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1.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 55(1): 111-117, 2024 Jan 20.
Artigo em Zh | MEDLINE | ID: mdl-38322531

RESUMO

Objective: To evaluate the inhibitory effect of ginsenoside Rg3 combined with 5-fluorouracil (5-FU) on tumor angiogenesis and tumor growth in colon cancer in mice. Methods: CT26 mouse model of colon cancer was established and the mice were randomly assigned to the control group, the ginsenoside Rg3 group, the 5-FU group, and the Rg3 combined with 5-FU group. The 5-FU group was injected intraperitoneally at the dose of 20 mg/kg, 0.2 mL/animal, and once a day for 10 days. Treatment for the Rg3 group was given at the dose of 20 mg/kg, 0.2 mL/animal, and once a day for 21 days via gastric gavage. The dose and the mode of treatment for the Rg3+5-FU combination group were the same as those for the 5-FU and the Rg3 group. The control group was intraperitoneally injected with 0.2 mL/d of normal saline for 10 days. The expression of vascular endothelial growth factor (VEGF) and CD31 and the microvascular density (MVD) of the tumor tissues were examined by immunohistochemistry. The blood flow signals and tumor necrosis were examined by color Doppler flow imaging (CDFI). The quality of life, survival rate, tumor volume, tumor mass, and tumor inhibition rate of the mice were monitored. Results: After 21 days of treatment, the tumor volume and the tumor mass of all treatment groups were significantly decreased compared with those the control group, with the combination treatment group exhibiting the most significant decrease. The tumor inhibition rates of the Rg3 group, the 5-FU group, and the combination group were 29.96%, 68.78%, and 73.42%, respectively. Rg3 treatment alone had inhibitory effect on tumor growth to a certain degree, while 5-FU treatment alone or 5-FU combined with Rg3 had a stronger inhibitory effect on tumor growth. The tumor inhibition rate of the combination group was higher than that of the 5-FU group, but the difference was not statistically significant (P>0.05). Color Doppler ultrasound showed that there were multiple localized and large tumor necrotic areas that were obvious and observable in the Rg3 group and the combination group, and that there were only small tumor necrotic areas in the 5-FU group and the control group. The tumor necrosis rate of the combination group was (55.63±3.12)%, which was significantly higher than those of the other groups (P<0.05). CDFI examination of the blood flow inside of the tumor of the mice showed that the blood flow signals in the combination group were mostly grade 0-Ⅰ, and that the blood flow signals in the control group were the most abundant, being mostly grade Ⅱ-Ⅲ. The abundance of the blood flow signals in the Rg3 and 5-FU groups were between those of the control group and the combination group. Compared with those of the control group, the expression levels of MVD and VEGF in the tumor tissues of the Rg3 group, the 5-FU group, and the combination group were significantly decreased, with the combination group showing the most significant decrease (P<0.05). HE staining results indicated that there was significant tumor necrosis in mice in the control group and that there were more blood vessels. In contrast, in the tumor of the Rg3 group and the 5-FU group, there were fewer blood vessels and necrotic gaps appeared within the tumors. In the combination group, the tumor tissues had the fewest blood vessels and rope-like necrosis was observed. The mice started dying on the 18th day after treatment started, and all the mice in the control group died on the 42nd day. By this time, there were 3, 5, and 7 mice still alive in the Rg3 group, the 5-FU group, and the combination group, respectively, presenting a survival rate of 30%, 50%, and 70%, respectively. All mice in all the groups died on day 60 after treatment started. Conclusion: Ginsenoside Rg3 combined with 5-FU can significantly inhibit tumor angiogenesis and tumor growth of colon cancer in mice and improve the survival and quality of life of tumor-bearing mice.


Assuntos
Neoplasias do Colo , Ginsenosídeos , Camundongos , Animais , Fluoruracila/uso terapêutico , Fator A de Crescimento do Endotélio Vascular/metabolismo , Angiogênese , Qualidade de Vida , Ginsenosídeos/farmacologia , Ginsenosídeos/uso terapêutico , Neovascularização Patológica/tratamento farmacológico , Necrose/tratamento farmacológico , Linhagem Celular Tumoral
2.
Stroke ; 50(12): 3456-3464, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31619153

RESUMO

Background and Purpose- Peripheral immune cells are activated after stroke and may in turn influence the fate of ischemic brain tissue, thus exerting a dual role in ischemic stroke. We evaluated the contribution of neutrophil and lymphocyte counts to hemorrhagic complications and functional outcome in stroke patients treated with mechanical thrombectomy (MT) with varying degrees of collateral circulation and reperfusion. Methods- We retrospectively analyzed 433 consecutive ischemic stroke patients treated with MT. Neutrophil and lymphocyte counts and the neutrophil-to-lymphocyte ratio (NLR) were collected before MT and 1 day after symptom onset. Outcome measures included categories of hemorrhagic transformation, symptomatic intracerebral hemorrhage, 3-month functional dependence (modified Rankin Scale, 3-6), and mortality. Patients were categorized according to their baseline collateral status and the degree of reperfusion after MT. Results- Neutrophil counts and NLR increased, whereas lymphocyte counts decreased after MT (P<0.001), and changes in neutrophils and NLR at day 1 were significantly greater in patients with poor reperfusion. Neutrophil counts and NLR were significantly higher already at admission in patients with poor 3-month outcome. In adjusted analysis, the impact of neutrophilia on poor functional outcome was more substantial in patients with good collaterals achieving successful reperfusion (aOR, 3.09 per quartile; 95% CI, 1.95-4.90), whereas admission lymphopenia (aOR, 4.08 per decreasing quartile; 95% CI, 1.56-10.64) and higher NLR (aOR, 3.76 per quartile; 95% CI, 1.44-9.79) predicted subsequent symptomatic intracerebral hemorrhage in patients with poor collaterals and successful reperfusion. Conclusions- In patients treated with MT, neutrophil and lymphocyte counts are dynamic parameters associated with hemorrhagic complications and long-term outcome. The extent of collateral circulation and the success of brain reperfusion influence the strength of these associations and highlight the dual role of leukocytes in acute stroke.


Assuntos
Circulação Colateral/fisiologia , Leucócitos , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/terapia , Trombectomia/métodos , Idoso , Idoso de 80 Anos ou mais , Isquemia Encefálica/complicações , Hemorragia Cerebral/epidemiologia , Hemorragia Cerebral/etiologia , Feminino , Humanos , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Reperfusão/métodos , Estudos Retrospectivos , Acidente Vascular Cerebral/complicações , Resultado do Tratamento
3.
Arterioscler Thromb Vasc Biol ; 38(8): 1761-1771, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29903733

RESUMO

Objective- Hemorrhagic transformation is a serious complication of ischemic stroke after recanalization therapies. This study aims to identify mechanisms underlying hemorrhagic transformation after cerebral ischemia/reperfusion. Approach and Results- We used wild-type mice and Selplg-/- and Fut7-/- mice defective in P-selectin binding and lymphopenic Rag2-/- mice. We induced 30-minute or 45-minute ischemia by intraluminal occlusion of the middle cerebral artery and assessed hemorrhagic transformation at 48 hours with a hemorrhage grading score, histological means, brain hemoglobin content, or magnetic resonance imaging. We depleted platelets and adoptively transferred T cells of the different genotypes to lymphopenic mice. Interactions of T cells with platelets in blood were studied by flow cytometry and image stream technology. We show that platelet depletion increased the bleeding risk only after large infarcts. Lymphopenia predisposed to hemorrhagic transformation after severe stroke, and adoptive transfer of T cells prevented hemorrhagic transformation in lymphopenic mice. CD4+ memory T cells were the subset of T cells binding P-selectin and platelets through functional P-selectin glycoprotein ligand-1. Mice defective in P-selectin binding had a higher hemorrhagic score than wild-type mice. Adoptive transfer of T cells defective in P-selectin binding into lymphopenic mice did not prevent hemorrhagic transformation. Conclusions- The study identifies lymphopenia as a previously unrecognized risk factor for secondary hemorrhagic transformation in mice after severe ischemic stroke. T cells prevent hemorrhagic transformation by their capacity to bind platelets through P-selectin. The results highlight the role of T cells in bridging immunity and hemostasis in ischemic stroke.


Assuntos
Transferência Adotiva , Plaquetas/metabolismo , Linfócitos T CD4-Positivos/transplante , Infarto da Artéria Cerebral Média/terapia , Hemorragias Intracranianas/prevenção & controle , Linfopenia/terapia , Selectina-P/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Reperfusão/efeitos adversos , Animais , Plaquetas/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , Fucosiltransferases/genética , Fucosiltransferases/metabolismo , Genótipo , Memória Imunológica , Infarto da Artéria Cerebral Média/genética , Infarto da Artéria Cerebral Média/imunologia , Infarto da Artéria Cerebral Média/metabolismo , Hemorragias Intracranianas/genética , Hemorragias Intracranianas/imunologia , Hemorragias Intracranianas/metabolismo , Linfopenia/genética , Linfopenia/imunologia , Linfopenia/metabolismo , Masculino , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Selectina-P/imunologia , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/imunologia , Traumatismo por Reperfusão/metabolismo , Fatores de Risco , Fatores de Tempo
4.
Brain Behav Immun ; 70: 346-353, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29548995

RESUMO

Ischemic stroke sets in motion a dialogue between the central nervous and the immune systems that includes the sympathetic/adrenal system. We investigated the course of immune cells and adrenocortical and adrenomedullary effectors in a cohort of 51 patients with acute stroke receiving reperfusion therapy (intravenous alteplase or mechanical thrombectomy) and its correlation with stroke outcomes and infarct growth. Cortisol increased rapidly and fleetingly after stroke, but 39% of patients who had larger infarctions on admission showed a positive delta cortisol at day 1. It was associated with enhanced infarct growth (p = 0.002) and poor outcome [OR (95% CI) 5.30 (1.30-21.69)], and correlated with less lymphocytes and T cells at follow up. Likewise, fewer circulating lymphocytes, T cells, and Tregs were associated with infarct growth. By contrast, metanephrines did not increase at clinical onset, and decreased over time. Higher levels of NMN correlated with more Treg and B cells. Eventually, complete reperfusion at the end of therapy headed the identification of more circulating Tregs at day 1. Then activation of cortical or medullar compartments of the adrenal gland result in specific signatures on leukocyte subpopulations. Manipulation of the adrenal gland hormone levels warrants further investigation.


Assuntos
Corticosteroides/análise , Reperfusão/métodos , Acidente Vascular Cerebral/terapia , Glândulas Suprarrenais/fisiologia , Idoso , Idoso de 80 Anos ou mais , Isquemia Encefálica/imunologia , Isquemia Encefálica/terapia , Feminino , Humanos , Hidrocortisona/análise , Hidrocortisona/sangue , Leucócitos , Contagem de Linfócitos , Linfócitos , Masculino , Metanefrina/análise , Metanefrina/sangue , Pessoa de Meia-Idade , Linfócitos T , Linfócitos T Reguladores , Ativador de Plasminogênio Tecidual/farmacologia , Resultado do Tratamento
5.
Brain Behav Immun ; 60: 142-150, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27742582

RESUMO

BACKGROUND: Infections represent the most frequent medical complications in stroke patients. Their main determinants are dysphagia and a transient state of immunodepression. We analyzed whether distinct anatomical brain regions were associated with the occurrence of stroke-associated infections or immunodepression. MATERIALS AND METHODS: In 106 patients with acute ischemic stroke, we evaluated the incidence of pneumonia, urinary tract infection, or other infections together with the characterization of biomarkers of immunodepression. Twenty control subjects served to provide reference values. Using voxel-based lesion-symptom mapping, the involvement of gray and white matter structures was correlated with clinical and laboratory findings in crude analyses and in volume adjusted models to rule out associations reflecting differences in the size of the infarction. RESULTS: Stroke-associated infection occurred in 22 (21%) patients and prevailed in patients with larger infarcts. Volume adjusted voxel-based lesion-symptom mapping revealed the involvement of the superior and middle temporal gyri, the orbitofrontal cortex, the superior longitudinal fasciculus and the inferior fronto-occipital fasciculus amongst infected patients. These associations were similar for pneumonia but not for urinary tract infections. Lymphopenia was associated with lesions of the superior and middle temporal gyri. Laterality did not influence stroke-associated infections or the presence of immunodepressive traits after volume control. The greatest overlap in the neuroanatomical correlates occurred between pneumonia and dysphagia. CONCLUSION: Infarct volume plays a relevant role in the occurrence of stroke-associated infections, but lesions in specific brain locations such as the superior and lateral temporal lobe and the orbitofrontal cortex are also associated with increased infectious risk, especially pneumonia.


Assuntos
Encéfalo/patologia , Tolerância Imunológica/imunologia , Terapia de Imunossupressão , Acidente Vascular Cerebral/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Mapeamento Encefálico/métodos , Feminino , Lateralidade Funcional/fisiologia , Humanos , Terapia de Imunossupressão/métodos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Acidente Vascular Cerebral/complicações
6.
J Cereb Blood Flow Metab ; 39(7): 1326-1335, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-29436885

RESUMO

Hypoperfusion is the typical perfusion pattern associated with recent small subcortical infarcts of the brain, but other perfusion patterns may be present in patients with these infarcts. Using CT perfusion, we studied 67 consecutive patients who had a small subcortical infarct at a follow-up MRI study to investigate the correlation between the perfusion pattern and the clinical and radiological course. On CT perfusion map analysis, 51 patients (76%) had focal hypoperfusion, 4 patients (6%) had hyperperfusion and the remaining 12 patients (18%) showed no abnormalities. On dynamic sequential imaging analysis obtained from the source perfusion images, 32 patients (48%) had a sustained hypoperfusion pattern, 11 patients (16%) had a reperfusion pattern, and 18 patients (27%) had a delayed compensation pattern. Systolic blood pressure was higher in patients with sustained hypoperfusion although the perfusion pattern was independent of the final volume of infarction. These results reinforce the notion that mechanisms other than hypoperfusion are at play in patients with small subcortical infarcts including the intervention of compensatory sources of blood flow. The ultimate clinical significance of these perfusion patterns remains to be determined in larger series of patients assessed longitudinally.


Assuntos
Encéfalo/irrigação sanguínea , Encéfalo/fisiopatologia , Infarto Cerebral/fisiopatologia , Circulação Cerebrovascular/fisiologia , Idoso , Pressão Sanguínea , Infarto Cerebral/cirurgia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Reperfusão , Tomografia Computadorizada por Raios X
7.
J Neurointerv Surg ; 11(10): 989-993, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30814327

RESUMO

OBJECTIVE: Stroke patients with good collateral circulation achieve the best recovery after mechanical thrombectomy (MT) but strict imaging selection may result in untreated patients that could benefit from MT. We assessed whether the extent of collaterals had modifying effects on the amount of ischemic tissue saved from infarction with MT over best medical treatment (BMT). METHODS: This was a single center cohort of consecutive patients (n=339) with proximal occlusions in the carotid territory. Patients were categorized according to a four point category scale on CT angiography as having good (scores 2-3) or poor (scores 0-1) collaterals. The primary outcome measure was the interaction between collaterals and MT on infarct growth. The secondary outcome assessed the treatment effect of MT over BMT on functional status in relation to collateral status. Safety outcomes were mortality and symptomatic intracranial hemorrhage. RESULTS: Collaterals had a modifying effect of MT on infarct growth (P=0.004), with a greater reduction in 96 patients with poor collaterals (38.8 mL) than in 243 patients with good collaterals (1.9 mL). There was also a significant (P<0.001) interaction between the effect of MT and functional outcome in relation to collateral status, with more benefits of MT in patients with poor collaterals. MT was associated with lower mortality than BMT in patients with poor collaterals only. CONCLUSION: Compared with BMT, the use of MT in the early time window in large vessel stroke results in a more substantial limitation of infarct growth in patients with poor collaterals.


Assuntos
Infarto Cerebral/diagnóstico por imagem , Infarto Cerebral/cirurgia , Circulação Colateral/fisiologia , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/cirurgia , Trombectomia/métodos , Idoso , Idoso de 80 Anos ou mais , Angiografia Cerebral/métodos , Estudos de Coortes , Angiografia por Tomografia Computadorizada/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Sistema de Registros , Resultado do Tratamento
8.
Sci Rep ; 8(1): 9498, 2018 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-29934530

RESUMO

The prognostic relevance of strokes in different locations is debated. For example, insular strokes have been associated with increased mortality, but this association could reflect their greater severity. In two independent cohorts of patients with supratentorial ischemic stroke (n = 90 and 105), we studied the prognostic consequences of lesion size and location using voxel-based lesion-symptom mapping before and after volume control, which better accounts for total lesion volume. Strokes affecting the insula were larger than non-insular strokes (28 vs 2cc and 25 vs 3cc, p < 0.001 in both cohorts). A number of supratentorial areas (mainly in the left hemisphere), including the insula, were associated with poor functional outcome in both cohorts before (4014 voxels) and after volume control (1378 voxels), while the associations with death were greatly reduced after volume control (from 8716 to 325 voxels). Exploratory analyses suggested that the method of lesion volume quantification, the National Institutes of Health Stroke Scale hemispheric bias and patient selection can result in false associations between specific brain lesions and outcomes. In conclusion, death in the first months after stroke is mainly explained by large infarct volumes, whereas lesions of specific supratentorial structures, mostly in the left hemisphere, also contribute to poor functional outcomes.


Assuntos
Infarto Cerebral/diagnóstico , Infarto Cerebral/patologia , Idoso , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Encéfalo/fisiopatologia , Infarto Cerebral/diagnóstico por imagem , Infarto Cerebral/fisiopatologia , Feminino , Seguimentos , Humanos , Imageamento por Ressonância Magnética , Masculino , Tamanho do Órgão , Prognóstico
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