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1.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 36(8): 712-718, 2020 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-32958128

RESUMO

Objective To investigate the effect of Yiqihuoxue herb Naoluoxintong on cerebral vascular regeneration in rats of middle cerebral artery occlusion-reperfusion(MCAO-R)experimental model with Qi deficiency and blood stasis syndrome, and explore the possible mechanisms. Methods A total of 60 SD rats were randomly divided into a control group, a model group and three Naoluoxintong-treated groups [(1 200, 800 and 400 mg/(kg.d)], with 12 rats each. Except for the control group, the other groups were treated with modified suture method combined with multi-factor compound simulation to establish the models with both MCAO-R and syndrome of Qi deficiency accompanied by blood stasis. Neural functional deficit, blood stasis syndrome and Qi deficiency syndrome were scored by quantitative criteria for biological characteristics score. The regional cerebral blood flow (rCBF) was dynamically monitored with laser Doppler scanning. HE staining was used to observe the pathological changes of brain tissue. The mRNA expression levels of Wnt5a, glycogen synthase kinase-3ß (GSK-3ß) were determined by real-time fluorescent quantitative PCR, and the protein expression levels of ß-catenin, vascular endothelial growth factor (VEGF), AngII in the rat brain tissue were detected by Western blotting. Results Naoluoxintong improved neural functional in the model rats, reduced the scores of neural functional deficit, blood stasis syndrome and Qi deficiency syndrome, and restored rCBF simultaneously. Meanwhile, Naoluoxintong high- and middle-dose groups were better than any other model groups in terms of pathological changes, and the up-regulation of Wnt5a mRNA expression in these two groups was the most obvious. However, it had no significant effect on GSK3ß mRNA in the model rats. Expression levels of ß-catenin, VEGF, AngII protein were obviously up-regulated in Naoluoxintong high- and middle-dose groups. Conclusion Naoluoxintong can improve the rCBF with the aid of promoting cerebral vascular regeneration, which might be related to high expression of pro-angiogenic factors that are affected by Wnt signal path activation.


Assuntos
Vasos Sanguíneos , Isquemia Encefálica , Encéfalo , Qi , Animais , Vasos Sanguíneos/efeitos dos fármacos , Encéfalo/irrigação sanguínea , Encéfalo/fisiologia , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/genética , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Regulação da Expressão Gênica/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/genética , Ratos , Ratos Sprague-Dawley , Regeneração/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/genética
2.
PLoS One ; 15(7): e0235135, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32628733

RESUMO

BACKGROUND: In patients on hemodialysis (HD), the various chemical elements in the dialysate may influence survival rates. In particular, calcium modifies mineral and bone metabolism and the vascular calcification rate. We studied the influence of the dialysate calcium concentration and the treatments prescribed for mineral bone disease (MBD) on survival. METHODS: All patients in REIN having initiated HD from 2010 to 2013 were classified according to their exposure to the different dialysate calcium concentrations in their dialysis unit. Data on the individual patients' treatments for MBD were extracted from the French national health database. Cox proportional hazard models were used to estimate mortality hazard ratios (HR) associated with time-dependent exposure to dialysate calcium concentrations and MBD therapies, adjusted for comorbidities, laboratory and technical data. RESULTS: Dialysate calcium concentration of 1.5 mmol/L was used by 81% of the dialysis centers in 2010 and in 83% in 2014. Most centers were using several formulas in up to 78% for 3 formulas in 2010 to 86% in 2014. In full adjusted Cox survival analyses, the percentage of calcium >1.5 mmol/L and <1.5 mmol/l by center and the number of formula used per center were not associated with survival. Depending on the daily dose used, the MBD therapies were associated with survival improvement for calcium, native vitamin D, active vitamin D, sevelamer, lanthanum and cinacalcet in the second and third tertiles of dose. CONCLUSION: No influence of the dialysate calcium concentration was evidenced on survival whereas all MBD therapies were associated with a survival improvement depending on the daily dose used.


Assuntos
Osso e Ossos/efeitos dos fármacos , Cálcio/análise , Soluções para Hemodiálise/análise , Sistema de Registros , Diálise Renal , Insuficiência Renal Crônica/terapia , Idoso , Vasos Sanguíneos/efeitos dos fármacos , Vasos Sanguíneos/metabolismo , Vasos Sanguíneos/fisiopatologia , Osso e Ossos/metabolismo , Osso e Ossos/fisiopatologia , Calcinose/epidemiologia , Calcinose/metabolismo , Calcinose/fisiopatologia , Cálcio/administração & dosagem , Cálcio/metabolismo , Cinacalcete/análise , Feminino , França/epidemiologia , Soluções para Hemodiálise/administração & dosagem , Soluções para Hemodiálise/química , Humanos , Lantânio/análise , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/mortalidade , Insuficiência Renal Crônica/fisiopatologia , Sevelamer/análise , Vitamina D/análise , Vitamina D/metabolismo
4.
Clin Immunol ; 217: 108493, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32526273

Assuntos
Complexo Antígeno-Anticorpo/biossíntese , Betacoronavirus/patogenicidade , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/imunologia , Doenças do Complexo Imune/imunologia , Pneumonia Viral/imunologia , Síndrome Respiratória Aguda Grave/imunologia , Vasculite/imunologia , Anticorpos Antivirais/biossíntese , Complexo Antígeno-Anticorpo/efeitos dos fármacos , Betacoronavirus/imunologia , Vasos Sanguíneos/efeitos dos fármacos , Vasos Sanguíneos/imunologia , Vasos Sanguíneos/patologia , Vasos Sanguíneos/virologia , Complemento C3/antagonistas & inibidores , Complemento C3/biossíntese , Inativadores do Complemento/uso terapêutico , Infecções por Coronavirus/complicações , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/complicações , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/virologia , Humanos , Doenças do Complexo Imune/complicações , Doenças do Complexo Imune/tratamento farmacológico , Doenças do Complexo Imune/virologia , Imunidade Humoral/efeitos dos fármacos , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Interleucina-6/antagonistas & inibidores , Interleucina-6/biossíntese , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Receptores de Interleucina-1/antagonistas & inibidores , Receptores de Interleucina-1/biossíntese , Síndrome Respiratória Aguda Grave/complicações , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Síndrome Respiratória Aguda Grave/virologia , Índice de Gravidade de Doença , Vasculite/complicações , Vasculite/tratamento farmacológico , Vasculite/virologia
5.
Am J Physiol Heart Circ Physiol ; 319(2): H271-H281, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32559139

RESUMO

The purpose of this study was to investigate the effect of race and subclinical elevations in blood pressure (i.e., prehypertension) on cutaneous sensory nerve-mediated and nitric oxide (NO)-dependent vasodilation. We recruited participants who self-identified as either non-Hispanic black (n = 16) or non-Hispanic white (n = 16). Within each group, participants were subdivided as either normotensive (n = 8 per group) or prehypertensive (n = 8 per group). Each participant was instrumented with four intradermal microdialysis fibers: 1) control (lactated Ringer's), 2) 5% lidocaine (sensory nerve inhibition), 3) 20 mM Nω-nitro-l-arginine methyl ester (l-NAME) (NO synthase inhibition), and 4) lidocaine + l-NAME. Skin blood flow was assessed via laser-Doppler flowmetry, and each site underwent local heating from 33°C to 39°C. At the plateau, 20 mM l-NAME were infused at control and lidocaine sites to quantify NO-dependent vasodilation. Maximal vasodilation was induced via 54 mM sodium nitroprusside and local heating to 43°C. Data are means ± SD. Sensory nerve-mediated cutaneous vasodilation was reduced in prehypertensive non-Hispanic white (34 ± 7%) and both non-Hispanic black groups (normotensive, 20 ± 9%, prehypertensive, 24 ± 15%) relative to normotensive non-Hispanic whites (54 ± 12%). NO-dependent vasodilation was also reduced in prehypertensive non-Hispanic white (41 ± 7%) and both non-Hispanic black groups (normotensive, 44 ± 7%, prehypertensive, 19 ± 7%) relative to normotensive non-Hispanic whites (60 ± 11%). The decrease in NO-dependent vasodilation in prehypertensive non-Hispanic blacks was further reduced relative to all other groups. These data suggest subclinical increases in blood pressure adversely affect sensory-mediated and NO-dependent vasodilation in both non-Hispanic blacks and whites.NEW & NOTEWORTHY Overt hypertension is known to reduce cutaneous sensory nerve-mediated and nitric oxide (NO)-dependent vasodilation, but the effect of subclinical increases in blood pressure (i.e., prehypertension) is unknown. The combined effect of race and prehypertension is also unknown. In this study, we found that prehypertension reduces cutaneous sensory nerve-mediated and NO-dependent vasodilation in both non-Hispanic white and black populations, with the greatest reductions observed in prehypertensive non-Hispanic blacks.


Assuntos
Pressão Sanguínea , Vasos Sanguíneos/inervação , Vasos Sanguíneos/metabolismo , Células Endoteliais/metabolismo , Óxido Nítrico/metabolismo , Pré-Hipertensão/fisiopatologia , Células Receptoras Sensoriais , Pele/irrigação sanguínea , Vasodilatação , Administração Cutânea , Adolescente , Adulto , Afro-Americanos , Anestésicos Locais/administração & dosagem , Vasos Sanguíneos/efeitos dos fármacos , Estudos de Casos e Controles , Células Endoteliais/efeitos dos fármacos , Inibidores Enzimáticos/administração & dosagem , Grupo com Ancestrais do Continente Europeu , Feminino , Georgia/epidemiologia , Humanos , Masculino , Microdiálise , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/metabolismo , Pré-Hipertensão/diagnóstico , Pré-Hipertensão/etnologia , Pré-Hipertensão/metabolismo , Fatores Raciais , Células Receptoras Sensoriais/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Vasodilatadores/administração & dosagem , Adulto Jovem
6.
Nutr Metab Cardiovasc Dis ; 30(6): 889-895, 2020 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-32409274

RESUMO

AIMS: Kisspeptin-10 (KP-10), a potent vasoconstrictor and inhibitor of angiogenesis, and its receptor, GPR54, have currently received much attention with respect to atherosclerosis, since both KP-10 and GPR54 are expressed at high levels in atheromatous plaques and restenotic lesions after wire-injury. The present review introduces the emerging roles of the KP-10/GPR54 system in atherosclerosis. DATA SYNTHESIS: KP-10 suppresses migration and proliferation of human umbilical vein endothelial cells (HUVECs), and induces senescence in HUVECs. KP-10 increases adhesion of human monocytes to HUVECs. KP-10 also stimulates expression of interleukin-6, tumor necrosis factor-α, monocyte chemotactic protein-1, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin genes in HUVECs. KP-10 enhances oxidized low-density lipoprotein-induced foam cell formation associated with upregulation of CD36 and acyl-coenzyme A: cholesterol acyltransferase-1 in human monocyte-derived macrophages. In human aortic smooth muscle cells, KP-10 suppresses angiotensin II-induced migration and proliferation, however, it enhances apoptosis and activities of matrix metalloproteinase (MMP)-2 and MMP-9 by upregulation of extracellular signal-regulated kinase 1/2, p38, Bax, and caspase-3. Four-week-infusion of KP-10 into Apoe-/- mice accelerates development of aortic atherosclerotic lesions with increased monocyte/macrophage infiltration and vascular inflammation, also, it decreases intraplaque vascular smooth muscle cell content. Proatherosclerotic effects of endogenous and exogenous KP-10 were completely attenuated upon infusion of P234, a GPR54 antagonist, in Apoe-/- mice. CONCLUSION: These findings suggest that KP-10 may contribute to acceleration of progression and to the instability of atheromatous plaques, leading to rupture of plaques. This GPR54 antagonist may be useful for the prevention and treatment of atherosclerosis. Thus, the KP-10/GPR54 system may serve as a novel therapeutic target for atherosclerotic diseases.


Assuntos
Aterosclerose/metabolismo , Vasos Sanguíneos/metabolismo , Kisspeptinas/metabolismo , Placa Aterosclerótica , Receptores de Kisspeptina-1/metabolismo , Animais , Apoptose , Aterosclerose/tratamento farmacológico , Aterosclerose/patologia , Vasos Sanguíneos/efeitos dos fármacos , Vasos Sanguíneos/patologia , Fármacos Cardiovasculares/uso terapêutico , Movimento Celular , Proliferação de Células , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Humanos , Macrófagos/metabolismo , Macrófagos/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Agregação Plaquetária , Receptores de Kisspeptina-1/antagonistas & inibidores , Transdução de Sinais
7.
Arch Biochem Biophys ; 688: 108408, 2020 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-32470460

RESUMO

Vascular dysfunction and injurious stimuli such as oxidative stress is closely related to the risk of cardiovascular diseases (CVD). Dietary polyphenols is reported to exert the beneficial effects on reducing the risk of CVD. Black soybean is rich in polyphenols, including isoflavones, anthocyanidins and flavan-3-ols, and its prevention effects on CVD risk were reported in the animal experiments. In this study, we investigated the effect of black soybean consumption on the vascular function and oxidative stress associating with the polyphenol concentrations in healthy women. Lowered vascular age was observed in 33 out of 44 volunteers who completed the 8-week trial. It was observed that improvement of the vascular stiffness, increasing in the urinary NO2 and NO3 level, and decreasing in the oxidative stress markers, 8-hydroxy-2'-deoxyguanosine, hexanoyl-lysine and myeloperoxidase. In addition, concentration of 12 polyphenols in black soybean increased in the plasma and urine. Increased concentration of polyphenols would be involved in the decreased oxidative stress. Thus, black soybean consumption improved the vascular function through an increase in nitric oxide and a decrease in oxidative stress accompanied by increasing the polyphenol concentrations in healthy women.


Assuntos
Antioxidantes/farmacologia , Vasos Sanguíneos/efeitos dos fármacos , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Polifenóis/farmacologia , Soja/química , Administração Oral , Adulto , Idoso , Animais , Antioxidantes/administração & dosagem , Antioxidantes/análise , Biomarcadores/sangue , Biomarcadores/metabolismo , Biomarcadores/urina , Pressão Sanguínea , Feminino , Humanos , Pessoa de Meia-Idade , Óxido Nítrico/sangue , Óxido Nítrico/urina , Fotopletismografia , Polifenóis/administração & dosagem , Polifenóis/sangue , Polifenóis/urina , Adulto Jovem
8.
Clin Sci (Lond) ; 134(7): 827-851, 2020 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-32271386

RESUMO

Major shifts in human lifestyle and dietary habits toward sedentary behavior and refined food intake triggered steep increase in the incidence of metabolic disorders including obesity and Type 2 diabetes. Patients with metabolic disease are at a high risk of cardiovascular complications ranging from microvascular dysfunction to cardiometabolic syndromes including heart failure. Despite significant advances in the standards of care for obese and diabetic patients, current therapeutic approaches are not always successful in averting the accompanying cardiovascular deterioration. There is a strong relationship between adipose inflammation seen in metabolic disorders and detrimental changes in cardiovascular structure and function. The particular importance of epicardial and perivascular adipose pools emerged as main modulators of the physiology or pathology of heart and blood vessels. Here, we review the peculiarities of these two fat depots in terms of their origin, function, and pathological changes during metabolic deterioration. We highlight the rationale for pharmacological targeting of the perivascular and epicardial adipose tissue or associated signaling pathways as potential disease modifying approaches in cardiometabolic syndromes.


Assuntos
Adipocinas/antagonistas & inibidores , Tecido Adiposo/efeitos dos fármacos , Anti-Inflamatórios/uso terapêutico , Vasos Sanguíneos/efeitos dos fármacos , Doenças Cardiovasculares/tratamento farmacológico , Mediadores da Inflamação/antagonistas & inibidores , Inflamação/tratamento farmacológico , Pericárdio/efeitos dos fármacos , Adipogenia/efeitos dos fármacos , Adipocinas/metabolismo , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Tecido Adiposo/fisiopatologia , Adiposidade/efeitos dos fármacos , Animais , Vasos Sanguíneos/metabolismo , Vasos Sanguíneos/patologia , Vasos Sanguíneos/fisiopatologia , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Doenças Cardiovasculares/fisiopatologia , Metabolismo Energético/efeitos dos fármacos , Humanos , Inflamação/metabolismo , Inflamação/patologia , Inflamação/fisiopatologia , Mediadores da Inflamação/metabolismo , Terapia de Alvo Molecular , Pericárdio/metabolismo , Pericárdio/patologia , Pericárdio/fisiopatologia , Transdução de Sinais
9.
Artigo em Inglês | MEDLINE | ID: mdl-32186933

RESUMO

Diabetes (especially Type II) is one of the primary threats to cardiovascular health. Wound healing defects and vascular dysfunction are common in diabetic patients, and the primary cause of deterioration is sustained high plasma glucose. microRNA, a noncoding RNA, has regulatory functions that are critical to maintaining homeostasis. MicroRNA (miR)-126-3p is a potential diabetes biomarker and a proangiogenic factor, and its plasma level decreases in diabetic patients. Previous studies have revealed the proangiogenic character of the gasotransmitter hydrogen sulfide (H2S). However, little is known about the relationship between H2S and miR-126-3p when the extracellular glucose level is high, let alone their influences on deteriorated endothelial cell migration, a key component of angiogenesis, which is crucial for wound healing. Human umbilical vein endothelial cells (HUVECs) were treated with high glucose (33.3 mmol/L) or normal glucose (5.5 mmol/L) for 48 h. Affymetrix miRNA profiling and real-time PCR were used to validate the miRNA expression. An H2S probe (HSip-1) was used to detect endogenous H2S. Scratch wound-healing assays were used to evaluate HUVEC migration. The protein levels were quantified by Western blot. Both exogenous and endogenous H2S could upregulate the miR-126-3p levels in HUVECs or muscle tissue. High glucose decreased the H2S level and the protein expression of the H2S-producing enzyme cystathionine γ-lyase (CSE) in HUVECs; however, the DNA methyltransferase 1 (DNMT1) protein level was upregulated. CSE overexpression not only increased the miR-126-3p level by decreasing the DNMT1 protein level but also rescued the deteriorated cell migration in HUVECs treated with high glucose. DNMT1 overexpression decreased the miR-126-3p level and inhibited the migration of HUVECs, whereas silencing DNMT1 improved cell migration. High glucose decreased the endogenous H2S and miR-126-3p levels and increased the DNMT1 expression, thus inducing the migration dysfunction of HUVECs. Treatment with exogenous H2S or the overexpression of the endogenously produced enzyme CSE would rescue this migration dysfunction through H2S-DNMT1-miR-126-3p.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Sulfeto de Hidrogênio/farmacologia , MicroRNAs/genética , Neovascularização Fisiológica/efeitos dos fármacos , Animais , Vasos Sanguíneos/efeitos dos fármacos , Vasos Sanguíneos/crescimento & desenvolvimento , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Movimento Celular/efeitos dos fármacos , Cistationina gama-Liase/genética , DNA (Citosina-5-)-Metiltransferase 1/genética , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Glucose/toxicidade , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Sulfeto de Hidrogênio/metabolismo , Camundongos , Neovascularização Fisiológica/genética , Transdução de Sinais/efeitos dos fármacos , Cicatrização/efeitos dos fármacos
10.
Molecules ; 25(3)2020 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-32046280

RESUMO

Due to its properties, such as biodegradability, low density, excellent biocompatibility and unique mechanics, spider silk has been used as a natural biomaterial for a myriad of applications. First clinical applications of spider silk as suture material go back to the 18th century. Nowadays, since natural production using spiders is limited due to problems with farming spiders, recombinant production of spider silk proteins seems to be the best way to produce material in sufficient quantities. The availability of recombinantly produced spider silk proteins, as well as their good processability has opened the path towards modern biomedical applications. Here, we highlight the research on spider silk-based materials in the field of tissue engineering and summarize various two-dimensional (2D) and three-dimensional (3D) scaffolds made of spider silk. Finally, different applications of spider silk-based materials are reviewed in the field of tissue engineering in vitro and in vivo.


Assuntos
Materiais Biocompatíveis/química , Regeneração/efeitos dos fármacos , Seda/química , Aranhas/química , Engenharia Tecidual/métodos , Animais , Materiais Biocompatíveis/isolamento & purificação , Materiais Biocompatíveis/metabolismo , Materiais Biocompatíveis/farmacologia , Vasos Sanguíneos/citologia , Vasos Sanguíneos/efeitos dos fármacos , Osso e Ossos/citologia , Osso e Ossos/efeitos dos fármacos , Cartilagem/citologia , Cartilagem/efeitos dos fármacos , Técnicas de Cultura de Células , Humanos , Hidrogéis/química , Nervos Periféricos/citologia , Nervos Periféricos/efeitos dos fármacos , Proteínas Recombinantes/química , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacologia , Regeneração/fisiologia , Seda/biossíntese , Seda/isolamento & purificação , Seda/farmacologia , Pele/citologia , Pele/efeitos dos fármacos , Aranhas/fisiologia , Substâncias Viscoelásticas/química
11.
Sci Rep ; 10(1): 2058, 2020 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-32029768

RESUMO

Humanised xenograft models allow for the analysis of human tissue within a physiological environment in vivo. However, current models often rely on the angiogenesis and ingrowth of recipient vasculature to perfuse tissues, preventing analysis of biological processes and diseases involving human blood vessels. This limits the effectiveness of xenografts in replicating human physiology and may lead to issues with translating findings into human research. We have designed a xenograft model of human vasculature to address this issue. Human subcutaneous fat was cultured in vitro to promote blood vessel outgrowth prior to implantation into immunocompromised mice. We demonstrate that implants survived, retained human vasculature and anastomosed with the circulatory system of the recipient mouse. Significantly, by performing transplants into the ear pinna, this system enabled intravital observation of xenografts by multiphoton microscopy, allowing us to visualise the steps leading to vascular cytoadherence of erythrocytes infected with the human parasite Plasmodium falciparum. This model represents a useful tool for imaging the interactions that occur within human tissues in vivo and permits visualization of blood flow and cellular recruitment in a system which is amenable to intervention for various studies in basic biology together with drug evaluation and mechanism of action studies.


Assuntos
Vasos Sanguíneos/transplante , Pavilhão Auricular/transplante , Xenoenxertos/transplante , Gordura Subcutânea/irrigação sanguínea , Adulto , Animais , Vasos Sanguíneos/efeitos dos fármacos , Vasos Sanguíneos/fisiologia , Avaliação Pré-Clínica de Medicamentos/métodos , Pavilhão Auricular/irrigação sanguínea , Feminino , Xenoenxertos/efeitos dos fármacos , Xenoenxertos/fisiologia , Humanos , Camundongos , Pessoa de Meia-Idade , Modelos Animais , Fluxo Sanguíneo Regional/efeitos dos fármacos , Fluxo Sanguíneo Regional/fisiologia , Técnicas de Cultura de Tecidos , Transplante Heterólogo/métodos , Adulto Jovem
12.
Life Sci ; 243: 117257, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31917992

RESUMO

Electrical field stimulation (EFS) has been used for decades in classical pharmacological preparations in order to characterize the mediators released by neural endings involved in smooth muscle contraction or relaxation. Since most of the human umbilical cord has no innervation, EFS has never been used in this preparation. This study aimed to investigate the effect of EFS on vascular responsiveness from human umbilical cord. Segments of the human umbilical cord were obtained from normotensive parturients and the human umbilical artery (HUA) and the human umbilical vein (HUV) were isolated and mounted in organ bath chambers. Electrical field stimulation-induced contractions in both HUA (2.35 ±â€¯1.31 mN and 3.77 ±â€¯2.31 mN for 8 Hz and 16 Hz respectively, n = 24) and HUV (3.81 ±â€¯2.54 mN and 6.26 ±â€¯4.51 mN for 8 Hz and 16 Hz respectively, n = 25). The addition of tetrodotoxin (1 µM) did not alter the EFS-induced contractions in both tissues (n = 5). Pre-incubation with atropine (10 and 100 µM), glibenclamide (10 µM) and indomethacin (10 µM) did not affect the EFS-induced contractions in both tissues. The contractions of both vessels were significantly reduced by pre-incubation of the tissues with phentolamine (10 and 100 µM). The endothelium removal almost abolished the EFS- induced contractions in both vessels (n = 5). In sandwich preparation, donor tissue (with endothelium) released a factor (s) that promoted contraction of the recipient tissue (endothelium removal) in both HUA and HUV (n = 5, respectively). Our findings indicate a potential role of endothelium-derived catecholamines in modulating HUA and HUV reactivities.


Assuntos
Vasos Sanguíneos/fisiologia , Estimulação Elétrica , Cordão Umbilical/irrigação sanguínea , Adulto , Atropina/farmacologia , Vasos Sanguíneos/efeitos dos fármacos , Glibureto/farmacologia , Humanos , Indometacina/farmacologia , Contração Muscular/efeitos dos fármacos , Tetrodotoxina/farmacologia , Adulto Jovem
13.
Sci Rep ; 10(1): 544, 2020 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-31953475

RESUMO

1 in 5 women report cannabis use during pregnancy, with nausea cited as their primary motivation. Studies show that (-)-△9-tetrahydrocannabinol (Δ9-THC), the major psychoactive ingredient in cannabis, causes fetal growth restriction, though the mechanisms are not well understood. Given the critical role of the placenta to transfer oxygen and nutrients from mother, to the fetus, any compromise in the development of fetal-placental circulation significantly affects maternal-fetal exchange and thereby, fetal growth. The goal of this study was to examine, in rats, the impact of maternal Δ9-THC exposure on fetal development, neonatal outcomes, and placental development. Dams received a daily intraperitoneal injection (i.p.) of vehicle control or Δ9-THC (3 mg/kg) from embryonic (E)6.5 through 22. Dams were allowed to deliver normally to measure pregnancy and neonatal outcomes, with a subset sacrificed at E19.5 for placenta assessment via immunohistochemistry and qPCR. Gestational Δ9-THC exposure resulted in pups born with symmetrical fetal growth restriction, with catch up growth by post-natal day (PND)21. During pregnancy there were no changes to maternal food intake, maternal weight gain, litter size, or gestational length. E19.5 placentas from Δ9-THC-exposed pregnancies exhibited a phenotype characterized by increased labyrinth area, reduced Epcam expression (marker of labyrinth trophoblast progenitors), altered maternal blood space, decreased fetal capillary area and an increased recruitment of pericytes with greater collagen deposition, when compared to vehicle controls. Further, at E19.5 labyrinth trophoblast had reduced glucose transporter 1 (GLUT1) and glucocorticoid receptor (GR) expression in response to Δ9-THC exposure. In conclusion, maternal exposure to Δ9-THC effectively compromised fetal growth, which may be a result of the adversely affected labyrinth zone development. These findings implicate GLUT1 as a Δ9-THC target and provide a potential mechanism for the fetal growth restriction observed in women who use cannabis during pregnancy.


Assuntos
Vasos Sanguíneos/efeitos dos fármacos , Dronabinol/efeitos adversos , Orelha Interna/embriologia , Retardo do Crescimento Fetal/induzido quimicamente , Placenta/irrigação sanguínea , Animais , Molécula de Adesão da Célula Epitelial/metabolismo , Feminino , Retardo do Crescimento Fetal/metabolismo , Retardo do Crescimento Fetal/patologia , Retardo do Crescimento Fetal/fisiopatologia , Transportador de Glucose Tipo 1/metabolismo , Placenta/efeitos dos fármacos , Gravidez , Ratos , Receptores de Glucocorticoides/metabolismo , Trofoblastos/efeitos dos fármacos , Trofoblastos/patologia
14.
Mol Biol Rep ; 47(3): 1649-1658, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31925643

RESUMO

Angiogenesis is a new vessel formation process that plays a role in various physiological and pathological conditions. This process is controlled by the balance between pro-angiogenic and anti-angiogenic mediators in the organism. Angiogenesis is needed for the growth and metastasis of solid tumors. Therefore, the anti-angiogenic treatment approach is seen as an interesting option in cancers. Fenretinide, a synthetic retinoic acid analog, is an effective agent on angiogenesis. In this study, we aimed to investigate the effects of the fenretinide on some miRNAs involving in angiogenesis process and on the expression of CDH5, FOXM1 and eNOS genes upregulated in angiogenesis. In addition, it was shown the effects of this agent on cell proliferation, cell migration and capillary-like tube formation. In our study, the data were analyzed using Kruskal-Wallis and Dunn's test. Fenretinide applied to the cells for 24 and 48 h periods reduced cell proliferation (P < 0.001) and cell migration, and suppressed tube formation (P < 0.001) as a dose dependent manner. Endothelial cells were cultured in growth-inducing media containing a variety of growth factors such as VEGF, FGF, IGF and EGF. As a result of simultaneous PCR analysis, we found that angiogenesis-promoting miR-10b was effectively suppressed (P < 0.001) and interestingly angiogenesis-modulating miR-126 was slightly increased (P < 0.05), but other miRNAs, including miR-31, miR-21, miR-101, miR-340, miR-29c, miR-206 and miR-146a were not affected. Besides, a significant decrease was observed in the levels of some angiogenesis-inducing genes, CDH5 (P < 0.001), FOXM1 (P < 0.001) and eNOS (P < 0.01 and P < 0.001) in endothelial cells treated with fenretinide. Our results have shown that fenretinide exhibited anti-angiogenic activity through the down-regulation of CDH5, FOXM1 and eNOS genes, and suppression of miR-10b.


Assuntos
Antígenos CD/genética , Vasos Sanguíneos/efeitos dos fármacos , Caderinas/genética , Fenretinida/farmacologia , Proteína Forkhead Box M1/genética , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , MicroRNAs/genética , Óxido Nítrico Sintase Tipo III/genética , Antineoplásicos/farmacologia , Vasos Sanguíneos/metabolismo , Vasos Sanguíneos/fisiologia , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Células Cultivadas , Regulação para Baixo/efeitos dos fármacos , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/fisiologia , Humanos
15.
Toxicol In Vitro ; 62: 104694, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31655124

RESUMO

AIM: Hyperglycemia status induces endothelial dysfunction, although the underlying pathogenic mechanisms are not fully understood. There are several studies connecting sugar/sweetened beverages to the cardiovascular disease. Currently, many sweeteners have been extensively introduced into lifestyle to normalize blood glucose levels without altering the sweet taste. However, there is growing concern for their impact on metabolic health. METHODS: Human endothelial cells were treated with Glucose, Fructose, Aspartame, Rebaudioside A, Stevioside, or Steviol. Morphological characteristics, in vitro angiogenesis and array gene expression were analyzed. RESULTS: High-glucose and fructose concentrations significantly decreased cell features such as angiogenic capability. Interestingly, non-caloric sweeteners did not significantly modified all cell characteristics and they did not compromised cell angiogenic ability. Array gene expression analysis revealed that the chemokine fractalkine (CX3CL1) and the enzyme transferase (HPRT1) were always significantly upregulated and downregulated respectively, after glucose and fructose treatments (P > .05), whereas they were non-differentially expressed with all the other sweeteners. Interestingly, both genes are considered as cardiovascular disease risk biomarkers. Specifically, upregulation of CX3CL1/CX3CR1 occurs in the human placenta and serum levels of the ligand are associated with markers of insulin resistance in GDM. CONCLUSIONS: Differently from glucose and fructose, steviol glycosides do not damage endothelial cells. Prospective preclinical studies and clinical trials are warranted to confirm the long-term safety of such compounds.


Assuntos
Vasos Sanguíneos/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Edulcorantes/farmacologia , Aspartame/farmacologia , Receptor 1 de Quimiocina CX3C/metabolismo , Quimiocina CX3CL1/metabolismo , Diterpenos de Caurano/farmacologia , Endotélio Vascular/citologia , Feminino , Frutose/farmacologia , Expressão Gênica/efeitos dos fármacos , Glucose/farmacologia , Glucosídeos/farmacologia , Humanos , Hipoxantina Fosforribosiltransferase/metabolismo , Neovascularização Fisiológica/efeitos dos fármacos , Placenta/efeitos dos fármacos , Placenta/metabolismo , Gravidez , Estudos Prospectivos
16.
Nat Commun ; 10(1): 5380, 2019 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-31772164

RESUMO

Despite the efficacy of current starvation therapies, they are often associated with some intrinsic drawbacks such as poor persistence, facile tumor metastasis and recurrence. Herein, we establish an extravascular gelation shrinkage-derived internal stress strategy for squeezing and narrowing blood vessels, occluding blood & nutrition supply, reducing vascular density, inducing hypoxia and apoptosis and eventually realizing starvation therapy of malignancies. To this end, a biocompatible composite hydrogel consisting of gold nanorods (GNRs) and thermal-sensitive hydrogel mixture was engineered, wherein GRNs can strengthen the structural property of hydrogel mixture and enable robust gelation shrinkage-induced internal stresses. Systematic experiments demonstrate that this starvation therapy can suppress the growths of PANC-1 pancreatic cancer and 4T1 breast cancer. More significantly, this starvation strategy can suppress tumor metastasis and tumor recurrence via reducing vascular density and blood supply and occluding tumor migration passages, which thus provides a promising avenue to comprehensive cancer therapy.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Hidrogéis/química , Hidrogéis/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Resinas Acrílicas/química , Animais , Antineoplásicos/química , Vasos Sanguíneos/efeitos dos fármacos , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Linhagem Celular Tumoral , Feminino , Ouro/química , Humanos , Terapia a Laser , Camundongos Nus , Nanotubos/química , Recidiva Local de Neoplasia , Neoplasias Pancreáticas/irrigação sanguínea , Neoplasias Pancreáticas/patologia , Ratos Sprague-Dawley , Reologia , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Breast Cancer Res ; 21(1): 116, 2019 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-31640747

RESUMO

BACKGROUND: Triple-negative breast cancer has extremely high risk of relapse due to the lack of targeted therapies, intra- and inter-tumoral heterogeneity, and the inherent and acquired resistance to therapies. In this study, we evaluate the potential of prostate-specific membrane antigen (PSMA) as target for radio-ligand therapy (RLT). METHODS: Tube formation was investigated after incubation of endothelial HUVEC cells in tumor-conditioned media and monitored after staining using microscopy. A binding study with 68Ga-labeled PSMA-addressing ligand was used to indicate targeting potential of PSMA on tumor-conditioned HUVEC cells. For mimicking of the therapeutic application, tube formation potential and vitality of tumor-conditioned HUVEC cells were assessed following an incubation with radiolabeled PSMA-addressing ligand [177Lu]-PSMA-617. For in vivo experiments, NUDE mice were xenografted with triple-negative breast cancer cells MDA-MB231 or estrogen receptor expressing breast cancer cells MCF-7. Biodistribution and binding behavior of [68Ga]-PSMA-11 was investigated in both tumor models at 30 min post injection using µPET. PSMA- and CD31-specific staining was conducted to visualize PSMA expression and neovascularization in tumor tissue ex vivo. RESULTS: The triple-negative breast cancer cells MDA-MB231 showed a high pro-angiogenetic potential on tube formation of endothelial HUVEC cells. The induced endothelial expression of PSMA was efficiently addressed by radiolabeled PSMA-specific ligands. 177Lu-labeled PSMA-617 strongly impaired the vitality and angiogenic potential of HUVEC cells. In vivo, as visualized by µPET, radiolabeled PSMA-ligand accumulated specifically in the triple-negative breast cancer xenograft MDA-MB231 (T/B ratio of 43.3 ± 0.9), while no [68Ga]-PSMA-11 was detected in the estrogen-sensitive MCF-7 xenograft (T/B ratio of 1.1 ± 0.1). An ex vivo immunofluorescence analysis confirmed the localization of PSMA on MDA-MB231 xenograft-associated endothelial cells and also on TNBC cells. CONCLUSIONS: Here we demonstrate PSMA as promising target for two-compartment endogenous radio-ligand therapy of triple-negative breast cancer.


Assuntos
Radioisótopos de Gálio/uso terapêutico , Glutamato Carboxipeptidase II/antagonistas & inibidores , Lutécio/uso terapêutico , Radioisótopos/uso terapêutico , Neoplasias de Mama Triplo Negativas/radioterapia , Animais , Antígenos de Superfície/metabolismo , Vasos Sanguíneos/efeitos dos fármacos , Vasos Sanguíneos/fisiologia , Vasos Sanguíneos/efeitos da radiação , Linhagem Celular Tumoral , Meios de Cultivo Condicionados/farmacologia , Dipeptídeos/metabolismo , Dipeptídeos/uso terapêutico , Ácido Edético/análogos & derivados , Ácido Edético/metabolismo , Ácido Edético/uso terapêutico , Glutamato Carboxipeptidase II/metabolismo , Compostos Heterocíclicos com 1 Anel/metabolismo , Compostos Heterocíclicos com 1 Anel/uso terapêutico , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/fisiologia , Células Endoteliais da Veia Umbilical Humana/efeitos da radiação , Humanos , Ligantes , Células MCF-7 , Camundongos Nus , Oligopeptídeos/metabolismo , Oligopeptídeos/uso terapêutico , Compostos Radiofarmacêuticos/uso terapêutico , Neoplasias de Mama Triplo Negativas/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
18.
Braz Oral Res ; 33: e092, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31576904

RESUMO

This study evaluated the effect of antimicrobial photodynamic therapy (aPDT) on the endodontic treatment of apical periodontitis (AP). AP was induced in 48 premolars of 6 dogs. After biomechanical preparation, the teeth were divided into 4 groups: Calcium-Hydroxide (CH)/120d and CH/180d: root canals filled with CH-based dressing for 15 days before obturation; aPDT/120d and aPDT/180d: conditioning with phenothiazine photosensitizer (10 mg/mL) for 1 minute and irradiation with diode laser in the same session as obturation. Root filling was performed with AH Plus sealer. After the experimental periods, animals were euthanized and teeth were submitted for histology. HE staining was performed for descriptive analysis of the periapical region, measurement of apical periodontitis and for inflammatory cells, and blood vessels count. Immunohistochemistry was performed for osteopontin (OPN) and alkaline phosphatase (ALP). Data were analyzed statistically by two-way ANOVA and chi-square test (α = 5%). Teeth in Group CH/120d presented only a slightly enlarged periodontal ligament (PL) with advanced repair. Group aPDT/120d presented the PL moderately enlarged, with moderate inflammatory infiltrate and few collagen fibers. The same pattern was observed at 180 days. AP lesions in CH-treated groups were smaller than those in aPDT-treated groups (p < 0.001) with more blood vessels (p < 0.0001), regardless of the evaluation period, without significant differences in the number of inflammatory cells (p > 0.05). CH-treated groups showed significantly more intense immunostaining for ALP and OPN (p < 0.001) in both periods. Although aPDT stimulated angiogenesis and expression of bone formation markers, the two-session endodontic treatment with CH-based dressing promoted better apical periodontitis repair.


Assuntos
Cimentos para Ossos/uso terapêutico , Hidróxido de Cálcio/uso terapêutico , Periodontite Periapical/tratamento farmacológico , Fotoquimioterapia/métodos , Tratamento do Canal Radicular/métodos , Animais , Vasos Sanguíneos/efeitos dos fármacos , Regeneração Óssea/efeitos dos fármacos , Imuno-Histoquímica , Neovascularização Fisiológica/efeitos dos fármacos , Periodontite Periapical/patologia , Reprodutibilidade dos Testes , Fatores de Tempo , Resultado do Tratamento
19.
Biomed Pharmacother ; 120: 109537, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31605951

RESUMO

BACKGROUND: Perivascular adipose tissue (PVAT) attenuates its anti-contractile effect through an endothelial-dependent mechanism that aggravates endothelial dysfunction in obesity. The present study was conducted to explore whether liraglutide could improve vascular dysfunction, including the anti-contractile effect of PVAT and endothelial function, by modulating PVAT-related signaling pathways in obesity. METHODS: C57BL/6 mice were fed a normal-chow diet or a high-fat diet (HFD) with or without liraglutide treatment. Vascular function of the thoracic aorta with or without PVAT were measured. Protein levels of components of the PKA-AMPK-PGC1α and antioxidant signaling pathway in PVAT were determined by western blotting. Brown adipose tissue-related gene in PVAT was measured by qRT-PCR. RESULTS: Metabolic profiles of HFD-fed mice were improved after treatment with liraglutide. Liraglutide improved PVAT-induced anti-contractile capability and PVAT-induced endothelial dysfunction in HFD-fed mice both in vivo and ex vivo. However, blocking PKA, or AMPK, but not cAMP, attenuated these beneficial effects of liraglutide. Treating HFD-fed mice with liraglutide activated the AMPK/eNOS pathway and induced browning-related gene expression. Moreover, liraglutide increased antioxidant capability. The protective effects were related to activation of a cAMP-independent PKA-AMPK pathway, as demonstrated by western blot and PCR. CONCLUSIONS: Liraglutide improved vascular dysfunction by modulating a cAMP-independent PKA-AMPK pathway in PVAT in HFD-induced obese mice. The findings provide a novel mechanism for the cardiovascular protection of liraglutide by modulating PVAT function in obesity.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Tecido Adiposo Marrom/irrigação sanguínea , Tecido Adiposo Marrom/enzimologia , Vasos Sanguíneos/fisiopatologia , AMP Cíclico/metabolismo , Liraglutida/farmacologia , Proteínas Quinases/metabolismo , Transdução de Sinais , Adiponectina/metabolismo , Animais , Vasos Sanguíneos/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiopatologia , Masculino , Metaboloma , Camundongos Endogâmicos C57BL , Camundongos Obesos , Óxido Nítrico Sintase Tipo III/metabolismo , Transdução de Sinais/efeitos dos fármacos
20.
Cardiol Clin ; 37(4): 365-384, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31587779

RESUMO

The introduction of targeted agents into modern cancer therapy pursued the goal of molecularly more specific, and thereby more effective and safer, therapies. Paradoxically, however, several toxicities were brought to greater attention, among these not only cardiac but also vascular toxicities. The latter reach far beyond venous thromboembolism and include a broad spectrum of presentations based on the vascular territories and pathomechanisms involved, including abnormal vascular reactivity, acute thrombosis, or accelerated atherosclerosis. This article provides an overview of the most common presentations and their management strategies.


Assuntos
Antineoplásicos/efeitos adversos , Vasos Sanguíneos/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Doenças Vasculares/induzido quimicamente , Cardiotoxicidade , Saúde Global , Humanos , Incidência , Fatores de Risco , Doenças Vasculares/epidemiologia
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