RESUMEN
This article describes a clinical case of a female patient with choroidal nevus, who was previously diagnosed in another clinic with "subretinal neovascular membrane as a result of central serous chorioretinopathy" and subsequently underwent multiple intravitreal anti-VEGF injections. Based on the analysis of OCT angiography images, the macular changes in this case were interpreted as a polypoidal form of neovascularization in a patient with subfoveolar choroidal nevus.
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Inhibidores de la Angiogénesis , Neoplasias de la Coroides , Angiografía con Fluoresceína , Inyecciones Intravítreas , Tomografía de Coherencia Óptica , Factor A de Crecimiento Endotelial Vascular , Humanos , Femenino , Neoplasias de la Coroides/diagnóstico , Neoplasias de la Coroides/tratamiento farmacológico , Angiografía con Fluoresceína/métodos , Tomografía de Coherencia Óptica/métodos , Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/efectos adversos , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Fondo de Ojo , Coroides/irrigación sanguínea , Coroides/diagnóstico por imagen , Coroides/patología , Neovascularización Coroidal/diagnóstico , Neovascularización Coroidal/tratamiento farmacológico , Neovascularización Coroidal/etiología , Persona de Mediana Edad , Nevo/diagnóstico , Diagnóstico Diferencial , Resultado del TratamientoRESUMEN
Concomitant direct oral anticoagulants (DOACs) and tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor (anti-VEGF TKI) have been associated with a higher risk of bleeding. Nevertheless, concomitant administration seems frequent in clinical practice in patients with cancer-associated thrombosis and appears to be safe according to the retrospective study by Boileve A. et al. But the risk of an additional pharmacokinetic interaction between anti-VEGF TKI and DOACs must be considered, in case of P-glycoprotein (P-gp) inhibition by the TKI. We describe a case report with a major bleeding event in a renal metastatic cancer patient treated with cabozantinib and rivaroxaban. This case highlights the difficult therapeutic decision in a complex patient with cancer-associated thrombosis, who refused the anticoagulant subcutaneous route. Accumulation of bleeding risk factors (genito-urinary tumor localization) was additive to several pharmacodynamic interactions (acetylsalicylic acid, venlafaxine) and a potential pharmacokinetic interaction between cabozantinib and rivaroxaban. Indeed, cabozantinib-related P-glycoprotein inhibition could have led to a supratherapeutic level of rivaroxaban, contributing partly to the bleeding event. Before combining an anti-VEGF TKI and DOACs, a multidisciplinary pretherapeutic assessment seems crucial to evaluate the patient's bleeding risk factors, pharmacodynamic interactions, and the risk of pharmacokinetic interactions mediated by P-gp.
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Anticoagulantes , Interacciones Farmacológicas , Piridinas , Rivaroxabán , Humanos , Anticoagulantes/administración & dosificación , Anticoagulantes/efectos adversos , Estudios Retrospectivos , Piridinas/efectos adversos , Piridinas/administración & dosificación , Piridinas/uso terapéutico , Piridinas/farmacocinética , Rivaroxabán/administración & dosificación , Rivaroxabán/efectos adversos , Rivaroxabán/farmacocinética , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Anilidas/administración & dosificación , Anilidas/efectos adversos , Anilidas/farmacocinética , Hemorragia/inducido químicamente , Neoplasias Renales/tratamiento farmacológico , Masculino , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacocinética , Trombosis/inducido químicamente , Trombosis/etiología , Neoplasias/tratamiento farmacológico , Neoplasias/complicaciones , Administración Oral , AncianoRESUMEN
OBJECTIVE: Precancerous lesions of gastric cancer (PLGC) are key pathological stages in the transformation of gastric "inflammation-cancer", and timely and effective intervention at this stage is of great importance in the prevention and treatment of gastric cancer. Zhiwei Fuwei Pills (ZWFW), as a traditional Chinese medicine formulation, has been proven to have good clinical efficacy in the treatment of PLGC, but its specific mechanism of action has not been fully explained. Thus, this study validated the efficacy and explored the potential mechanisms of ZWFW in treating PLGC by integrating network pharmacology analyses and experimental verification. METHODS: The TCMSP database was used to obtain the active ingredients of ZWFW and their corresponding targets, and the GeneCards database was used to retrieve PLGC-related targets. The intersecting targets between ZWFW and PLGC were obtained through mapping, and protein-protein interaction (PPI) networks and "drug-active ingredient-target" networks were constructed by using Cytoscape software. The DAVID database was used for GO functional enrichment analysis and KEGG pathway enrichment analysis. AutoDockTools software was used for molecular docking of key active ingredients and key targets. In order to verify the analysis results of network pharmacology, TEM and H&E were used to observe the effects of different dosage groups of ZWFW on gastric mucosal microvasculature in PLGC rats. Subsequently, the ELISA, IF, IHC, RT-PCR and western blot were used to detected the expression levels of relevant targets in the tissues, so as to verify the potential mechanism of ZWFW in intervening PLGC. RESULTS: After the screening, 258 effective active ingredients and 325 targets were obtained, and 1294 disease-related targets were determined, resulting in 139 intersection targets through mapping. The KEGG enrichment results showed that PI3K/Akt and HIF-1 signaling pathway might play important roles in the treatment mechanism of PLGC. The molecular docking results showed that active ingredients of ZWFW all had a strong affinity and stable structure with key targets, including AKT1 and VEGF. In vivo experiments confirmed that ZWFW could improve gastric mucosal microvascular abnormalities in PLGC, effectively intervene in gastric mucosal pathological grading. Meanwhile, compared with the model group, this formulation could reduce the expression levels of PI3K, Akt, mTOR, HIF-1α, and VEGF in gastric mucosa, showing a dose-effect relationship. CONCLUSION: ZWFW can intervene in the neovascularization and pathological evolution of PLGC, and this mechanism of action may be achieved by inhibiting abnormal activation of the PI3K/Akt/mTOR/HIF-1α/VEGF signaling pathway.
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Medicamentos Herbarios Chinos , Neovascularización Patológica , Farmacología en Red , Lesiones Precancerosas , Neoplasias Gástricas , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/patología , Animales , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Neovascularización Patológica/tratamiento farmacológico , Masculino , Lesiones Precancerosas/tratamiento farmacológico , Lesiones Precancerosas/patología , Mapas de Interacción de Proteínas , Factor A de Crecimiento Endotelial Vascular/metabolismo , Ratas Sprague-Dawley , Ratas , Simulación del Acoplamiento Molecular , AngiogénesisRESUMEN
Aberrant long non-coding RNA (lncRNA) expression has been shown to be involved in the pathological process of pre-eclampsia (PE), yet only a small portion of lncRNAs has been characterized concerning the function and molecular mechanisms involved in PE. This study aimed to investigate the regulatory mechanism of the lncRNA AC092100.1 (AC092100.1) in angiogenesis in PE. In our study, bioinformatics analysis was performed to screen for differentially expressed lncRNAs between normal subjects and PE patients. The levels of AC092100.1 in placental tissues of patients with or without PE were validated using qRT-PCR. The effect of AC092100.1 overexpression on the proliferation, migration, and tube formation of human umbilical vein endothelial cells (HUVECs) was investigated. The binding of AC092100.1 and YT521-B homology domain-containing 2 (YTHDC2) was predicted and verified. The effect of AC092100.1/YTHDC2 on the expression of vascular endothelial growth factor-A (VEGFA) in HUVECs was determined. Finally, a PE mice model was conducted. Fetal mouse growth, the abundance of mesenchymal morphology markers, including hypoxia-inducible factor 1-alpha (HIF-1α), soluble fms-like tyrosine kinase-1 (sFlt-1), soluble endoglin (sEng), Slug, and Vimentin, and endothelial markers, including placental growth factor (PLGF), CD31, and vascular endothelial (VE)-cadherin, in placental tissues were assessed. Here, we found that AC092100.1 was abnormally downregulated in placental tissues from PE patients. We established that AC092100.1 overexpression promoted HUVEC proliferation, migration, and tube formation in vitro. Mechanistically, AC092100.1 induced the accumulation of YTHDC2 and VEGFA through binding to YTHDC2 in HUVECs. Inhibition of YTHDC2 or VEGFA reversed AC092100.1-promoted tube formation. AC092100.1 overexpression contributed to alleviating fetal growth disorder, decreased levels of sEng, HIF-1α, sFlt-1, Slug, and Vimentin, and increased levels of VEGFA, PLGF, CD31, and VE-cadherin in PE mice. Our findings provided evidence supporting the role of the AC092100.1/YTHDC2/VEGFA axis in regulating angiogenesis, which demonstrated a therapeutic pathway for PE targeting angiogenesis.
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Células Endoteliales de la Vena Umbilical Humana , Preeclampsia , ARN Largo no Codificante , Transducción de Señal , Factor A de Crecimiento Endotelial Vascular , Preeclampsia/metabolismo , Preeclampsia/genética , Preeclampsia/patología , Humanos , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Animales , Femenino , Embarazo , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Ratones , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética , Proliferación Celular , Movimiento Celular , Neovascularización Patológica/metabolismo , Neovascularización Patológica/genética , Placenta/metabolismo , AngiogénesisRESUMEN
INTRODUCTION: Vascular Endothelial Growth Factor (VEGF) is associated with abnormal fundus neovascularization. Consequently, Anti-VEGF agents are vital for ophthalmic treatment. This paper reviews the application of anti-VEGF agents in ophthalmology over the past two decades with the aim of providing insights for further research. METHODS: A meticulous search strategy was employed in the Web of Science Core Collection literature from 2003 to 2023 to gather relevant literature, which was then analyzed using VOSviewer, CiteSpace, and the R package Bibliometrix. RESULTS: The study included 3,602 publications from 83 countries and 3,445 institutions. The United States and China have emerged as leading contributors in terms of the publication volume. Johns Hopkins University, the University of Sydney, and Genentech Inc were identified as frontrunners in this field. "Retina" had the highest publication volume, whereas "Ophthalmology" had the highest citation frequency. Among the 15,918 scholars, Bressler NM, Holz FG, Glassman AR, and Bandello F led in publication volume, while Brown DM was the most cited author. High-frequency keywords included "Endothelial Growth Factor," "Therapy," "Safety," and "Randomized Clinical Trial." CONCLUSION: Anti-VEGF drugs have shown notable success in treating neovascular eye diseases, especially wet age-related macular degeneration and diabetic macular edema, focusing on clinical efficacy, injection regimens, and safety. Future directions include developing new anti-VEGF drugs, drug delivery systems, non-invasive administration, multi-target drugs, leveraging big data and artificial intelligence, and addressing the current treatment limits. Continuous innovation and method improvement in this field promise more breakthroughs, providing effective, safe, and economical options for eye disease treatment.
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Inhibidores de la Angiogénesis , Bibliometría , Factor A de Crecimiento Endotelial Vascular , Humanos , Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/uso terapéutico , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Oftalmología/tendencias , Inyecciones IntravítreasRESUMEN
Obstructive uropathy is a common kidney disease caused by elevated hydrostatic pressure (HP), but relevant molecular and cellular mechanisms have not yet been well understood. In this study, we ex vivo investigated the effects of elevated HP on human renal epithelial cells (HREpCs). Primary HREpCs were subjected to 100 cmH2O HP for 8 or 48 h. Then, the cells were cultured without HP stimulation for another 24 h or 72 h. Cell morphology showed almost no change after 8h HP treatment, but exhibited reversible elongation after 48h HP treatment. HP treatment for 8 h increased the expression of TGFB1 and VEGFA but decreased the expression of CSF2 and TGFB2. On the other hand, HP treatment for 48 h downregulated the expression of CSF2, TGFB2, PDGFB, VEGFA, and VEGFB, while upregulated the expression of TGFB3. Interestingly, all changes induced by 48 h HP treatment were detected more severe compared to 8 h HP treatment. In conclusion, elongated ex vivo HP loading to renal epithelial cells induces reversible changes on cell morphology and disturbs the expression of several growth factors, which provides novel mechanistic insight on elevated HP-caused kidney injury such as obstructive uropathy.
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Células Epiteliales , Presión Hidrostática , Riñón , Humanos , Células Epiteliales/metabolismo , Riñón/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Péptidos y Proteínas de Señalización Intercelular/genética , Células Cultivadas , Factor A de Crecimiento Endotelial Vascular/metabolismo , Regulación de la Expresión Génica , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
PURPOSE: To investigate the efficacy and outcomes of switching neovascular age-related macular degeneration (nAMD) patients from aflibercept to faricimab, focusing on visual acuity, retinal fluid management, and treatment intervals. The primary aim was to assess the early outcomes in nAMD patients refractory to aflibercept and explore faricimab's potential as a longer-lasting therapeutic alternative. METHODS: A single-center retrospective study was conducted on 50 refractory nAMD patients at Cleveland Clinic Abu Dhabi from September 2022-May 2023. Patients were switched from aflibercept to faricimab, having met specific criteria for refractory nAMD. The study analyzed best-corrected visual acuity (BCVA), central subfield thickness (CST), and fluid changes post-switch, using Optical Coherence Tomography (OCT). RESULTS: After three faricimab injections, significant reductions in CST were observed, with a notable decrease in retinal fluid. The mean BCVA remained stable throughout the study period. Although there was a decrease in the maximum pigment epithelial detachment (PED) height, it was not statistically significant. Treatment intervals post-switch showed that the majority of patients maintained or extended their treatment intervals, with a significant proportion achieving resolution of intraretinal fluid (IRF) and subretinal fluid (SRF). CONCLUSIONS: Switching to faricimab from aflibercept in refractory nAMD patients led to significant improvements in retinal fluid management and CST, with stable BCVA outcomes. Faricimab presents a promising alternative for patients requiring frequent aflibercept injections, potentially offering a more manageable treatment regimen with extended dosing intervals. This study highlights the need for personalized therapeutic strategies in nAMD treatment, though further research is necessary to optimize treatment switches.
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Inhibidores de la Angiogénesis , Inyecciones Intravítreas , Receptores de Factores de Crecimiento Endotelial Vascular , Proteínas Recombinantes de Fusión , Tomografía de Coherencia Óptica , Agudeza Visual , Degeneración Macular Húmeda , Humanos , Receptores de Factores de Crecimiento Endotelial Vascular/administración & dosificación , Receptores de Factores de Crecimiento Endotelial Vascular/uso terapéutico , Proteínas Recombinantes de Fusión/administración & dosificación , Proteínas Recombinantes de Fusión/uso terapéutico , Estudios Retrospectivos , Masculino , Femenino , Tomografía de Coherencia Óptica/métodos , Anciano , Degeneración Macular Húmeda/tratamiento farmacológico , Degeneración Macular Húmeda/diagnóstico , Degeneración Macular Húmeda/fisiopatología , Inhibidores de la Angiogénesis/administración & dosificación , Anciano de 80 o más Años , Sustitución de Medicamentos/métodos , Resultado del Tratamiento , Estudios de Seguimiento , Angiografía con Fluoresceína/métodos , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Fondo de OjoRESUMEN
The significance of anterior cruciate ligament (ACL) remnants during reconstruction remains unclear. Co-culturing ACL remnant cells and bone marrow stromal cells (BMSCs) may reduce apoptosis and enhance hamstring tendon activity. This study investigated whether extracellular vesicles (EVs), which facilitate cell-cell interactions, act as the active components, improving graft maturation in this co-culture. The effects of EVs on cell viability, proliferation, migration and gene expression in the rabbit ACL remnant cells and BMSCs were assessed using control (BMSC-only culture), co-culture (ACL remnant cells and BMSCs, CM) and co-culture without EVs (CM ∆ EVs) media. EVs were isolated from control (BMSC-EV) and co-culture (CM-EV) media and characterized. CM significantly enhanced the proliferation, migration and expression of transforming growth factor (TGF-ß)-, vascular endothelial growth factor (VEGF)-, collagen synthesis- and tenogenesis-related genes. However, CM-induced effects were reversed by the CM ∆ EVs treatment. CM-EV treatment exhibited higher potential to enhance proliferation, migration and gene expression in the ACL remnant cells and BMSCs than BMSC-EV and non-EV treatments. In conclusion, EVs, secreted under the coexistence of ACL remnant cells and BMSCs, primarily increase the cell viability, proliferation, migration and gene expression of collagen synthesis-, TGF-ß-, VEGF- and tenogenesis-related genes in both cell types.
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Ligamento Cruzado Anterior , Movimiento Celular , Proliferación Celular , Supervivencia Celular , Técnicas de Cocultivo , Vesículas Extracelulares , Células Madre Mesenquimatosas , Vesículas Extracelulares/metabolismo , Animales , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/citología , Conejos , Ligamento Cruzado Anterior/citología , Ligamento Cruzado Anterior/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética , Células Cultivadas , Regulación de la Expresión Génica , Comunicación Celular , Factor de Crecimiento Transformador beta/metabolismo , MasculinoRESUMEN
This study is to elucidate the effect of the LINC00663/EBF1/NR2F1 axis on inflammation and angiogenesis in bladder cancer (BC) and related molecular mechanisms. After transfection, functional experiments were conducted to test cell proliferation and invasion, tube formation ability, and content of inflammatory factors, Snail, E-cadherin, and VEGFA. Meanwhile, the relationships among LINC00663, EBF1, and NR2F1 were predicted and verified. In addition, xenograft experiments in nude mice were performed to observe the oncogenicity of 5637 BC cells in vivo. In BC tissues and cells, LINC00663 and NR2F1 were upregulated. Silencing NR2F1 or LINC00663 repressed cell proliferation and invasion, weakened vascular mimicry in vitro, decreased inflammatory factor, Snail, and VEGFA levels, and increased expression of E-cadherin. LINC00663 positively regulated NR2F1 expression through EBF1. Additionally, in vivo experiments showed that NR2F1 upregulation reversed the suppression effects of LINC00663 silencing on tumour growth, inflammation, and angiogenesis. Silencing LINC00663 decreased NR2F1 expression by mediating EBF1, thereby inhibiting BC inflammation and angiogenesis.
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Factor de Transcripción COUP I , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Inflamación , Neovascularización Patológica , ARN Largo no Codificante , Transactivadores , Neoplasias de la Vejiga Urinaria , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/metabolismo , Neoplasias de la Vejiga Urinaria/patología , Humanos , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Neovascularización Patológica/genética , Neovascularización Patológica/metabolismo , Animales , Ratones , Línea Celular Tumoral , Factor de Transcripción COUP I/metabolismo , Factor de Transcripción COUP I/genética , Inflamación/metabolismo , Inflamación/genética , Inflamación/patología , Transactivadores/metabolismo , Transactivadores/genética , Femenino , Masculino , Ratones Desnudos , Silenciador del Gen , Movimiento Celular , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética , AngiogénesisRESUMEN
The aim of the present study was to evaluate the photothermal effects of a subdermal high-power diode laser at a wavelength (λ) of 1470 nm in the skin of rats. Twenty male Wistar rats were used, divided into 2 groups: placebo laser (PL) and active laser (AL). A high-power diode laser equipment was applied to 5 subdermal vectors on the animal's back region. The results demonstrated that active laser animals showed a better arrangement of collagen fiber bands, an increase in the thickness of the dermis and the number of vessels. Furthermore, animals treated with active laser showed an increased immunoexpression of TGF-ß and VEGF compared to the placebo. The present work demonstrated that the subdermal high-power diode laser increases the vascularization and the expression of factors that enhance skin regeneration and may be promising resource in the esthetic and dermatology clinical treatment of skin rejuvenation.
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Láseres de Semiconductores , Ratas Wistar , Piel , Animales , Masculino , Ratas , Láseres de Semiconductores/uso terapéutico , Piel/efectos de la radiación , Piel/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Rejuvenecimiento , Modelos AnimalesRESUMEN
BACKGROUND: Oral cancers, which include tumors of the oral cavity, salivary glands, and pharynx, are becoming increasingly prevalent worldwide. Squamous cell carcinoma accounts for over 90% of malignant oral lesions, with oral squamous cell carcinoma (OSCC) being notably common in the Indian subcontinent and other regions of Asia. This is especially true in South-Central Asia, including Sri Lanka, where it is particularly prevalent among men. This study aims to evaluate the levels of Vascular Endothelial Growth Factor-A (VEGF-A) and Cytokeratin-19 (CK-19) mRNAs in whole blood as a potential method for the early detection of OSCC. METHODS: The study included 40 patients (each from OSCC, Oral Submucous Fibrosis (OSF), Oral Leukoplakia (OLK), Oral Lichen Planus (OLP), and 10 healthy controls. The expression levels of VEGF-A and CK-19 mRNAs were measured from extracellular RNA extracted from whole blood samples using real-time reverse transcription polymerase chain reaction (RT-PCR) with sequence-specific primers. Receiver operating characteristic (ROC) curve analysis was used to evaluate the effectiveness of these biomarkers in detecting OSCC. RESULTS: The results demonstrated a significant increase in blood transcripts of the candidate mRNAs CK-19 and VEGF-A in patients with OSCC, OSF, OLK, and OLP. The Wilcoxon signed-rank test revealed a p-value of 0.002 for each specific comparison between diseased patients and healthy controls (i.e., OSCC vs. HC, OSF vs. HC, OLP vs. HC, OLK vs. HC) for both CK-19 and VEGF-A. When these two biomarkers were used together, they provided a 60% predictive probability for patients with OSCC (p = 0.023). CONCLUSION: This study highlights the efficacy of blood mRNA transcriptome diagnostics in detecting OSCC. This innovative clinical approach has the potential to be a robust, efficient, and reliable tool for early cancer detection. Blood-based transcriptomes could be further explored for their effectiveness in various health contexts and for routine health monitoring.
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Biomarcadores de Tumor , Carcinoma de Células Escamosas , Queratina-19 , Leucoplasia Bucal , Neoplasias de la Boca , Fibrosis de la Submucosa Bucal , ARN Mensajero , Factor A de Crecimiento Endotelial Vascular , Humanos , Factor A de Crecimiento Endotelial Vascular/sangre , Factor A de Crecimiento Endotelial Vascular/genética , Neoplasias de la Boca/sangre , Neoplasias de la Boca/genética , Carcinoma de Células Escamosas/sangre , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/diagnóstico , Masculino , ARN Mensajero/sangre , Fibrosis de la Submucosa Bucal/sangre , Fibrosis de la Submucosa Bucal/genética , Femenino , Leucoplasia Bucal/sangre , Leucoplasia Bucal/genética , Persona de Mediana Edad , Biomarcadores de Tumor/sangre , Queratina-19/sangre , Adulto , Liquen Plano Oral/sangre , Liquen Plano Oral/genética , Estudios de Casos y Controles , Lesiones Precancerosas/sangre , Lesiones Precancerosas/genética , Lesiones Precancerosas/diagnóstico , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Detección Precoz del Cáncer/métodos , Anciano , Reacción en Cadena en Tiempo Real de la Polimerasa , Curva ROCRESUMEN
Rationale: Neovascular ocular diseases (NODs) represent the leading cause of visual impairment globally. Despite significant advances in anti-angiogenic therapies targeting vascular endothelial growth factor (VEGF), persistent challenges remain prevalent. As a proof-of-concept study, we herein demonstrate the effectiveness of targeted degradation of VEGF with bispecific aptamer-based lysosome-targeting chimeras (referred to as VED-LYTACs). Methods: VED-LYTACs were constructed with three distinct modules: a mannose-6-phosphate receptor (M6PR)-binding motif containing an M6PR aptamer, a VEGF-binding module with an aptamer targeting VEGF, and a linker essential for bridging and stabilizing the two-aptamer structure. The degradation efficiency of VED-LYTACs via the autophagy-lysosome system was examined using an enzyme-linked immunosorbent assay (ELISA) and immunofluorescence staining. Subsequently, the anti-angiogenic effects of VED-LYTACs were evaluated using in vitro wound healing assay, tube formation assay, three-dimensional sprouting assay, and ex vivo aortic ring sprouting assay. Finally, the potential therapeutic effects of VED-LYTACs on pathological retinal neovascularization and vascular leakage were tested by employing mouse models of NODs. Results: The engineered VED-LYTACs promote the interaction between M6PR and VEGF, consequently facilitating the translocation and degradation of VEGF through the lysosome. Our data show that treatment with VED-LYTACs significantly suppresses VEGF-induced angiogenic activities both in vitro and ex vivo. In addition, intravitreal injection of VED-LYTACs remarkably ameliorates abnormal vascular proliferation and leakage in mouse models of NODs. Conclusion: Our findings present a novel strategy for targeting VEGF degradation with an aptamer-based LYTAC system, effectively ameliorating pathological retinal angiogenesis. These results suggest that VED-LYTACs have potential as therapeutic agents for managing NODs.
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Aptámeros de Nucleótidos , Lisosomas , Neovascularización Retiniana , Factor A de Crecimiento Endotelial Vascular , Animales , Aptámeros de Nucleótidos/farmacología , Factor A de Crecimiento Endotelial Vascular/metabolismo , Ratones , Neovascularización Retiniana/tratamiento farmacológico , Neovascularización Retiniana/metabolismo , Humanos , Lisosomas/metabolismo , Lisosomas/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Inhibidores de la Angiogénesis/farmacología , AngiogénesisRESUMEN
The present study aimed to compare the effect of photobiomodulation with different energy densities on the angiogenic differentiation of human periodontal ligament stem cells (hPDLSCs) and stem cells from human exfoliated deciduous teeth (SHED). Photobiomodulation therapy with a 660 nm diode laser (2.4 J/cm2 and 3.9 J/cm2) on two consecutive days post-culture was applied to two types of stem cells (hPDLSCs and SHED). The Quantitative Real-time Polymerase Chain Reaction (RT-qPCR) test was undertaken to investigate Vascular Endothelial Growth Factor-A (VEGF-A) and Angiopoietin I (ANG-I) genes on days 1, 3, 5, 7, and 10 after the first session of laser application. The 4',6-diamidino-2-phenylindole (DAPI) staining and Methyl Thiazolyl Tetrazolium (MTT) test were conducted on days 1, 3, and 5 after the first session of laser application, to assess the cell viability. The Two-way ANOVA with Tukey post hoc test was used to analyze the outcomes of the MTT and RT-qPCR tests. The results of the MTT and DAPI convergently illustrated that the groups receiving photobiomodulation with 2.4 J/cm2 had higher cell viability compared to 3.9 J/cm2. All experimental groups showed an upregulation of VEGF-A and ANG-I gene expression from day 1 to 5, followed by a downregulation from day 5 to 10. The groups with cultured hPDLSCs and SHED receiving photobiomodulation using 2.4 J/cm2 had the most amounts of VEGF-A and ANG-I gene expression on day 5, respectively. In conclusion, the 660 nm mediated photobiomodulation therapy of cultured SHED and hPDLSCs with 2.4 J/cm2 energy density may be associated with higher angiogenic differentiation (the expression of VEGF-A and ANG-I) as well as higher cell viability compared to the photobiomodulation therapy with 3.9 J/cm2.
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Diferenciación Celular , Terapia por Luz de Baja Intensidad , Ligamento Periodontal , Células Madre , Diente Primario , Factor A de Crecimiento Endotelial Vascular , Humanos , Diferenciación Celular/efectos de la radiación , Terapia por Luz de Baja Intensidad/métodos , Ligamento Periodontal/citología , Ligamento Periodontal/efectos de la radiación , Factor A de Crecimiento Endotelial Vascular/metabolismo , Células Madre/efectos de la radiación , Diente Primario/citología , Neovascularización Fisiológica/efectos de la radiación , Reacción en Cadena en Tiempo Real de la Polimerasa , Angiopoyetina 1 , Supervivencia Celular/efectos de la radiación , Láseres de Semiconductores/uso terapéutico , Técnicas In Vitro , Células CultivadasRESUMEN
AIMS AND OBJECTIVES: This study aimed to investigate the effects of Umbilical Cord Mesencymal Stem Cell Conditioning Medium (UC MSC-CM) administration on body weight recovery and the level of four molecular biomarkers, namely Superoxide Dismutase (SOD), vascular Endothelial Growth Factor (VEGF), C-Reactive Protein (CRP), and myostatin. MATERIALS AND METHODS: Secretome was injected intramuscularly twice at 1.5 mL (day 7 and 14) into the right thigh of high-dose, short-term galactose-induced aging rats. The data of day 7 (before) and day 21 (after the administration) were evaluated. The body weights and the four biomarkers were measured before (day 7) and after intervention (day 21). RESULTS: This study showed that the UC MSC-CM intramuscular administrations did not influence body weight regeneration. However, it could increase SOD and VEGF levels and decrease CRP and myostatin levels. CONCLUSION: Treatment with UC MSC-CM is a promising and potential agent in treating sarcopenia.
Résumé Buts et objectifs:Cette étude visait à examiner les effets de l'administration d'un milieu de conditionnement de cellules souches mésencéphaliques de cordon ombilical (UC MSC-CM) sur la récupération du poids corporel et le niveau de quatre biomarqueurs moléculaires, à savoir la superoxyde dismutase (SOD), le facteur de croissance endothéliale vasculaire (VEGF), la protéine C-réactive (CRP) et la myostatine.Matériels et méthodes:Le sécrétome (UC MSC-CM) a été injecté par voie intramusculaire deux fois à 1,5 ml (jour 7 et 14) dans la cuisse droite de rats vieillissant à forte dose et à court terme induits par le galactose. Les données du jour 7 (avant) et du jour 21 (après l'administration) ont été évaluées. Le poids corporel et les quatre biomarqueurs ont été mesurés avant (jour 7) et après l'intervention (jour 21).Résultats:Cette étude a montré que les administrations intramusculaires de CSM-CM d'UC n'ont pas influencé la régénération du poids corporel. Cependant, elle a pu augmenter les niveaux de SOD et de VEGF et diminuer les niveaux de CRP et de myostatine.Conclusion:Le traitement par UC MSC-CM est un agent prometteur et potentiel dans le traitement de la sarcopénie.
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Biomarcadores , Proteína C-Reactiva , Células Madre Mesenquimatosas , Miostatina , Superóxido Dismutasa , Factor A de Crecimiento Endotelial Vascular , Animales , Ratas , Biomarcadores/metabolismo , Biomarcadores/sangre , Factor A de Crecimiento Endotelial Vascular/metabolismo , Proteína C-Reactiva/metabolismo , Superóxido Dismutasa/metabolismo , Miostatina/metabolismo , Masculino , Sarcopenia/metabolismo , Modelos Animales de Enfermedad , Músculo Esquelético/metabolismo , Medios de Cultivo Condicionados/farmacología , Cordón Umbilical/citología , Peso Corporal , Inyecciones Intramusculares , Trasplante de Células Madre Mesenquimatosas/métodosRESUMEN
BACKGROUND: Neuroendocrine tumours (NETs) are a heterogeneous group of tumours, which is characterized by rich vascularization. The role of angiogenesis in NETs has been widely researched. Peptide receptor radionuclide therapy (PRRT) is an effective treatment method for patients with disease progression in NETs. Due to the heterogeneousness of NETs, the response to treatment varies. Currently, the finding of efficient markers helpful in assessing the response to treatment in NETs is crucial. The aim of this study was to assess chromogranin A (CgA) and angiogenic factors in gastro-entero-pancreatic (GEP) and broncho-pulmonary (BP) NET patients treated with PRRT. MATERIAL AND METHODS: The study group included 40 patients with GEP NETs and BP NETs who completed four cycles of PRRT. Serum levels of CgA and angiogenic factors such as vascular endothelial growth factor (VEGF), its receptors (VEGF-R1, VEGF-R2, VEGF-R3), were assessed before and after four cycles of PRRT. All tests were determined using ELISA. RESULTS: The concentration of CgA, VEGF-R1 and VEGF-R2 decreased significantly, whereas VEGF-R3 increased significantly after PRRT. PRRT did not affect VEGF, it was similar before and after the radioisotope treatment. Based on AUROC, only for VEGF-R1 AUC was a consequence of 0.7 which can be considered as a good response to PRRT treatment. CONCLUSIONS: VEGF-R1 may be a potential biomarker useful in assessing the effectiveness of PRRT in NET patients.
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Cromogranina A , Tumores Neuroendocrinos , Humanos , Tumores Neuroendocrinos/radioterapia , Tumores Neuroendocrinos/sangre , Femenino , Masculino , Persona de Mediana Edad , Adulto , Anciano , Cromogranina A/sangre , Receptores de Péptidos/metabolismo , Biomarcadores de Tumor/sangre , Factor A de Crecimiento Endotelial Vascular/sangre , Neovascularización Patológica/radioterapia , Neovascularización Patológica/sangre , Octreótido/análogos & derivados , Octreótido/uso terapéutico , Neoplasias Pancreáticas/radioterapia , Neoplasias Pancreáticas/sangre , Resultado del TratamientoRESUMEN
BACKGROUND: The traditional Chinese medicine (TCM) Xiaoliu Pingyi recipe (XLPYR) has been clinically used for several decades, demonstrating favorable therapeutic effects. However, the underlying regulatory mechanisms remain unclear. The aim of this study was to explore the anti-tumor effects of XLPYR and its regulatory role in the vascular microenvironment through in vivo and in vitro experiment. MATERIALS AND METHODS: In the in vivo study, a C57BL/6J mouse model of lung adenocarcinoma (LUAD) allografts was established, and various interventions were administered for 14 days (Model group: administered normal saline via oral gavage; Pemetrexed (PEM) group: intraperitoneally injected with a solution of pemetrexed, once every 3d; XLPYR group: administered XLPYR via oral gavage; Combination (COMBI) group: received XLPYR via oral gavage simultaneously with intraperitoneal injection of pemetrexed solution). Tumor volume and weight were then compared among the groups. The impact of XLPYR on the tumor vascular microenvironment was assessed using immunohistochemistry staining. In the in vitro study, XLPYR-containing serum was prepared by oral administration to SD rats. The CCK-8 assay evaluated the effect of the serum on the proliferation of normal lung epithelial BEAS-2B cells and LUAD A549 cells, determining the optimal intervention concentrations. The cell migration and invasion abilities were evaluated using the wound-healing assay and Transwell assay, respectively. Finally, ELISA assay measured VEGF secretion levels in the LUAD cell supernatant, and RT-qPCR and Western Blot were employed to detect differences in HIF-1α, VEGFA, Ang-2, and PI3K/Akt mRNA and protein expression levels in both in vivo and in vitro experiments. RESULTS: In the in vivo study, XLPYR significantly inhibited the growth of mice LUAD allografts, with enhanced anti-tumor effects observed with prolonged drug intervention. Immunohistochemistry staining revealed reduced MVD and increased pericyte coverage in all intervention groups. Regarding vascular function, FITC-Dextran extravasation in the tumor tissues of the Model group was significantly higher than in the intervention groups, particularly with lower extravasation in the COMBI group compared to the PEM group. In the in vitro study, XLPYR demonstrated a time- and concentration-dependent inhibitory effect on LUAD cells, and with greater sensitivity in inhibiting LUAD cells compared to BEAS-2B cells. The wound-healing assay and Transwell assay confirmed that XLPYR significantly suppressed the migration and invasion abilities of LUAD cells. ELISA experiments further revealed a significant decrease in VEGF expression in the supernatant of each intervention group. RT-qPCR and Western Blot results showed consistent findings between the in vivo and in vitro experiments. HIF-1α, VEGFA, and Ang-2 mRNA and protein expression levels were significantly downregulated in the PEM group, XLPYR group, and COMBI group. There were no significant differences in the expression of PI3K and Akt mRNA and total protein, but the expression levels of phosphorylated p-PI3K and p-Akt were notably downregulated. CONCLUSION: XLPYR significantly inhibited C57BL/6J mouse LUAD allograft growth and improved the vascular microenvironment, thereby intervening in tumor angiogenesis and inducing vascular normalization. It suppressed LUAD cell proliferation, migration, and invasion, while reducing VEGF concentration in the cell supernatant. The regulatory mechanism may involve inhibiting PI3K/Akt protein phosphorylation and downregulating angiogenesis-related factors, such as HIF-1α, VEGF, and Ang-2.
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Adenocarcinoma del Pulmón , Medicamentos Herbarios Chinos , Neoplasias Pulmonares , Ratones Endogámicos C57BL , Microambiente Tumoral , Animales , Medicamentos Herbarios Chinos/farmacología , Microambiente Tumoral/efectos de los fármacos , Ratones , Adenocarcinoma del Pulmón/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Humanos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Factor A de Crecimiento Endotelial Vascular/metabolismo , Masculino , Pemetrexed/farmacología , Neovascularización Patológica/tratamiento farmacológico , Movimiento Celular/efectos de los fármacos , Medicina Tradicional China/métodosRESUMEN
To evaluate the changes of choroidal thickness (CT) and blood flow related to myopia, and its effects of vascular endothelial growth factor (VEGFA) on choroidal vessels in myopia. Subjects were included and divided into emmetropia (EM), non-high myopia (Non-HM) and high myopia (HM) groups. we measured choroidal thickness (CT), choriocapillaris vessel density (VD), and VEGFA content in tears in humans (137 subjects for CT, VD and 84 for tear) and detected the role of VEGFA in the choroid in form-deprivation myopia (FDM) in guinea pigs. Twenty-four guinea pigs were divided into control and FDM groups, and the expression changes of choroidal vessels and VEGFA were observed and compared using immunohistochemistry and Western blotting. Twenty-one guinea pigs were divided into control, FDM + Vehicle and FDM + Conbercept groups. The changes of diopter, axis length and choroidal vessels after intravitreal injection of Conbercept were observed. There were significant differences in CT and VD among the three groups (p < 0.05). VEGFA levels in tears were significantly lower in the myopic groups, with a decreasing trend from EM to Non-HM to HM. The choroidal vascular area fraction of FDM decreased compared to the control group. FDM guinea pigs exhibited reduced choroidal vasculature and significant downregulation of VEGFA expression. Following intravitreal injection of conbercept, the FDM + Conbercept group showed greater myopia, longer axial length, and lower choroidal vascular area fraction compared to the control group. VEGFA may participate in the regulation of choroidal blood vessels and blood flow in the progression of myopia. The reduction in VEGFA may accelerates the progression of myopia.
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Coroides , Miopía , Factor A de Crecimiento Endotelial Vascular , Coroides/metabolismo , Coroides/irrigación sanguínea , Coroides/patología , Factor A de Crecimiento Endotelial Vascular/metabolismo , Animales , Cobayas , Miopía/metabolismo , Miopía/patología , Masculino , Humanos , Femenino , Adulto , Biomarcadores/metabolismo , Tomografía de Coherencia Óptica , Densidad Microvascular , Modelos Animales de Enfermedad , Proteínas Recombinantes de FusiónRESUMEN
BACKGROUND: This study aimed to compare the regressive effects of aflibercept and faricimab on pigment epithelial detachment (PED) in patients with neovascular age-related macular degeneration. METHODS: In total, 41 eyes of 40 patients diagnosed with type 1 macular neovascularization were retrospectively analyzed using multimodal imaging. Of these, 23 eyes were treated with intravitreal aflibercept injections (IVA group), and 18 eyes were treated with intravitreal faricimab (IVFa group), with 3 consecutive injections administered as loading dose therapy. Before treatment and at 1, 2, and 3 months after the first treatment, the maximum height (MH) and maximum diameter (MD) of the PED were measured using optical coherence tomography in each treatment group. RESULTS: In the IVA group, the MH at baseline (215 ± 177 µm) was reduced to 141 ± 150 (P = 0.06), 119 ± 150 (P < 0.01), and 107 ± 150 µm (P < 0.0001) at 1, 2, and 3 months after treatment, respectively. Similarly, in the IVFa group, the MH decreased from 240 ± 195 µm before treatment to 165 ± 170 µm (P = 0.24), 139 ± 142 µm (P < 0.05), and 117 ± 112 µm (P < 0.01) at 1, 2, and 3 months after treatment, respectively. The reduction at 2 and 3 months was significant in both treatments. The mean changes of MH from baseline were -108 ± 142 µm in the IVA group and -124 ± 112 µm in the IVFa group, with no significant difference (P = 0.21). In both groups, the MD did not regress significantly. CONCLUSIONS: The results suggested that the MH of the PED between the IVA and IVFa groups regressed similarly after each loading therapy.
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Inhibidores de la Angiogénesis , Inyecciones Intravítreas , Receptores de Factores de Crecimiento Endotelial Vascular , Proteínas Recombinantes de Fusión , Desprendimiento de Retina , Epitelio Pigmentado de la Retina , Tomografía de Coherencia Óptica , Agudeza Visual , Humanos , Receptores de Factores de Crecimiento Endotelial Vascular/uso terapéutico , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Proteínas Recombinantes de Fusión/uso terapéutico , Proteínas Recombinantes de Fusión/administración & dosificación , Masculino , Femenino , Estudios Retrospectivos , Desprendimiento de Retina/tratamiento farmacológico , Desprendimiento de Retina/diagnóstico , Anciano , Tomografía de Coherencia Óptica/métodos , Inhibidores de la Angiogénesis/uso terapéutico , Epitelio Pigmentado de la Retina/patología , Epitelio Pigmentado de la Retina/efectos de los fármacos , Degeneración Macular Húmeda/tratamiento farmacológico , Degeneración Macular Húmeda/diagnóstico , Degeneración Macular Húmeda/fisiopatología , Anciano de 80 o más Años , Persona de Mediana Edad , Angiografía con Fluoresceína , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidoresRESUMEN
There is an ongoing search for novel biomarkers of endothelial damage, active disease, and organ dysfunction in systemic lupus erythematosus (SLE). We investigated the role of the vascular endothelial growth factor (VEGF) as a candidate biomarker by conducting a systematic review and meta-analysis of studies examining VEGF concentrations in SLE patients and healthy controls. We searched electronic databases (PubMed, Scopus, and Web of Science) from inception to 31 May 2024 (inclusion criteria: VEGF measurement in SLE patients and healthy controls and SLE patients with and without active disease or specific organ dysfunction in case-control studies, recruitment of adult participants, and availability of the full text in the English language; exclusion criteria: non-case-control studies, participants under 18 years, articles reporting duplicate or irrelevant data, and animal studies). We assessed the risk of bias and the certainty of evidence using the JBI Critical Appraisal Checklist and GRADE, respectively (PROSPERO registration number: CRD42024561636). Circulating VEGF concentrations were significantly higher in SLE patients than in controls (22 studies; standardised mean difference, SMD = 0.71, 95% CI 0.44 to 0.98, p < 0.001; low certainty of evidence). In SLE patients, VEGF concentrations were significantly higher in those with active disease (six studies; SMD = 1.10, 95% CI 0.27 to 1.92, p = 0.009; very low certainty of evidence) and lupus nephritis (four studies; SMD = 0.80, 95% CI 0.03 to 1.57, p = 0.042; very low certainty of evidence). Only one study reported VEGF concentrations in SLE patients with and without pulmonary arterial hypertension. The effect size of the differences in VEGF concentrations between SLE patients and controls was not associated with disease duration, use of glucocorticoids and immunosuppressors, biological matrix assessed, or analytical method used. However, it was significantly associated with the study's geographical location. The evidence was limited by the high but partially explainable heterogeneity and the presence of publication bias which was addressed with the "trim-and-fill" method (SLE presence), the high but partially explainable heterogeneity and lack of assessment of publication bias because of the limited study number (active disease), and the limited study number preventing the identification of sources of heterogeneity, sensitivity analysis, and assessment of publication bias (lupus nephritis). Our results highlight VEGF's potential role as a SLE biomarker and the need for further research, also given the aforementioned limitations, investigating VEGF concentrations in a wide range of SLE patient subgroups.
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Biomarcadores , Lupus Eritematoso Sistémico , Factor A de Crecimiento Endotelial Vascular , Lupus Eritematoso Sistémico/sangre , Humanos , Biomarcadores/sangre , Factor A de Crecimiento Endotelial Vascular/sangre , Adulto , Estudios de Casos y Controles , FemeninoRESUMEN
Tumor proliferation and metastasis are intricately linked to blood vessel formation, with vascular endothelial growth factor (VEGF) playing a pivotal role in orchestrating angiogenesis throughout tumor progression. Pseudolaric acid B (PAB) has emerged as a potent inhibitor of tumor cell proliferation, migration, and angiogenesis. In efforts to enhance its efficacy, 37 derivatives of PAB were synthesized and assessed for their capacity to suppress VEGF secretion in SiHa cells under hypoxic conditions. Notably, majority of these derivatives exhibited significant inhibition of VEGF protein secretion without inducing cytotoxicity. Among them, compound M2 displayed the most potent inhibitory activity, with an IC50 value of 0.68 µM, outperforming the lead compound PAB (IC50 = 5.44 µM). Compound M2 not only curbed the migration and angiogenesis of HUVECs under hypoxic conditions but also hindered the invasion of SiHa cells. Mechanistic investigations unveiled that compound M2 may impede the accumulation and nuclear translocation of hypoxia-inducible factor 1α (HIF-1α) in SiHa cells, thereby downregulating VEGF expression. This inhibitory effect on HIF-1α was corroborated by experiments utilizing the protease inhibitor MG-132 and protein synthesis inhibitor CHX, indicating that compound M2 diminishes HIF-1α levels by reducing its synthesis. Furthermore, compound M2 was observed to modulate the PI3K/AKT/mTOR and MAPK signaling pathways in tumor cells, thereby regulating HIF-1α translation and synthesis. In vivo studies demonstrated that compound M2 exhibited low toxicity and effectively curbed tumor growth. Immunohistochemistry analyses validated that compound M2 effectively suppressed the expression of HIF-1α and VEGF in tumor tissues, underscoring its potential as a promising therapeutic agent for targeting tumor angiogenesis.