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1.
Invest Ophthalmol Vis Sci ; 63(1): 10, 2022 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-34994770

RESUMO

Purpose: There is conflicting evidence regarding whether a loss of radial peripapillary capillaries (RPCs) precedes neuronal loss in glaucoma. We examined the time course of in vivo changes in RPCs, optic nerve head (ONH) structure, and retinal nerve fiber layer thickness (RNFLT) in experimental glaucoma (EG). Methods: Spectral domain optical coherence tomography images were acquired before and approximately every two weeks after inducing unilateral EG in nine rhesus monkeys to quantify mean anterior lamina cribrosa surface depth (ALCSD), minimum rim width (MRW), and RNFLT. Perfused RPC density was measured from adaptive optics scanning laser ophthalmoscope images acquired on the temporal half of the ONH. The time of first significant change was quantified as when values fell and remained outside of the 95% confidence interval established from control eyes. Results: Mean ALCSD and/or MRW were the first parameters to change in eight EG eyes. RPC density changed first in the ninth. At their first points of change, mean ALCSD posteriorly deformed by 100.2 ± 101.2 µm, MRW thinned by 82.3 ± 65.9 µm, RNFLT decreased by 25 ± 14 µm, and RPC density decreased by 4.5 ± 2.1%. RPC density decreased before RNFL thinning in 5 EG eyes. RNFLT decreased before RPC density decreased in two EG eyes, whereas two EG eyes had simultaneous changes. Conclusions: In most EG eyes, RPC density decreased before (or simultaneous with) a change in RNFLT, suggesting that vascular factors may play a role in axonal loss in some eyes in early glaucoma.


Assuntos
Modelos Animais de Doenças , Glaucoma/fisiopatologia , Fibras Nervosas/patologia , Disco Óptico/irrigação sanguínea , Células Ganglionares da Retina/patologia , Vasos Retinianos/fisiologia , Animais , Capilares/fisiologia , Feminino , Seguimentos , Pressão Intraocular , Macaca mulatta , Masculino , Oftalmoscopia , Fatores de Tempo , Tomografia de Coerência Óptica
2.
J Chromatogr A ; 1662: 462714, 2022 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-34902721

RESUMO

Herein, we report the first use of Polymyxin-B antibiotic as a enantio-selector in polymer monolithic capillary. The capillaries were functionalised, characterized and tested for the enantioselective nano-HPLC separation of 50 racemic pharmaceutical drugs. They have been easily prepared by immobilizing Polymyxin-B over the organic polymer for 48 h (P1) or encapsulating Polymyxin-B within the organic polymer (P2) and tested for the enantioselective resolution of racemic drugs. Acceptable resolution was achieved for 21 drugs using RP-HPLC conditions on both (P1) and (P2) capillary columns, while no separation was observed under NP-HPLC conditions. Polymyxin-B is commercially available, easily solubilized and stable in both acidic and neutral media. The developed Polymyxin-B-based polymer monolithic capillaries provide a promising expansion of platform in enantioselective HPLC separations.


Assuntos
Preparações Farmacêuticas , Polímeros , Capilares , Cromatografia Líquida de Alta Pressão , Polimixina B , Estereoisomerismo
3.
Rev. ecuat. pediatr ; 22(3): 1-9, 30 de diciembre del 2021.
Artigo em Espanhol | LILACS | ID: biblio-1352440

RESUMO

Introducción: no existe un criterio único para evaluar el estado hemodinámico de los recién nacidos y prematuros y las diferentes variables en el grupo de recién nacidos, como la edad gestacional, el peso al nacer y los períodos de nacimiento. Métodos: Se trata de un estudio observacional descriptivo, transversal, epidemiológico con dos cohortes de pacientes. Los recién nacidos a término y Pretérmino, atendidos en la Unidad de Neonatal del Hospital Pablo Arturo Suárez, participan durante los meses comprendidos entre Noviembre de 2019 a enero de 2020. Resultados: la medición ecográfica del flujo de la vena cava inferior (FVCI) es útil para el tratamiento de manejo del paciente neonatal hemodinámicamente inestable. La muestra estuvo conformada por 110 recién nacidos atendidos en el servicio de neonatología del Hospital Pablo Arturo Suárez desde noviembre de 2019 a enero de 2020. Quito, Pichincha, Ecuador. Las variables bajo peso al nacer y prematuridad moderada tienen un valor estadística-mente significativo para el uso de inotrópicos. Las demás variables no presentan valor esta-dísticamente significativo. La frecuencia cardíaca, el gasto urinario, la presión arterial media, el ácido láctico, el llenado capilar, el flujo de la vena cava superior y el flujo de la vena cava inferior tienen valores estadísticamente significativos. Las comparaciones de FVCI y superior (FVCS) con frecuencia cardíaca, gasto urinario, presión arterial media, ácido láctico, llenado capilar tienen un valor estadísticamente significativo, excepto para el llenado capilar >3 segundos en FCVI. Se utilizó el análisis multivariado de Componentes Principales Categóricos (CATPCA) para caracterizar el estado hemodinámico e inotrópico, que resultaron significativos en el análisis bivariado. Dimensión, uno de los gráficos bidimensionales, discrimina el uso o no de inotrópicos y las categorías de parámetros hemodinámicos TAM <35 mmHg, ácido láctico, llenado capilar, FVCI y FVCS. La dimensión dos discrimina entre las categorías de gasto urinario y FC. Conclusión: En recién nacidos a término y prematuros con bajo peso y adecuado peso al nacer con inestabilidad hemodinámica en general, que fueron evaluados con ecografía para medir el flujo de la vena cava, la concordancia entre los criterios clínicos y la valoración ecográfica del flujo fue de 0.4 cm / seg en ambos métodos. Esta situación significa que la medición de los flujos cava venosos por ecografía es útil para evaluar el estado hemodinámico de los pacientes neonatales.


Introduction: There is no single criterion available to assess the hemodynamic state of new-born in-fants and preterm infants and the different variables in the group of newborns, such as gestational age, birth weight, and periods of birth. Methods: This is an epidemiological, cross-sectional, descriptive observational study with two patient cohorts. Newborn-to-term and preterm neonates assisted at the Neonatal Unit of the Pablo Arturo Suarez Hospital participated during the months between November 2019 to January 2020. Results: Ultrasound measurement of the vena cava (FVC) flow is useful for the management treatment of hemodynamically unstable neonatal patients. The sample was made up of 110 newborns treated in the Pablo Arturo Suarez Hospital's neonatology service from November 2019 to January 2020. Quito, Pichincha, Ecuador. The variables low birth weight and moder-ate prematurity have a statistically sig-nificant value for inotropic use.The other variables do not present statistically significant values. Heart rate, urinary output, mean blood pressure, lactic acid, capillary filling, upper vena cava flow, and lower vena cava flow had statistically significant values. FVCI and FVCS comparisons with heart rate, urinary output, mean blood pressure, lactic acid, and capillary filling had statistically significant values, except for capil-lary filling >3 sec in FCVI. Multivariate analysis of categorical main components (CATPCA) was used to characterize the hemodynamic state and inotropic state, which were significant in the bivariate analysis. Dimension, one of the two-dimensional graphs, discriminates the use or not of inotropics and the categories of hemodynamic parameters TAM <35 mmHg, lactic acid, capillary filling, FVCI, and FVCS. Dimension IIdiscriminates between the categories of urinary expenditure and HR. Conclusion: In term and preterm infants with low weight and adequate birth weight with hemody-namic instability in general, who were evaluated with ultrasonography to measure the flow of the vena cava, the agreement between the clinical criteria and the ultrasound assessment of the flow was 0.4 cm/sec in both methods. This situation means that the measurement of venous cava flows by echo sonography is useful for assessing neonatal patients' hemodynamic status.


Assuntos
Humanos , Recém-Nascido , Choque , Veias Cavas , Recém-Nascido , Pressão Arterial , Capilares , Ácido Láctico , Diurese , Frequência Cardíaca
4.
BMJ Case Rep ; 14(12)2021 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-34969807

RESUMO

Megalencephaly-capillary malformation-polymicrogyria syndrome (MCAP) is a rare disorder that arises as a result of a somatic mosaic mutation in the PIK3CA gene. It characteristically presents with postnatal or congenital megalencephaly, cutaneous capillary malformations, postaxial polydactyly and often segmental or focal body overgrowth. We report a 7-year-old boy with known MCAP who was diagnosed at around 10 months old with a mosaic change in the PIK3CA gene. He was found to have hall-mark clinical signs; macrocephaly and four-limb postaxial polydactyly. Since diagnosis, he has had multiple clinical features, most of which typically present in children with MCAP. He has now been diagnosed with autism spectrum disorder (ASD), demand avoidance and is under assessment for attention deficit hyperactivity disorder. Although some cases have been raised to the M-CM Network, to our knowledge this is the first case of ASD in MCAP to be reported in the literature.


Assuntos
Transtorno do Espectro Autista , Megalencefalia , Polimicrogiria , Transtorno do Espectro Autista/genética , Capilares/anormalidades , Criança , Humanos , Lactente , Masculino , Megalencefalia/diagnóstico por imagem , Megalencefalia/genética , Mutação , Polimicrogiria/diagnóstico por imagem , Polimicrogiria/genética , Malformações Vasculares
5.
Biomed Res ; 42(6): 257-264, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34937825

RESUMO

Inactivity causes muscle atrophy and capillary regression in skeletal muscle. Chlorogenic acid has an antioxidant capacity and may prevent capillary regression. Therefore, the protective effects of chlorogenic acid on inactivity-induced capillary regression in rat soleus muscle were investigated. Twenty male Wistar rats were randomly divided into four groups: control (CON), chlorogenic acid supplementation (CGA), 2-week hindlimb unloading (HU), 2-week hindlimb unloading plus chlorogenic acid supplementation (HU+CGA). The rats in CGA and HU+CGA groups were orally administrated chlorogenic acid (850 mg/kg/day). Unloading resulted in a decrease in capillary number, oxidative capacity, and an increase in oxidative stress of the soleus muscle, whereas chlorogenic acid supplementation prevented capillary and metabolic changes resulting from unloading by reducing oxidative stress. In conclusion, chlorogenic acid supplementation may qualify as an effective treatment to reduce capillary regression in skeletal muscle caused by disuse muscle atrophy.


Assuntos
Ácido Clorogênico , Elevação dos Membros Posteriores , Animais , Capilares , Ácido Clorogênico/farmacologia , Masculino , Músculo Esquelético/patologia , Atrofia Muscular/tratamento farmacológico , Atrofia Muscular/etiologia , Atrofia Muscular/prevenção & controle , Ratos , Ratos Wistar
6.
Cell Mol Life Sci ; 79(1): 28, 2021 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-34936031

RESUMO

Microgravity and space radiation (SR) are two highly influential factors affecting humans in space flight (SF). Many health problems reported by astronauts derive from endothelial dysfunction and impaired homeostasis. Here, we describe the adaptive response of human, capillary endothelial cells to SF. Reference samples on the ground and at 1g onboard permitted discrimination between the contribution of microgravity and SR within the combined responses to SF. Cell softening and reduced motility occurred in SF cells, with a loss of actin stress fibers and a broader distribution of microtubules and intermediate filaments within the cytoplasm than in control cells. Furthermore, in space the number of primary cilia per cell increased and DNA repair mechanisms were found to be activated. Transcriptomics revealed the opposing effects of microgravity from SR for specific molecular pathways: SR, unlike microgravity, stimulated pathways for endothelial activation, such as hypoxia and inflammation, DNA repair and apoptosis, inhibiting autophagic flux and promoting an aged-like phenotype. Conversely, microgravity, unlike SR, activated pathways for metabolism and a pro-proliferative phenotype. Therefore, we suggest microgravity and SR should be considered separately to tailor effective countermeasures to protect astronauts' health.


Assuntos
Autofagia , Capilares/citologia , Radiação Cósmica , Células Endoteliais/efeitos da radiação , Transdução de Sinais , Ausência de Peso , Apoptose , Biomarcadores/metabolismo , Linhagem Celular , Sobrevivência Celular , Cromossomos Humanos/metabolismo , Citoesqueleto/metabolismo , Dano ao DNA , Fluorescência , Regulação da Expressão Gênica , Genoma Humano , Humanos , Masculino , Mecanotransdução Celular , Modelos Biológicos , Transdução de Sinais/efeitos da radiação , Voo Espacial , Estresse Fisiológico , Homeostase do Telômero , Transcriptoma/genética
7.
BMJ Case Rep ; 14(10)2021 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-34620633

RESUMO

Necrotising myopathy with pipestem capillaries is a distinct form of inflammatory myopathy exhibiting only sparse inflammation on biopsy, with clinical presentation and histopathological profile entirely different from dermatomyositis, polymyositis or inclusion body myositis. A 51-year-old non-diabetic man presents with progressively worsening shortness of breath and myalgias with only mild proximal muscle weakness and elevated serum creatine kinase. Autoimmune workup, ordered after ruling out infectious and cardiac aetiologies, returned positive for Sjögren's syndrome antibody (SSA/Ro-52). Lung imaging and biopsy were suggestive of cryptogenic organising pneumonia and muscle biopsy showed myositis with pipestem capillaries and abnormal deposition of membrane attack complex with only sparse inflammation. The patient received high-dose steroids, mycophenolate mofetil, intravenous immunoglobulin and rituximab with improvement in muscle symptoms. However, his pulmonary findings progressed, requiring evaluation for a lung transplant. This case emphasises the need for further research to better understand this disease entity and improve mortality and morbidity in these patients.


Assuntos
Doenças Pulmonares Intersticiais , Miosite de Corpos de Inclusão , Miosite , Síndrome de Sjogren , Capilares , Humanos , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/tratamento farmacológico , Doenças Pulmonares Intersticiais/etiologia , Masculino , Pessoa de Meia-Idade , Miosite/diagnóstico , Miosite/tratamento farmacológico , Miosite/etiologia , Síndrome de Sjogren/complicações , Síndrome de Sjogren/diagnóstico , Síndrome de Sjogren/tratamento farmacológico
8.
Invest Ophthalmol Vis Sci ; 62(13): 1, 2021 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-34605880

RESUMO

Purpose: The purpose of this study was to assess density and morphology of cone photoreceptors (PRs) and corresponding retinal sensitivity in ischemic compared to nonischemic retinal capillary areas of diabetic eyes using adaptive optics optical coherence tomography (AO-OCT) and microperimetry (MP). Methods: In this cross-sectional, observational study five eyes of four patients (2 eyes with proliferative diabetic retinopathy (DR) and 3 eyes moderate nonproliferative DR) were included. PR morphology and density was manually assessed in AO-OCT en face images both at the axial position of the inner-segment outer segment (IS/OS) and cone outer segment tips (COSTs). Retinal sensitivity was determined by fundus-controlled microperimetry in corresponding areas (MP-3, Nidek). Results: In AO-OCT, areas affected by capillary nonperfusion showed severe alterations of cone PR morphology at IS/OS and COST compared to areas with intact capillary perfusion (84% and 87% vs. 9% and 8% of area affected for IS/OS and COST, respectively). Mean reduction of PR signal density in affected areas compared to those with intact superficial capillary plexus (SCP) and deep capillary plexus (DCP) perfusion of similar eccentricity was -38% at the level of IS/OS (P = 0.01) and -39% at the level of COST (P = 0.01). Mean retinal sensitivity was 10.8 ± 5.4 in areas affected by DCP nonperfusion and 28.2 ± 1.5 outside these areas (P < 0.001). Conclusions: Cone PR morphology and signal density are severely altered in areas of capillary nonperfusion. These structural changes are accompanied by a severe reduction of retinal sensitivity, indicating the importance of preventing impaired capillary circulation in patients with DR.


Assuntos
Retinopatia Diabética/diagnóstico , Isquemia/diagnóstico , Células Fotorreceptoras Retinianas Cones/patologia , Vasos Retinianos/diagnóstico por imagem , Tomografia de Coerência Óptica/métodos , Acuidade Visual , Testes de Campo Visual/métodos , Adulto , Capilares/patologia , Estudos Transversais , Retinopatia Diabética/complicações , Retinopatia Diabética/fisiopatologia , Feminino , Humanos , Isquemia/etiologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
9.
Int J Mol Sci ; 22(19)2021 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-34638535

RESUMO

Lung endothelial cell dysfunction plays a central role in septic-induced lung injury. We hypothesized that endothelial cell subsets, capillary endothelial cells (capEC) and post capillary venules (PCV), might play different roles in regulating important pathophysiology in sepsis. In order to reveal global transcriptomic changes in endothelial cell subsets during sepsis, we induced sepsis in C57BL/6 mice by cecal ligation and puncture (CLP). We confirmed that CLP induced systemic and lung inflammation in our model. Endothelial cells (ECs) from lung capillary and PCV were isolated by cell sorting and transcriptomic changes were analyzed by bioinformatic tools. Our analysis revealed that lung capEC are transcriptionally different than PCV. Comparison of top differentially expressed genes (DEGs) of capEC and PCV revealed that capEC responses are different than PCV during sepsis. It was found that capEC are more enriched with genes related to regulation of coagulation, vascular permeability, wound healing and lipid metabolic processes after sepsis. In contrast, PCV are more enriched with genes related to chemotaxis, cell-cell adhesion by integrins, chemokine biosynthesis, regulation of actin filament process and neutrophil homeostasis after sepsis. In addition, we predicted some transcription factor targets that regulate a significant number of DEGs in sepsis. We proposed that targeting certain DEGs or transcriptional factors would be useful in protecting against sepsis-induced lung damage.


Assuntos
Capilares/metabolismo , Células Endoteliais/metabolismo , Pulmão/patologia , Sepse/patologia , Vênulas/metabolismo , Animais , Ceco/lesões , Modelos Animais de Doenças , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Sepse/mortalidade , Sepse/terapia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transcriptoma/genética
10.
Anal Chim Acta ; 1185: 339002, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34711332

RESUMO

As the SARS-CoV-2 pandemic continues to spread, the necessity for rapid, easy diagnostic capabilities could never have been more crucial. With this aim in mind, we have developed a cost-effective and time-saving testing methodology/strategy that implements a sensitive reverse transcriptase loop-mediated amplification (RT-LAMP) assay within narrow, commercially available and cheap, glass capillaries for detection of the SARS-CoV-2 viral RNA. The methodology is compatible with widely used laboratory-based molecular testing protocols and currently available infrastructure. It employs a simple rapid extraction protocol that lyses the virus, releasing sufficient genetic material for amplification. This extracted viral RNA is then amplified using a SARS-CoV-2 RT-LAMP kit, at a constant temperature and the resulting amplified product produces a colour change which can be visually interpreted. This testing protocol, in conjunction with the RT-LAMP assay, has a sensitivity of ∼100 viral copies per reaction of a sample and provides results in a little over 30 min. As the assay is carried out in a water bath, commonly available within most testing laboratories, it eliminates the need for specialised instruments and associated skills. In addition, our testing pathway requires a significantly reduced quantity of reagents per test while providing comparable sensitivity and specificity to the RT-LAMP kit used in this study. While the conventional technique requires 25 µl of reagent, our test only utilises less than half the quantity (10 µl). Thus, with its minimalistic approach, this capillary-based assay could be a promising alternative to the conventional testing, owing to the fact that it can be performed in resource-limited settings, using readily available apparatus, and has the potential of increasing the overall testing capacity, while also reducing the burden on supply chains for mass testing.


Assuntos
COVID-19 , Teste para COVID-19 , Capilares , Técnicas de Laboratório Clínico , Análise Custo-Benefício , Humanos , Técnicas de Diagnóstico Molecular , Técnicas de Amplificação de Ácido Nucleico , Sistemas Automatizados de Assistência Junto ao Leito , Testes Imediatos , RNA Viral/genética , DNA Polimerase Dirigida por RNA , SARS-CoV-2 , Sensibilidade e Especificidade
11.
ACS Biomater Sci Eng ; 7(10): 4971-4981, 2021 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-34503336

RESUMO

Simulating the structure and function of blood capillaries is very important for an in-depth insight into their role in the human body and treatment of capillary-related diseases. Due to the similar composition and structure, hollow hydrogel microfibers are well-recognized as potential biomimetic blood capillaries. In this paper, we report a novel, facile, and reproducible method to fabricate coaxial microfluidic chips via 3D printing-assisted soft lithography and then hollow hydrogel microfibers using the as-prepared coaxial microfluidic chips. Instead of traditional photoresist-based lithography, 3D printing of gelatin hydrogel under various extrusion pressures is used to construct sacrificial templates of coaxial microfluidic chips. Various solid and hollow hydrogel microfibers with complicated and hierarchical structures can be obtained via multitype coaxial microfluidic chips or a combination of coaxial microfluidic fabrication and post-treatment. The as-formed hollow hydrogel microfibers are evaluated in detail as biomimetic blood capillaries, including physicochemical and cytological properties. Our results prove that the hollow hydrogel microfibers exhibit excellent mass transport capacity, hemocompatibility, semipermeability, and mechanical strength, and their barrier function can be further enhanced in the presence of endothelial cells. Overall, our 3D printing-assisted fabrication strategy provides a new technique to construct microfluidic chips with complicated 3D microchannels, and the resulting hollow hydrogel microfibers are promising candidates for blood capillaries.


Assuntos
Hidrogéis , Microfluídica , Biomimética , Capilares , Células Endoteliais , Humanos , Impressão Tridimensional , Engenharia Tecidual
12.
Biomater Sci ; 9(19): 6574-6583, 2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34582534

RESUMO

Porphyromonas gingivalis, the pathogen of periodontal disease, is thought to be involved in various diseases throughout the body via gingival tissue blood capillaries. However, the dynamic analysis of the infection mechanism, particularly the deep invasion process of the gingival tissue, has not yet been elucidated because of the lack of both in vivo and in vitro models. In this study, we developed a vascularized three-dimensional (3D) gingival model with an epithelial barrier expressing cell-cell junctions using collagen microfibers (CMFs) to enable the dynamic analysis of the P. gingivalis invasion process. Lipid raft disruption experiments in the gingival epithelial cell layer demonstrated that P. gingivalis migrates into the deeper epithelium via the intercellular pathway rather than intracellular routes. P. gingivalis was shown to invade the 3D gingival model, being found inside blood capillaries during two days of culture. Notably, the number of bacteria had increased greatly at least two days later, whereas the mutant P. gingivalis lacking the cysteine proteases, gingipains, showed a significantly lower number of survivors. The secretion of interleukin-6 (IL-6) from the gingival tissue decreased during the two days of infection with the wild type P. gingivalis, but the opposite was found for the mutant suggesting that P. gingivalis infection disturbs IL-6 secretion at an early stage. By allowing the dynamic observation of the P. gingivalis invasion from the epithelial cell layer into the blood capillaries for the first time, this model will be a powerful tool for the development of novel therapeutics against periodontal infection related diseases.


Assuntos
Capilares , Porphyromonas gingivalis , Células Cultivadas , Células Epiteliais , Gengiva , Humanos
13.
Development ; 148(19)2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34559199

RESUMO

The therian-specific gene paternally expressed 10 (Peg10) plays an essential role in placenta formation: Peg10 knockout mice exhibit early embryonic lethality as a result of severe placental defects. The PEG10 protein exhibits homology with long terminal repeat (LTR) retrotransposon GAG and POL proteins; therefore, we generated mice harboring a mutation in the highly conserved viral aspartic protease motif in the POL-like region of PEG10 because this motif is essential for the life cycle of LTR retrotransposons/retroviruses. Intriguingly, frequent perinatal lethality, not early embryonic lethality, was observed with fetal and placental growth retardation starting mid-gestation. In the mutant placentas, severe defects were observed in the fetal vasculature, where PEG10 is expressed in the three trophoblast cell layers that surround fetal capillary endothelial cells. Thus, Peg10 has essential roles, not only in early placenta formation, but also in placental vasculature maintenance from mid- to late-gestation. This implies that along the feto-maternal placenta interface an interaction occurs between two retrovirus-derived genes, Peg10 and retrotransposon Gag like 1 (Rtl1, also called Peg11), that is essential for the maintenance of fetal capillary endothelial cells.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Capilares/metabolismo , Proteínas de Ligação a DNA/metabolismo , Placenta/irrigação sanguínea , Proteínas de Ligação a RNA/metabolismo , Motivos de Aminoácidos , Animais , Proteínas Reguladoras de Apoptose/química , Capilares/embriologia , Proteínas de Ligação a DNA/química , Células Endoteliais/metabolismo , Endotélio Vascular/citologia , Endotélio Vascular/metabolismo , Feminino , Camundongos , Placenta/embriologia , Gravidez , Proteínas da Gravidez/química , Proteínas da Gravidez/metabolismo , Proteínas de Ligação a RNA/química
14.
PLoS Biol ; 19(9): e3001358, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34520451

RESUMO

Several lines of study suggest that peripheral metabolism of amyloid beta (Aß) is associated with risk for Alzheimer disease (AD). In blood, greater than 90% of Aß is complexed as an apolipoprotein, raising the possibility of a lipoprotein-mediated axis for AD risk. In this study, we report that genetic modification of C57BL/6J mice engineered to synthesise human Aß only in liver (hepatocyte-specific human amyloid (HSHA) strain) has marked neurodegeneration concomitant with capillary dysfunction, parenchymal extravasation of lipoprotein-Aß, and neurovascular inflammation. Moreover, the HSHA mice showed impaired performance in the passive avoidance test, suggesting impairment in hippocampal-dependent learning. Transmission electron microscopy shows marked neurovascular disruption in HSHA mice. This study provides causal evidence of a lipoprotein-Aß /capillary axis for onset and progression of a neurodegenerative process.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides/biossíntese , Hepatócitos/metabolismo , Peptídeos beta-Amiloides/genética , Animais , Barreira Hematoencefálica/patologia , Encéfalo/irrigação sanguínea , Capilares/patologia , Modelos Animais de Doenças , Humanos , Inflamação , Aprendizagem , Lipoproteínas/metabolismo , Masculino , Camundongos Transgênicos , Degeneração Neural
15.
Biophys J ; 120(21): 4859-4873, 2021 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-34536388

RESUMO

Hepatic sinusoids present complex anatomical structures such as the endothelial sieve pores and the Disse space, which govern the microscopic blood flow in the sinusoids and are associated with structural variations in liver fibrosis and cirrhosis. However, the contributions of the permeability of endothelial and collagen layers and the roughness of hepatocyte microvilli to the features of this microflow remain largely unknown. Here, an immersed boundary method coupled with a lattice Boltzmann method was adopted in an in vitro hepatic sinusoidal model, and flow field and erythrocyte deformation analyses were conducted by introducing three new source terms including permeability of the endothelial layer, resistance of hepatocyte microvilli and collagen layers, and deformation of red blood cells (RBCs). Numerical calculations indicated that alterations in endothelial permeability could significantly affect the flow velocity and flow rate distributions in hepatic sinusoids. Interestingly, a biphasic regulating pattern of shear stress occurred simultaneously on the surface of hepatocytes and the lower side of endothelium, i.e., the shear stress increased with increased thickness of hepatocyte microvilli and collagen layer when the endothelial permeability was high but decreased with the increase of the thickness at low endothelial permeability. Additionally, this specified microflow manipulates typical RBC deformation inside the sinusoid, yielding one-third of the variation of deformable index with varied endothelial permeability. These simulations not only are consistent with experimental measurements using in vitro liver sinusoidal chip but also elaborate the contributions of endothelial and collagen layer permeability and wall roughness. Thus, our results provide a basis for further characterizing this microflow and understanding its effects on cellular migration and deformation in the hepatic sinusoids.


Assuntos
Capilares , Fígado , Eritrócitos , Hemodinâmica , Hepatócitos
16.
Am J Physiol Renal Physiol ; 321(5): F600-F616, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34541901

RESUMO

Following our previous reports on mesangial sclerosis and vascular proliferation in diabetic nephropathy (DN) (Kriz W, Löwen J, Federico G, van den Born J, Gröne E, Gröne HJ. Am J Physiol Renal Physiol 312: F1101-F1111, 2017; Löwen J, Gröne E, Gröne HJ, Kriz W. Am J Physiol Renal Physiol 317: F399-F410, 2019), we now describe the advanced stages of DN terminating in glomerular obsolescence and tubulointerstitial fibrosis based on a total of 918 biopsies. The structural aberrations emerged from two defects: 1) increased synthesis of glomerular basement membrane (GBM) components by podocytes and endothelial cells leading to an accumulation of GBM material in the mesangium and 2) a defect of glomerular vessels consisting of increased leakiness and an increased propensity to proliferate. Both defects may lead to glomerular degeneration. The progressing compaction of accumulated worn-out GBM material together with the retraction of podocytes out of the tuft and the collapse and hyalinosis of capillaries results in a shrunken tuft that fuses with Bowman's capsule (BC) to glomerular sclerosis. The most frequent pathway to glomerular decay starts with local tuft expansions that result in contacts of structurally intact podocytes to the parietal epithelium initiating the formation of tuft adhesions, which include the penetration of glomerular capillaries into BC. Exudation of plasma from such capillaries into the space between the parietal epithelium and its basement membrane causes the formation of insudative fluid accumulations within BC spreading around the glomerular circumference and, via the glomerulotubular junction, onto the tubule. Degeneration of the corresponding tubule develops secondarily to the glomerular damage, either due to cessation of filtration in cases of global sclerosis or due to encroachment of the insudative spaces. The degenerating tubules induce the proliferation of myofibroblasts resulting in interstitial fibrosis.NEW & NOTEWORTHY Based on analysis of 918 human biopsies, essential derangement in diabetic nephropathy consists of accumulation of worn-out glomerular basement membrane in the mesangium that may advance to global sclerosis. The most frequent pathway to nephron dropout starts with the penetration of glomerular capillaries into Bowman's capsule (BC), delivering an exudate into BC that spreads around the entire glomerular circumference and via the glomerulotubular junction onto the tubule, resulting in glomerular sclerosis and chronic tubulointerstitial damage.


Assuntos
Nefropatias Diabéticas/patologia , Glomerulonefrite/patologia , Néfrons/patologia , Biópsia , Cápsula Glomerular/patologia , Capilares/patologia , Permeabilidade Capilar , Nefropatias Diabéticas/metabolismo , Progressão da Doença , Células Endoteliais/patologia , Fibrose , Membrana Basal Glomerular/patologia , Glomerulonefrite/metabolismo , Humanos , Microscopia Eletrônica de Transmissão , Neovascularização Patológica , Néfrons/metabolismo , Néfrons/ultraestrutura , Podócitos/patologia
17.
Medicine (Baltimore) ; 100(35): e27069, 2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34477141

RESUMO

ABSTRACT: To investigate the difference in chorioretinal microcirculation between acute central serous chorioretinopathy (aCSC) and chronic central serous chorioretinopathy (cCSC) using optical coherence tomography angiography.In total, 65 patients previously diagnosed with central serous chorioretinopathy (33 aCSC and 32 cCSC) were included in our cross-sectional study. All patients underwent complete ophthalmologic assessment including logarithm of the minimum angle of resolution best-corrected visual acuity, fundus fluorescein angiography, and optical coherence tomography angiography. Sixty eyes of 60 refractive error and age matched healthy people were selected as control.The vessel density of inner retina in patients with aCSC were higher than that in patients with cCSC (51.32 ±â€Š2.01 vs 49.15 ±â€Š3.68, P = .004), however, the vessel density of superficial choroid layer in aCSC were significantly lower than that in cCSC (49.83 ±â€Š6.96 vs 53.42 ±â€Š6.28, P = .033). Further analysis of the data reveals the presence of a distinct choroidal neovascularization (CNV) in 8 patients (25%) with cCSC while there was no evidence of CNV in patients with aCSC.Our study can contribute to a better understanding of the difference in retinochoroid microcirculation between aCSC and cCSC. The vessel density of inner retina was lower and the vessel density of superficial choroid was higher in cCSC, and patients with cCSC were more susceptible to CNV than patients with aCSC.


Assuntos
Capilares/fisiopatologia , Coriorretinopatia Serosa Central/classificação , Microcirculação/fisiologia , Adulto , Neovascularização de Coroide/fisiopatologia , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Acuidade Visual/fisiologia
18.
Nat Protoc ; 16(10): 4564-4610, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34480130

RESUMO

The formation of new blood vessels and the establishment of vascular networks are crucial during brain development, in the adult healthy brain, as well as in various diseases of the central nervous system. Here, we describe a step-by-step protocol for our recently developed method that enables hierarchical imaging and computational analysis of vascular networks in postnatal and adult mouse brains. The different stages of the procedure include resin-based vascular corrosion casting, scanning electron microscopy, synchrotron radiation and desktop microcomputed tomography imaging, and computational network analysis. Combining these methods enables detailed visualization and quantification of the 3D brain vasculature. Network features such as vascular volume fraction, branch point density, vessel diameter, length, tortuosity and directionality as well as extravascular distance can be obtained at any developmental stage from the early postnatal to the adult brain. This approach can be used to provide a detailed morphological atlas of the entire mouse brain vasculature at both the postnatal and the adult stage of development. Our protocol allows the characterization of brain vascular networks separately for capillaries and noncapillaries. The entire protocol, from mouse perfusion to vessel network analysis, takes ~10 d.


Assuntos
Capilares , Microscopia Eletrônica de Varredura , Microtomografia por Raio-X , Animais , Humanos , Imageamento Tridimensional , Camundongos
19.
Am J Physiol Regul Integr Comp Physiol ; 321(5): R732-R741, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34549626

RESUMO

Although hypertension disrupts the blood-brain barrier (BBB) integrity within the paraventricular nucleus of hypothalamus (PVN) and increases the leakage into the brain parenchyma, exercise training (T) was shown to correct it. Since there is scarce and contradictory information on the mechanism(s) determining hypertension-induced BBB deficit and nothing is known about T-induced improvement, we sought to evaluate the paracellular and transcellular transport across the BBB within the PVN in both conditions. Spontaneously hypertensive rats (SHR) and WKY submitted to 4-wk aerobic T or sedentary (S) protocol were chronically catheterized for hemodynamic recordings at rest and intra-arterial administration of dyes (Rhodamine-dextran 70 kDa + FITC-dextran 10 kDa). Brains were harvesting for FITC leakage examination, qPCR evaluation of different BBB constituents and protein expression of caveolin-1 and claudin-5, the main markers of transcytosis and paracellular transport, respectively. Hypertension was characterized by increased arterial pressure and heart rate, augmented sympathetic modulation of heart and vessels, and reduced cardiac parasympathetic control, marked FITC extravasation into the PVN which was accompanied by increased caveolin-1 gene and protein expression, without changes in claudin-5 and others tight junctions' components. SHR-T vs. SHR-S showed a partial pressure reduction, resting bradycardia, improvement of autonomic control of the circulation simultaneously with correction of both FITC leakage and caveolin-1 expression; there was a significant increase in claudin-5 expression. Caveolin-1 content was strongly correlated with improved autonomic control after exercise. Data indicated that within the PVN the transcytosis is the main mechanism governing both hypertension-induced BBB leakage, as well as the exercise-induced correction.


Assuntos
Barreira Hematoencefálica/metabolismo , Capilares/metabolismo , Permeabilidade Capilar , Caveolina 1/metabolismo , Claudina-5/metabolismo , Terapia por Exercício , Hipertensão/terapia , Núcleo Hipotalâmico Paraventricular/irrigação sanguínea , Condicionamento Físico Animal , Junções Íntimas/metabolismo , Transcitose , Animais , Barreira Hematoencefálica/fisiopatologia , Capilares/fisiopatologia , Sistema Cardiovascular/inervação , Caveolina 1/genética , Claudina-5/genética , Modelos Animais de Doenças , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Masculino , Esforço Físico , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Sistema Nervoso Simpático/fisiopatologia
20.
Am J Physiol Renal Physiol ; 321(3): F335-F351, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34338031

RESUMO

Ischemia-reperfusion injury (IRI) is a major risk factor for chronic renal failure. Caspase-3, an effector responsible for apoptosis execution, is activated within the peritubular capillary (PTC) in the early stage of IRI-induced acute kidney injury (AKI). Recently, we showed that caspase-3-dependent microvascular rarefaction plays a key role in fibrosis development after mild renal IRI. Here, we further characterized the role of caspase-3 in microvascular dysfunction and progressive renal failure in both mild and severe AKI, by performing unilateral renal artery clamping for 30/60 min with contralateral nephrectomy in wild-type (C57BL/6) or caspase-3-/- mice. In both forms of AKI, caspase-3-/- mice showed better long-term outcomes despite worse initial tubular injury. After 3 wk, they showed reduced PTC injury, decreased PTC collagen deposition and α-smooth muscle actin expression, and lower tubular injury scores compared with wild-type animals. Caspase-3-/- mice with severe IRI also showed better preservation of long-term renal function. Intravital imaging and microcomputed tomography revealed preserved PTC permeability and better terminal capillary density in caspase-3-/- mice. Collectively, these results demonstrate the pivotal importance of caspase-3 in regulating long-term renal function after IRI and establish the predominant role of PTC dysfunction as a major contributor to progressive renal dysfunction.NEW & NOTEWORTHY Our findings demonstrate the pivotal importance of caspase-3 in regulating renal microvascular dysfunction, fibrogenesis, and long-term renal impairment after acute kidney injury induced by ischemia-reperfusion injury. Furthermore, this study establishes the predominant role of peritubular capillary integrity as a major contributor to progressive renal dysfunction after ischemia-reperfusion injury.


Assuntos
Injúria Renal Aguda/metabolismo , Caspase 3/metabolismo , Insuficiência Renal Crônica/metabolismo , Traumatismo por Reperfusão/metabolismo , Animais , Apoptose/fisiologia , Capilares/metabolismo , Feminino , Rim/metabolismo , Camundongos Endogâmicos C57BL , Rarefação Microvascular/patologia , Traumatismo por Reperfusão/patologia
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