In Vitro and in Vivo Evaluation of Scutellarin-phospholipid Complex Nanoemulsion and Analysis of Its Activity in Ameliorating LPS-induced Vascular Endothelial Injury / 中国实验方剂学杂志

ObjectiveTo evaluate some properties of scutellarin-phospholipid complex nanoemulsion（SCU-PC-NE）， such as release， cell uptake and tissue distribution， and to investigate its effect on ameliorating lipopolysaccharide（LPS）-induced vascular endothelial injury. MethodSCU-PC-NE was prepared by weighting SCU-PC， ethyl oleate， Kolliphor HS15， 1，2-propylene glycol（50， 400， 514.3， 85.7 mg）， respectively. And the appearance of SCU-PC-NE was observed by transmission electron microscope， the average paticle size and Zeta potential were measured by nanopotential particle size analyzer. The cumulative release of SCU-PC-NE in vitro was measured by dynamic dialysis， thiazolyl blue（MTT） colorimetric assay was used to investigate the effect of SCU-PC-NE on the viability of human umbilical vein endothelial cells（HUVECs）， the inverted fluorescence microscope and flow cytometry were used to investigate cell uptake of HUVECs by SCU-PC-NE in vitro using coumarin 6 as a fluorescent probe， the tissue distribution of DiR/SCU-PC-NE labeled by near infrared fluorescent dyes was obeserved by small animal in vivo imaging system. The inflammation injury model was established by co-incubation with LPS（1 mg·L-1） and HUVECs， the effect of SCU-PC-NE on the levels of interleukin（IL）-1β and IL-6 were determined by enzyme-linked immunosorbent assay（ELISA）， 18 Kunming male mice were randomly divided into blank group， model group， blank preparation group（equivalent to high dose group）， SCU group and SCU-PC-NE low and high dose groups（5， 10 mg·kg-1）， 3 mice in each group， and the drug administration groups were administered once in the tail vein at the corresponding dose every 48 h， equal volume of normal saline was given to the blank group and the model group， and the drug was administered for 4 consecutive times. Except for the blank group， the endothelial inflammatory injury was induced by intraperitoneal injection of LPS（10 mg·kg-1） at 12 h before the last administration in each group. Hematoxylin-eosin（HE） staining was used to investigate the effect of SCU-PC-NE on the histopathological changes in the thoracic aorta of mice. ResultThe appearance of SCU-PC-NE displayed pale yellow milky light， mostly spherical with rounded appearance and relatively uniform particle size distribution， with the average particle size of 35.31 nm， Zeta potential of 7.23 mV， and the encapsulation efficiency of 75.24%. The cumulative release in vitro showed that SCU-PC-NE exhibited sustained release properties compared with SCU. The cell viability of SCU-PC-NE was >90% at a concentration range of 1.05-8.4 mg·L-1. The results of cellular uptake experiments showed that the cellular uptake ability of SCU-PC-NE was significantly enhanced when compared with the SCU group（P<0.01）. Compared with normal mice， the results of tissue distribution showed that the fluorescence intensity of DiR/SCU-PC-NE was significantly enhanced in the spleen， kidney， brain and thoracic aorta of mice at different time points after intraperitoneal injection of LPS（P<0.05， P<0.01）， especially in thoracic aorta. ELISA results showed that the levels of IL-1β and IL-6 in the model group were significantly increased when compared with the blank group（P<0.05， P<0.01）， and compare with the model group， all administration groups significantly down-regulated IL-1β level， with the strongest effect in the SCU-PC-NE high-dose group（P<0.01）， and all administration groups significantly down-regulated IL-6 level， with the strongest effect in the SCU-PC-NE low-dose group（P<0.05）. Compare with the blank group， the results of HE staining showed that the endothelial cells were damaged， the elastic fibers were broken and arranged loosely in the model group， although similar vascular injury could be observed in the blank preparation group， SCU group and SCU-PC-NE low-dose group， the vascular endothelial damage was significantly reduced in the high-dose group of SCU-PC-NE， which had a better effect than that in the SCU group. ConclusionSCU-PC-NE can promote the uptake of drugs by endothelial cells and effectively enriched in the site of vascular endothelial injury caused by LPS， suggesting that it has a protective effect on vascular endothelial injury and is a good carrier of SCU.

Manually prepared lamellae for Descemet stripping endothelial keratoplasty (Pachy-DSEK): comparison of four dissection depths / Lamelas manualmente dissecadas para transplante endotelial de córnea (Pachy-DSEK): comparação entre quatro profundidades de dissecção

ABSTRACT Purpose: This study aimed to compare four depths of manual dissection for the preparation of Descemet stripping endothelial keratoplasty lamellae. Methods: Eye bank corneas were randomized into four groups according to dissection depths: Pachy-100 (incision depth = central corneal thickness-safety margin of 100 µm), Pachy-50 (safety margin of 50 µm), Pachy-0 (no safety margin), and Pachy+50 (incision depth = central corneal thickness + 50 µm). All endothelial lamellae were prepared using a standardized method of manual dissection (Pachy-DSEK). The central, paracentral (3.0-mm zone), and peripheral (6.0-mm zone) lamella thicknesses and incision depths were measured by optical coherence tomography. The 3.0-mm and 6.0-mm zone central-to-peripheral thickness ratios were calculated. Results: Endothelial perforation occurred only in the Pachy+50 group (n=3, 30%). Central lamella's thickness in Pachy-100, Pachy-50, Pachy-0, and Pachy+50 groups measured 185 ± 42 µm, 122 ± 29 µm, 114 ± 29 µm, and 58 ± 31 µm, respectively (p<0.001). The overall 3.0- and 6.0-mm C/P ratios were 0.97 ± 0.06 and 0.92 ± 0.14, respectively. Preoperative donor characteristics were not correlated with most thickness outcomes. The planned incision depth correlated significantly with most lamella's thickness parameters (p<0.001). The overall thickness of the lamella negatively correlated with the planned incision depth (p<0.001, r=-0.580). The best outcome was found in the Pachy-0 group, as 75% of the lamellae measured <130 µm and there was no endothelial perforation. Conclusions: By using a standardized method of dissection, most manually prepared lamellae presented a planar shape. Setting the incision depth to the central corneal thickness did not result in endothelial perforation and a high percentage of ultrathin lamellae was achieved.

RESUMO Objetivo: Comparar quatro profundidades de dissecção manual usadas no preparo de lamelas para transplante endotelial. Métodos: Córneas humanas de treinamento disponibilizadas foram randomizadas em quatro grupos: Pachy-100 (profundidade de incisão = espessura corneana central - margem de segurança de 100 µm), Pachy-50 (margem de segurança de 50 µm), Pachy-0 (sem margem de segurança) e Pachy+50 (profundidade de incisão = espessura corneana central + 50 µm). Todas as lamelas foram dissecadas através um método padronizado e já publicado (Pachy-DSEK). As espessuras das lamelas (centro, zona de 3,0mm e zona de 6,0mm) foram medidas com tomografia de coerência óptica. A razão de espessura centro-periferia foi calculada aos 3,0 e 6,0 mm de diâmetro. Resultados: Perfuração endotelial ocorreu apenas no grupo Pachy+50 (n=3, 30%). A espessura central da lamela nos grupos Pachy-100, Pachy-50, Pachy-0 e Pachy+50 foi de 185 ± 42 µm, 122 ± 29 µm, 114 ± 29 µm, e 58 ± 31 µm, respectivamente (p<0,001). As razões C/P aos 3,0 e 6,0 mm foram de 0,97 ± 0,06 e 0,92 ± 0,14, respectivamente. Os parâmetros de características do doador não se correlacionaram com os resultados de espessura de lamela. A profundidade planejada de incisão se correlacionou com a maioria dos parâmetros de espessura de lamela (p<0,001). A espessura de lamela se correlacionou negativamente com a profundidade planejada da incisão (p<0.001, r=-0,580). O melhor resultado foi observado no grupo Pachy-0, em que 75% das lamelas mediram abaixo de 130 µm e não houve perfuração endotelial. Conclusão: Através de um método padronizado de dissecção, a maioria das lamelas endoteliais apresentou uma configuração planar. O planejamento de profundidade de incisão igual à espessura corneana central resultou em alta porcentagem de lamelas ultrafinas sem ocorrência de perfuração.

El endotelio sano y su disfunción en el riesgo cardiovascular / Healthy Endothelium and its Dysfunction in Cardiovascular Risk

Resumen El endotelio es una monocapa formada por células aplanadas llamadas w, que revisten la parte más interna del corazón, los vasos sanguíneos y los linfáticos. Es considerado un órgano que tiene una función de barrera, pero además se encarga de regular la permeabilidad y tono vascular, hemostasia, inflamación y angiogénesis. Esta revisión se centra sobre todo en las generalidades del endotelio vascular sano y su disfunción. Se analizan los conceptos de activación y disfunción, en donde la activación se considera como un proceso autolimitado, indispensable para la hemostasia y la inflamación. La disfunción endotelial, en cambio, es un proceso patológico, de mayor duración y que se presenta cuando el endotelio ya no puede autorregularse y cambia a un fenotipo proinflamatorio y protrombótico permanente. Esta disfunción es el primer cambio que lleva a la ateroesclerosis y al aumento del riesgo cardiovascular, por esta razón se revisan los principales biomarcadores de disfunción endotelial y riesgo cardiovascular. A medida que se avance en el conocimiento básico del endotelio y su disfunción, será posible diseñar nuevas medidas preventivas o terapéuticas que puedan disminuir dicho riesgo.

Abstract The endothelium is a monolayer of flatten cells named endothelial cells that form the inner layer of the heart, blood, and lymphatic vessels. Its function is not just as a barrier, but it is a regulator of vascular permeability and tone, hemostasis, inflammation, and angiogenesis. This review is about the general aspects of vascular endothelium and endothelial dysfunction that leads to increased vascular risk. Activation and dysfunction are discussed, considering the endothelial activation as a self-limiting process, necessary to promote inflammation and hemostasis. Endothelial dysfunction is a pathological process in which the endothelium loses its ability for self-regulation and acquires a prothrombotic and proinflammation phenotype. Endothelial dysfunction is the initial step for atherosclerosis and increased cardiovascular risk, so the main biomarkers of endothelial dysfunction are reviewed. As basic knowledge about endothelium increases, preventive or therapeutic measures can be designed as treatment or prevention the risk of its dysfunction.

Evaluación de la disfunción del endotelio para el pronóstico de riesgo cardiovascular / Evaluation of endothelial dysfunction for cardiovascular risk prediction i: en

Introducción: Las enfermedades cardiovasculares constituyen la primera causa de muerte en el mundo, por lo que la identificación y modificación de los factores de riesgo asociados a ellas constituyen estrategias priorizadas por la Organización Mundial de la Salud. Contar con un modelo de predicción del riesgo cardiovascular enriquecido con la evaluación de la disfunción endotelial influiría positivamente en estas metas. Objetivos: Identificar la presencia de disfunción endotelial en pacientes con enfermedades cardiovasculares o sin estas y determinar la asociación entre ambas. Métodos: Se realizó un estudio observacional y descriptivo, de serie de casos, en el Centro de Cardiología y Cirugía Cardiovascular del Hospital Provincial Docente Clínico-Quirúrgico Saturnino Lora de Santiago de Cuba, desde enero del 2022 hasta igual mes del 2023, donde se analizaron como variables los factores de riesgo cardiovascular tradicionales y los biomarcadores de disfunción endotelial. Secundariamente, se llevó a cabo un estudio analítico de casos y controles en el cual se aplicó la regresión logística binaria multivariada. Resultados: Se confirmó la presencia de disfunción endotelial asociada a la aparición de las enfermedades cardiovasculares, lo que se evaluó a través del índice de vasodilatación, mediado por el flujo de la arteria braquial y las concentraciones plasmáticas de fibrinógeno. Conclusiones: Las características epidemiológicas y clínicas de los pacientes con enfermedades cardiovasculares o sin estas no difirieron de lo registrado en la literatura especializada acerca de la base de identificación de los factores de riesgo tradicionales.

Introduction: Cardiovascular diseases constitute the first death cause worldwide, reason why the identification and modification of associated risk factors constitute prioritized strategies by the World Health Organization. To have a prediction model of cardiovascular risk enriched with the evaluation of the endothelial dysfunction would influence positively in these goals. Objectives: To identify the presence of endothelial dysfunction in patients with or without cardiovascular diseases and to determine the association between them. Methods: An observational and descriptive cases series study was carried out in the Cardiology and Cardiovascular Surgery Center at Saturnino Lora Teaching Clinical Surgical Provincial Hospital in Santiago de Cuba, from January, 2022 to the same month, 2023, where the traditional cardiovascular risk factors and endothelial dysfunction biomarkers were analyzed as variables. Secondarily, an analytic case-control study was carried out in which multivariate binary logistic regression was applied. Results: The presence of endothelial dysfunction associated with the onset of cardiovascular diseases was confirmed, what was evaluated through the vasodilatation index, mediated by the brachial artery flow and the fibrinogen plasmatic concentrations. Conclusions: The clinical and epidemiological pattern of patients with or without cardiovascular diseases did not differ from that reported in the specialized literature on the base of the identification of traditional risk factors.

Clinical outcomes of epithelial ingrowth following laser in situ keratomileusis with mechanical debridement and compressed heating air flow: a case series / Resultado visual do tratamento do crescimento epitelial após laser in situ ceratomileuse através da remoção mecânica e aplicação de ar comprimido aquecido: série de casos

ABSTRACT Purpose: To describe the clinical outcomes of manual scraping of epithelial ingrowth followed by compressed heating air flow after laser in situ keratomileusis (LASIK). Methods: We underwent a retrospective, noncomparative, and interventional case series. Twenty eyes of 17 patients were included in this study. Each patient with a history of LASIK underwent epithelial removal with mechanical debridement followed by compressed heating air flow. Our primary outcome was the recurrence of epithelial ingrowth after 3 months of follow-up, while our secondary outcomes were uncorrected distance visual acuity, corrected distance visual acuity, and complications after surgery. Results: Ten patients (58.8%) were male, and eight eyes of seven (41.2%) patients underwent primary LASIK surgery, while12 eyes of 10 patients had flap-lift retreatment LASIK; sixteen eyes (80.0%) underwent mechanical microkeratome LASIK and four (20.0%) underwent femtosecond laser-assisted LASIK. Mean age at surgical removal of epithelial ingrowth was 37.0 years ± 9.3 years (range 24 to 55 years). There was recurrence of ingrowth in two eyes (10%) after 3 months of follow-up. The mean corrected distance visual acuity of patients before surgery was 0.07 ± 0.09 logMAR, and after the last follow-up was 0.02 ± 0.04 logMAR (p=0.06). The odds ratio of presenting with epithelial ingrowth after LASIK enhancement compared to primary LASIK was 29.41. Conclusion: Manual scraping followed by compressed heating air flow is a safe and effective treatment of clinically significant epithelial ingrowth after LASIK. At the last follow-up, no eye lost any line in corrected distance visual acuity.

RESUMO Objetivo: Descrever os resultados clínicos do tratamento do crescimento epitelial através da técnica de remoção manual seguido da utilização de um compressor de ar comprimido aquecido após a cirurgia de laser in situ keratomileusis (LASIK). Métodos: Vinte olhos de 17 pacientes foram incluídos no estudo. Cada paciente havia sido submetido a cirurgia de LASIK com presença de crescimento epitelial e foi submetido a tratamento cirúrgico para sua retirada. O objetivo primário foi identificar a presença de crescimento epitelial recorrente ao final de 3 meses de seguimento. Os objetivos secundários foram as medidas de acuidade visual sem correção, acuidade visual com correção, e complicações pós-operatórias. Resultados: Dez pacientes (58,8%) eram homens e 7 mulheres. Oito olhos de sete (41,2%) pacientes apresentavam cirurgia de LASIK primária e 12 olhos de 10 pacientes tinham cirurgia de LASIK com retratamento; dezesseis olhos (80%) utilizaram microcerátomo manual e quatro (20%) laser de femtosegundo. A média de idade no momento da cirurgia de remoção do epitélio era de 37,0 anos ± 9,3 (DP) (variando de 24 a 55 anos). Ocorreu recidiva do crescimento epithelial em dois olhos (10%) após 3 meses de seguimento. A acuidade visual sem correção antes da cirurgia era de 0,07 ± 0,09 logMAR, e após a cirurgia passou para 0,02 ± 0,04 logMAR (p=0,06). A chance (odds ration) de aparecimento do crescimento epithelial após uma reoperação de LASIK é 29,41 vezes maior do que no LASIK primário. Conclusão: A técnica de remoção epitelial manual seguida da utilização de ar comprimido aquecido é segura e efetiva no tratamento do crescimento epitelial após LASIK. Ao final do último acompanhamento, nenhum olho apresentou perda de linhas de visão.

Efficacy and safety of three days continuous intravenous pumping of recombinant human endostatin combined with platium-contained chemotherapeutic agents in patients with advanced non-small cell lung cancer aged 60 years or older / 中华老年医学杂志

Objective:To investigate the efficacy and safety of recombinant human endostatin(Endostar)combined with platium-contained chemotherapeutic agents in advanced non-small cell lung cancer(NSCLC)patients over 60 years old.Methods:93 advanced NSCLC patients from January 2019 to June 2021 were selected as the research objects.The patients received three days of continuous intravenous infusion of Endostar(210 mg for 72 hours)combined with platinum-containing chemotherapy.The efficacy and toxicities were evaluated according to Response Evaluation Criteria in Solid Tumors(RECIST)version1.1 and National Cancer Institute Common Terminology Criteria for Adverse Events(NCI-CTCAE version 4.0), respectively.Follow-up data were obtained to perform the Kaplan-Meier survival analysis.Results:In our study, the objective remission rate(ORR)and disease control rate(DCR)were 38.7% and 78.5%, respectively.The median progression-free survival(PFS)and overall survival(OS)were 6.8 months and 16.5 months, respectively.A Multivariate analysis showed that tumor staging and TP53 mutation were independent prognostic factors related to PFS and OS in advanced NSCLC patients.Adverse reactions related to Endostar during treatment included arrhythmia in 2 cases(2.2%), myocardial ischemia in 1 case(1.07%)and bloody sputum in 1 case(1.07%), all of which were Grade 1 or Grade 2.Conclusions:The application of three days continuous intravenous infusion of Endostar combined with platium-contained chemotherapeutic agents is worthy to be recommended for clinical application in elderly patients with advanced NSCLC due to its high effective rate and survival advantage, as well as good safety.

Change in corneal endothelial cell density and morphology in different stages of keratoconus / 中华实验眼科杂志

Objective:To assess the changes in corneal endothelial cell density (CD) and morphology in patients with different stages of keratoconus.Methods:A cross-sectional study was conducted.One hundred and nineteen patients (199 eyes) with keratoconus who were treated in the Eye Hospital of Shandong First Medical University were included from March 2018 to October 2021.The 199 eyes were classified into stage Ⅰ (111 eyes of 58 cases), stage Ⅱ (41 eyes of 30 cases), stage Ⅲ (47 eyes of 31 cases) keratoconus groups according to the Amsler-Krumeich classification.In the same period, 25 age- and sex-matched healthy subjects (50 eyes) were enrolled as a normal control group.Corneal topography and anterior segment parameters such as keratometry (K), central corneal thickness (CCT), thinnest corneal thickness (TCT), anterior chamber depth (ACD), corneal diameter and corneal volume were obtained by Pentacam 3-dimensional anterior segment imaging and analysis system.The corneal endothelial CD, percentage of hexagonal cells (6A), average cell area (AVE), maximum cell area (MAX), minimum cell area (MIN), cell area standard deviation (SD) and cell area coefficient of variation (CV) in the central area were evaluated by non-contact specular microscopy.The correlation between corneal endothelial CD, morphological parameters and corneal topographic parameters was analyzed by Spearman rank correlation.This study adhered to the Declaration of Helsinki and was approved by the Ethics Committee of Shandong Eye Hospital (No.SDSYKYY201803). All patients were informed of the purpose and methods of the study and written informed consent was obtained before any medical examination.Results:The CD of the normal control group and stage Ⅰ, Ⅱ, Ⅲ keratoconus groups was 2 941(2 809, 3 072), 2 825(2 667, 3 030), 2 747(2 475, 2 903) and 2 370(2 142, 2 525) cells/mm 2, respectively.With the progression of keratoconus, CD decreased gradually, and there was a significant difference in CD among the four groups ( H=94.862, P<0.001). There were significant differences in CV and 6A among the four groups ( H=45.018, 20.421; both at P<0.001). CV was significantly higher in stage Ⅲ keratoconus group than that of the normal control group and stage Ⅰ and Ⅱ keratoconus groups and 6A was significantly lower in stage Ⅲ keratoconus group than that of the normal control group and stage Ⅰ keratoconus group (all at P<0.05). With the progression of keratoconus, MAX, MIN, AVE and SD increased gradually, and there were significant differences in MAX, MIN, AVE and SD among the four groups ( H=37.905, 32.437, 110.182, 72.941; all at P<0.001). MAX and MIN in stage Ⅲ keratoconus group were significantly higher than those in stage Ⅰ keratoconus groups and normal control group (all at P<0.05). AVE and SD in stage Ⅲ keratoconus group were significantly higher than those in normal control group and stage Ⅰ and Ⅱ keratoconus groups (all at P<0.05). In patients with keratoconus, CD was moderately positively correlated with CCT ( rs=0.47, P<0.001) and TCT ( rs=0.53, P<0.001), and was moderately negatively correlated with mean keratometry (Km) ( rs=-0.59, P<0.001).6A was weakly positively correlated with CCT ( rs=0.18, P=0.01) and TCT ( rs=0.22, P=0.002), and was weakly negatively correlated with Km ( rs=-0.32, P<0.001). CV was weakly negatively correlated with CCT ( rs=-0.35, P<0.001) and TCT ( rs=-0.37, P<0.001), and was moderately positively correlated with Km ( rs=0.48, P<0.001). There was no correlation between CD, CV, 6A and ACD, or corneal volume. Conclusions:As the keratoconus progresses, the cornea protrudes and becomes thinner with CD and 6A decreasing while CV increasing.Corneal topographic parameters are related to the density and morphology of corneal endothelial cells.

Role of homocysteinylation in cerebral atherosclerosis / 国际脑血管病杂志

Homocysteine is closely associated with extracranial and intracranial atherosclerosis, and its main pathogenesis includes oxidative stress, lipid metabolism disorder and vascular endothelial dysfunction. As a protein modification related to homocysteine, homocysteinylation can promote the occurrence and development of cerebral atherosclerosis by promoting oxidation, changing lipid function and destroying vascular endothelial function. This article reviews the role of homocysteinylation in cerebral atherosclerosis, and discusses the possibility of preventing cerebral atherosclerosis by homocysteinylation.

Pathogenesis of cerebral small vessel disease / 国际脑血管病杂志

Cerebral small vessel disease (CSVD) is an important cause of ischemic stroke and vascular dementia, which brings heavy burden to families and society. The prevention and treatment of CSVD has always been a research hotspot, but its pathogenesis is still not completely clear. This article reviews the pathogenesis of CSVD, including chronic cerebral hypoperfusion, blood-brain barrier dysfunction, vascular endothelial dysfunction, interstitial fluid reflux disorder, inflammatory response, and genetic factors, in order to provide more sufficient theoretical basis for early intervention and treatment of CSVD.

In vivo confocal microscopic observations of 49 patients with posterior polymorphous corneal dystrophy / 国际眼科杂志(Guoji Yanke Zazhi)

AIM: To explore the imaging features of 49 patients with posterior polymorphous corneal dystrophy(PPCD)by in vivo confocal microscopy(IVCM).METHODS: Retrospective case series study. A total of 49 patients(86 eyes), including 32 males and 17 females diagnosed with PPCD between January 2013 and January 2021 were collected. The mean age was 42.5±22.9 years. All patients were scanned by IVCM to analyze the density of corneal endothelial cells and described IVCM characteristics of different types of PPCD.RESULTS: The number of endothelial cells in the lesion area of all patients was lower than that in the peripheral area. Under IVCM, 44 eyes(51%)were categorized into type 1 PPCD(vesicular lesions), characterized by single or multiple, central round or irregular crater-like lesion on paracentral corneal endothelial layer; 16 eyes(19%)were categorized into type 2 PPCD(band lesions), which displayed curved and raised edge with scattered or banded-distributed gutta-like lesion between edges. Type 3 PPCD(diffuse lesion)were in 26 eyes(30%), which showed that endothelial cells were missing in many areas. The blurred images of endothelium in most areas featured with spikes lined in a streak, and the clear images in some areas featured with a band lesions. Two patients were followed up for 4-5a. The IVCM images showed different lesions, including the decrease of central corneal endothelial cell density and the iron deposit in the corneal epithelium, etc.CONCLUSION: IVCM is able to scan the characteristic microstructural alterations at the level of endothelium and Descemet membrane in patients with PPCD, and provide an effective image diagnosis for PPCD.

Research progress of endothelial-mesenchymal transdifferentiation in fibrotic diseases / 中国药理学通报

Fibrosis is a repair response initiated by tissues and organs after injury, and is a self-protection mechanism of the body. It has been found that endothelium-to-interstitial transdifferentiation (EndMT) is involved in the physiological and pathological processes of various organ fibrosis, which has become a focus of the research on fibrotic diseases. In recent years, the study has found that EndMT plays an important role in many pathological processes in cardiovascular system, lungs, kidneys, liver, pancreas fibrosis, and so on. This article summarizes EndMT regulatory mechanism and its role in each organ fibrosis, as well as the related treatment progress of EndMT targets, so as to provide new targets for prevention and control of organ fibrosis.

Pulmonary endothelium-targeted nanoassembly of indomethacin and superoxide dismutase relieves lung inflammation

Lung inflammation is an essential inducer of various diseases and is closely related to pulmonary-endothelium dysfunction. Herein, we propose a pulmonary endothelium-targeted codelivery system of anti-inflammatory indomethacin (IND) and antioxidant superoxide dismutase (SOD) by assembling the biopharmaceutical SOD onto the "vector" of rod-like pure IND crystals, followed by coating with anti-ICAM-1 antibody (Ab) for targeting endothelial cells. The codelivery system has a 237 nm diameter in length and extremely high drug loading of 39% IND and 2.3% SOD. Pharmacokinetics and biodistribution studies demonstrate the extended blood circulation and the strong pulmonary accumulation of the system after intravenous injection in the lipopolysaccharide (LPS)-induced inflammatory murine model. Particularly, the system allows a robust capacity to target pulmonary endothelium mostly due to the rod-shape and Ab coating effect. In vitro, the preparation shows the synergistic anti-inflammatory and antioxidant effects in LPS-activated endothelial cells. In vivo, the preparation exhibits superior pharmacodynamic efficacy revealed by significantly downregulating the inflammatory/oxidative stress markers, such as TNF-α, IL-6, COX-2, and reactive oxygen species (ROS), in the lungs. In conclusion, the codelivery system based on rod-like pure crystals could well target the pulmonary endothelium and effectively alleviate lung inflammation. The study offers a promising approach to combat pulmonary endothelium-associated diseases.

Quality evaluation of Galli Gigerii Endothelium Corneum based on HPLC fingerprints and content determination of nucleosides / 中国中药杂志

Galli Gigerii Endothelium Corneum(GGEC), the dried gizzard membrane of Gallus gallus domesticus is a Chinese medicinal material commonly used for digestion. However, due to the particularity of texture and composition, its active ingre-dients have not been clarified so far, and there is also a lack of quality evaluation indicators. In this study, UPLC-Q-TOF-MS was used to analyze the chemical components from the water extract of GGEC, and ten nucleosides were identified for the first time. HPLC fingerprints of the water extracts of GGEC were established and the content of seven nucleosides was determined. The fingerprint similarities of 40 batches of GGEC samples ranged from 0.765 to 0.959, indicating that there were great differences among the GGEC products processed with different methods. In addition, SPSS 22.0 and SIMCA 14.1 were used for hierarchical cluster analysis(HCA) and principal component analysis(PCA) on the 19 common peaks of the HPLC fingerprints of GGEC, and the 40 batches of samples were divided into three categories: raw GGEC, fried GGEC and vinegar-processed GGEC. Eight differential components in GGEC were marked by orthogonal partial least squares discrimination analysis(OPLS-DA), two of which were adenine and thymine. The results of content determination showed that the total content of the seven nucleosides in raw GGEC, fried GGEC and vinegar-processed GGEC were 182.5-416.8, 205.3-368.7, and 194.2-283.0 μg·g~(-1), respectively. There were significant differences in the content of hypoxanthine, thymine and thymidine among the GGEC products processed with different methods(P<0.05), which were graded in the order of fried GGEC>vinegar-processed GGEC>raw GGEC. This suggested that the content of hypoxanthine, thymine and thymidine tended to increase during the frying process, and the variation range might be related to the degree of heat exposure. The established methods in this study were simple and reproducible, and could be used for qualitative and quantitative analysis of GGEC and its processed pro-ducts. This study also provided reference for the establishment of quality standards of GGEC with chemical components as control index.

Pharmacodynamic Material Basis of Astragali Radix and Angelicae Sinensis Radix Drug Pair in Supplementing Qi and Activating Blood Circulation / 中国实验方剂学杂志

ObjectiveTo evaluate the effect of Astragali Radix （AR）-Angelicae Sinensis Radix （ASR） drug pair on supplementing Qi and activating blood circulation in rats with Qi deficiency and blood stasis and provide a theoretical basis for clinical rational medication and identification and quality control of compound pharmacodynamic substances from the three aspects of characteristic map， identification of pharmacodynamic substances， and comparison of blood components. MethodHigh-performance liquid chromatography （HPLC） was employed to establish the fingerprint of AR∶ASR （3∶1）， and ultra-high performance liquid chromatography-Q-Exactive Orbitrap-mass spectrometry （UPLC-Q-Exactive Orbitrap-MS） was employed to analyze the ingredients of the decoction. Adult male Wistar rats with SPF grades were selected and randomly divided into a blank group， a model group， a 3∶1 group， and a 5∶1 group. The rat model of Qi deficiency and blood stasis syndrome was prepared by controlling food intake and swimming in cold water every day. In parallel， each group was given medicine （or water） once a day. The dose of drug groups was 10.2 g∙kg-1， and the model group and blank group were given the same amount of distilled water for 15 d. Animal behavior， body weight， whole blood and plasma viscosity， thymus index， spleen index， the levels of adenosine triphosphate （ATP）， adenosine diphosphate（ADP）， von willebrand factor （vWF）， and ATP/ADP value in serum of rats were recorded. The morphology of vascular endothelium was observed by hematoxylin-eosin （HE） staining and scanning electron microscopy. UPLC-Q-Exactive Orbitrap-MS was used to analyze prototype and metabolic components in serum. ResultThe fingerprint of AR-ASR drug pair （AR-ASR 3∶1） was established. UPLC-Q-Exactive Orbitrap MS identified 49 chemical components in vitro and preliminarily identified 11 prototype components absorbed into blood in vivo. As compared with the blank group， the body mass decreased significantly （P<0.01）， the whole blood （high shear， middle shear， and low shear） viscosity and plasma viscosity were significantly increased （P<0.05， P<0.01）， the thymus index and spleen index decreased significantly （P<0.05， P<0.01）， serum ATP content decreased significantly （P<0.01）， ADP content increased significantly （P<0.01）， ATP/ADP value decreased significantly （P<0.01）， and vWF content increased significantly （P<0.01）. The results of HE staining and scanning electron microscopy showed that the vessels were partially damaged， showing the structural disorder of the intima， the bulge， defect， and roughness of the endothelium， and the obvious cell adhesion and migration in the model group. As compared with the model group， the body mass also increased significantly （P<0.01）. The results of whole blood and plasma viscosity showed that the whole blood low shear viscosity was significantly decreased in the 3∶1 group （P<0.05）. The results of thymus index and spleen index showed that 5∶1 group significantly increased the thymus index of rats （P<0.05）. The results of serum ATP and ADP levels showed that the 5∶1 group had more significant effects on ATP and ADP levels （P<0.05）， and both groups significantly reduced ATP/ADP values （P<0.01）. The results of serum vWF level showed that the vWF content in the 3∶1 group decreased significantly （P<0.05）. The results of HE staining and scanning electronic microscopy showed that the damage of vascular endothelium was improved in the treatment group and the structure of intima was neat. ConclusionAR-ASR drug pair can improve the macro and micro indexes of rats with qi deficiency and blood stasis in the 3∶1 and 5∶1 groups. Overall， the 5∶1 ratio has a better effect on supplementing Qi but 3∶1 ratio has a better effect on promoting blood circulation.

Phosphorylated PKM2 regulates endothelium-dependent vasodilation in diabetes / 中南大学学报(医学版)

OBJECTIVES@#Endothelium-dependent vasodilation dysfunction is the pathological basis of diabetic macroangiopathy. The utilization and adaptation of endothelial cells to high glucose determine the functional status of endothelial cells. Glycolysis pathway is the major energy source for endothelial cells. Abnormal glycolysis plays an important role in endothelium-dependent vasodilation dysfunction induced by high glucose. Pyruvate kinase isozyme type M2 (PKM2) is one of key enzymes in glycolysis pathway, phosphorylation of PKM2 can reduce the activity of pyruvate kinase and affect the glycolysis process of glucose. TEPP-46 can stabilize PKM2 in its tetramer form, reducing its dimer formation and phosphorylation. Using TEPP-46 as a tool drug to inhibit PKM2 phosphorylation, this study aims to explore the impact and potential mechanism of phosphorylated PKM2 (p-PKM2) on endothelial dependent vasodilation function in high glucose, and to provide a theoretical basis for finding new intervention targets for diabetic macroangiopathy.@*METHODS@#The mice were divided into 3 groups: a wild-type (WT) group (a control group, C57BL/6 mice) and a db/db group (a diabetic group, db/db mice), which were treated with the sodium carboxymethyl cellulose solution (solvent) by gavage once a day, and a TEPP-46 group (a treatment group, db/db mice+TEPP-46), which was gavaged with TEPP-46 (30 mg/kg) and sodium carboxymethyl cellulose solution once a day. After 12 weeks of treatment, the levels of p-PKM2 and PKM2 protein in thoracic aortas, plasma nitric oxide (NO) level and endothelium-dependent vasodilation function of thoracic aortas were detected. High glucose (30 mmol/L) with or without TEPP-46 (10 μmol/L), mannitol incubating human umbilical vein endothelial cells (HUVECs) for 72 hours, respectively. The level of NO in supernatant, the content of NO in cells, and the levels of p-PKM2 and PKM2 protein were detected. Finally, the effect of TEPP-46 on endothelial nitric oxide synthase (eNOS) phosphorylation was detected at the cellular and animal levels.@*RESULTS@#Compared with the control group, the levels of p-PKM2 in thoracic aortas of the diabetic group increased (P<0.05). The responsiveness of thoracic aortas in the diabetic group to acetylcholine (ACh) was 47% lower than that in the control group (P<0.05), and that in TEPP-46 treatment group was 28% higher than that in the diabetic group (P<0.05), while there was no statistically significant difference in the responsiveness of thoracic aortas to sodium nitroprusside (SNP). Compared with the control group, the plasma NO level of mice decreased in the diabetic group, while compared with the diabetic group, the phosphorylation of PKM2 in thoracic aortas decreased and the plasma NO level increased in the TEPP-46 group (both P<0.05). High glucose instead of mannitol induced the increase of PKM2 phosphorylation in HUVECs and reduced the level of NO in supernatant (both P<0.05). HUVECs incubated with TEPP-46 and high glucose reversed the reduction of NO production and secretion induced by high glucose while inhibiting PKM2 phosphorylation (both P<0.05). At the cellular and animal levels, TEPP-46 reversed the decrease of eNOS (ser1177) phosphorylation induced by high glucose (both P<0.05).@*CONCLUSIONS@#p-PKM2 may be involved in the process of endothelium-dependent vasodilation dysfunction in Type 2 diabetes by inhibiting p-eNOS (ser1177)/NO pathway.

Stable Angina Pectoris with Sleep Disorders Treated by Modified Tongmai Anshen Formula （通脉安神方加减）： An Clinical Observation of 74 Cases / 中医杂志

ObjectiveTo observe the clinical efficacy of the Modified Tongmai Anshen Formula （通脉安神方加减， MTAF） in the treatment of stable angina pectoris （SAP） with sleep disorders. MethodsA total of 148 patients suffering from SAP with sleep disorder were included and randomly divided into control group and treatment group， with 74 patients in each group. The control group received conventional western medicine， and the treatment group additionally received MTAF （1 dose per day）， both for 4 weeks. The changes in angina pectoris symptoms， traditional Chinese medicine （TCM） syndromes， sleep quality， quality of life， serological indicators including serum intercellular adhesion molecule-1 （ICAM-1） and vascular cell adhesion molecule-1 （VCAM-1）， brain-derived nerve growth factor （BDNF） and tyrosine kinase receptor B （TrkB） were compared between groups before and after treatment， and the safety was evaluated. ResultsIn the treatment group and the control group， the total effective rates of TCM syndromes（82.43% vs 52.70%）， angina pectoris （79.73% vs 64.86%） and sleep （89.19% vs 68.92%） showing significant difference （P＜0.001）. After treatment， the total TCM syndrome score， primary symptom score， secondary symptom score， and secondary symptoms sleeplessness， restlessness， tiredness and fatigue individual score， angina pectoris score， PSQI total score and each item score were all significantly reduced in both groups， while the SF-36 single item score significantly increased （P＜0.05）. The total TCM syndromes and primary symptom scores， secon-dary symptoms sleeplessness， restlessness， tiredness and fatigue individual score， angina pectoris score， time to fall asleep， sleep quality， hypnotic medication， sleep disturbance， daytime dysfunction score and PSQI total score were significantly lower in the treatment group than those in the control group after treatment （P＜0.05）， while the somatic pain， general health status， social functioning， emotional functioning， mental health， and health change were significantly higher in the treatment group （P＜0.05）. After treatment， ICAM-1 and VCAM-1 level significantly decreased （P＜0.05）， and BDNF and TrkB levels increased （P＜0.05） in the treatment group， while BDNF level significantly decreased in the control group （P＜0.05）. The TrkB level was significantly higher in the treatment group compared to the control group after treatment （P＜0.05）. A total of four adverse events occurred during the treatment， none of which were considered to be related to this study. ConclusionMTAF can significantly improve angina pectoris symptoms， TCM syndromes， sleep quality and quality of life in patients suffering from SAP with sleep disorders， the mechanism of which may be related to the protection of vascular endothelial function and central neurons.

Endothelial METRNL determines circulating METRNL level and maintains endothelial function against atherosclerosis

METRNL is a recently identified secreted protein with emerging functions. This study is to find major cellular source of circulating METRNL and to determine METRNL novel function. Here, we show METRNL is abundant in human and mouse vascular endothelium and released by endothelial cells using endoplasmic reticulum-Golgi apparatus pathway. By creating endothelial cell-specific Metrnl knockout mice, combined with bone marrow transplantation to produce bone marrow-specific deletion of Metrnl, we demonstrate that most of circulating METRNL (approximately 75%) originates from the endothelial cells. Both endothelial and circulating METRNL decrease in atherosclerosis mice and patients. By generating endothelial cell-specific Metrnl knockout in apolipoprotein E-deficient mice, combined with bone marrow-specific deletion of Metrnl in apolipoprotein E-deficient mice, we further demonstrate that endothelial METRNL deficiency accelerates atherosclerosis. Mechanically, endothelial METRNL deficiency causes vascular endothelial dysfunction including vasodilation impairment via reducing eNOS phosphorylation at Ser1177 and inflammation activation via enhancing NFκB pathway, which promotes the susceptibility of atherosclerosis. Exogenous METRNL rescues METRNL deficiency induced endothelial dysfunction. These findings reveal that METRNL is a new endothelial substance not only determining the circulating METRNL level but also regulating endothelial function for vascular health and disease. METRNL is a therapeutic target against endothelial dysfunction and atherosclerosis.

Comparison of efficacy of small incision extracapsular excision or phacoemulsification in the treatment of cataract / 国际眼科杂志(Guoji Yanke Zazhi)

AIM: To investigate the effects of small incision extracapsular excision and phacoemulsification on the number of corneal endothelial cells, macular thickness and surgically induced corneal astigmatism in cataract patients.METHODS: Retrospective research. A total of 296 age-related cataract patients(296 eyes)admitted to our hospital from May 2019 to February 2023 were selected. They were divided into a small incision extracapsular excision group(144 eyes)and a phacoemulsification group(152 eyes)according to surgical method. The uncorrected visual acuity, best corrected visual acuity, numbers of corneal endothelial cells, macular thickness, surgically induced corneal astigmatism and postoperative complications between the two groups of patients at 7d, 1 and 3mo after surgery were compared.RESULTS: The uncorrected visual acuity and best corrected visual acuity of patients in the small incision extracapsular excision group after 7d of surgery were better than those of the phacoemulsification group, the number of corneal endothelial cells after 7d and 1, 3mo of surgery were higher than that of the phacoemulsification group, the macular thickness after 7d and 1mo of surgery was lower than that of the phacoemulsification group, and the incidence rate of postoperative corneal edema and incidence rate of total complications were lower than those of the phacoemulsification group(all P&#x003C;0.05). Furthermore, there was no statistical significance in the values of surgically induced corneal astigmatism after 1, 7d and 1, 3mo of surgery compared with phacoemulsification group(P&#x003E;0.05).CONCLUSION: Compared with phacoemulsification, the changes in the number of corneal endothelial cells and thickness of the macular area after small incision extracapsular excision are relatively small, visual recovery is faster, and the complications reduced.

Anthropometric measurements and their association with endothelial function and arterial stiffness of eutrophic individuals and with overweight

ABSTRACT Objective: The objective of the study was to assess the association of anthropometric measurements with endothelial function and arterial stiffness of eutrophic individuals and with overweight. Subjects and methods: A cross-sectional study was carried out with individuals with body mass index (BMI) between 18.5 kg/m² and < 30 kg/m², low to intermediate global cardiovascular risk scores, and aged ≥ 18 and < 60 years. We assessed the sociodemographic data, anthropometric variables (body weight, height, circumferences of the waist [WC], neck [NC], hip [HC], sagittal abdominal diameter [SAD], [BMI], waist-to-hip ratio [WHR], and waist-to-height ratio [WHtR]), biochemical parameters (lipid profile and nitric oxide), endothelial function (flow-mediated dilation [FMD], by ultrasound), and arterial stiffness (pulse wave velocity [PWV] and the amplification index [AIx@75] by oscillometry). Thirty-six individuals were included, 18 eutrophic and 18 with overweight, with a mean age of 37.5 ± 10.2 years, mostly at low cardiovascular risk (86.1%), female (80.6%), single (52.8%), employed with formal contracts (44.4%), and with over twelve years of education (88.9%). Results: The PWV presented positive and moderate correlation with the WC (r = 0.584; P = 0.001), WHR (r = 0.513; P = 0.001), and WHtR (r = 0.590; P = 0.001), and positive and low correlation with the NC (r = 0.372; P = 0.013) and SAD (r = 0.356; P = 0.033). Moreover, no anthropometric parameter presented a correlation with the AIx@75 or the FMD percentage in the total sample. Conclusion: Our findings show that in eutrophic individuals and with overweight the WC, WHR, WHtR, SAD, and NC were positively correlated with the PWV but not to the endothelial function in the overall sample. These are hypothesis-generating findings and they should be replicated in other studies.