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.

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.

Exosomes derived from Nr-CWS pretreated MSCs facilitate diabetic wound healing by promoting angiogenesis via the circIARS1/miR-4782-5p/VEGFA axis / 中国天然药物

Mesenchymal stem cell (MSC)-derived exosomes (Exos) were reported to a prospective candidate in accelerating diabetic wound healing due to their pro-angiogenic effect. MSCs pretreated with chemistry or biology factors were reported to advance the biological activities of MSC-derived exosomes. Hence, this study was designed to explore whether exosomes derived from human umbilical cord MSCs (hucMSCs) preconditioned with Nocardia rubra cell wall skeleton (Nr-CWS) exhibited superior proangiogenic effect on diabetic wound repair and its underlying molecular mechanisms. The results showed that Nr-CWS-Exos facilitated the proliferation, migration and tube formation of endothelial cells in vitro. In vivo, Nr-CWS-Exos exerted great effect on advancing wound healing by facilitating the angiogenesis of wound tissues compared with Exos. Furthermore, the expression of circIARS1 increased after HUVECs were treated with Nr-CWS-Exos. CircIARS1 promoted the pro-angiogenic effects of Nr-CWS-Exos on endothelial cellsvia the miR-4782-5p/VEGFA axis. Taken together, those data reveal that exosomes derived from Nr-CWS-pretreated MSCs might serve as an underlying strategy for diabetic wound treatment through advancing the biological function of endothelial cells via the circIARS1/miR-4782-5p/VEGFA axis.

Kunxian Capsule Extract Inhibits Angiogenesis in Zebrafish Embryos via PI3K/AKT-MAPK-VEGF Pathway / 中国结合医学杂志

OBJECTIVE@#To investigate the anti-angiogenic activity of Kunxian Capsule (KX) extract and explore the underlying molecular mechanism using zebrafish.@*METHODS@#The KX extract was prepared with 5.0 g in 100 mL of 40% methanol followed by ultrasonication and freeze drying. Freeze dried KX extract of 10.00 mg was used as test stock solution. Triptolide and icariin, the key bioactive compounds of KX were analyzed using ultra-high performance liquid chromatography. The transgenic zebrafish Tg(flk1:GFP) embryos were dechorionated at 20-h post fertilization (hpf) and treated with PTK 787, and 3.5, 7, 14 and 21 µg/mL of KX extract, respectively. After 24-h post exposure (hpe), mortality and malformation (%), intersegmental vessels (ISV) formation, and mRNA expression level of angiogenic pathway genes including phosphoinositide 3-kinase (PI3K), protein kinase B (AKT), extracellular signal-regulated kinases (ERKs), mitogen-activated protein kinase (MAPK), vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF-2) were determined. Further, the embryos at 72 hpf were treated with KX extract to observe the development of sub-intestinal vein (SIV) after 24 hpe.@*RESULTS@#The chromatographic analysis of test stock solution of KX extract showed that triptolide and icariin was found as 0.089 mg/g and 48.74 mg/g, respectively, which met the requirements of the national drug standards. In zebrafish larvae experiment, KX extract significantly inhibited the ISV (P<0.01) and SIV formation (P<0.05). Besides, the mRNA expression analysis showed that KX extract could significantly suppress the expressions of PI3K and AKT, thereby inhibiting the mRNA levels of ERKs and MAPK. Moreover, the downstream signaling cascade affected the expression of VEGF and its receptors (VEGFR and VEGFR-2). FGF-2, a strong angiogenic factor, was also down-regulated by KX treatment in zebrafish larvae.@*CONCLUSION@#KX extract exhibited anti-angiogenic effects in zebrafish embryos by regulating PI3K/AKT-MAPK-VEGF pathway and showed promising potential for RA treatment.

The action mechanism of glioblastoma cell-derived exosome: a review / 生物工程学报

Patients with glioblastoma (GBM) generally have a bad prognosis and short overall survival after being treated with surgery, chemotherapy or radiotherapy due to the histological heterogeneity, strong invasive ability and rapid postoperative recurrence of GBM. The components of GBM cell-derived exosome (GBM-exo) can regulate the proliferation and migration of GBM cell via cytokines, miRNAs, DNA molecules and proteins, promote the angiogenesis via angiogenic proteins and non-coding RNAs, mediate tumor immune evasion by targeting immune checkpoints with regulatory factors, proteins and drugs, and reduce drug resistance of GBM cells through non-coding RNAs. GBM-exo is expected to be an important target for the personalized treatment of GBM and a marker for diagnosis and prognosis of this kind of disease. This review summarizes the preparation methods, biological characteristics, functions and molecular mechanisms of GBM-exo on cell proliferation, angiogenesis, immune evasion and drug resistance of GBM to facilitate developing new strategies for the diagnosis and treatment of GBM.

Hollow copper sulfide nanoparticles loading deferoxamine for photothermal antibacterial therapy and promoting angiogenesis / 药学学报

Diabetic ulcer is recognized as a chronic nonhealing wound, often associated with bacterial infection and tissue necrosis, which seriously affect patients' health and quality of life. The traditional treatment methods exist some problems, such as bacterial resistance and secondary trauma, so it is urgent to find new methods to meet the requirements of diabetic ulcer treatment. In this study, we prepared a drug delivery system (DFO@CuS nanoparticles) based on hollow copper sulfide (CuS) nanoparticles loaded with deferoxamine (DFO), which realized the synergistic therapy of promoting angiogenesis and photothermal antibacterial. The morphological structure and particle size distribution of DFO@CuS nanoparticles were characterized by transmission electron microscopy and particle size analyzer, respectively. The antibacterial effect of DFO@CuS nanoparticles was evaluated by the plate coating method. The effects of DFO@CuS nanoparticles on the proliferation, migration, and tube formation of human umbilical vein endothelial cells (HUVECs) were evaluated by CCK-8 (cell counting kit-8) assay, cell scratch assay, and tube formation assay. The results showed that DFO@CuS nanoparticles were hollow and spherical in shape with an average particle size of (200.9 ± 8.6) nm. DFO@CuS nanoparticles could effectively inhibit the growth of methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa (PA) under near-infrared (NIR) light irradiation. DFO@CuS nanoparticles showed negligible cytotoxicity and effective acceleration of cell migration and tube formation in a certain concentration range. In conclusion, the prepared DFO@CuS nanoparticles exhibit good photothermal antibacterial properties and pro-angiogenic effects, providing a basis for their application in the treatment of diabetic ulcer.

Emerging Role of Galectins as Molecular Targets for Cancer Therapy: A Review

@#In recent decades cancer incidences and mortality rates have increased. Although there is significant progress in identifying the root causes and emerging therapies, there are many molecular, cellular mechanism’s unrevealed and current treatments have yet to deliver on their promises. Common characteristics of cancer that are controlled by various mechanisms, including those involving glycosylation-dependent proliferative signalling, the ability of tumor cells and their microenvironment to sustain proliferative signalling, enhancing the replicative immortality, evading the effects of growth suppressors, resisting apoptosis, sustaining invasion and metastasis, stimulation of angiogenesis and triggering immune response are few to name. An evolutionarily conserved family of glycan-binding proteins known as galectins has a significant impact in controlling these cascades. Galectins belong to animal lectin family that function by interacting with matrix glyco-proteins on extracellular surface and also with nuclear proteins modulating the cell signalling cascades intracellularly. In this review, we analyse how galectins influence the cellular pathways that control tumor activity, providing relevant examples and highlighting their therapeutic perspective in the fight against cancer.

Protective effect of salvianolic acid B on retina and its influence on angiogenesis in retinal vein occlusion injured rat model / 国际眼科杂志(Guoji Yanke Zazhi)

AIM: To investigate the protective effect of salvianolic acid B on retina and its influence on angiogenesis in retinal vein occlusion(RVO)injured rats.METHODS: SD rats were randomly divided into control group, model group and salvianolic acid B group, with 10 rats in each group. In addition to the control group, rats in model group and salvianolic acid B group were induced RVO by Bengal red combined with laser photodynamic method. The rats in salvianolic acid B group were intraperitoneally injected with salvianolic acid B 50 mg/(kg·d), while the rats in control group and model group were only given the same amount of normal saline for 21 consecutive days. Fundus fluorescein angiography(FFA)was used to observe the retinal vein structure before and after administration. HE staining was used to observe the pathological changes of rat retina. The retinal function of rats was evaluated by electroretinogram(ERG). The fluorescence expression of vascular endothelial growth factor A(VEGFA)in retina of rats in each group was detected by immunofluorescence staining. The relative expression of HIF-1α, STAT3, p-STAT3 and VEGFA proteins in retinal tissue were detected by Western blotting.RESULTS: Compared with the control group, the blood flow at the retinal obstruction in the model group was recanalized, and the effective collateral circulation was abundant, but the shape was irregular, and there was fluorescence leakage. In salvianolic acid B group, the retinal vein circulation recovered, the shape became regular gradually, and the collateral vessels decreased. The retina of the model group and salvianolic acid B group showed different degrees of pathological damage. At the same time, the amplitude of ERG a wave and b wave, the thickness of retinal total layer(RTL), inner nuclear layer(INL)and outer nuclear layer(ONL)decreased, the fluorescence intensity of VEGFA enhanced, and the relative expression of HIF-1α, p-STAT3 and VEGFA protein increased(P&#x0026;#x003C;0.05). Compared with the model group, the retinal histopathological damage of salvianolic acid B rats was alleviated, the amplitude of ERG a-wave and b-wave, the thickness of RTL, INL and ONL were increased, the fluorescence intensity of VEGFA was weakened, and the relative expression of HIF-1α, p-STAT3 and VEGFA proteins was decreased(P&#x0026;#x003C;0.05).CONCLUSION: Salvianolic acid B can alleviate the retinal histopathological injury and improve retinal function in RVO rats, which may be related to inhibiting the activation of HIF-1α/STAT3/VEGFA pathway and reducing angiogenesis.

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.