement for apolipoprotein and demonstrate its tumor targeting and antitumor efficacy. Methods: The amino groups of BSA were covalently conjugated with FA through the amide reaction. PTX-loaded nanostructured lipid carrier (termed as P-NLC) consisting of phospholipid, cholesteryl ester, triglyceride and cholesterol was prepared by the emulsification-evaporation method and utilized as the lipid core. FA-modified BSA (FA-BSA) was characterized for the protein substitute degree and attached with NLC by incubation-insert method to form the lipoprotein-mimic nanocomplex (termed as PFB-rLips). The morphology of nanoparticles was observed under transmission electron microscopy (TEM), and the particle size and zeta potential were determined using dynamic light scattering. In vitro release behavior of PTX from PFB-rLips was investigated with the dialysis method. Hemolysis tests were conducted to evaluate the biosecurity of PFB-rLips. Cell uptake and cytotoxicity assays were performed on human hepatocytes (LO2) and human hepatoma cells (HepG2). Tumor targeting was assessed using in vivo imaging system in H22 tumor-bearing mice model. Antitumor efficacy in vivo was investigated and compared between Taxol® (paclitaxel) formulation and PTX-incorporated nanoparticles in the same tumor model. Results: A fixed molar ratio 50:1 of FA to BSA was chosen as the optimal input ratio based on the balance between appropriate degree of protein substitution and amphiphilicity of FA-BSA. The morphology of FB-rLips exhibited as a homogeneous spherical structure featured by lipid cores surrounded with a cloudy protein shell observed under TEM. The particle size, zeta potential and encapsulation efficiency were 174.6±3.2 nm, -17.26±0.9 mV and 82.2±2.4%, respectively. In vitro release behavior of PTX from PFB-rLips was slow and sustained. The uptake of FB-rLips was much higher in HepG2 cells than in LO2 cells. Furthermore, the uptake of FB-rLips was significantly higher than that of rLips without FA involved (termed as B-rLips) and NLC in HepG2 cells. Hemolysis and cytotoxicity assays showed good biocompatibility of FB-rLips. The internalization mechanism of FB-rLips mainly depended on clathrin-mediated and caveolin-mediated endocytosis coupling with energy consumption, and FA receptors expressed on tumor cells played a critical role in cellular uptake process. CCK-8 studies demonstrated that PFB-rLips exhibited significantly better tumor killing ability than Taxol® (paclitaxel) formulation in vitro. Moreover, FB-rLips produced more excellent tumor-targeting properties than NLC through in vivo imaging assays. On the basis of this, PTX-loaded FB-rLips also performed more remarkable anticancer activity than other therapy groups in H22 tumor-bearing mice. Conclusion: FB-rLips would serve as a potential nanocarrier for improving tumor-targeting and therapeutic efficacy while reducing the side effects on normal tissues and organs.


Assuntos
Portadores de Fármacos/química , Ácido Fólico/uso terapêutico , Lipoproteínas/química , Nanopartículas/química , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Liberação Controlada de Fármacos , Endocitose/efeitos dos fármacos , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Ácido Fólico/síntese química , Ácido Fólico/química , Hemólise/efeitos dos fármacos , Humanos , Camundongos , Nanopartículas/ultraestrutura , Neoplasias/patologia , Paclitaxel/química , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Tamanho da Partícula , Coelhos , Soroalbumina Bovina/química , Eletricidade Estática
6.
Ecotoxicol Environ Saf ; 201: 110824, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32544747

RESUMO

The aim of the study was to investigate the effects of sublethal concentrations (0.3, 0.6 and 1.2 mg L-1) of the herbicide Ronstar on the hematology and some immune parameters in Clarias gariepinus juvenile (mean weight and length 58.72 ± 2.46 g and 27.60 ± 1.62 cm, respectively). The hematological and some immune parameters were studied for 21 days in a static renewal bioassay system in which the water and the herbicide were changed daily. The erythrocyte count, hemoglobin concentration (Hb), and packed cell volume (PCV) were significantly (p < 0.05) reduced in the treatment groups. When compared with the control, there were significant (p < 0.05) leucocytosis, lymphocytosis, neutropenia and monocytopenia in the treatment groups. Both the mean corpuscular hemoglobin (MCH) and mean corpuscular volume (MCV) were reduced ((p < 0.05) in the Ronstar-exposed fish. The result showed that the treated fish suffered hypochromic microcytic anemia. The total immunoglobulin and phagocytic indices (phagocytic capacity and phagocytic index) were significantly (p < 0.05) reduced in the treatment groups. while the respiratory burst was significantly (p < 0.05) increased in the treatment groups. The result showed that exposure to Ronstar had adverse effects on the hematology and immunocompetency of the fish.


Assuntos
Peixes-Gato , Herbicidas/toxicidade , Imunoglobulinas/sangue , Oxidiazóis/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Peixes-Gato/sangue , Peixes-Gato/imunologia , Relação Dose-Resposta a Droga , Contagem de Eritrócitos , Índices de Eritrócitos/efeitos dos fármacos , Eritrócitos/citologia , Eritrócitos/efeitos dos fármacos , Hematócrito , Hemoglobinas/análise , Fagócitos/citologia , Fagócitos/efeitos dos fármacos
7.
Chem Biol Interact ; 326: 109139, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32454005

RESUMO

Since several decades oximes have been used as part of treatment of nerve agent intoxication with the aim to restore the biological function of the enzyme acetylcholinesterase after its covalent inhibition by organophosphorus compounds such as pesticides and nerve agents. Recent findings have illustrated that, besides oximes, certain Mannich phenols can reactivate the inhibited enzyme very effectively, and may therefore represent an attractive complementary class of reactivators. In this paper we further probe the effect of structural variation on the in vitro efficacy of Mannich phenol based reactivators. Thus, we present the synthesis of 14 compounds that are close variants of the previously reported 4-amino-2-(1-pyrrolidinylmethyl)-phenol, a very effective non-oxime reactivator, and 3 dimeric Mannich phenols. All compounds were assessed for their ability to reactivate human acetylcholinesterase inhibited by the nerve agents VX, tabun, sarin, cyclosarin and paraoxon in vitro. It was confirmed that the potency of the compounds is highly sensitive to small structural changes, leading to diminished reactivation potency in many cases. However, the presence of 4-substituted alkylamine substituents (as exemplified with the 4-benzylamine-variant) was tolerated. More surprisingly, the dimeric compounds demonstrated non-typical behavior and displayed some reactivation potency as well. Both findings may open up new avenues for designing more effective non-oxime reactivators.


Assuntos
Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Agentes Neurotóxicos/química , Agentes Neurotóxicos/farmacologia , Oximas/química , Oximas/farmacologia , Substâncias para a Guerra Química/química , Substâncias para a Guerra Química/farmacologia , Reativadores da Colinesterase/metabolismo , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Humanos , Relação Estrutura-Atividade
8.
Clin Chim Acta ; 508: 98-102, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32405079

RESUMO

BACKGROUND: Novel coronavirus infectious disease (COVID-19) has been spreading worldwide, and tracking laboratory indexes during the diagnosis and treatment of patients with severe COVID-19 can provide a reference for patients in other countries and regions. METHODS: We closely tracked the epidemiological history, diagnosis and treatment process, as well as dynamic changes in routine blood indicators, of a severe COVID-19 patient who was hospitalized for 26 days. RESULTS: Our study found that the patient's condition worsened in the first week after admission, white blood cells (WBCs), neutrophils, lymphocytes, monocytes, eosinophils, red blood cells (RBCs), hemoglobin, neutrophil lymphocyte ratio (NLR), platelets (PLT) and platelet lymphocyte ratio (PLR) decreased. On the 7th day of admission, the levels of these cells decreased to their lowest values, though the red blood cell distribution width (RDW) and C-reactive protein (CRP) level remained at high values. From 8 to 14 days of admission, the patient's condition improved, hypoxemia was corrected, and mechanical ventilation was discontinued. The number of WBCs, neutrophils, monocytes, eosinophils and lymphocytes increased gradually, and the erythrocyte parameters stopped declining and stabilized in a certain range; CRP decreased rapidly. On the 20th day of admission, the nucleic acid test was negative, WBC, neutrophil, CRP, NLR and PLR decreased gradually, and monocyte, lymphocyte, and eosinophil counts increased. Although RBCs and hemoglobin (Hb) levels continued to decrease, RDW gradually increased, indicating the recovery of hematopoiesis. In addition, it should be noted that monocytes and eosinophils were at extremely low levels within 10 days after admission; the recovery time of eosinophils was approximately 12 days after admission, which was earlier than other parameters, which might be of great value in judging the progress of the disease. CONCLUSIONS: Dynamic changes in routine blood parameters might be helpful for the prognosis of COVID-19 patients and evaluation of the treatment effect.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/sangue , Infecções por Coronavirus/diagnóstico , Pneumonia Viral/sangue , Pneumonia Viral/diagnóstico , Antibacterianos/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Biomarcadores/sangue , Plaquetas/efeitos dos fármacos , Plaquetas/patologia , Plaquetas/virologia , Proteína C-Reativa/metabolismo , Contagem de Células , Convalescença , Infecções por Coronavirus/fisiopatologia , Infecções por Coronavirus/terapia , Eritrócitos/efeitos dos fármacos , Eritrócitos/patologia , Eritrócitos/virologia , Feminino , Humanos , Pessoa de Meia-Idade , Monócitos/efeitos dos fármacos , Monócitos/patologia , Monócitos/virologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/patologia , Neutrófilos/virologia , Oseltamivir/uso terapêutico , Pandemias , Pneumonia Viral/fisiopatologia , Pneumonia Viral/terapia , Prognóstico , Respiração Artificial , Índice de Gravidade de Doença
9.
PLoS One ; 15(5): e0227932, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32469873

RESUMO

BACKGROUND AND OBJECTIVE: For many pathological states, microparticles are supposed to be one of the causes of hypercoagulation. Although there are some indirect data about microparticles participation in coagulation activation and propagation, the integral hemostasis test Thrombodynamics allows to measure micropaticles participation in these two coagulation phases directly. Demonstrates microparticles participation in coagulation activation by influence on the appearance of coagulation centres in the plasma volume and the rate of clot growth from the surface with immobilized tissue factor.Methods: Microparticles were obtained from platelets and erythrocytes by stimulation with thrombin receptor-activating peptide (SFLLRN) and calcium ionophore (A23187), respectively, from monocytes, endothelial HUVEC culture and monocytic THP cell culture by stimulation with lipopolysaccharides. Microparticles were counted by flow cytometry and titrated in microparticle-depleted normal plasma in the Thrombodynamics test. RESULTS: Monocyte microparticles induced the appearance of clotting centres through the TF pathway at concentrations approximately 100-fold lower than platelet and erythrocyte microparticles, which activated plasma by the contact pathway. For endothelial microparticles, both activation pathways were essential, and their activity was intermediate. Monocyte microparticles induced plasma clotting by the appearance of hundreds of clots with an extremely slow growth rate, while erythrocyte microparticles induced the appearance of a few clots with a growth rate similar to that from surface covered with high-density tissue factor. Patterns of clotting induced by platelet and endothelial microparticles were intermediate. Platelet, erythrocyte and endothelial microparticles impacts on the rate of clot growth from the surface with tissue factor did not differ significantly within the 0-200·103/ul range of microparticles concentrations. However, at concentrations greater than 500·103/ul, erythrocyte microparticles increased the stationary clot growth rate to significantly higher levels than do platelet microparticles or artificial phospholipid vesicles consisting of phosphatidylcholine and phosphatidylserine. CONCLUSION: Microparticles of different origins demonstrated qualitatively different characteristics related to coagulation activation and propagation.


Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Micropartículas Derivadas de Células/efeitos dos fármacos , Trombina/metabolismo , Trombose/sangue , Plaquetas/efeitos dos fármacos , Calcimicina/farmacologia , Cálcio/metabolismo , Micropartículas Derivadas de Células/metabolismo , Células Endoteliais/efeitos dos fármacos , Eritrócitos/efeitos dos fármacos , Citometria de Fluxo , Células Endoteliais da Veia Umbilical Humana , Humanos , Monócitos/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Trombose/tratamento farmacológico , Trombose/patologia
10.
Am J Physiol Regul Integr Comp Physiol ; 319(1): R19-R25, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32401629

RESUMO

Microvascular endothelial dysfunction, a precursor to atherosclerotic cardiovascular disease, increases with aging. Endothelium-derived hyperpolarizing factors (EDHFs), which act through K+ channels, regulate blood flow and are important to vascular health. It is unclear how EDHFs change with healthy aging. To evaluate microvascular endothelial reliance on K+ channel-mediated dilation as a function of age in healthy humans. Microvascular function was assessed using intradermal microdialysis in healthy younger (Y; n = 7; 3 M/4 W; 26 ± 1 yr) and older adults (O; n = 12; 5 M/7 W; 64 ± 2 yr) matched for V̇o2peak (Y: 39.0 ± 3.8, O: 37.6 ± 3.1 mL·kg-1·min-1). Participants underwent graded local infusions of: the K+ channel activator Na2S (10-6 to 10-1 M), acetylcholine (ACh, 10-10 to 10-1 M), ACh + the K+ channel inhibitor tetraethylammonium (TEA; 25 or 50 mM), and ACh + the nitric oxide synthase-inhibitor l-NAME (15 mM). Red blood cell flux was measured with laser-Doppler flowmetry and used to calculate cutaneous vascular conductance (CVC; flux/mean arterial pressure) as a percentage of each site-specific maximum (%CVCmax, 43°C+28 mM sodium nitroprusside). The %CVCmax response to Na2S was higher in older adults (mean, O: 51.7 ± 3.9% vs. Y: 36.1 ± 5.3%; P = 0.03). %CVCmax was lower in the ACh+TEA vs. the ACh site starting at 10-5 M (ACh: 34.0 ± 5.7% vs. ACh+TEA: 19.4 ± 4.5%; P = 0.002) in older and at 10-4 M (ACh: 54.5 ± 9.4% vs. ACh+TEA: 31.2 ± 6.7%; P = 0.0002) in younger adults. %CVCmax was lower in the ACh+l-NAME vs. the ACh site in both groups starting at 10-4 M ACh (Y: P < 0.001; O: P = 0.02). Healthy active older adults have enhanced K+ channel-dependent endothelial vasodilatory mechanisms, suggesting increased responsiveness to EDHFs with age.


Assuntos
Endotélio Vascular/fisiologia , Envelhecimento Saudável/fisiologia , Canais de Potássio/fisiologia , Vasodilatação/fisiologia , Adulto , Idoso , Envelhecimento/fisiologia , Limiar Anaeróbio/fisiologia , Fatores Biológicos/fisiologia , Inibidores Enzimáticos/farmacologia , Eritrócitos/efeitos dos fármacos , Eritrócitos/fisiologia , Feminino , Humanos , Masculino , Microcirculação , Pessoa de Meia-Idade , NG-Nitroarginina Metil Éster/farmacologia , Bloqueadores dos Canais de Potássio/farmacologia , Canais de Potássio/agonistas , Fluxo Sanguíneo Regional/fisiologia
11.
Am J Physiol Regul Integr Comp Physiol ; 319(1): R69-R78, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32432916

RESUMO

The production of H2S and its effect on bioenergetics in mammalian cells may be evolutionarily preserved. Erythrocytes of birds, but not those of mammals, have a nucleus and mitochondria. In the present study, we report the endogenous production of H2S in chicken erythrocytes, which was mainly catalyzed by 3-mercaptopyruvate sulfur transferase (MST). ATP content of erythrocytes was increased by MST-generated endogenous H2S under normoxic, but not hypoxic, conditions. NaHS, a H2S salt, increased ATP content under normoxic, but not hypoxic, conditions. ATP contents in the absence or presence of NaHS were eliminated by different inhibitors for mitochondrial electron transport chain in chicken erythrocytes. Succinate and glutamine, but not glucose, increased ATP content. NaHS treatment similarly increased ATP content in the presence of glucose, glutamine, or succinate, respectively. Furthermore, the expression and activity of sulfide:quinone oxidoreductase were enhanced by NaHS. The structural integrity of chicken erythrocytes was largely maintained during 2-wk NaHS treatment in vitro, whereas most of the erythrocytes without NaHS treatment were lysed. In conclusion, H2S may regulate cellular bioenergetics as well as cell survival of chicken erythrocytes, in which the functionality of the electron transport chain is involved. H2S may have different regulatory roles and mechanisms in bioenergetics of mammalian and bird cells.


Assuntos
Metabolismo Energético/efeitos dos fármacos , Eritrócitos/metabolismo , Sulfeto de Hidrogênio/farmacologia , Trifosfato de Adenosina/sangue , Animais , Galinhas , Transporte de Elétrons/efeitos dos fármacos , Eritrócitos/efeitos dos fármacos , Feminino , Glucose/farmacologia , Glutamina/farmacologia , Hipóxia/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Ácido Succínico/farmacologia , Sulfurtransferases/metabolismo
12.
Clin Chim Acta ; 508: 98-102, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: covidwho-245188

RESUMO

BACKGROUND: Novel coronavirus infectious disease (COVID-19) has been spreading worldwide, and tracking laboratory indexes during the diagnosis and treatment of patients with severe COVID-19 can provide a reference for patients in other countries and regions. METHODS: We closely tracked the epidemiological history, diagnosis and treatment process, as well as dynamic changes in routine blood indicators, of a severe COVID-19 patient who was hospitalized for 26 days. RESULTS: Our study found that the patient's condition worsened in the first week after admission, white blood cells (WBCs), neutrophils, lymphocytes, monocytes, eosinophils, red blood cells (RBCs), hemoglobin, neutrophil lymphocyte ratio (NLR), platelets (PLT) and platelet lymphocyte ratio (PLR) decreased. On the 7th day of admission, the levels of these cells decreased to their lowest values, though the red blood cell distribution width (RDW) and C-reactive protein (CRP) level remained at high values. From 8 to 14 days of admission, the patient's condition improved, hypoxemia was corrected, and mechanical ventilation was discontinued. The number of WBCs, neutrophils, monocytes, eosinophils and lymphocytes increased gradually, and the erythrocyte parameters stopped declining and stabilized in a certain range; CRP decreased rapidly. On the 20th day of admission, the nucleic acid test was negative, WBC, neutrophil, CRP, NLR and PLR decreased gradually, and monocyte, lymphocyte, and eosinophil counts increased. Although RBCs and hemoglobin (Hb) levels continued to decrease, RDW gradually increased, indicating the recovery of hematopoiesis. In addition, it should be noted that monocytes and eosinophils were at extremely low levels within 10 days after admission; the recovery time of eosinophils was approximately 12 days after admission, which was earlier than other parameters, which might be of great value in judging the progress of the disease. CONCLUSIONS: Dynamic changes in routine blood parameters might be helpful for the prognosis of COVID-19 patients and evaluation of the treatment effect.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/sangue , Infecções por Coronavirus/diagnóstico , Pneumonia Viral/sangue , Pneumonia Viral/diagnóstico , Antibacterianos/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Biomarcadores/sangue , Plaquetas/efeitos dos fármacos , Plaquetas/patologia , Plaquetas/virologia , Proteína C-Reativa/metabolismo , Contagem de Células , Convalescença , Infecções por Coronavirus/fisiopatologia , Infecções por Coronavirus/terapia , Eritrócitos/efeitos dos fármacos , Eritrócitos/patologia , Eritrócitos/virologia , Feminino , Humanos , Pessoa de Meia-Idade , Monócitos/efeitos dos fármacos , Monócitos/patologia , Monócitos/virologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/patologia , Neutrófilos/virologia , Oseltamivir/uso terapêutico , Pandemias , Pneumonia Viral/fisiopatologia , Pneumonia Viral/terapia , Prognóstico , Respiração Artificial , Índice de Gravidade de Doença
13.
J Microbiol Biotechnol ; 30(3): 382-390, 2020 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-32238758

RESUMO

Periplanetasin-4 is an antimicrobial peptide with 13 amino acids identified in cockroaches. It has been reported to induce fungal cell death by apoptosis and membrane-targeted action. Analogs were designed by substituting arginine residues to modify the electrostatic and hydrophobic interactions accordingly and explore the effect of periplanetasin-4 through the increase of net charge and the decrease of hydrophobicity. The analogs showed lower activity than periplanetasin-4 against gram-positive and gram-negative bacteria. Similar to periplanetasin-4, the analogs exhibited slight hemolytic activity against human erythrocytes. Membrane studies, including determination of changes in membrane potential and permeability, and fluidity assays, revealed that the analogs disrupt less membrane integrity compared to periplanetasin-4. Likewise, when the analogs were treated to the artificial membrane model, the passage of molecules bigger than FD4 was difficult. In conclusion, arginine substitution could not maintain the membrane disruption ability of periplanetasin-4. The results indicated that the attenuation of hydrophobic interactions with the plasma membrane caused a reduction in the accumulation of the analogs on the membrane before the formation of electrostatic interactions. Our findings will assist in the further development of antimicrobial peptides for clinical use.


Assuntos
Membrana Celular/efeitos dos fármacos , Antibacterianos/farmacologia , Eritrócitos/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Humanos , Interações Hidrofóbicas e Hidrofílicas
14.
Artigo em Inglês | MEDLINE | ID: mdl-32330807

RESUMO

Honey-processed Astragalus is a dosage form of radix Astragali processed with honey, which is deemed to contain better qi-tonifying effects in traditional Chinese medicine theroy. Our previous study has demonstrated that honey-processed Astragalus exhibited a better effect on reinforcing qi (vital energy) and immune improvement toward spleen qi deficiency compared with radix Astragali. However, the detailed mechanisms related to qi-tonifying effects of honey-processed Astragalus is still unclear. In this study, we evaluated the qi-tonifying effects of honey-processed Astragalus on spleen qi deficiency rats and predicted the mechanisms by aggregating metabonomics, lipidomics and network pharmacology. The results revealed that body weights, symptom scores, the levels of red blood cell, white blood cell, lymphocyte, spleen and thymus indexes, and three cytokines (TNF-α, IL-6, IFN-γ) in honey-processed Astragalus treated rats were improved in comparison with spleen qi deficiency rats. In parallel, based on the 26 biomarkers screened in metabonomics and lipidomics, we inferred that glycerophospholipid metabolism significantly regulated in pathway analysis was connected with qi-tonifying effects. Moreover, the network pharmacology analysis concluded that the compounds targets of honey-processed Astragalus CDK2, NOS3, MAPK14, PTGS1 and PTGS2 interacted with markers targets PLA2G(s) family and LYPLA1 could be responsible for regulation of glycerophospholipid metabolism to develop qi-tonifying effects. What's more, the above processes were possibly through VEGF signaling and MAPK signaling pathways.


Assuntos
Astrágalo (Planta)/química , Citocinas/sangue , Medicamentos de Ervas Chinesas/farmacologia , Espectrometria de Massas em Tandem/métodos , Animais , Biomarcadores/sangue , Peso Corporal/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Citocinas/metabolismo , Composição de Medicamentos/métodos , Eritrócitos/efeitos dos fármacos , Feminino , Mel , Humanos , Leucócitos/efeitos dos fármacos , Lipidômica , Linfócitos/efeitos dos fármacos , Qi , Ratos , Ratos Sprague-Dawley , Baço/efeitos dos fármacos , Timo/efeitos dos fármacos
15.
Lancet Infect Dis ; 20(8): 964-975, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32275867

RESUMO

BACKGROUND: (+)-SJ000557733 (SJ733) is a novel, orally bioavailable inhibitor of Plasmodium falciparum ATP4. In this first-in-human and induced blood-stage malaria phase 1a/b trial, we investigated the safety, tolerability, pharmacokinetics, and antimalarial activity of SJ733 in humans. METHODS: The phase 1a was a single-centre, dose-escalation, first-in-human study of SJ733 allowing modifications to dose increments and dose-cohort size on the basis of safety and pharmacokinetic results. The phase 1a took place at St Jude Children's Research Hospital and at the University of Tennessee Clinical Research Center (Memphis, TN, USA). Enrolment in more than one non-consecutive dose cohort was allowed with at least 14 days required between doses. Participants were fasted in seven dose cohorts and fed in one 600 mg dose cohort. Single ascending doses of SJ733 (75, 150, 300, 600, 900, or 1200 mg) were administered to participants, who were followed up for 14 days after SJ733 dosing. Phase 1a primary endpoints were safety, tolerability, and pharmacokinetics of SJ733, and identification of an SJ733 dose to test in the induced blood-stage malaria model. The phase 1b was a single-centre, open-label, volunteer infection study using the induced blood-stage malaria model in which fasted participants were intravenously infected with blood-stage P falciparum and subsequently treated with a single dose of SJ733. Phase 1b took place at Q-Pharm (Herston, QLD, Australia) and was initiated only after phase 1a showed that exposure exceeding the threshold minimum exposure could be safely achieved in humans. Participants were inoculated on day 0 with P falciparum-infected human erythrocytes (around 2800 parasites in the 150 mg dose cohort and around 2300 parasites in the 600 mg dose cohort), and parasitaemia was monitored before malaria inoculation, after inoculation, immediately before SJ733 dosing, and then post-dose. Participants were treated with SJ733 within 24 h of reaching 5000 parasites per mL or at a clinical score higher than 6. Phase 1b primary endpoints were calculation of a parasite reduction ratio (PRR48) and parasite clearance half-life, and safety and tolerability of SJ733 (incidence, severity, and drug-relatedness of adverse events). In both phases of the trial, SJ733 hydrochloride salt was formulated as a powder blend in capsules containing 75 mg or 300 mg for oral administration. Healthy men and women (of non-childbearing potential) aged 18-55 years were eligible for both studies. Both studies are registered with ClinicalTrials.gov (NCT02661373 for the phase 1a and NCT02867059 for the phase 1b). FINDINGS: In the phase 1a, 23 healthy participants were enrolled and received one to three non-consecutive doses of SJ733 between March 14 and Dec 7, 2016. SJ733 was safe and well tolerated at all doses and in fasted and fed conditions. 119 adverse events were recorded: 54 (45%) were unrelated, 63 (53%) unlikely to be related, and two (2%) possibly related to SJ733. In the phase 1b, 17 malaria-naive, healthy participants were enrolled. Seven participants in the 150 mg dose cohort were inoculated and dosed with SJ733. Eight participants in the 600 mg dose cohort were inoculated, but two participants could not be dosed with SJ733. Two additional participants were subsequently inoculated and dosed with SJ733. SJ733 exposure increased proportional to the dose through to the 600 mg dose, then was saturable at higher doses. Fasted participants receiving 600 mg exceeded the target area under the concentration curve extrapolated to infinity (AUC0-∞) of 13 000 µg × h/L (median AUC0-∞ 24 283 [IQR 16 135-31 311] µg × h/L, median terminal half-life 17·4 h [IQR 16·1-24·0], and median timepoint at which peak plasma concentration is reached 1·0 h [0·6-1·3]), and this dose was tested in the phase 1b. All 15 participants dosed with SJ733 had at least one adverse event. Of the 172 adverse events recorded, 128 (74%) were mild. The only adverse event attributed to SJ733 was mild bilateral foot paraesthesia that lasted 3·75 h and resolved spontaneously. The most common adverse events were related to malaria. Based on parasite clearance half-life, the derived log10PRR48 and corresponding parasite clearance half-lives were 2·2 (95% CI 2·0-2·5) and 6·47 h (95% CI 5·88-7·18) for 150 mg, and 4·1 (3·7-4·4) and 3·56 h (3·29-3·88) for 600 mg. INTERPRETATION: The favourable pharmacokinetic, tolerability, and safety profile of SJ733, and rapid antiparasitic effect support its development as a fast-acting component of combination antimalarial therapy. FUNDING: Global Health Innovative Technology Fund, Medicines for Malaria Venture, and the American Lebanese Syrian Associated Charities.


Assuntos
Antimaláricos/uso terapêutico , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Isoquinolinas/uso terapêutico , Malária Falciparum/tratamento farmacológico , Malária Falciparum/parasitologia , Plasmodium falciparum/efeitos dos fármacos , Inibidores da Bomba de Prótons/uso terapêutico , Adulto , Antimaláricos/administração & dosagem , Antimaláricos/efeitos adversos , Antimaláricos/farmacocinética , Estudos de Casos e Controles , Eritrócitos/efeitos dos fármacos , Eritrócitos/parasitologia , Feminino , ATPase Trocadora de Hidrogênio-Potássio/metabolismo , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Compostos Heterocíclicos de 4 ou mais Anéis/efeitos adversos , Compostos Heterocíclicos de 4 ou mais Anéis/farmacocinética , Humanos , Isoquinolinas/administração & dosagem , Isoquinolinas/efeitos adversos , Isoquinolinas/farmacocinética , Estágios do Ciclo de Vida/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Plasmodium falciparum/crescimento & desenvolvimento , Plasmodium falciparum/metabolismo , Inibidores da Bomba de Prótons/administração & dosagem , Inibidores da Bomba de Prótons/efeitos adversos , Inibidores da Bomba de Prótons/farmacocinética , Resultado do Tratamento , Adulto Jovem
16.
J Med Microbiol ; 69(4): 605-616, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32125268

RESUMO

Introduction. Against the backdrop of increasing resistance to conventional antibiotics, bacteriocins represent an attractive alternative, given their potent activity, novel modes of action and perceived lack of issues with resistance.Aim. In this study, the nature of the antibacterial activity of a clinical isolate of Streptococcus gallolyticus was investigated.Methods. Optimization of the production of an inhibitor from strain AB39 was performed using different broth media and supplements. Purification was carried out using size exclusion, ion exchange and HPLC. Gel diffusion agar overlay, MS/MS, de novo peptide sequencing and genome mining were used in a proteogenomics approach to facilitate identification of the genetic basis for production of the inhibitor.Results. Strain AB39 was identified as representing Streptococcus gallolyticus subsp. pasteurianus and the successful production and purification of the AB39 peptide, named nisin P, with a mass of 3133.78 Da, was achieved using BHI broth with 10 % serum. Nisin P showed antibacterial activity towards clinical isolates of drug-resistant bacteria, including methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus and penicillin-resistant Streptococcus pneumoniae. In addition, the peptide exhibited significant stability towards high temperature, wide pH and certain proteolytic enzymes and displayed very low toxicity towards sheep red blood cells and Vero cells.Conclusion. To the best of our knowledge, this study represents the first production, purification and characterization of nisin P. Further study of nisin P may reveal its potential for treating or preventing infections caused by antibiotic-resistant Gram-positive bacteria, or those evading vaccination regimens.


Assuntos
Nisina/isolamento & purificação , Nisina/farmacologia , Streptococcus gallolyticus/metabolismo , Sequência de Aminoácidos , Animais , Cromatografia , Cromatografia Líquida de Alta Pressão , Eritrócitos/citologia , Eritrócitos/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Hemólise/efeitos dos fármacos , Estrutura Molecular , Nisina/química , Nisina/metabolismo , Ovinos , Streptococcus gallolyticus/química , Streptococcus gallolyticus/classificação , Streptococcus gallolyticus/genética , Espectrometria de Massas em Tandem
17.
Bull Environ Contam Toxicol ; 104(3): 366-372, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32020242

RESUMO

Fish were separately exposed to 1/2 LC50/96 h values of bulk-Zn and nano-Zn for 7, 14, and 28 days. The induction of micronuclei (MN) and other eight nuclear abnormalities in erythrocytes showed marked time and size dependence. The frequencies of all nuclear anomalies were progressively elevated (p < 0.05) with increasing the time of exposure to both bulk-Zn and nano-Zn. Throughout the study periods, fish exposed to nano-Zn showed the maximum elevation in all studied nuclear anomalies. Based on the fragmented DNA values, both Zn forms induced tissue-specific DNA damage as following gills > liver > muscles. Moreover, nano-Zn exposed groups revealed a maximum percentage of DNA damage among all studied groups, especially after 14 days. The percentage of DNA damage was decreased in all tissues on the 28th day, which reflected the presence of an effective repair mechanism. Finally, nano-Zn exhibited more genotoxic effects than that of its bulk counterparts.


Assuntos
Ciclídeos/genética , Dano ao DNA , Micronúcleos com Defeito Cromossômico/induzido quimicamente , Nanopartículas/toxicidade , Poluentes Químicos da Água/toxicidade , Zinco/toxicidade , Animais , Eritrócitos/efeitos dos fármacos , Eritrócitos/patologia , Brânquias/efeitos dos fármacos , Brânquias/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Músculos/efeitos dos fármacos , Músculos/patologia , Nanopartículas/química , Tamanho da Partícula , Poluentes Químicos da Água/química , Zinco/química
18.
Chem Biol Interact ; 318: 108974, 2020 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-32032594

RESUMO

AIM: The aim of this study was the synthesis of ion doped silica-based nanoparticles and the evaluation of their toxic effect on erythrocytes. MATERIALS & METHODS: Their synthesis was performed using the sol-gel method, by the progressive addition of calcium, magnesium and copper ions on pure silica nanoparticles. The toxicity evaluation was based on hemolysis, lipid peroxidation, ROS, H2O2 species and antioxidant enzyme production. RESULTS: The addition of Mg and Cu in the SNs presented better hemocompatibility by protecting erythrocytes from oxidative stress. CONCLUSION: Ion doping with magnesium in the investigated calcium silicate system induces a protective effect in erythrocyte membrane in compare with pure silica nanoparticles.


Assuntos
Cobre/toxicidade , Eritrócitos/efeitos dos fármacos , Magnésio/toxicidade , Nanopartículas/química , Nanopartículas/toxicidade , Dióxido de Silício/química , Células Cultivadas , Cobre/química , Eritrócitos/metabolismo , Glutationa/metabolismo , Humanos , Peróxido de Hidrogênio , Magnésio/química , Malondialdeído/metabolismo , Microscopia Eletrônica de Transmissão , Espectroscopia de Infravermelho com Transformada de Fourier
19.
Chem Biol Interact ; 319: 109019, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32092302

RESUMO

The inhibition of the enzyme acetylcholinesterase (AChE) is a frequently used therapeutic option to treat Alzheimer's disease (AD). By decreasing the levels of acetylcholine degradation in the synaptic space, some cognitive functions of patients suffering from this disease are significantly improved. Rivastigmine is one of the most widely used AChE inhibitors. The objective of this work was to determine the effects of this drug on human erythrocytes, which have a type of AChE in the cell membrane. To that end, human erythrocytes and molecular models of its membrane constituted by dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylethanolamine (DMPE) were used. They correspond to classes of phospholipids present in the outer and inner monolayers of the human erythrocyte membrane, respectively. The experimental results obtained by X-ray diffraction and differential scanning calorimetry (DSC) indicated that rivastigmine molecules were able to interact with both phospholipids. Fluorescence spectroscopy results showed that rivastigmine produce a slight change in the acyl chain packing order and a weak displacement of the water molecules of the hydrophobic-hydrophilic membrane interface. On the other hand, observations by scanning electron microscopy (SEM) showed that the drug changed the normal biconcave shape of erythrocytes in stomatocytes (cup-shaped cells) and echinocytes (speculated shaped).


Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Eritrócitos/efeitos dos fármacos , Rivastigmina/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Varredura Diferencial de Calorimetria/métodos , Forma Celular/efeitos dos fármacos , Dimiristoilfosfatidilcolina/metabolismo , Membrana Eritrocítica/efeitos dos fármacos , Membrana Eritrocítica/metabolismo , Eritrócitos/metabolismo , Humanos , Microscopia Eletrônica de Varredura/métodos , Modelos Moleculares , Fosfatidiletanolaminas/metabolismo , Fosfolipídeos/metabolismo , Espectrometria de Fluorescência/métodos , Difração de Raios X/métodos
20.
Chemosphere ; 247: 125967, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32069732

RESUMO

The initiation of eryptosis as a result of genotoxic action of Cr(VI), seen through micronucleus and comet assay in the peripheral erythrocytes of Ctenopharyngodon idellus was evaluated through RT-qPCR. For this, fish was exposed to sublethal concentration of hexavalent chromium (5.30 and 10.63 mg/L), and the blood was sampled on different endpoints (15, 30 and 45 days). Accumulation of chromium in the erythrocytes was also studied, which depicted a significant increase in toxicant concentration and time dependent manner. Both concentrations of hexavalent chromium induced DNA damage, visible in the form of comet tails. The presence of micronuclei in the erythrocytes was accompanied with occurrence of nuclear bud (NBu), lobed nucleus (Lb), notched nucleus (Nt), vacuolated nucleus (Vn), binucleated cell (Bn) as nuclear abnormalities; and acanthocytes (Ac), echinocytes (Ec), notched cells (Nc), microcytes (Mc) and vacuolated cytoplasm (Vc) as cytoplasmic abnormalities. The expression of genes related to intrinsic apoptotic pathway induced by Cr(VI) presented significant (p < 0.05) upregulation in the expression of p53, Bax, Apaf-1, caspase9 and caspase3, and downregulation of Bcl2; inferring the initiation of apoptotic pathway. The ration of Bax and Bcl2 also appended the apoptotic state of the erythrocytes. From the present investigation, it can be concluded that genotoxicity induced by hexavalent chromium lead to eryptosis in C. idellus.


Assuntos
Carpas/sangue , Cromo/toxicidade , Dano ao DNA/efeitos dos fármacos , Eriptose/efeitos dos fármacos , Animais , Ensaio Cometa , Eritrócitos/efeitos dos fármacos
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