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Open AccessArticle

Visual Outcomes of Anti-VEGF Treatment on Neovascular Age-Related Macular Degeneration: A Real-World Population-Based Cohort Study

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Pharmaceuticals 2023, 16(7), 927; https://doi.org/10.3390/ph16070927 - 26 Jun 2023

Viewed by 561

Abstract

Neovascular age-related macular degeneration (nAMD) leads to visual impairment if not treated promptly. Intravitreal anti-VEGF drugs have revolutionized nAMD treatment in the past two decades. We evaluated the visual outcomes of anti-VEGF treatment in nAMD. A real-life population-based cohort study. The data included [...] Read more.

Neovascular age-related macular degeneration (nAMD) leads to visual impairment if not treated promptly. Intravitreal anti-VEGF drugs have revolutionized nAMD treatment in the past two decades. We evaluated the visual outcomes of anti-VEGF treatment in nAMD. A real-life population-based cohort study. The data included parameters for age, sex, age at diagnosis, laterality, chronicity, symptoms, visual outcomes, lens status, and history of intravitreal injections. A total of 1088 eyes (827 patients) with nAMD were included. Visual acuity was stable or improved in 984 eyes (90%) after an average of 36 ± 25 months of follow-up. Bevacizumab was the first-line drug in 1083 (99.5%) eyes. Vision improved ≥15 ETDRS letters in 377 (35%), >5 ETDRS letters in 309 (28%), and was stable (±5 ETDRS letters) in 298 (27%) eyes after anti-VEGF treatment. The loss of 5 ≤ 15 ETDRS letters in 44 (4%) eyes and ≥15 ETDRS letters in 60 (6%) eyes was noted. At the diagnosis of nAMD, 110 out of 827 patients (13%) fulfilled the criteria for visual impairment, whereas 179 patients (22%) were visually impaired after the follow-up. Improvement or stabilization in vision was noted in 90% of the anti-VEGF-treated eyes with nAMD. In addition, anti-VEGF agents are crucial in diminishing nAMD-related visual impairment. Full article

(This article belongs to the Special Issue Vascular Endothelial Growth Factor (VEGF) and VEGF Receptor Inhibitors in Health and Disease)

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Open AccessArticle

A VEGFB-Based Peptidomimetic Inhibits VEGFR2-Mediated PI3K/Akt/mTOR and PLCγ/ERK Signaling and Elicits Apoptotic, Antiangiogenic, and Antitumor Activities

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Pharmaceuticals 2023, 16(6), 906; https://doi.org/10.3390/ph16060906 - 20 Jun 2023

Viewed by 734

Abstract

Vascular endothelial growth factor receptor 2 (VEGFR2) mediates VEGFA signaling mainly through the PI3K/AKT/mTOR and PLCγ/ERK1/2 pathways. Here we unveil a peptidomimetic (VGB3) based on the interaction between VEGFB and VEGFR1 that unexpectedly binds and neutralizes VEGFR2. Investigation of the cyclic and linear [...] Read more.

Vascular endothelial growth factor receptor 2 (VEGFR2) mediates VEGFA signaling mainly through the PI3K/AKT/mTOR and PLCγ/ERK1/2 pathways. Here we unveil a peptidomimetic (VGB3) based on the interaction between VEGFB and VEGFR1 that unexpectedly binds and neutralizes VEGFR2. Investigation of the cyclic and linear structures of VGB3 (named C-VGB3 and L-VGB3, respectively) using receptor binding and cell proliferation assays, molecular docking, and evaluation of antiangiogenic and antitumor activities in the 4T1 mouse mammary carcinoma tumor (MCT) model showed that loop formation is essential for peptide functionality. C-VGB3 inhibited proliferation and tubulogenesis of human umbilical vein endothelial cells (HUVECs), accounting for the abrogation of VEGFR2, p-VEGFR2 and, subsequently, PI3K/AKT/mTOR and PLCγ/ERK1/2 pathways. In 4T1 MCT cells, C-VGB3 inhibited cell proliferation, VEGFR2 expression and phosphorylation, the PI3K/AKT/mTOR pathway, FAK/Paxillin, and the epithelial-to-mesenchymal transition cascade. The apoptotic effects of C-VGB3 on HUVE and 4T1 MCT cells were inferred from annexin-PI and TUNEL staining and activation of P53, caspase-3, caspase-7, and PARP1, which mechanistically occurred through the intrinsic pathway mediated by Bcl2 family members, cytochrome c, Apaf-1 and caspase-9, and extrinsic pathway via death receptors and caspase-8. These data indicate that binding regions shared by VEGF family members may be important in developing novel pan-VEGFR inhibitors that are highly relevant in the pathogenesis of angiogenesis-related diseases. Full article

(This article belongs to the Special Issue Vascular Endothelial Growth Factor (VEGF) and VEGF Receptor Inhibitors in Health and Disease)

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Open AccessArticle

Suramin Affects the Renal VEGF-A/VEGFR Axis in Short-Term Streptozotocin-Induced Diabetes

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Gabriela Chyła-Danił

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Kornelia Sałaga-Zaleska

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Ewelina Kreft

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Aleksandra Krzesińska

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Sylwia Herman

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Agnieszka Kuchta

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Monika Sakowicz-Burkiewicz

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Małgorzata Lenartowicz

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Maciej Jankowski

Pharmaceuticals 2023, 16(3), 470; https://doi.org/10.3390/ph16030470 - 22 Mar 2023

Viewed by 1160

Abstract

Diabetic nephropathy (DN) accounts for approximately 50% of end-stage renal diseases. Vascular endothelial growth factor A (VEGF-A) is thought to be a critical mediator of vascular dysfunction in DN, but its role is unclear. The lack of pharmacological tools to modify renal concentrations [...] Read more.

Diabetic nephropathy (DN) accounts for approximately 50% of end-stage renal diseases. Vascular endothelial growth factor A (VEGF-A) is thought to be a critical mediator of vascular dysfunction in DN, but its role is unclear. The lack of pharmacological tools to modify renal concentrations further hinders the understanding of its role in DN. In this study, rats were evaluated after 3 weeks of streptozotocin-induced diabetes and two suramin treatments (10 mg/kg, ip). Vascular endothelial growth factor A expression was evaluated by western blot of glomeruli and immunofluorescence of the renal cortex. RT-PCR for receptors Vegfr1 mRNA and Vegfr2 mRNA quantitation was performed. The soluble adhesive molecules (sICAM-1, sVCAM-1) in blood were measured by ELISA and the vasoreactivity of interlobar arteries to acetylcholine was evaluated using wire myography. Suramin administration reduced the expression and intraglomerular localisation of VEGF-A. Increased VEGFR-2 expression in diabetes was reduced by suramin to non-diabetic levels. Diabetes reduced the sVCAM-1 concentrations. Suramin in diabetes restored acetylcholine relaxation properties to non-diabetic levels. In conclusion, suramin affects the renal VEGF-A/VEGF receptors axis and has a beneficial impact on endothelium-dependent relaxation of renal arteries. Thus, suramin may be used as a pharmacological agent to investigate the potential role of VEGF-A in the pathogenesis of renal vascular complications in short-term diabetes. Full article

(This article belongs to the Special Issue Vascular Endothelial Growth Factor (VEGF) and VEGF Receptor Inhibitors in Health and Disease)

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Open AccessArticle

Mechanism Underlying Triple VEGFR Inhibitor Tivozanib-Induced Hypertension in Mice Model

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Wael A. Alanazi

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Abdulrahman S. Alanazi

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Doaa M. El-Nagar

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Abdullah M. Aljuraybah

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Sary Alsanea

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Metab Alharbi

Pharmaceuticals 2023, 16(2), 295; https://doi.org/10.3390/ph16020295 - 14 Feb 2023

Cited by 1 | Viewed by 1115

Abstract

Tivozanib is a triple vascular endothelial growth factor receptor inhibitor, recently approved for the treatment of refractory advanced renal cell carcinoma. Clinical studies showed that around 46% of patients who received tivozanib suffer from hypertension in all grades. Thus, the present study was [...] Read more.

Tivozanib is a triple vascular endothelial growth factor receptor inhibitor, recently approved for the treatment of refractory advanced renal cell carcinoma. Clinical studies showed that around 46% of patients who received tivozanib suffer from hypertension in all grades. Thus, the present study was conducted to identify the role of angiotensin-II (AngII) in the mechanism underlying tivozanib-induced vascular toxicity and hypertension. C57BL/6 male mice received tivozanib (1 mg/kg) with or without losartan (10 or 30 mg/kg) for 3 weeks. Blood pressure was recorded every 3 days, and proteinuria was measured every week. On day 21, all mice were euthanized, and samples were harvested for further analysis. Tivozanib elevated blood pressure until systolic blood pressure reached 163 ± 6.6 mmHg on day 21 of treatment with low urination and high proteinuria. AngII and its receptors, endothelin-1, and oxidative stress markers were significantly increased. While nitric oxide (NO) levels were reduced in plasma and aortic tissues. AngII type 1 receptor blockade by losartan prevented these consequences caused by tivozanib and kept blood pressure within normal range. The results showed that AngII and ET-1 might be potential targets in the clinical studies and management of hypertension induced by tivozanib. Full article

(This article belongs to the Special Issue Vascular Endothelial Growth Factor (VEGF) and VEGF Receptor Inhibitors in Health and Disease)

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Open AccessArticle

Preclinical Studies of Chiauranib Show It Inhibits Transformed Follicular Lymphoma through the VEGFR2/ERK/STAT3 Signaling Pathway

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Pharmaceuticals 2023, 16(1), 15; https://doi.org/10.3390/ph16010015 - 22 Dec 2022

Cited by 3 | Viewed by 1303

Abstract

Transformed follicular lymphoma (t-FL), for which there is no efficient treatment strategy, has a rapid progression, treatment resistance, and poor prognosis, which are the main reasons for FL treatment failure. In this study, we identified a promising therapeutic approach with chiauranib, a novel [...] Read more.

Transformed follicular lymphoma (t-FL), for which there is no efficient treatment strategy, has a rapid progression, treatment resistance, and poor prognosis, which are the main reasons for FL treatment failure. In this study, we identified a promising therapeutic approach with chiauranib, a novel orally developed multitarget inhibitor targeting VEGFR/Aurora B/CSF-1R. We first determined the cytotoxicity of chiauranib in t-FL cell lines through CCK-8, EdU staining, flow cytometry, and transwell assays. We also determined the killing effect of chiauranib in a xenograft model. More importantly, we identified the underlying mechanism of chiauranib in t-FL tumorigenesis by immunofluorescence and Western blotting. Treatment with chiauranib significantly inhibited cell growth and migration, promoted apoptosis, induced cell cycle arrest in G2/M phase, and resulted in significant killing in vivo. Mechanistically, chiauranib suppresses the phosphorylation level of VEGFR2, which has an anti-t-FL effect by inhibiting the downstream MEK/ERK/STAT3 signaling cascade. In conclusion, chiauranib may be a potential therapy to treat t-FL, since it inhibits tumor growth and migration and induces apoptosis by altering the VEGFR2/ERK/STAT3 signaling pathway. Full article

(This article belongs to the Special Issue Vascular Endothelial Growth Factor (VEGF) and VEGF Receptor Inhibitors in Health and Disease)

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Review

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Open AccessReview

Intravitreal Anti-Vascular Endothelial Growth Factor Therapies for Retinal Disorders

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Pharmaceuticals 2023, 16(8), 1140; https://doi.org/10.3390/ph16081140 - 11 Aug 2023

Viewed by 600

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Vascular endothelial growth factors (VEGFs) are key mediator of retinal and choroidal neovascularization as well as retinal vascular leakage leading to macular edema. As such, VEGF plays an important role in mediating visually significant complications associated with common retinal disorders such as diabetic [...] Read more.

Vascular endothelial growth factors (VEGFs) are key mediator of retinal and choroidal neovascularization as well as retinal vascular leakage leading to macular edema. As such, VEGF plays an important role in mediating visually significant complications associated with common retinal disorders such as diabetic retinopathy, retinal vein occlusion, and age-related macular degeneration. Various drugs that inhibit vascular endothelial growth factors (anti-VEGF therapies) have been developed to minimize vision loss associated with these disorders. These drugs are injected into the vitreous cavity in a clinic setting at regular intervals. This article provides an overview of the various anti-VEGF drugs used in ophthalmology and the common retinal conditions that benefit from this therapy. Full article

(This article belongs to the Special Issue Vascular Endothelial Growth Factor (VEGF) and VEGF Receptor Inhibitors in Health and Disease)

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Open AccessReview

Structure-Based Design of Peptides Targeting VEGF/VEGFRs

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Rossella Di Stasi

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Lucia De Rosa

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Luca Domenico D’Andrea

Pharmaceuticals 2023, 16(6), 851; https://doi.org/10.3390/ph16060851 - 07 Jun 2023

Viewed by 757

Abstract

Vascular endothelial growth factor (VEGF) and its receptors (VEGFRs) play a main role in the regulation of angiogenesis and lymphangiogenesis. Furthermore, they are implicated in the onset of several diseases such as rheumatoid arthritis, degenerative eye conditions, tumor growth, ulcers and ischemia. Therefore, [...] Read more.

Vascular endothelial growth factor (VEGF) and its receptors (VEGFRs) play a main role in the regulation of angiogenesis and lymphangiogenesis. Furthermore, they are implicated in the onset of several diseases such as rheumatoid arthritis, degenerative eye conditions, tumor growth, ulcers and ischemia. Therefore, molecules able to target the VEGF and its receptors are of great pharmaceutical interest. Several types of molecules have been reported so far. In this review, we focus on the structure-based design of peptides mimicking VEGF/VEGFR binding epitopes. The binding interface of the complex has been dissected and the different regions challenged for peptide design. All these trials furnished a better understanding of the molecular recognition process and provide us with a wealth of molecules that could be optimized to be exploited for pharmaceutical applications. Full article

(This article belongs to the Special Issue Vascular Endothelial Growth Factor (VEGF) and VEGF Receptor Inhibitors in Health and Disease)

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Open AccessReview

Aptamers Versus Vascular Endothelial Growth Factor (VEGF): A New Battle against Ovarian Cancer

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Pharmaceuticals 2023, 16(6), 849; https://doi.org/10.3390/ph16060849 - 06 Jun 2023

Viewed by 818

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Cancer is one of the diseases that causes a high mortality as it involves unregulated and abnormal cell growth proliferation that can manifest in any body region. One of the typical ovarian cancer symptoms is damage to the female reproductive system. The death [...] Read more.

Cancer is one of the diseases that causes a high mortality as it involves unregulated and abnormal cell growth proliferation that can manifest in any body region. One of the typical ovarian cancer symptoms is damage to the female reproductive system. The death rate can be reduced through early detection of the ovarian cancer. Promising probes that can detect ovarian cancer are suitable aptamers. Aptamers, i.e., so-called chemical antibodies, have a strong affinity for the target biomarker and can typically be identified starting from a random library of oligonucleotides. Compared with other probes, ovarian cancer targeting using aptamers has demonstrated superior detection effectiveness. Various aptamers have been selected to detect the ovarian tumor biomarker, vascular endothelial growth factor (VEGF). The present review highlights the development of particular aptamers that target VEGF and detect ovarian cancer at its earliest stages. The therapeutic efficacy of aptamers in ovarian cancer treatment is also discussed. Full article

(This article belongs to the Special Issue Vascular Endothelial Growth Factor (VEGF) and VEGF Receptor Inhibitors in Health and Disease)

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Open AccessEditor’s ChoiceReview

Recombinant Endostatin as a Potential Radiosensitizer in the Treatment of Non-Small Cell Lung Cancer

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Pharmaceuticals 2023, 16(2), 219; https://doi.org/10.3390/ph16020219 - 31 Jan 2023

Viewed by 2216

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Non-small cell lung cancer (NSCLC) is the most prevalent type of lung cancer, which is the leading cause of cancer-related deaths worldwide. Over the past decades, tumour angiogenesis has been intensely studied in the treatment of NSCLC due to its fundamental role in [...] Read more.

Non-small cell lung cancer (NSCLC) is the most prevalent type of lung cancer, which is the leading cause of cancer-related deaths worldwide. Over the past decades, tumour angiogenesis has been intensely studied in the treatment of NSCLC due to its fundamental role in cancer progression. Several anti-angiogenic drugs, such as recombinant endostatin (RE), have been evaluated in several preclinical and clinical trials, with mixed and often disappointing results. However, there is currently an emerging interest in RE due to its ability to create a vascular normalization window, which could further improve treatment efficacy of the standard NSCLC treatment. This review provides an overview of preclinical and clinical studies that combined RE and radiotherapy for NSCLC treatment. Furthermore, it highlights the ongoing challenges that have to be overcome in order to maximize the benefit; as well as the potential advantage of combinations with particle therapy and immunotherapy, which are rapidly gaining momentum in the treatment landscape of NSCLC. Different angiogenic and immunosuppressive effects are observed between particle therapy and conventional X-ray radiotherapy. The combination of RE, particle therapy and immunotherapy presents a promising future therapeutic triad for NSCLC. Full article

(This article belongs to the Special Issue Vascular Endothelial Growth Factor (VEGF) and VEGF Receptor Inhibitors in Health and Disease)

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