Celecoxib: Antiangiogenic and Antitumoral Action / Celecoxib: Acción Antiangiogénica y Antitumoral

SUMMARY: Angiogenesis, a process by which new blood vessels are generated from pre-existing ones, is significantly compromised in tumor development, given that due to the nutritional need of tumor cells, pro-angiogenic signals will be generated to promote this process and thus receive the oxygen and nutrients necessary for its development, in addition to being a key escape route for tumor spread. Although there is currently an increase in the number of studies of various anti-angiogenic therapies that help reduce tumor progression, it is necessary to conduct a review of existing studies of therapeutic alternatives to demonstrate their importance.

La angiogénesis, proceso por el cual se generan nuevos vasos sanguíneos a partir de otros preexistentes, se encuentra comprometida de forma importante en el desarrollo tumoral, dado que por necesidad nutritiva de las células tumorales se generarán señales pro angiogénicas para promover este proceso y así recibir el oxígeno y los nutrientes necesarios para su desarrollo, además de ser una ruta de escape clave para la diseminación tumoral. Si bien, actualmente existe un aumento en la cantidad de estudios de diversas terapias anti angiogénicas que ayudan a reducir el avance tumoral, es necesario realizar una revisión de los estudios existentes de alternativas terapéuticas para demostrar su importancia.

Is there a relationship between the first-day results of anti-VEGF therapy for macular edema due to vascular diseases and longterm outcomes? / Há alguma relação entre os resultados do primeiro dia de terapia anti-VEGF para edema macular devido a doenças vasculares e o resultado a longo prazo?

ABSTRACT Purpose: To evaluate early changes after the first antivascular endothelial growth factor injection for macular edema secondary to diabetic retinopathy and retinal vein occlusion and the relationship between longterm outcomes. Methods: The study enrolled patients who received anti-vascular endothelial growth factor injections for treatment-naive macular edema due to retinal vein occlusion and diabetic retinopathy. The central macular thickness was measured at baseline, post-injection day 1, week 2, and month 1, and at the last visit using spectral-domain optical coherence tomography. A good response was defined as a central macular thickness reduction of ≥10% on post-injection day 1. Patients were reassessed at the last visit with regard to treatment response on post-injection day 1 based on the favorable anatomic outcome defined as a central macular thickness <350 µm. Results: In total, 26 (44.8%) patients had macular edema-retinal vein occlusion and 32 (55.2%) had macular edema-diabetic retinopathy. The mean follow-up time was 24.0 (SD 8.5) months. A statistically significant decrease in the central macular thickness was observed in both patients with macular edema-retinal vein occlusion and macular edema-diabetic retinopathy after antivascular endothelial growth factor injection therapy (p<0.001 for both). All patients with macular edema-retinal vein occlusion were good responders at post-injection day 1. All nongood responders at post-injection day 1 belong to the macular edema-diabetic retinopathy group (n=16.50%). The rate of hyperreflective spots was higher in nongood responders than in good responders of the macular edema-diabetic retinopathy group (p=0.03). Of 42 (2.4%) total good responders, one had a central macular thickness >350 µm, whereas 5 (31.2%) of 16 total nongood responders had a central macular thickness >350 µm at the last visit (p=0.003). Conclusion: The longterm anatomical outcomes of macular edema secondary to retinal vein occlusion and diabetic retinopathy may be predicted by treatment response 1 day after antivascular endothelial growth factor injection.

RESUMO Objetivo: Avaliar as alterações precoces após a primeira injeção de anticorpos antifator de crescimento endotelial vascular (anti-VEGF) em casos de edema macular secundário à retinopatia diabética e oclusão da veia da retina e a relação entre essas alterações e o resultado a longo prazo. Métodos: Foram incluídos no estudo pacientes que receberam uma injeção de antifator de crescimento endotelial vascular para edema macular, virgem de tratamento e devido à oclusão da veia retiniana ou a retinopatia diabética. A espessura macular central foi medida no início do tratamento e no 1º dia, 2ª semana e 1º mês após a injeção, bem como na última visita, através de tomografia de coerência óptica de domínio espectral. Definiu-se uma "boa resposta" como uma redução ≥10% na espessura macular central no 1º dia após a injeção. Os pacientes foram reavaliados na última visita com relação à resposta ao tratamento no 1º dia após a injeção, com base em um resultado anatômico favorável, definido como uma espessura macular central <350 µm. Resultado: Foram registrados 26 (44,8%) pacientes com edema macular e oclusão da veia da retina e 32 (55,2%) com edema macular e retinopatia diabética. O tempo médio de acompanhamento foi de 24,0 meses (desvio-padrão de 8,5 meses). Foi observada uma diminuição estatisticamente significativa da espessura macular central após o tratamento antifator de crescimento endotelial vascular tanto em pacientes com edema macular e oclusão da veia retiniana quanto naqueles com edema macular e retinopatia diabética (p<0,001 para ambos). Todos os pacientes com edema macular e oclusão da veia retiniana responderam bem no 1º dia pós-injeção. Todos os que responderam mal no 1º dia pós-injeção pertenciam ao grupo com edema macular e retinopatia diabética (n=16,50%). A presença de manchas hiperrefletivas foi maior nos pacientes que responderam mal do que naqueles que tiveram boa resposta no grupo com edema macular e retinopatia diabética (p=0,03). Um dos 42 (2,4%) pacientes com boa resposta total teve espessura macular central >350 um, enquanto 5 (31,2%) do total de 16 pacientes com resposta ruim apresentaram espessura macular central >350 µm na última visita (p=0,003). Conclusão: O resultado anatômico de longo prazo do edema macular secundário à oclusão da veia retiniana e à retinopatia diabética pode ser previsto pela resposta ao tratamento no 1º dia após a injeção de antifator de crescimento endotelial vascular.

Antiangiogenic activity of photobiomodulation in experimental model using chorioallantoic embryonic membrane of chicken eggs / Atividade antiangiogênica da fotobiomodulação em modelo experimental usando membrana embrionária corioalantóide de ovos de galinhas

ABSTRACT Purpose: The purpose of this study was to investigate the vascular effects of photobiomodulation using a light-emitting diode on the chorioallantoic embryonic membrane of chicken eggs grouped into different times of exposure and to detect the morphological changes induced by the light on the vascular network architecture using quantitative metrics. Methods: We used a phototherapy device with light-emitting diode (670 nm wavelength) as the source of photobiomodulation. We applied the red light at a distance of 2.5 cm to the surface of the chorioallantoic embryonic membrane of chicken eggs in 2, 4, or 8 sessions for 90 s and analyzed the vascular network architecture using AngioTool software (National Cancer Institute, USA). We treated the negative control group with 50 μl phosphate-buffered-saline (pH 7.4) and the positive control group (Beva) with 50 μl bevacizumab solution (Avastin, Produtos Roche Químicos e Farmacêuticos, S.A., Brazil). Results: We found a decrease in total vessel length in the Beva group (24.96% ± 12.85%) and in all the groups that received 670 nm red light therapy (2× group, 34.66% ± 8.66%; 4× group, 42.42% ± 5.26%; 8× group, 38.48% ± 6.96%), compared with the negative control group. The fluence of 5.4 J/cm2 in 4 sessions (4×) showed more regular vessels. The number of junctions in the groups that received a higher incidence of 670 nm red light (4× and 8×) significantly decreased (p<0.0001). Conclusion: Photo-biomodulation helps reduce vascularization in chorioallantoic embryonic membrane of chicken eggs and changes in the network architecture. Our results open the possibility of future clinical studies on using this therapy in patients with retinal diseases with neovascular components, especially age-related macular degeneration.

RESUMO Objetivo: investigar os efeitos vasculares da foto-biomodulação com diodo emissor de luz utilizando membrana embrionária corioalantóide de ovos de galinhas em grupos com diferentes tempos de exposição e detectar as alterações morfológicas por meio de métricas quantitativas promovidas pela luz na arquitetura da rede vascular. Métodos: Um aparelho de fototerapia com diodo emissor de luz no comprimento de onda de 670 nm foi usado como fonte de fotobiomodulação. A luz vermelha foi aplicada a uma distância de 2,5 cm da superfície da membrana embrionária corioalantóide em 2, 4 ou 8 sessões de 90 s a arquitetura da rede vascular foi analisada por meio do software AngioTool (National Cancer Institute, USA). Usamos um grupo controle negativo tratado com 50 µL de solução salina tamponada com fosfato (PBS) pH 7,4 e um grupo controle positivo (Beva) tratado com 50 µL de solução de bevacizumabe (Avastin, Produtos Roche Químicos e Farmacêuticos S.A., Brasil). Resultados: Uma diminuição no comprimento total do vaso foi detectada para o grupo Beva (24,96 ± 12,85%), e para todos os grupos que receberam terapia de luz vermelha de 670 nm, 34,66 ± 8,66% (2x), 42,42 ± 5,26% (4x) e 38,48 ± 6,96% (8x) em comparação ao grupo controle. A incidência de 5,4 J/cm2 em 4 sessões (4x) mostrou vasos mais regulares. A redução foi mais intensa nos grupos que receberam maior incidência de luz vermelha de 670 nm (4x e 8x). Conclusão: A fotobiomodulação contribui para a redução da vascularização nos vasos da membrana embrionária corioalantóide de ovos de galinhas e mudanças na arquitetura da rede. Os achados deste experimento abrem a possibilidade de considerar um estudo clínico usando esta terapia em pacientes com doenças retinais com componentes neovasculares, especialmente degeneração macular relacionada à idade.

Profile of patients treated with intravitreal antiangiogenics in a Brazilian public service with high level of complexity / Perfil de pacientes tratados com antiangiogênicos intravítreo em serviço público brasileiro de alto nível de complexidade

ABSTRACT Purpose: Intravitreal antiangiogenic therapy is currently the most invasive ophthalmic procedure performed worldwide. This study aimed to describe the clinical and epidemiological profile of patients undergoing intravitreal antiangiogenic therapy in a tertiary referral hospital in Brazil. Methods: This cross-sectional, retrospective, and observational study analyzed medical records of patients who received intravitreal injections of antiangiogenic agents for the treatment of retinal diseases at the ophthalmology outpatient clinic in the Hospital das Clínicas at Unicamp between January and December 2020. Results: The study included 429 patients and 514 eyes. The study population was predominantly male (51.28%), white (80.89%), between 50 and 80 years old (mean age, 60.92 years), had complete or incomplete first-grade education (56.88%), and did not belong to the Regional Health Department of which Campinas is a part (78.55%). Bevacizumab was the most commonly used intravitreal injectable medicine (79.38%), pro re nata was the most commonly used treatment regimen (90.27%), and macular edema was the most prevalent pathology indicative of treatment (60.12%), with diabetes etiology accounting for 48.25%. The average number of injections per patient was 3.83, with the macular neovascularization group and the pro re nata group having the highest and lowest with five and three injections, respectively. Treatment adherence was associated with the patient's pathology, and the macular edema (52.24%) and macular neovascularization (49.48%) groups had the lowest adherence rates. Conclusions: This study evaluated the epidemiological and clinical profile of patients undergoing antiangiogenic therapy in a high-complexity public hospital, which is fundamental for a better understanding of the demand for ophthalmic reference service in Brazil, and the analysis of functional results and user adherence profile promotes optimization of indications and leverages the benefits of intravitreal therapy.

RESUMO Objetivo: A terapia antiangiogênica intravítrea revolucionou o tratamento de inúmeras patologias de relevância global, sendo atualmente o procedimento oftalmológico invasivo mais realizado no mundo. Objetiva-se no presente estudo descrever o perfil clínico e epidemiológico dos pacientes submetidos a terapia intravítrea com antiangiogênicos em hospital terciário de referência no Brasil. Métodos: Trata-se de um estudo transversal, retrospectivo e observacional que foi realizado através da análise de prontuários de pacientes submetidos a injeção intravítrea de antiangiogênicos para tratamento de doenças retinianas no ambulatório de oftalmologia do Hospital das Clínicas da Unicamp no período de janeiro a dezembro de 2020. Resultados: O estudo analisou 429 pacientes e 514 olhos. A maioria pertencia ao sexo masculino (51,28%), raça branca (80,89%), possuía entre 50-80 anos com idade média de 60,92 anos e escolaridade de 1º grau completo ou incompleto (56,88%) e não pertenciam (78,55%) a área de abrangência do Departamento Regional de Saúde do qual Campinas faz parte. O fármaco mais utilizado nas injeções intravítreas foi o bevacizumabe (79,38%), o principal regime de tratamento foi o pro re nata (90,27%) e a principal grupo de patologia indicativa de tratamento foi o edema macular (60,12%), sendo 48,25% desses de etiologia diabética. A média de injeções foi de 3,83/paciente, sendo o grupo de neovascularização macular o de maior mediana com 5 injeções/paciente e o esquema pro re nata o regime de tratamento com menor mediana, 3 injeções/paciente. A adesão ao tratamento associou-se a patologia do paciente, sendo as menores taxas de adesão as dos grupos com edema macular (52,24%) e neovascularização macular (49,48%). Conclusões: O presente estudo avaliou o perfil epidemiológico e clínico dos pacientes submetidos a terapia antiangiogênica em hospital público de alta complexidade, o que é fundamental para melhor conhecimento da demanda de serviço oftalmológico de referência no Brasil e possibilita, a partir da análise dos resultados funcionais e perfil de adesão dos usuários, otimizar as indicações e alavancar os benefícios de terapia intravítrea.

Research progress on the mechanisms of microglia in retinal angiogenesis / 国际眼科杂志(Guoji Yanke Zazhi)

As resident immune cells of the retina, retinal microglia constantly monitor the changes of their surroundings and maintain homeostasis through signal transduction with other retinal cells. Retinal microglia play a crucial role not only in the development and physiological processes of the retinal vascular system, but also in pathological neovascularization. In certain retinopathies, activated microglia can stimulate abnormal angiogenesis through neurovascular coupling, leading to irreversible damage. However, the exact mechanisms underlying this process are still unclear. In this review, a brief overview of the relationship between microglia and retinal neovascularization was provided, and the involved cellular and molecular signaling mechanisms were reviewed, aiming to offer new and effective strategies for the prevention and treatment of retinal neovascularization diseases.

Inhibition of HSP70 release by geniposide improves angiogenesis in moist heat arthralgia spasm syndrome collagen induced arthritis rats / 中国药理学通报

Aim To investigate the relation between the effect of geniposide (GE) in improving angiogenesis in arthralgia spasm syndrome collagen induced arthritis (CIA) rats and the modulation of heat shock proteins 70 (HSP70) release. Methods A CIA model was constructed by multiple intradermal injections of complete Freund's adjuvant (CFA) and an equal volume mixture of chicken type II collagen (CCII) into the dorsal and caudal root regions of rats, on the basis of which a rheumatic fever stimulus was given to build up a moist heat arthralgia spasm syndrome in CIA rats. After successful modeling, the groups were randomly grouped, and the administered groups were gavaged with GE (60, 120 mg · kg

Application progress of mesenchymal stem cells in islet transplantation for type 1 diabetes mellitus / 器官移植

Islet transplantation is considered as one of the most effective approach for type 1 diabetes mellitus, although its efficacy is limited by several factors. Anoxia, stress and rejection occurring during the isolation, culturing and transplantation of islets may have impact on the outcome of the islet transplantation. Due to the biological properties such as anti-inflammation, angiogenetic promotion and immune regulation, mesenchymal stem cells (MSCs) are all the way focused by researchers. Additionally, exosome, a derivative of MSC, also plays an import role in regulating anoxia-induced oxidative stress modulation, angiogenetic promotion, and immune regulation. MSC-based islet transplantation may be a useful therapeutic tool in treating type 1 diabetes. Therefore, in this review, the potential effect of MSC prior and posterior to the operation of the islet transplantation, its clinical application as well as its limitations were reviewed, aiming to offer insights into the future application of islet transplantation in treating type 1 diabetes.

Bioceramic scaffolds with two-step internal/external modification of copper-containing polydopamine enhance antibacterial and alveolar bone regeneration capability / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Magnesium-doped calcium silicate (CS) bioceramic scaffolds have unique advantages in mandibular defect repair; however, they lack antibacterial properties to cope with the complex oral microbiome. Herein, for the first time, the CS scaffold was functionally modified with a novel copper-containing polydopamine (PDA(Cu2+‍)) rapid deposition method, to construct internally modified (*P), externally modified (@PDA), and dually modified (*P@PDA) scaffolds. The morphology, degradation behavior, and mechanical properties of the obtained scaffolds were evaluated in vitro. The results showed that the CS*P@PDA had a unique micro-/nano-structural surface and appreciable mechanical resistance. During the prolonged immersion stage, the release of copper ions from the CS*P@PDA scaffolds was rapid in the early stage and exhibited long-term sustained release. The in vitro evaluation revealed that the release behavior of copper ions ascribed an excellent antibacterial effect to the CS*P@PDA, while the scaffolds retained good cytocompatibility with improved osteogenesis and angiogenesis effects. Finally, the PDA(Cu2+)-modified scaffolds showed effective early bone regeneration in a critical-size rabbit mandibular defect model. Overall, it was indicated that considerable antibacterial property along with the enhancement of alveolar bone regeneration can be imparted to the scaffold by the two-step PDA(Cu2+) modification, and the convenience and wide applicability of this technique make it a promising strategy to avoid bacterial infections on implants.

Inverse correlation of CD3 & vascular endothelial growth factor in incisional oral squamous cell carcinoma biopsies predicts nodal metastasis & poor survival of patients

Background & objectives: Oral squamous cell carcinoma (OSCC) is widely prevalent in the Indian subcontinent mainly due to habit-associated aetiologies. Immune regulation and angiogenesis are the part of tumourigenesis that play a crucial role in metastasis and survival. However, the concurrent expression of vascular endothelial growth factor (VEGF) and CD3 (immune regulator receptor on T-lymphocyte) in the same OSCC tissue samples has not been reported in the Indian population. The present study evaluated the expression of CD3+ T-cells and VEGF in OSCC tissue samples and studied the clinicopathological correlation and survival analysis in an Indian population. Methods: This was a retrospective study conducted on 30 formalin-fixed and paraffin embedded sections which were histologically diagnosed as OSCC cases comprising of 15 metastatic OSCC and 15 non- metastatic OSCC with available clinical data and survival status. Results: Reduced expression of CD3+ T-cells and increased VEGF expression were observed in metastatic OSCC samples. The correlation of expression of CD3+ T-cells and VEGF with clinicopathological parameters showed a significant association between these markers with age, nodal status, site of the lesion and survival. Interpretation & conclusions: Reduced expression of CD3+ T-cells in OSCC was found to be associated with a significantly poor survival. VEGF was found to be over expressed in metastatic OSCC as compared to that in non-metastatic OSCC. The study findings suggest that the evaluation of CD3 and VEGF in incisional OSCC biopsies can be considered for predicting the survival outcome and metastasis

Prospective evaluation of the effectiveness of combined treatment of macular edema secondary to retinal vein occlusion with intravitreal bevacizumab and dexamethasone implants / Estudo intervencionista prospectivo para avaliar a eficácia da associação do bevacizumabe intravítreo ao implante de dexametasona para edema macular secundário à oclusão da veia retiniana

ABSTRACT Purpose: To evaluate the effectiveness of in­­­travitreal bevacizumab injections following a single dexamethasone implant in the treatment of macular edema secondary to branch and central retinal vein occlusion. Methods: This was a prospective interventional non-comparative study, 44 eyes of patients with naïve macular edema related to branch and central retinal vein occlusion were treated with a dexamethasone implant. Patients were followed-up at four-week intervals from the second to the sixth month. If persistent or recurrent macular edema occurred during this period, the patient was treated with intravitreal bevacizumab injections on an as-needed basis. The outcome measures were best-corrected visual acuity and central macular thickness changes. Results: The mean best-corrected visual acuity changed from 0.97 ± 0.33 LogMAR at baseline to 0.54 ± 0.40 at the six-month post-implant examination (p<0.00001). Improvement ≥3 Snellen lines were seen in 20 eyes (45.54%). The mean central macular thickness at baseline was 670.25 ± 209.9 microns. This had decreased to 317.43 ± 112.68 microns at the six-month follow-up (p<0.00001). The mean number of intravitreal bevacizumab injections received in the six months post-implant was 2.32. The mean time from dexamethasone implant to first anti-VEGF injection was 3.45 months. Conclusions: Intravitreal bevacizumab injections following a single dexamethasone implant were found to improve best-corrected visual acuity and central macular thickness in patients with macular edema due to branch and central retinal vein occlusion at six months, with few intravitreal injections required.

RESUMO Objetivo: Avaliar a eficácia da combinação de in­jeções intravítreas de bevacizumabe em olhos com edema macular secundário à oclusão de ramo e da veia central da retina após um único implante de dexametasona. Métodos: Foi realizado um estudo prospectivo intervencionista não comparativo com 44 olhos de pacientes com edema macular relacionado à oclusão de ramo e veia central da retina, sem tratamento prévio e tratados com um único implante de dexametasona, que foram acompanhados em intervalos de quatro semanas do segundo ao sexto mês. Se fosse constatado edema macular persistente ou recorrente durante esse período, os pacientes eram tratados com injeções intravítreas de bevacizumabe em um regime ajustado conforme a necessidade. Foram estudadas a melhor acuidade visual corrigida e alterações da espessura macular central. Resultados: A média da melhor acuidade visual corrigida mudou de 0,97 ± 0,33 LogMAR iniciais para 0,54 ± 0,40 no exame de 6 meses (p<0,00001). Vinte olhos (45,54%) melhoraram 3 linhas de Snellen ou mais. A média da espessura macular central inicial foi de 670,25 ± 209,9 μm e diminuiu para 317,43 ± 112,68 μm na visita de 6 meses (p<0,00001). O número médio de injeções intravítreas de bevacizumabe em 6 meses foi de 2,32 e o tempo médio entre o implante de dexametasona e a primeira injeção de anti-VEGF foi de 3,45 meses. Conclusão: Injeções intravítreas de bevacizumabe após um único implante de dexametasona podem proporcionar um aumento da melhor acuidade visual corrigida e diminuição da espessura macular central aos 6 meses em pacientes com edema macular devido à oclusão de ramo e da veia central da retina, com poucas injeções intravítreas.

Activation of CTHRC1 by HOXB9 Promotes Angiogenesis through Fatty Acid Metabolism in Lung Adenocarcinoma

Abstract Background: CTHRC1 is highly expressed in various cancers. Objectives: The aim of the study was to study the role of CTHRC1 played in lung adenocarcinoma (LUAD) development and its underlying biological functions. Methods: Enriched pathways and upstream transcription factors of CTHRC1 were explored by bioinformatics analysis. Dual-luciferase assay and Chromatin immunoprecipitation assay were used to verify the binding relationship between CTHRC1 and HOXB9. CCK-8 was utilized to detect cell viability. Expression levels of CTHRC1, HOXB9, and angiogenesis-related genes were assessed by quantitative real time-polymerase chain reaction. Angiogenesis assay was used to detect angiogenesis ability. Quantitative analysis of metabolites were used to detect the accumulation of neutral lipids, the levels of free fatty acids (FAs), and glycerol. Western blot was conducted to measure expression of metabolic enzymes of FA. Results: CTHRC1 was enriched in FA metabolic pathway, which was positively correlated and bound with HOXB9. CTHRC1 and HOXB9 expression was remarkably up-regulated in LUAD cells. Overexpression of CTHRC1 promoted FA metabolic pathway and angiogenesis, and FA inhibitor Orlistat restored it to NC group level. Meanwhile, CTHRC1 affected LUAD angiogenesis by activating HOXB9 to regulate FA metabolism. Conclusions: This study found that activation of CTHRC1 by HOXB9 induces angiogenesis by mediating FA metabolism. CTHRC1 may be a potential target for LUAD diagnosis.

EGFR, VEGF, and angiogenesis promote the development of lipoma in the oral cavity

Abstract This study aimed to detect, quantify and compare the immunohistochemical expression of EGFR and VEGF and microvessel count (MVC) in oral lipomas, and to correlate the findings with clinical and morphological characteristics of the cases studied. The sample consisted of 54 oral lipomas (33 classic and 21 non-classic) and 23 normal adipose tissue specimens. Cytoplasmic and/or nuclear immunohistochemical staining of EGFR and VEGF was analyzed. The angiogenic index was determined by MVC. Cells were counted using the Image J® software. The Statistical Package for the Social Sciences was used for data analysis, adopting a level of significance of 5% for all statistical tests. A statistically significant difference in EGFR immunoexpression (p=0.047), especially, between classic lipomas and normal adipose tissue. There was a significant difference in MVC between non-classic lipomas and normal adipose tissue (p=0.022). In non-classic lipomas, only VEGF immunoexpression showed a significant moderate positive correlation (r=0.607, p=0.01) with MVC. In classic lipomas, the number of EGFR-immunostained adipocytes was directly proportional to the number of VEGF-positive cells, demonstrating a significant moderate positive correlation (r=0.566, p=0.005). The results suggest that EGFR, VEGF, and angiogenesis participate in the development of oral lipomas but are not primarily involved in the growth of these tumors.

Resumo Lipomas são as neoplasias mesenquimais benignas mais comuns, no entanto sua etiopatogenia ainda permanece desconhecida. Dessa forma, essa pesquisa teve como objetivo detectar, quantificar e comparar a expressão imunoistoquímica do EGFR, VEGF e contagem microvascular (MVC) dos lipomas orais, relacionando-os com as características clínicas e morfológicas dos casos estudados. A amostra foi composta por 54 lipomas orais (33 clássicos e 21 não clássicos) e 23 casos de tecido adiposo normal. A análise da expressão imunoistoquímica de EGFR e VEGF foi fundamentada na marcação citoplasmática e/ou nuclear. O índice angiogênico foi avaliado por meio da MVC. A contagem de células foi realizada utilizando software IMAGE J®. Os dados obtidos foram analisados no software Statistical Package for Social Science. O nível se significância de 5% foi adotado para os testes estatístico. A análise da imunoexpressão das proteínas revelou para o EGFR diferença estatisticamente significativa (p=0,041) entre o lipoma clássico e o tecido adiposo normal. Houve diferença significativa na MVC entre lipomas não clássicos e tecido adiposo normal (p=0,022). Nos lipomas não clássicos, apenas a imunoexpressão de VEGF apresentou correlação do tipo moderada, positiva e significativa (r=0,607; p=0,010) em relação a MVC. Ademais, nos lipomas clássicos foi percebido que os adipócitos imunomarcados para EGFR estiveram diretamente proporcionais a imunoexpressão de VEGF, apresentando correlação do tipo moderada, positiva e estatisticamente significativa (r=0,566; p = 0,005). Com base nos resultados, pode-se sugerir que o EGFR, VEGFR e MCV participam do desenvolvimento nos lipomas orais, contudo, não estão primariamente envolvidos no crescimento tumoral dessas neoplasias.

Molecular docking and cytotoxicity interactions of naringenin and its nano-structured lipid carriers in ER? positive breast cancer

Phytoestrogens are known to have beneficial properties in various carcinomas. They exhibit its efficacy at cellular levels. Naringenin a flavonoidal phytoestrogen is been explored for its antioxidant, cardio protective and cytotoxic function. The low absorbtion and poor bioavailability of naringenin makes it less efficient in targeting tumours at cellular levels. Due to the structural similarity of naringenin with estradiol and considering the affinity of naringenin with estrogen receptor, this study explores the interactions of naringenin on important signaling proteins involved in ER positive breast cancer through molecular docking studies and the prepared naringenin solid lipid nano particles were characterized and studied for its preventive potential against breast cancer cell lines. The lipidoid form of phytoestrogen shows promising cytotoxic potential compared with naringenin.

Role of SOX9 and Hif-1α expression in placentas of patients with HELLP

Purpose: In this study, we investigated the immunohistochemical staining of SRY-box transcription factor 9 (SOX9) and Hif-1α expression in placentas of pregnant woman with hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome. Methods: Placentas of 20 normotensive and 20 women with HELLP syndrome were processed for routine histological tissue processing. The biochemical and clinical parameters of patients were recorded. Placentas were stained with hematoxylin-eosin and SOX9 and Hif-1α immunostaining. Results: Normotensive placentas showed normal histology of placenta, however placentas of HELLP syndrome showed intense thrombosis, thinning of the villi membrane and vascular dilatation. In placentas of normotensive patients, SOX9 reaction was immunohistochemically negative, however placentas of HELLP group showed SOX9 expression in decidual cells, and syncytial regions of floating villi and inflammatory cells. In placentas of normotensive patients, Hif-1α reaction was mainly negative in vessels and connective tissue cells. Placentas of HELLP group showed increased Hif-1α expression in decidual cell and especially inflammatory cells in the maternal region. Conclusions: Hif-1α and SOX9 proteins can be used as a marker to show severity of preeclampsia and regulation of cell proliferation and angiogenesis during placental development.

Stem cell-derived exosomes from human exfoliated deciduous teeth promote angiogenesis in hyperglycemic-induced human umbilical vein endothelial cells

Abstract Objective To investigate the angiogenesis in human umbilical vein endothelial cells (HUVEC) under high glucose concentration, treated with exosomes derived from stem cells from human exfoliated deciduous teeth (SHED). Methodology SHED-derived exosomes were isolated by differential centrifugation and were characterized by nanoparticle tracking analysis, transmission electron microscopy, and flow cytometric assays. We conducted in vitro experiments to examine the angiogenesis in HUVEC under high glucose concentration. Cell Counting Kit-8, migration assay, tube formation assay, quantitative real-time PCR, and immunostaining were performed to study the role of SHED-derived exosomes in cell proliferation, migration, and angiogenic activities. Results The characterization confirmed SHED-derived exosomes: size ranged from 60-150 nm with a mode of 134 nm, cup-shaped morphology, and stained positively for CD9, CD63, and CD81. SHED-exosome significantly enhanced the proliferation and migration of high glucose-treated HUVEC. A significant reduction was observed in tube formation and a weak CD31 staining compared to the untreated-hyperglycemic-induced group. Interestingly, exosome treatment improved tube formation qualitatively and demonstrated a significant increase in tube formation in the covered area, total branching points, total tube length, and total loop parameters. Moreover, SHED-exosome upregulates angiogenesis-related factors, including the GATA2 gene and CD31 protein. Conclusions Our data suggest that the use of SHED-derived exosomes potentially increases angiogenesis in HUVEC under hyperglycemic conditions, which includes increased cell proliferation, migration, tubular structures formation, GATA2 gene, and CD31 protein expression. SHED-exosome usage may provide a new treatment strategy for periodontal patients with diabetes mellitus.

Dill seed oil as a possible contraceptive agent: antiangiogenic effects on endothelial cells

Abstract Dill (Anethum graveolens L.) essential oil is wide spread in the food, beverage and pharmaceutical sectors. Dill is a member of the Apiaceae (Umbelliferae) family. It has the following biological activities: antioxidant, antifungal, antibacterial, antimicrobial, antihyperlipidemic, antihypercholesterolemic, antispasmodic, antiproliferative and anti-inflammatory. Aqueous extract of dill seed has reported effects on sex hormones and infertility potential. Moreover, boiled dill seed has an impact on reducing labor duration in giving birth. Implantation and placentation are necessary for a healthy pregnancy in the early stages. Angiogenesis is responsible for these essential processes. This study aimed to investigate dill seed oil's cytotoxic and antiangiogenic effects on rat adipose tissue endothelial cells (RATECs). Dill seed oil showed dose-dependent cytotoxicity on RATECs. It disrupted endothelial tube formation and depolymerized F-actin stress fibers. According to this study, depolymerization of F-actin stress fiber by dill seed oil could inhibit angiogenesis by suppressing endothelial cell proliferation, tube formation and motility. In other words, dill seed oil can be a new anti-angiogenic agent and a novel contraceptive.

Study on the effects and mechanism of luteolin on osteogenic repair of bone defects / 中国药房

OBJECTIVE To investigate the effects and mechanism of luteolin on osteogenic repair of bone defects. METHODS The targets and potential pathways of luteolin in the treatment of bone defects were screened by network pharmacology method， and then the top 2 targets were selected by Hub gene screening for molecular docking verification， with binding energy as the evaluation standard. In vitro experiments were conducted on rat bone mesenchymal stem cells （BMSC） and rat umbilical vein endothelial cells （RUVEC）. Phenotypic validation was performed using alkaline phosphatase staining， alizarin red S staining， and in vitro angiogenesis experiments. Western blot assay was used to detect the protein expressions of phosphatidylinositol 3 kinase （PI3K） and protein kinase 1 （Akt1）， so as to validate the mechanism of luteolin on osteogenic differentiation of BMSC and angiogenesis of RUVEC in vitro. RESULTS The results of network pharmacology showed that the effects of luteolin on vascular formation and bone repair in bone defects were mainly related to Akt1， SRC， estrogen receptor 1， epidermal growth factor receptor， cyclooxygenase 2， matrix metalloproteinase 9 targets， and were closely related to PI3K-Akt signaling pathway. The results of molecular docking showed that luteolin binding to Akt1 and SRC proteins was stable. The results of in vitro experiments showed that luteolin could significantly improve the expressions and activities of alkaline phosphatase in BMSC， increased the number of calcium salt deposits and calcified nodules， and promoted calcification of BMSC. Compared with luteolin 0 μmol/L group， the angiogenesis ability of RUVEC was enhanced significantly in luteolin 1， 10 μmol/L groups， the length of blood vessels and the protein expressions of PI3K and Akt1 were significantly increased （P＜0.05 or P＜0.01）； the higherthe concentration， the better the effect. CONCLUSIONS Luteolin may play a role in promoting angiogenesis and bone repair at the fracture site by activating PI3K/Akt signaling pathway and promoting the protein expressions of PI3K and Akt1.

Clinical analysis and curative effect of reactivation of retinopathy of prematurity after intravitreous injection of ranibizumab / 中华眼底病杂志

Objective:To observe the clinical characteristics and therapeutic effect of reactivation of retinopathy of prematurity (ROP) patients after intravitreal injection of ranibizumab (IVR).Methods:A retrospective case series study. Eleven children with ROP (21 eyes) who were reactivated after IVR in Shenzhen Eye Hospital from January 2019 to October 2021 were included in the study. Among them, there were 6 males (11 eyes) and 5 females (10 eyes), with the gestational age of (27.6±2.2) weeks and birth weight of (1 034.6±306.5) g. At the first IVR treatment, 14 eyes (63.7%, 14/22) had acute ROP (AROP), 8 eyes (36.3%, 8/22) had threshold lesions. Post-reactivation treatments include IVR, retinal laser photocoagulation (LP), or minimally invasive vitrectomy (MIVS). The follow-up time after treatment was 12 to 18 months. Birth gestational age, birth weight, treatment method, corrected gestational age at treatment, lesion stage before and after treatment, lesion reactivation and regression time were recorded. The clinical characteristics and efficacy were observed and analyzed.Results:The time from initial IVR treatment to reactivation was (8.2±3.5) weeks. The corrected gestational age of the child was (43.62±4.08) weeks. In 21 eyes, AROP, threshold lesion, prethreshold lesion, and stage 4 lesion were in 2, 4, 12, and 3 eyes, respectively. The patients were treated with IVR, LP, IVR+LP, IVR+MIVS in 2, 13, 4 and 2 eyes, respectively. After the first reactivation treatment, the time of regression and stability was (8.4±4.9) weeks after treatment. There were 5 eyes with secondary reactivation of the lesion, and the lesion stages were stage 3, stage 4a and stage 5 in 2, 1 and 2 eyes, respectively. The mean reactivation time was (19.3±6.0) weeks after the last treatment. The patients in stage 3, stage 4a and stage 5 were treated with LP, LP+MIVS and IVR, respecitively, and the lesions subsided steadily during follow-up. At the last follow-up, 19 out of 21 eyes showed complete regression of the lesions, stable photocoagulation, regression of crista-like lesions, no additional lesions, and retinal leveling. All retinal detachment was "funnel-shaped" in 2 eyes.Conclusions:The lesion reactivation of AROP after IVR treatment is more common. The early reactivation rate is higher after treatment. There is a possibility of reactivation twice after re-treatment.

Clinical characteristics and effect of anti-vascular endothelial growth factor therapy in retinopathy of prematurity in Sichuan province / 中华眼底病杂志

Objective:To analyze the clinical characteristics and evaluate the effect and safety of anti-vascular endothelial growth factor (VEGF) therapy in retinopathy of prematurity (ROP) in Sichuan province.Methods:A retrospective study. From January 2013 to January 2022, 156 patients (306 eyes) with ROP who received intravitreal anti-VEGF therapy for the first time in the Department of Ophthalmology, West China Hospital of Sichuan University were selected. According to the type of anti-VEGF drugs, the children were divided into intravitreal injection of ranibizumab (IVR) group and intravitreal injection of conbercept (IVC) group; IVC group was divided into hospital group and referral group according to the different paths of patients. After treatment, the patients were followed up until the disease degenerated (vascular degeneration or complete retinal vascularization) or were hospitalized again for at least 6 months. If the disease recurred or progressed, the patients were re-admitted to the hospital and received anti-VEGF drug treatment, laser treatment or surgical treatment according to the severity of the disease. Clinical data of these children was collected, including general clinical characteristics: gender, gestational age at birth (GA), birth weight (BW), history of oxygen inhalation; pathological condition: ROP stage, zone, whether there were plus lesions; treatment: treatment time, postmenstrual gestational age at the time of the first anti-VEGF drug treatment; prognosis: re-treat or not, time of re-treatment, mode of re-treatment; adverse events: corneal edema, lens opacity, endophthalmitis, retinal injury, and treatment-related systemic adverse reactions. The measurement data between groups were compared by t test, and the count data were compared by χ2 test or rank sum test. Results:Of the 306 eyes of 156 children with ROP, 74 were male (47.44%, 74/156) and 82 were female (52.56%, 82/156). Each included child had a history of oxygen inhalation at birth. The GA was (28.43±2.19) (23.86-36.57) weeks, BW was (1 129±335) (510-2 600) g, and the postmenstrual gestational age was (39.80±3.04) (31.71-49.71) weeks at the time of the first anti-VEGF drug treatment. All patients were diagnosed as type 1 ROP, including 26 eyes (8.50%, 26/306) of aggressive ROP (A-ROP), 39 eyes (12.74%, 39/306) of zone Ⅰ lesions, and 241 eyes (78.76%, 241/306) of zone Ⅱ lesions. The children were treated with intravitreal injection of anti-VEGF drugs within 72 hours after diagnosis. Among them, 134 eyes (43.79%, 134/306) of 68 patients were treated with IVR, and 172 eyes (56.21%, 172/306) of 88 patients were treated with IVC. In IVC group, 67 eyes of 34 patients (38.95%, 67/172) were in the hospital group and 105 eyes of 54 patients (61.05%, 105/172) were in the referral group. 279 eyes (91.18%, 279/306) were improved after one treatment, 15 eyes (4.90%, 15/306) were improved after two treatments, and 12 eyes (3.92%, 12/306) were improved after three treatments. The one-time cure rate of IVR group was lower than that of IVC group, but the difference was not statistically significant ( χ2=1.665, P=0.197). In different ROP categories, IVC showed better therapeutic effect in A-ROP, and its one-time cure rate was higher than that in IVR group, with statistically significant difference ( χ2=7.797, P<0.05). In the hospital group of IVC group, the GA, BW and the postmenstrual gestational age at first time of anti-VEGF drug treatment were lower than those in the referral group, and the difference was statistically significant ( t=-2.485, -2.940, -3.796; P<0.05). The one-time cure rate of the hospital group and the referral group were 94.94%, 92.38%, respectively. The one-time cure rate of the hospital group was slightly higher than that of the referral group, but the difference was not statistically significant ( χ2=0.171, P=0.679). In this study, there were no ocular and systemic adverse reactions related to drug or intravitreal injection in children after treatment. Conclusions:Compared with the characteristics of ROP in developed countries, the GA, BW and postmenstrual gestational age of the children in Sichuan province are higher. Both IVR and IVC can treat ROP safely and effectively. There is no significant difference between the two drugs in the overall one-time cure effect of ROP, but IVC performed better in the treatment of A-ROP in this study.

Keypoints in Evidence-based guidelines for diagnosis and treatment of diabetic retinopathy in China (2022) / 中华眼底病杂志

Evidence-based guidelines for diagnosis and treatment of diabetic retinopathy in China (2022) is based on evidences in recent clinical trials and a system of Grading of Recommendations, Assessment, Development and Evaluation of evidence quality and strength of recommendations. The main key points around why the diabetic macular edema (DME) changes the classification, what thresholds for initiating anti-vascular endothelial growth factor (VEGF) drug therapy; eyes with center-involved DME (CI-DME) and good vision for clinical significant macular edema still treated by focal laser even with good vision, the clinical pathway for CI-DME changes first-line treatment from laser to anti-VEGF, loading dose of anti-VEGF for CI-DME in non-proliferative diabetic retinopathy (DR) from 3 injections up to 4-5 injections is recommended; severe non-proliferative DR and proliferative DR with vision impairment but without hemorrhages and retinal traction could be considered first treatment of anti-VEGF comparing to initiate pan-retinal photocoagulation (PRP) (weakly recommended), PRP is still gold-standard for progressive non-perfusion area of retina. With the rapid development of DR evaluation devices such as optical coherence tomography, wide-angle optical coherence tomography angiography and wide-angle fluorescein fundus angiography, imaging biomarkers have been provided for the degree of DR lesion, treatment response and prognosis. It is believed that the clinical practice will be promoted a new height by the 2022 edition of Chinese DR guideline.