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1.
Sci Rep ; 12(1): 6523, 2022 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-35444193

RESUMO

We investigated the associations of time-dependent DWI, non-Gaussian DWI, and CEST parameters with histological biomarkers in a breast cancer xenograft model. 22 xenograft mice (7 MCF-7 and 15 MDA-MB-231) were scanned at 4 diffusion times [Td = 2.5/5 ms with 11 b-values (0-600 s/mm2) and Td = 9/27.6 ms with 17 b-values (0-3000 s/mm2), respectively]. The apparent diffusion coefficient (ADC) was estimated using 2 b-values in different combinations (ADC0-600 using b = 0 and 600 s/mm2 and shifted ADC [sADC200-1500] using b = 200 and 1500 s/mm2) at each of those diffusion times. Then the change (Δ) in ADC/sADC between diffusion times was evaluated. Non-Gaussian diffusion and intravoxel incoherent motion (IVIM) parameters (ADC0, the virtual ADC at b = 0; K, Kurtosis from non-Gaussian diffusion; f, the IVIM perfusion fraction) were estimated. CEST images were acquired and the amide proton transfer signal intensity (APT SI) were measured. The ΔsADC9-27.6 (between [Formula: see text] and [Formula: see text] and ΔADC2.5_sADC27.6 (between [Formula: see text] and [Formula: see text]) was significantly larger for MCF-7 groups, and ΔADC2.5_sADC27.6 was positively correlated with Ki67max and APT SI. ADC0 decreased significantly in MDA-MB-231 group and K increased significantly with Td in MCF-7 group. APT SI and cellular area had a moderately strong positive correlation in MDA-MB-231 and MCF-7 tumors combined, and there was a positive correlation in MDA-MB-231 tumors. There was a significant negative correlation between APT SI and the Ki-67-positive ratio in MDA-MB-231 tumors and when combined with MCF-7 tumors. The associations of ΔADC2.5_sADC27.6 and API SI with Ki-67 parameters indicate that the Td-dependent DW and CEST parameters are useful to predict the histological markers of breast cancers.


Assuntos
Neoplasias da Mama , Animais , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/patologia , Imagem de Difusão por Ressonância Magnética/métodos , Feminino , Humanos , Antígeno Ki-67 , Camundongos , Microvasos/diagnóstico por imagem , Microvasos/patologia , Movimento (Física) , Reprodutibilidade dos Testes
2.
Invest Ophthalmol Vis Sci ; 63(3): 27, 2022 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-35348587

RESUMO

Purpose: To investigate parapapillary choroidal microvasculature dropout (MvD) in branch retinal vein occlusion (BRVO) patients and compare them with open-angle glaucoma (OAG) patients using optical coherence tomography angiography (OCT-A). Methods: In total, 85 eyes of BRVO patients and 85 eyes of OAG patients, matched by age, spherical equivalent, and baseline mean deviation (MD) of the visual field (VF), were assessed. MvD was defined as complete loss of microvasculature within the choroidal layer on OCT-A. Linear regression analysis was used to obtain the slope of the MD change of the VF. Results: The presence of MvD on OCT-A was significantly more frequent in OAG eyes (63.1%) compared to BRVO eyes (31.8%). BRVO eyes with MvD showed worse baseline MD of the VF than BRVO eyes without MvD (-10.19 ± 8.50 and -7.77 ± 6.46 dB, respectively; P = 0.045). The presence of MvD was the only factor significantly associated with MD change of the VF in OAG eyes. Lower baseline average RNFL thickness, greater MvD angle, and lower macular superficial vessel density were significantly associated with MD change of the VF in BRVO eyes. Conclusions: OCT-A of the parapapillary area showed choroidal microvasculature impairment in both BRVO and OAG patients. However, the frequency was higher in glaucoma patients with similar degrees of VF damage, which suggests that the glaucomatous process contributes to MvD development. The effect of MvD on VF change was different between BRVO and OAG, suggesting that the underlying pathogenesis may also be different.


Assuntos
Glaucoma de Ângulo Aberto , Disco Óptico , Oclusão da Veia Retiniana , Glaucoma de Ângulo Aberto/diagnóstico , Glaucoma de Ângulo Aberto/patologia , Humanos , Pressão Intraocular , Microvasos/patologia , Fibras Nervosas/patologia , Disco Óptico/irrigação sanguínea , Células Ganglionares da Retina/patologia , Oclusão da Veia Retiniana/diagnóstico , Oclusão da Veia Retiniana/patologia
3.
Dis Markers ; 2022: 1946104, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35126785

RESUMO

OBJECTIVE: The purpose of this project is to make sequential and indepth observation of the variations of retinal microvascular, microstructure, and inflammatory mediators at the early stage of diabetic retinopathy (DR) in streptozotocin-induced diabetes mellitus (DM) rats. METHODS: DM was induced by a single intraperitoneal injection of 60 mg/kg body weight streptozotocin (STZ). The fluorescein fundus angiography, hematoxylin and eosin staining, periodic acid-Schiff staining, fluorescence imaging techniques, quantitative real-time PCR, and vascular endothelial growth factor- (VEGF-) A ELISA were performed on the 8th day, at the 4th week, 6th week, 8th week, and 10th week after DM induction, respectively. RESULTS: In this study, we observed not only the decrease of retinal ganglion cells (RGCs) and the increase of endotheliocytes to pericytes (E/P) ratio, acellular capillaries, and type IV collagen-positive strands began to occur on the 8th day after induction but the vascular permeability and new vessel buds began to appear in the diabetes group at the 8th week, while the expression of VEGF-A, VEGF mRNA, IL-6 mRNA, ICAM mRNA, and TNF-α mRNA were significantly higher in the diabetes group compared with the normal group(P < 0.01) on the 8th day after induction and maintained a high expression level throughout the 10-week observation period. However, the expression of CD18 mRNA began to increase significantly at the 4th week after induction and reached a peak at the 6th week. CONCLUSION: Our study indicated the abnormal alterations of microvessels, microstructure, and inflammatory mediators at the early stage of DR, which confirms and supplements the previous research, and also promotes an indepth understanding and exploration of the pathophysiology and underlying pathogenesis of DR.


Assuntos
Antígenos CD18/metabolismo , Retinopatia Diabética , Molécula 1 de Adesão Intercelular/metabolismo , Interleucina-6/metabolismo , Microvasos/patologia , Fator de Necrose Tumoral alfa/metabolismo , Animais , Retinopatia Diabética/imunologia , Retinopatia Diabética/metabolismo , Retinopatia Diabética/patologia , Modelos Animais de Doenças , Masculino , Ratos , Ratos Sprague-Dawley
4.
Brain Res ; 1780: 147804, 2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-35101385

RESUMO

The socio-economic impact of diseases associated with cognitive impairment is increasing. According to the Alzheimer's Society there are over 850,000 people with dementia in the UK, costing the UK £26 billion in 2013. Therefore, research into treatment of those conditions is vital. Research into the cerebral endothelial glycocalyx (CeGC) could offer effective treatments. The CeGC, consisting of proteoglycans, glycoproteins and glycolipids, is a dynamic structure covering the luminal side oftheendothelial cells of capillaries throughout the body. The CeGC is thicker in cerebral micro vessels, suggesting specialisation for its function as part of the blood-brain barrier (BBB). Recent research evidences that the CeGC is vital in protecting fragile parenchymal tissue and effective functioning of the BBB, as one particularly important CeGC function is to act as a protective barrier and permeability regulator. CeGC degradation is one of the factors which can lead to an increase in BBB permeability. It occurs naturally in aging, nevertheless, premature degradationhas beenevidencedin multipleconditions linked to cognitive impairment, such as inflammation,brain edema, cerebral malaria, Alzheimer's and recently Covid-19. Increasing knowledge of the mechanisms of CeGC damage has led to research into preventative techniques showing that CeGC is a possible diagnostic marker and a therapeutic target. However, the evidence is relatively new, inconsistent and demonstrated mainly in experimental models. This review evaluates the current knowledge of the CeGC, its structure, functions, damage and repair mechanisms and the impact of its degeneration on cognitive impairment in multiple conditions, highlighting the CeGC as a possible diagnostic marker and a potential target for therapeutic treatment.


Assuntos
Barreira Hematoencefálica/metabolismo , Disfunção Cognitiva/metabolismo , Endotélio Vascular/metabolismo , Glicocálix/metabolismo , Microvasos/metabolismo , Barreira Hematoencefálica/patologia , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/patologia , Endotélio Vascular/patologia , Glicocálix/patologia , Humanos , Microvasos/patologia
5.
Sci Rep ; 12(1): 2103, 2022 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-35136185

RESUMO

To evaluate differences in macular and optic disc circulation in patients affected by Wolfram Syndrome (WS) employing optical coherence tomography-angiography (OCTA) imaging. In this retrospective study, 18 eyes from 10 WS patients, 16 eyes of 8 patients affected by type I diabetes and 17 eyes from 17 healthy controls were enrolled. All patients were imaged through OCT and OCTA and vascular parameters, as perfusion density (PD) and vessel length density (VLD) were measured. OCTA showed reduced PD in WS patients at the macular superficial capillary plexus (SCP, 27.8 ± 5.3%), deep vascular complex (DVC, 33.2 ± 1.9%) and optic nerve head (ONH, 21.2 ± 9.1%) compared to both diabetic patients (SCP 33.9 ± 1.9%, P < 0.0001; DVC 33.2 ± 0.7%, P = 1.0; ONH 33.9 ± 1.3, P < 0.0001) and healthy controls (SCP 31.6 ± 2.5, P = 0.002; DVC 34.0 ± 0.7%, P = 0.089; ONH 34.6 ± 0.8%, P < 0.0001). Similarly, VLD was lower in WS patients at the SCP (10.9 ± 2.7%) and ONH levels (7.5 ± 4.1%) compared to diabetic patients (SCP 13.8 ± 1.2%, P = 0.001; DVC 13.8 ± 0.2%, P < 0.0001; ONH 13.0 ± 0.7%, P = < 0.0001), but higher in DVC (15.7 ± 1.2%, P < 0.0001). Furthermore, VLD was lower in WS patients in all the vascular parameters compared to controls (SCP 13.8 ± 1.5%, P < 0.0001; DVC 17.3 ± 0.6%, P < 0.0001; ONH 15.7 ± 0.5%, P < 0.0001). A significant microvasculature impairment in the macular SCP and ONH microvasculature was demonstrated in eyes affected by WS. Microvascular impairment may be considered a fundamental component of the neurodegenerative changes in WS.


Assuntos
Macula Lutea/irrigação sanguínea , Microcirculação , Microvasos/patologia , Disco Óptico/irrigação sanguínea , Síndrome de Wolfram/diagnóstico por imagem , Adolescente , Adulto , Angiografia , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Tomografia de Coerência Óptica , Síndrome de Wolfram/patologia , Síndrome de Wolfram/fisiopatologia , Adulto Jovem
6.
Sci Rep ; 12(1): 752, 2022 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-35031636

RESUMO

This meta-analysis aimed to analyze retinal microvasculature features in eyes with Behçet's disease (BD) using optical coherence tomography angiography (OCTA). Electronic databases, including PubMed, Web of Science, Embase, and Cochrane Library, were comprehensively searched for published studies comparing retinal microvasculature characteristics between eyes with BD and controls. Continuous variables were calculated using the mean difference (MD) with 95% confidence interval (CI). Review Manager software (version 5.30) was used to conduct statistical analysis. A total of 13 eligible studies involving 599 eyes with BD and 622 control eyes were included in the meta-analysis. The pooled results showed that the macular whole enface superficial and deep vessel density (VD) values measured by OCTA were significantly lower in eyes with BD than in control eyes (superficial VD: MD = - 3.05, P < 0.00001; deep VD: MD = - 4.05, P = 0.0004). The foveal superficial and deep VD values were also significantly lower in the BD group than in the control group (superficial VD: MD = - 1.50, P = 0.009; deep VD: MD = - 4.25, - = 0.03). Similarly, the analysis revealed a significant reduction in the parafoveal superficial and deep VD in eyes with BD than in control eyes (superficial VD: MD = - 3.68, P < 0.00001; deep VD: MD = - 4.95, P = 0.0007). In addition, the superficial and deep foveal avascular zones (FAZs) were significantly larger in patients with BD than in controls (superficial FAZ: MD = 0.06, P = 0.02; deep FAZ: MD = 0.12, P = 0.03). The present meta-analysis found that macular whole enface VD, foveal VD, and parafoveal VD were lower in eyes with BD, and the FAZ was larger in patients with BD. The findings suggest that OCTA can assist clinicians in diagnosing and monitoring the status of patients with BD.


Assuntos
Síndrome de Behçet/patologia , Microvasos/patologia , Vasos Retinianos/patologia , Adulto , Síndrome de Behçet/complicações , Síndrome de Behçet/diagnóstico por imagem , Feminino , Fóvea Central/irrigação sanguínea , Humanos , Macula Lutea/irrigação sanguínea , Edema Macular/diagnóstico por imagem , Edema Macular/etiologia , Masculino , Microvasos/diagnóstico por imagem , Pessoa de Meia-Idade , Vasculite Retiniana/diagnóstico por imagem , Vasculite Retiniana/etiologia , Vasos Retinianos/diagnóstico por imagem , Tomografia de Coerência Óptica
7.
Int J Mol Sci ; 23(2)2022 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-35054783

RESUMO

Of increasing prevalence, diabetes is characterised by elevated blood glucose and chronic inflammation that precedes the onset of multiple secondary complications, including those of the kidney and the eye. As the leading cause of end stage renal disease and blindness in the working population, more than ever is there a demand to develop clinical interventions which can both delay and prevent disease progression. Connexins are membrane bound proteins that can form pores (hemichannels) in the cell membrane. Gated by cellular stress and injury, they open under pathophysiological conditions and in doing so release 'danger signals' including adenosine triphosphate into the extracellular environment. Linked to sterile inflammation via activation of the nod-like receptor protein 3 inflammasome, targeting aberrant hemichannel activity and the release of these danger signals has met with favourable outcomes in multiple models of disease, including secondary complications of diabetes. In this review, we provide a comprehensive update on those studies which document a role for aberrant connexin hemichannel activity in the pathogenesis of both diabetic eye and kidney disease, ahead of evaluating the efficacy of blocking connexin-43 specific hemichannels in these target tissues on tissue health and function.


Assuntos
Conexina 43/metabolismo , Complicações do Diabetes/terapia , Olho/patologia , Inflamação/metabolismo , Inflamação/terapia , Rim/patologia , Animais , Humanos , Microvasos/patologia
8.
Sci Rep ; 12(1): 264, 2022 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-34997031

RESUMO

Diabetes can cause microvessel impairment. However, these conjunctival pathological changes are not easily recognized, limiting their potential as independent diagnostic indicators. Therefore, we designed a deep learning model to explore the relationship between conjunctival features and diabetes, and to advance automated identification of diabetes through conjunctival images. Images were collected from patients with type 2 diabetes and healthy volunteers. A hierarchical multi-tasking network model (HMT-Net) was developed using conjunctival images, and the model was systematically evaluated and compared with other algorithms. The sensitivity, specificity, and accuracy of the HMT-Net model to identify diabetes were 78.70%, 69.08%, and 75.15%, respectively. The performance of the HMT-Net model was significantly better than that of ophthalmologists. The model allowed sensitive and rapid discrimination by assessment of conjunctival images and can be potentially useful for identifying diabetes.


Assuntos
Algoritmos , Túnica Conjuntiva/irrigação sanguínea , Diabetes Mellitus Tipo 2/patologia , Angiopatias Diabéticas/patologia , Diagnóstico por Computador , Técnicas de Diagnóstico Oftalmológico , Interpretação de Imagem Assistida por Computador , Microvasos/patologia , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/complicações , Angiopatias Diabéticas/etiologia , Humanos , Valor Preditivo dos Testes , Estudos Prospectivos , Reprodutibilidade dos Testes
9.
Medicine (Baltimore) ; 101(3): e28647, 2022 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-35060554

RESUMO

ABSTRACT: Nonsmall cell lung cancer (NSCLC) is the most common type of lung cancer. This study aimed to categorize the microvessels in advanced NSCLC and determine the relationship between intratumoral microvascular density (MVD) and the efficacy of anlotinib for NSCLC.The clinical data of 68 patients receiving anlotinib as third-line treatment or beyond for advanced NSCLC were retrospectively collected. Microvessels were stained for CD31 and CD34 by using immunohistochemical staining and were classified as undifferentiated (CD31+ CD34-) and differentiated vessels (CD31+ CD34+). The relationship between MVD and anlotinib efficacy and patient prognosis was analyzed.Patients were divided into the high or low MVD groups according to the median MVD of differentiated (9.4 vessels/field) and undifferentiated microvessels (6.5 vessels/field). There were significantly more patients with high undifferentiated-vessel MVD in the disease control group than in the disease progression group (72.7% vs 16.7%, P < .001). Patients with high undifferentiated-vessel MVD had significantly longer median progression-free survival than those with low undifferentiated-vessel MVD (7.1 vs 3.7 months, P < .001).Anlotinib as third- or beyond line therapy is safe and effective for advanced NSCLC. Patients with a higher density of undifferentiated microvessels have better response to anlotinib and longer progression-free survival.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/irrigação sanguínea , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Indóis/uso terapêutico , Neoplasias Pulmonares/irrigação sanguínea , Neoplasias Pulmonares/tratamento farmacológico , Densidade Microvascular , Microvasos/patologia , Quinolinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD34/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Microvasos/metabolismo , Pessoa de Meia-Idade , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Prognóstico , Estudos Retrospectivos , Resultado do Tratamento
11.
Cell Mol Neurobiol ; 42(4): 985-996, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-33136275

RESUMO

Diabetes is strongly linked to the development of Alzheimer's disease (AD), though the mechanisms for this enhanced risk are unclear. Because vascular inflammation is a consistent feature of both diabetes and AD, the cerebral microcirculation could be a key target for the effects of diabetes in the brain. The goal of this study is to explore whether brain endothelial cells, injured by diabetes-related insults, glucose and hypoxia, can affect inflammatory and activation processes in microglia in vitro. Human brain microvascular endothelial cells (HBMVECs) were either treated with 5 mM glucose (control), 30 mM glucose (high glucose), exposed to hypoxia, or exposed to hypoxia plus high glucose. HBMVEC-conditioned medium was then used to treat BV-2 microglia. Alterations in microglia phenotype were assessed through measurement of nitric oxide (NO), cytokine production, microglial activation state markers, and microglial phagocytosis. HBMVECs were injured by exposure to glucose and/or hypoxia, as assessed by release of LDH, interleukin (IL)-1ß, and reactive oxygen species (ROS). HBMVECs injured by glucose and hypoxia induced increases in microglial production of NO, tumor necrosis factor-α (TNFα) and matrix metalloproteinase (MMP)-9. Injured HBMVECs significantly increased microglial expression of CD11c and CLEC7A, and decreased expression of the homeostatic marker P2RY12. Finally, bead uptake by BV-2 cells, an index of phagocytic ability, was elevated by conditioned media from injured HBMVECs. The demonstration that injury to brain endothelial cells by diabetic-associated insults, glucose and hypoxia, promotes microglial inflammation supports the idea that the cerebral microcirculation is a critical locus for the deleterious effects of diabetes in the AD brain.


Assuntos
Células Endoteliais , Microglia , Encéfalo , Células Endoteliais/metabolismo , Glucose/metabolismo , Glucose/toxicidade , Humanos , Hipóxia/metabolismo , Microglia/metabolismo , Microvasos/patologia , Fenótipo
12.
Schizophr Bull ; 48(1): 80-89, 2022 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-34554256

RESUMO

BACKGROUND: Retinovascular changes are reported on fundus imaging in schizophrenia (SZ). This is the first study to use swept-source optical coherence tomography angiography (OCT-A) to comprehensively examine retinal microvascular changes in SZ. METHODS: This study included 30 patients with SZ/schizoaffective disorder (8 early and 15 chronic) and 22 healthy controls (HCs). All assessments were performed at Beth Israel Deaconess Medical Center and Massachusetts Eye and Ear. All participants underwent swept-source OCT-A of right (oculus dextrus [OD]) and left (oculus sinister [OS]) eye, clinical, and cognitive assessments. Macular OCT-A images (6 × 6 mm) were collected with the DRI Topcon Triton for superficial, deep, and choriocapillaris vascular regions. Microvasculature was quantified using vessel density (VD), skeletonized vessel density (SVD), fractal dimension (FD), and vessel diameter index (VDI). RESULTS: Twenty-one HCs and 26 SZ subjects were included. Compared to HCs, SZ patients demonstrated higher overall OD superficial SVD, OD choriocapillaris VD, and OD choriocapillaris SVD, which were primarily observed in the central, central and outer superior, and central and outer inferior/superior, respectively. Early-course SZ subjects had significantly higher OD superficial VD, OD choriocapillaris SVD, and OD choriocapillaris FD compared to matched HCs. Higher bilateral (OU) superficial VD correlated with lower Positive and Negative Syndrome Scale (PANSS) positive scores, and higher OU deep VDI was associated with higher PANSS negative scores. CONCLUSIONS AND RELEVANCE: These results suggest the presence of microvascular dysfunction associated with early-stage SZ. Clinical associations with microvascular alterations further implicate this hypothesis, with higher measures being associated with worse symptom severity and functioning in early stages and with lower symptom severity and better functioning in later stages.


Assuntos
Microvasos/patologia , Transtornos Psicóticos/patologia , Vasos Retinianos/patologia , Esquizofrenia/patologia , Tomografia de Coerência Óptica , Adulto , Angiografia , Feminino , Humanos , Masculino , Microvasos/diagnóstico por imagem , Pessoa de Meia-Idade , Transtornos Psicóticos/diagnóstico por imagem , Transtornos Psicóticos/fisiopatologia , Vasos Retinianos/diagnóstico por imagem , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/fisiopatologia , Adulto Jovem
13.
Am J Respir Cell Mol Biol ; 66(1): 12-22, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34555309

RESUMO

In vivo intravital imaging in animal models in the lung remains challenging owing to respiratory motion artifacts. Here we describe a novel intravital imaging approach based on the computer-vision stabilization algorithm, Computer-Vision Stabilized Intravital Imaging. This method corrects lung movements and deformations at submicron precision in respiring mouse lungs. The precision enables high-throughput quantitative analysis of intravital pulmonary polymorphonuclear neutrophil (PMN) dynamics in lungs. We quantified real-time PMN patrolling dynamics of microvessels in the basal state and PMN recruitment resulting from sequestration in a model of endotoxemia in mice. We focused on determining the marginated pool of PMNs in the lung. Direct visualization of marginated PMNs revealed that they are not static but highly dynamic and undergo repeated cycles of "catch and release." PMNs briefly arrest in larger diameter capillary junction (∼10 µm) and then squeeze into narrower, approximately 5-µm diameter vessels through PMN deformation. We also observed that the sequestered PMNs in lung microvessels lost their migratory capabilities in association with cell morphological change following prolonged endotoxemia. These observations underscore the value of direct visualization and quantitative analysis of PMN dynamics in lungs to study PMN physiology and pathophysiology and role in inflammatory lung injury.


Assuntos
Simulação por Computador , Microscopia Intravital , Pulmão/diagnóstico por imagem , Pulmão/patologia , Neutrófilos/patologia , Animais , Endotoxemia/diagnóstico por imagem , Pulmão/irrigação sanguínea , Camundongos Endogâmicos C57BL , Microvasos/diagnóstico por imagem , Microvasos/patologia
14.
Stroke ; 53(2): e37-e41, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34743535

RESUMO

BACKGROUND AND PURPOSE: Neuroprotective strategies for stroke remain inadequate. Nanoliposomes comprised of phosphatidylcholine, cholesterol, and monosialogangliosides (nanoliposomes) induced an antioxidant protective response in endothelial cells exposed to amyloid insults. We tested the hypotheses that nanoliposomes will preserve human neuroblastoma (SH-SY5Y) and human brain microvascular endothelial cells viability following oxygen-glucose deprivation (OGD)-reoxygenation and will reduce injury in mice following middle cerebral artery occlusion. METHODS: SH-SY5Y and human brain microvascular endothelial cells were exposed to oxygen-glucose deprivation-reoxygenation (3 hours 0.5%-1% oxygen and glucose-free media followed by 20-hour ambient air/regular media) without or with nanoliposomes (300 µg/mL). Viability was measured (calcein-acetoxymethyl fluorescence) and protein expression of antioxidant proteins HO-1 (heme oxygenase-1), NQO1 (NAD[P]H quinone dehydrogenase 1), and SOD1 (superoxide dismutase 1) were measured by Western blot. C57BL/6J mice were treated with saline (n=8) or nanoliposomes (10 mg/mL lipid, 200 µL, n=7) while undergoing 60-minute middle cerebral artery occlusion followed by reperfusion. Day 2 postinjury neurological impairment score and infarction size were compared. RESULTS: SH-SY5Y and human brain microvascular endothelial cells showed reduced viability post-oxygen-glucose deprivation-reoxygenation that was reversed by nanoliposomes. Nanoliposomes increased protein expressions of HO-1, NQO1 in both cell types and SOD1 in human brain microvascular endothelial cells. Nanoliposomes-treated mice showed reduced neurological impairment and brain infarct size (18.8±2% versus 27.3±2.3%, P=0.017) versus controls. CONCLUSIONS: Nanoliposomes reduced stroke injury in mice subjected to middle cerebral artery occlusion likely through induction of an antioxidant protective response. Nanoliposome is a candidate novel agent for stroke.


Assuntos
Infarto da Artéria Cerebral Média/tratamento farmacológico , Lipossomos/uso terapêutico , Nanopartículas/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Animais , Antioxidantes/metabolismo , Linhagem Celular , Endotélio Vascular/patologia , Glucose/deficiência , Heme Oxigenase-1/biossíntese , Heme Oxigenase-1/genética , Humanos , Hipóxia , Infarto da Artéria Cerebral Média/complicações , Infarto da Artéria Cerebral Média/patologia , Masculino , Proteínas de Membrana/biossíntese , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Microvasos/patologia , NAD(P)H Desidrogenase (Quinona)/biossíntese , NAD(P)H Desidrogenase (Quinona)/genética , Traumatismo por Reperfusão/patologia , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/patologia , Superóxido Dismutase-1/biossíntese , Superóxido Dismutase-1/genética
15.
Circulation ; 145(2): 134-150, 2022 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-34743558

RESUMO

BACKGROUND: The microvasculature, the smallest blood vessels in the body, has key roles in maintenance of organ health and tumorigenesis. The retinal fundus is a window for human in vivo noninvasive assessment of the microvasculature. Large-scale complementary machine learning-based assessment of the retinal vasculature with phenome-wide and genome-wide analyses may yield new insights into human health and disease. METHODS: We used 97 895 retinal fundus images from 54 813 UK Biobank participants. Using convolutional neural networks to segment the retinal microvasculature, we calculated vascular density and fractal dimension as a measure of vascular branching complexity. We associated these indices with 1866 incident International Classification of Diseases-based conditions (median 10-year follow-up) and 88 quantitative traits, adjusting for age, sex, smoking status, and ethnicity. RESULTS: Low retinal vascular fractal dimension and density were significantly associated with higher risks for incident mortality, hypertension, congestive heart failure, renal failure, type 2 diabetes, sleep apnea, anemia, and multiple ocular conditions, as well as corresponding quantitative traits. Genome-wide association of vascular fractal dimension and density identified 7 and 13 novel loci, respectively, that were enriched for pathways linked to angiogenesis (eg, vascular endothelial growth factor, platelet-derived growth factor receptor, angiopoietin, and WNT signaling pathways) and inflammation (eg, interleukin, cytokine signaling). CONCLUSIONS: Our results indicate that the retinal vasculature may serve as a biomarker for future cardiometabolic and ocular disease and provide insights into genes and biological pathways influencing microvascular indices. Moreover, such a framework highlights how deep learning of images can quantify an interpretable phenotype for integration with electronic health record, biomarker, and genetic data to inform risk prediction and risk modification.


Assuntos
Aprendizado Profundo/normas , Estudo de Associação Genômica Ampla/métodos , Genômica/métodos , Análise da Randomização Mendeliana/métodos , Microvasos/patologia , Retina/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
16.
J Vasc Res ; 59(1): 1-15, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34535606

RESUMO

Metabolic syndrome (MetS) is a complex pathological state consisting of metabolic risk factors such as hypertension, insulin resistance, and obesity. The interconnectivity of cellular pathways within various biological systems suggests that each individual component of MetS may share common pathological sources. Additionally, MetS is closely associated with vasculopathy, including a reduction in microvessel density (MVD) (rarefaction) and elevated risk for various cardiovascular diseases. Microvascular impairments may contribute to perfusion-demand mismatch, where local metabolic needs are insufficiently met due to the lack of nutrient and oxygen supply, thus creating pathological positive-feedback loops and furthering the progression of disease. Sexual dimorphism is evident in these underlying cellular mechanisms, which places males and females at different levels of risk for cardiovascular disease and acute ischemic events. Estrogen exhibits protective effects on the endothelium of pre-menopausal women, while androgens may be antagonistic to cardiovascular health. This review examines MetS and its influences on MVD, as well as sex differences relating to the components of MetS and cardiovascular risk profiles. Finally, translational relevance and interventions are discussed in the context of these sex-based differences.


Assuntos
Doenças Cardiovasculares/etiologia , Síndrome Metabólica/patologia , Densidade Microvascular , Rarefação Microvascular , Microvasos/patologia , Animais , Fatores de Risco Cardiometabólico , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Doenças Cardiovasculares/fisiopatologia , Feminino , Humanos , Masculino , Síndrome Metabólica/complicações , Síndrome Metabólica/metabolismo , Síndrome Metabólica/fisiopatologia , Microvasos/metabolismo , Prognóstico , Medição de Risco , Caracteres Sexuais , Fatores Sexuais
17.
Microvasc Res ; 140: 104282, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34813858

RESUMO

The brain microvasculature is altered in normal aging and in the presence of disease processes, such as neurodegeneration or ischemia, but there are few methods for studying living tissues. We now report that viable microvessels (MV) are readily isolated from brain tissue of subjects enrolled in studies of neurodegenerative diseases who undergo rapid autopsy (performed with <12 h postmortem interval - PMI). We find that these MV retain their morphology and cellular components and are fairly uniform in size. Sufficient MV (~3-5000) are obtained from 3 to 4 g of tissue to allow for studies of cellular composition as well as extracellular matrix (ECM). Using live/dead assays, these MV are viable for up to 5 days in tissue culture media (2D) designed to support endothelial cells and up to 11 days post-isolation in a 3-dimensional (3D) matrix (Low Growth Factor Matrigel™). Assays that measure the reducing potential of live cells \demonstrated that the majority of the MV maintain high levels of metabolic activity for a similar number of days as the live/dead assays. Functional cellular components (such as tight junctions and transporter proteins) and ECM of MV in tissue culture media, and to a lesser extent in 3D matrices, were readily visualized using immunofluorescence techniques. MV in tissue culture media are lysed and protein content analyzed, but MV in 3D matrix first require removal of the supporting matrix, which can confound the analysis of MV ECM. Finally, MV can be preserved in cryoprotective media, whereby over 50% retain their baseline viability upon thawing. In summary, we find that MV isolated from human brains undergoing rapid autopsy are viable in standard tissue culture for up to 5 days and the timeframe for experiments can be extended up to 11 days by use of a supportive 3D matrix. Viable human MV allow for temporal and spatial analysis of relevant cellular and ECM components that have implications for microvascular function in neurodegenerative diseases, vascular brain injury, and neurotrauma.


Assuntos
Envelhecimento/patologia , Córtex Cerebral/irrigação sanguínea , Microvasos/patologia , Doenças Neurodegenerativas/patologia , Fatores Etários , Autopsia , Criopreservação , Meios de Cultura , Matriz Extracelular/patologia , Humanos , Fatores de Tempo , Técnicas de Cultura de Tecidos , Sobrevivência de Tecidos
18.
J Histochem Cytochem ; 70(1): 99-110, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34751042

RESUMO

The poor clinical prognosis and microvascular patterns of glioblastoma (GBM) are of serious concern to many clinicians and researchers. However, very few studies have examined the correlation between microvascular niche patterns (MVNPs) and proteomic distribution. In this study, CD34 immunofluorescence staining and matrix-assisted laser desorption ionization-mass spectrometry imaging (MALDI-IMS) technology were used to investigate the protein distributions in MVNPs. CD34+ microvascular phenotype could be divided into four types: microvascular sprouting (MS), vascular cluster (VC), vascular garland (VG), and glomeruloid vascular proliferation (GVP). Based on such characteristics, MVNPs were divided into two types by cluster analysis, namely, type I, comprising primarily MS and VC, and type II, comprising many VGs and GVPs. Survival analysis indicated the type of MVNPs to be an independent prognostic factor for progression-free and overall survival in GBM. MALDI-IMS results showed the peaks at m/z 1037 and 8960 to exhibit stronger ion signals in type II, while those at m/z 3240 and 3265 exhibited stronger ion signals in type I. The findings may assist future research on therapy and help predict prognosis in GBM. However, due to the limited number of studies, more well-designed studies are warranted to further verify our results.


Assuntos
Antígenos CD34/análise , Biomarcadores Tumorais/análise , Glioblastoma/diagnóstico , Microvasos/patologia , Neovascularização Patológica/diagnóstico , Adolescente , Adulto , Idoso , Feminino , Imunofluorescência , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Nicho de Células-Tronco , Adulto Jovem
20.
Cardiovasc Res ; 118(2): 531-541, 2022 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-33605403

RESUMO

AIMS: The aim of this study was to study changes in coronary microcirculation status during and after several cycles of anthracycline treatment. METHODS AND RESULTS: Large-white male pigs (n=40) were included in different experimental protocols (ExPr.) according to anthracycline cumulative exposure [0.45 mg/kg intracoronary (IC) doxorubicin per injection] and follow-up: control (no doxorubicin); single injection and sacrifice either at 48 h (ExPr. 1) or 2 weeks (ExPr. 2); 3 injections 2 weeks apart (low cumulative dose) and sacrifice either 2 weeks (ExPr. 3) or 12 weeks (ExPr. 4) after third injection; five injections 2 weeks apart (high cumulative dose) and sacrifice 8 weeks after fifth injection (ExPr. 5). All groups were assessed by serial cardiac magnetic resonance (CMR) to quantify perfusion and invasive measurement of coronary flow reserve (CFR). At the end of each protocol, animals were sacrificed for ex vivo analyses. Vascular function was further evaluated by myography in explanted coronary arteries of pigs undergoing ExPr. 3 and controls. A single doxorubicin injection had no impact on microcirculation status, excluding a direct chemical toxicity. A series of five fortnightly doxorubicin injections (high cumulative dose) triggered a progressive decline in microcirculation status, evidenced by reduced CMR-based myocardial perfusion and CFR-measured impaired functional microcirculation. In the high cumulative dose regime (ExPr. 5), microcirculation changes appeared long before any contractile defect became apparent. Low cumulative doxorubicin dose (three bi-weekly injections) was not associated with any contractile defect across long-term follow-up, but provoked persistent microcirculation damage, evident soon after third dose injection. Histological and myograph evaluations confirmed structural damage to arteries of all calibres even in animals undergoing low cumulative dose regimes. Conversely, arteriole damage and capillary bed alteration occurred only after high cumulative dose regime. CONCLUSION: Serial in vivo evaluations of microcirculation status using state-of-the-art CMR and invasive CFR show that anthracyclines treatment is associated with progressive and irreversible damage to the microcirculation. This long-persisting damage is present even in low cumulative dose regimes, which are not associated with cardiac contractile deficits. Microcirculation damage might explain some of the increased incidence of cardiovascular events in cancer survivors who received anthracyclines without showing cardiac contractile defects.


Assuntos
Circulação Coronária , Vasos Coronários/fisiopatologia , Cardiopatias/fisiopatologia , Microcirculação , Microvasos/fisiopatologia , Animais , Antibióticos Antineoplásicos , Cardiotoxicidade , Vasos Coronários/diagnóstico por imagem , Vasos Coronários/patologia , Modelos Animais de Doenças , Doxorrubicina , Cardiopatias/induzido quimicamente , Cardiopatias/diagnóstico por imagem , Cardiopatias/patologia , Imageamento por Ressonância Magnética , Masculino , Microvasos/diagnóstico por imagem , Microvasos/patologia , Imagem de Perfusão do Miocárdio , Sus scrofa , Fatores de Tempo
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