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The receptor tyrosine kinase EphB4 is involved in tumor angiogenesis, proliferation, and metastasis. Designed ankyrin repeat proteins (DARPins) binding to the EphB4 extracellular domain were identified from a combinatorial library using phage display. Surface plasmon resonance (SPR) allowed us to distinguish between DARPins that either compete with the EphB4 ligand ephrin-B2 for binding to a common site or target a different epitope. The identified DARPins all prevent ligand-induced EphB4 phosphorylation and impair tube formation by endothelial cells in vitro. The competitive DARPin AB1 was additionally shown to inhibit vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF)-induced angiogenesis in vivo. In summary, we have isolated DARPins that exert antiangiogenic effects by specifically binding to EphB4 and may potentially lead to new cancer therapeutics.

Inhibition of angiogenesis, either as monotherapy or in conjunction with other treatments, holds significant promise in cancer treatment. However, the limited efficacy of clinically approved anti-angiogenic agents underscores the urgent need for the development of novel drugs and therapeutic strategies. In this study, we demonstrate the highly selective inhibitory effects of clioquinol, a topical antifungal and antibiotic agent, on the angiogenic activity of endothelial cells (ECs) in a series of in vitro angiogenesis assays. Moreover, clioquinol effectively suppressed blood vessel formation in ex vivo aortic ring and in vivo Matrigel plug assays. Mechanistic studies revealed that clioquinol directly binds to the ATP-binding site of vascular endothelial growth factor receptor 2 (VEGFR2), promoting its degradation through both proteasome and lysosome pathways. This led to the down-regulation of the downstream extracellular signal-regulated kinase (ERK) pathway. In addition, the combination with the AKT inhibitor MK-2206 synergistically boosted the anti-angiogenic efficacy of clioquinol in vitro and in an in vivo dorsal skinfold chamber model of triple-negative breast cancer (TNBC), leading to the suppression of TNBC growth. Accordingly, clioquinol, either alone or in combination with AKT inhibitors, represents a promising therapeutic agent for future anti-angiogenic cancer treatment., Competing Interests: Declarations. Ethical approval: All experiments involving mice were conducted in compliance with the German legislation governing animal welfare and the principles outlined in the Guide for the Care and Use of Laboratory Animals (8th Edition, 2011). Protocols for these experiments were approved by the local animal protection committee (permit number: 01/2019). Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Numerous diseases, such as diabetic retinopathy and age-related macular degeneration, can lead to retinal neovascularization, which can seriously impair the visual function and potentially result in blindness. The presence of the blood-retina barrier makes it challenging for ocularly administered drugs to penetrate physiological barriers and reach the ocular posterior segments, including the retina and choroid. Herein, we developed an innovative bifunctional peptide, Tat-C-RP7, which exhibits excellent penetration capabilities and antiangiogenic properties aimed at treating retinal neovascularization diseases. RP7 is an NRP-1 targeting peptide that blocks vascular endothelial growth factor receptor-2 (VEGFR-2) signaling and inhibits angiogenesis, while Tat facilitates the delivery of various cargoes across biological barriers, such as the blood-retina barrier. By combining these attributes, Tat-C-RP7 is anticipated to traverse ocular barriers via ocular topical administration and exert its antiangiogenic effects in the ocular posterior segment. Experimental results demonstrated that Tat-C-RP7 significantly inhibited the proliferation and migration of rat retinal microvascular endothelial cells and effectively reduced tubule formation in vitro . Its antiangiogenic activity was confirmed in zebrafish. The outstanding penetrative capabilities of FITC-labeled Tat-C-RP7 have been validated through cell uptake assays, in vitro cell barrier models, ex-vivo ocular tissues, and in vivo studies. Besides, the half-life of Tat-C-RP7 was longer than that of RP7. In an oxygen-induced retinopathy model, Tat-C-RP7 was shown to reduce the area of angiogenesis following ocular administration. Additionally, it produced no irritating effects on the eyes of rabbits. Overall, Tat-C-RP7 demonstrates excellent ocular penetrability and antiangiogenic effects and represents a promising therapeutic option for treating retinal neovascularization diseases.

Antibody therapy has become a mature cancer treatment strategy, but only one antibody drug, bevacizumab (BEV) has been approved to treat glioblastoma (GBM). The natural blood-brain barrier (BBB) significantly limits the penetration of therapeutic antibodies into the brain. In this study, an antibody delivery platform based on exosomes (EXOs) has been developed, which can cross the BBB and effectively enter the brain tissue to deliver BEV for safe and effective GBM therapy. In vitro experiments have shown that EXO-BEV could efficiently penetrate the BBB and significantly inhibit the migration of endothelial cells. Biodistribution studies in vivo have revealed that EXO serves as an effective carrier for transporting a higher concentration of BEV across the BBB into the brain. Furthermore, in vivo antiglioma experiments have illustrated that the introduction of EXO-BEV into the brain can improve the degeneration of pathological tissues, increase the apoptosis of tumor cells, and significantly extend the survival time of the model animals. All of the results suggested that EXO-BEV could cross the BBB, thereby enhancing the apoptosis of tumor cells and mitigating angiogenesis in GBM. In conclusion, this innovative platform for antibody delivery emerges as a highly promising therapeutic strategy for the clinical treatment of GBM and other neurological disorders.

General modeling strategies for sporadic cerebral small blood vessel diseases (CSVDs) include limiting blood stream in large blood vessels and inducing systemic hypertension, in which small blood vessel deficit is either a secondary or concomitant pathology. In the current study, we introduce that intra-cisterna-magna Bevacizumab injection (ICM-BI) directly causes cerebral small blood vessel injury by neutralizing VEGF-A, the indispensable growth factor for angiogenesis. ICM-BI reproduces neuro-functional impairment, tight junction loss, cerebral micro-bleeds (CMBs), amyloid peptide accumulation, neuronal injury, white matter loss, and glial cell activation, which are common manifestations of sporadic CSVDs. Compared with existing CSVD models, small blood vessel injury is more prominent in the ICM-BI brain. Moreover, no significant alteration in large blood vessels or peripheral organs after ICM-BI is recorded. We thus propose that ICM-BI is a neat, economic and applicable methodology to establish murine sporadic CSVD model., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Purpose: Metastasis is one of the most important factors contributing to poor prognosis in hepatocellular carcinoma. Radiation therapy (RT), along with its induced abscopal effect, is a promising treatment for metastatic patients. However, the incidence of abscopal effect in clinical practice is rare, even when RT is combined with immune checkpoint inhibitors (ICIs). In this study, we aim to investigate the role of antiangiogenic treatment on the abscopal effect induced by RT + ICIs., Methods and Materials: Bilateral subcutaneous and orthotopic Hepa1-6 and Hep53.4 models were established and treated with different combination treatments. We evaluated changes in the immune microenvironment and vascular normalization by flow cytometry, T cell receptor sequencing, chemotactic gene array, enzyme linked immunosorbent assays, and immunofluorescence., Results: Our studies showed that antiangiogenic treatment with RT + ICIs increased the antitumor response of the unirradiated lesions. Mechanistically, the blockade of vascular endothelial receptor 2 (anti-VEGFR2) increased the activation and maturation of dendritic cells and promoted the production of CD8 + T cells in irradiated tumors. These CD8 + T cells were attracted by anti-VEGFR2-induced CCL5 secretion from M1 macrophages in unirradiated tumors. Besides that, anti-VEGFR2 enhanced the function of CD8 + T cells by reducing myeloid-derived suppressor cells and regulatory T cells., Conclusions: This study demonstrated that the combination of antiangiogenic treatment with RT and ICIs enhanced the abscopal effects. The application of triple therapy and its induced abscopal effect may offer a novel therapeutic approach for hepatocellular carcinoma, particularly for cases with multiple metastatic lesions., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Aims: Angiogenesis is tightly controlled by growth factors and cytokines in pathophysiological settings. Despite the importance of Interleukin 29 (IL-29), a newly identified cytokine of type III interferon family, its role in angiogenesis remains unknown. We aimed to elucidate IL-29's impact on angiogenesis under both and physiological and pathological conditions., Methods: We employed various assays to evaluate IL-29's effect on proliferation, apoptosis, migration and tube formation of human umbilical vein endothelial cells (HUVEC) in vitro. IL-29's angiogenic effect was assessed using mouse aortic rings ex vivo, and oxygen-induced retinopathy (OIR) mouse model in vivo. Signaling pathways possibly involved in IL-29-induced angiogenesis were investigated by Western blot. Finally, IL-29's impact on tube formation was blocked by inhibiting IL-29/interleukin 10 receptor 2 (IL-10R2) binding., Results: IL-29 treatment inhibited endothelial cell migration, tube formation and vessel sprouting, without affecting proliferation or apoptosis. Notably, IL-29 (100 ng/ml) attenuated vessel growth in pathological angiogenesis in OIR mice, accompanied by decreased expression of vascular endothelial growth factor (VEGF) and hypoxia inducible factor-1α (HIF-1α). Mechanistically, IL-29 activated Stat3 signaling pathway, and blocking IL-29/IL-10R2 binding remarkably reversed IL-29's anti-angiogenic effect on tube formation., Conclusions: Our findings demonstrated that IL-29, at a relative low concentration, modulates angiogenesis in both physiological and pathological contexts. Targeting IL-29 or its receptor IL-10R2 offers a promising strategy for angiogenesis regulation in various conditions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier Ltd. All rights reserved.)

Suppressing vascular endothelial growth factor (VEGF), its receptor (VEGFR2), and the VEGF/VEGFR2 signaling cascade system to inhibit angiogenesis has emerged as a possible cancer therapeutic target. The present work was designed to discover and evaluate bioactive phytochemicals from the Clerodendrum inerme (L.) Gaertn plant for their anti-angiogenic potential. Molecular docking of twenty-one phytochemicals against the VEGFR-2 (PDB ID: 3VHE) protein was performed, followed by ADMET profiling and molecular docking simulations. These investigations unveiled two hit compounds, cirsimaritin (- 12.29 kcal/mol) and salvigenin (- 12.14 kcal/mol), with the highest binding energy values when compared to the reference drug, Sorafenib (- 15.14 kcal/mol). Furthermore, only nine phytochemicals (cirsimaritin and salvigenin included) obeyed Lipinski's rule of five and passed ADMET filters. Molecular dynamics simulations run over 100 ns revealed that the protein-ligand complexes remained stable with minimal backbone fluctuations. The binding free energy values of cirsimaritin (- 52.35 kcal/mol) and salvigenin (- 55.89 kcal/mol), deciphered by MM-GBSA analyses, further corroborated the docking interactions. The HOMO-LUMO band energy gap (ΔE) was calculated using density-functional theory (DFT) and substantiated using density of state (DOS) spectra. The chemical reactivity analyses revealed that salvigenin exhibited the highest chemical softness value (6.384 eV), the lowest hardness value (0.07831 eV), and the lowest ΔE value (0.1566 eV), which implies salvigenin was less stable and chemically more reactive than cirsimaritin and sorafenib. These findings provide further evidence that cirsimaritin and salvigenin have the ability to prevent angiogenesis and the development of cancer. Nevertheless, more in vitro and in vivo confirmation is necessary., Competing Interests: Declarations. Conflicts of interest: The authors declare they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Ethics approval: Not applicable. Consent to participate: Yes. All authors agreed to participate in this research. Consent for publication: Yes. All authors have approved the last version of the manuscript for its submission., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Ursolic acid (UA) is an abundant natural product and has shown great promise for treating diseases related to the appearance of new blood vessels. However, its clinical use is limited due to its low solubility in aqueous media, resulting in reduced bioavailability. The present study aimed to synthetize poly(lactic-co-glycolic acid) nanoparticles loaded with UA by nanoprecipitation method and to evaluate the toxicity and anti-angiogenic activity using the in vivo chorioallantoic model. The nanoparticles were obtained in the size range that varied from 103.0 to 169.3 nm, they presented a uniform distribution (polydispersity index <0.2), and a negatively charged surface, with an encapsulation efficiency close to 50%. The release profile of the developed nanoformulation showed an initial burst in the first 2 h and demonstrated no acute toxicity (irritation index <0.9). Moreover, the chorioallantoic assay showed a significant reduction in both geometrical and topological parameters compared to saline control ( p  < .05). In conclusion, the study revealed a quick and simple way to obtain poly(lactic-co-glycolic) acid nanoparticles, a drug delivery system to UA, which showed potential antiangiogenic action and can be used to treat diseases involving neovascularisation.

Ethnopharmacological Relevance: Gekko swinhonis Guenther, commonly referred to as Gecko in the following text, belongs to the genus Gekko within the family Gekko. Its dried whole body is a widely utilized traditional Chinese medicine, demonstrating significant efficacy in the treatment of gastrointestinal malignancies, particularly gastric cancer (GC). Nevertheless, the composition of the gecko is complex, necessitating further research into its active ingredients for the treatment of GC., Aim of the Study: Isolation and characterization of the most active components in Gecko based on their anti-GC mechanisms of vascular endothelial cell inhibition and anti-neovascularization., Materials and Methods: We utilized the enzymatic hydrolysate of Geckos to investigate its effectiveness and underlying mechanisms. Initially, we assessed its efficacy in ectopic and in-situ GC tumor-bearing mouse models. Subsequently, we evaluated the effectiveness of peptides, aliphatics, and small molecules derived from Gecko using CCK-8 and 3D tumor spheroid assays. The activities of peptides S1-S4 were further examined through these experiments. Finally, we screened, synthesized, and investigated five potential peptides for their pharmacodynamics in the CCK-8 assay and in the in-situ GC model mice., Results: The Gecko can inhibit the formation of blood vessels in the tumor microenvironment, providing a localized treatment for GC. The peptide components significantly inhibit vascular endothelial cells and impede the formation of new blood vessels, with the S2 peptide sections (0.3 KD - 3 KD) demonstrating the most potent inhibitory activity against angiogenesis. One of the active peptides effectively suppresses the growth of in-situ GC in nude mice through angiogenesis inhibition and also modulates immunity, all while exhibiting excellent biosafety., Conclusions: We have achieved a significant breakthrough in the local treatment of GC using Gecko. Through pharmacodynamic experiments and a systematic process of isolation and identification, we identified the most effective anti-GC ingredients of Gecko, based on their mechanisms of inhibiting vascular endothelial cells and promoting anti-angiogenesis. Furthermore, we synthesized a lead peptide that demonstrates promising therapeutic efficacy and safety., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Excessive vascularization during tracheal in-stent restenosis (TISR) is a significant but frequently overlooked issue. We developed an anti-inflammatory coupled anti-angiogenic airway stent (PAGL) incorporating anlotinib hydrochloride and silver nanoparticles using advanced electrospinning technology. PAGL exhibited hydrophobic surface properties, exceptional mechanical strength, and appropriate drug-release kinetics. Moreover, it demonstrated a remarkable eradication effect against methicillin-resistant Staphylococcus aureus. It also displayed anti-proliferative and anti-angiogenic properties on human umbilical vein endothelial cells and lung fibroblasts. PAGL was implanted into the tracheae of New Zealand rabbits to evaluate its efficacy in inhibiting bacterial infection, suppressing the inflammatory response, reducing angiogenesis, and attenuating excessive fibroblast activation. RNA sequencing analysis revealed a significant downregulation of genes associated with fibrosis, intimal hyperplasia, and cell migration following PAGL treatment. This study provides insight into the development of airway stents that target angiogenesis and inflammation to address problems associated with TISR effectively and have the potential for clinical translation., Competing Interests: Declarations. Ethics approval and consent to participate: All animal experiments were granted approval by the animal care committee of the First Affiliated Hospital of Zhengzhou University (2023042602). Consent for publication: Written informed consent for publication was obtained from all participants. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Adenomyosis is characterized by abnormal uterine bleeding, dysmenorrhea and subfertility. Increased expression of angiogenesis markers in adenomyosis presents a treatment opportunity and was studied in an adenomyosis mouse model. Mice were administered tamoxifen (1 mg/kg) on neonatal days 2-5. At six weeks of age, mice received oral treatment with axitinib 3 mg/kg ('dose I/AX3', n = 34), axitinib 25 mg/kg ('dose II/AX25' n = 34), or with vehicle-only ('placebo', n = 34). The prevalence and severity of adenomyosis were assessed. An adenomyosis severity index was calculated by multiplying mean grade/mouse by the percentage affected surface area. Angiogenesis-related gene expression was evaluated using real-time quantitative PCR. 101 mice completed adenomyosis induction and could be analyzed. The prevalence of adenomyosis was 30/33 (90.0%) in dose I, 29/34 (85.3%) in dose II, and 30/34 (88.2%) in placebo treated mice (p = 0.78). High grade (2/3) adenomyosis was significantly less prevalent in mice treated with axitinib dose II (n = 19, 55.9%) than in the placebo group (n = 27, 79.4%, p < 0.05). The adenomyosis severity index was reduced by 48% in the axitinib-treated groups (dose I, p < 0.05). The expression of angiogenic growth factors was reduced in the dose I and II axitinib-treated groups compared to the placebo-treated group. Following these promising first results, further research should focus on commonality among different angiostatic drugs, potential side effects, as well as the method and timing of application., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests., (© 2025. The Author(s).)

In this study, the in vitro photodynamic therapy (PDT) activity of two zinc phthalocyanines (ZnPc1 and ZnPc2) was systematically examined in human umbilical vein endothelial cells, focusing on PDT-induced cytotoxicity, reactive oxygen species (ROS) generation, and inhibition of angiogenic processes. Both the ZnPcs demonstrated minimal cytotoxicity in the absence of light, confirming their safety as photosensitizers. ZnPc-PDT led to significant cell death via apoptosis. ZnPc1 exhibited enhanced ROS generation, particularly at elevated concentrations. Furthermore, ZnPc1-mediated PDT showed more pronounced inhibition of endothelial cell migration, invasion, and capillary-like tube formation than ZnPc2. Wound-healing assays revealed a substantial delay in human umbilical vein endothelial cell (HUVEC) migration following ZnPc1-PDT, which also displayed a more significant inhibition of VEGF-induced directional migration and invasion. Endothelial tube formation was more effectively disrupted by ZnPc1-PDT, even at lower concentrations, compared to ZnPc2. Collectively, these findings highlight the superior cytotoxic and anti-angiogenic properties of ZnPc1 compared with ZnPc2, highlighting its potential as a highly effective photosensitizer for photodynamic therapy. The ability of ZnPc1 to simultaneously target tumor cells and disrupt angiogenesis establishes it as a potent candidate for integrated cancer therapies that combine both antitumor and antiangiogenic strategies, offering a more effective approach to combat cancer progression., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Dual inhibition of the angiopoietin (Ang)/Tie and vascular endothelial growth factor (VEGF) signalling pathways in patients with retinal diseases, such as neovascular age-related macular degeneration (nAMD) and diabetic macular oedema (DME), may induce greater vascular stability and contribute to increased treatment efficacy and durability compared with treatments that only target the VEGF pathway. Faricimab, a bispecific intravitreal agent that inhibits both VEGF and Ang-2, is the first injectable ophthalmic drug to achieve treatment intervals of up to 16 weeks in Phase 3 studies for nAMD and DME while exhibiting improvements in visual acuity and retinal thickness. Data from real-world studies have supported the safety, visual and anatomic benefits and durability of faricimab, even in patients who were previously treated with other intravitreal agents. These evidence-based expert recommendations from a panel of retina specialists consolidate current evidence with clinical experience for the optimal use of faricimab in patients with nAMD or DME, with a focus on switching from an anti-VEGF agent to faricimab., Competing Interests: Competing interests: DTW has received consulting fees from AbbVie, Alcon, Apellis, Astellas, Bausch Health, Bayer, Biogen, Hoffmann-La Roche, Novartis, Regeneron, Ripple Therapeutics and Zeiss and has received grants/research support from Bayer, Hoffmann-La Roche and Novartis. SA has been a consultant for Hoffmann-La Roche, Bayer, Novartis and Apobiologix and a speaker for Hoffmann-La Roche. DM has been an advisor for Alcon, Apellis, Bayer, Hoffmann-La Roche, Novartis, Novo Nordisk and Preceyes and has received research support from Alcon, Apellis, Bayer, Ionis, Janssen, Opthea, RegenXBio, Preceyes and Hoffmann-La Roche. SS has been a consultant to Novartis, Bayer, Biogen and Hoffman-La Roche and has received research funding from Novartis and Bayer. DY has received honoraria from Hoffmann-La Roche, Bayer, Novartis and Apellis and has received research grants from Hoffmann-La Roche and Alimera Sciences., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Bevacizumab is an anti-angiogenic therapeutic agent that targets vascular endothelial growth factor (VEGF) and has been approved for the treatment of several types of cancer, including colon cancer. Herein, a GC-MS based metabolomics approach was employed to investigate the impact of bevacizumab on the serum metabolome of colon cancer rats. Multivariate chemometric analysis models such as PCA and PLS-DA showed a clear separation between the control, cancer and bevacizumab-treated groups, suggesting that bevacizumab administration induced significant metabolic alterations. Furthermore, pairwise comparisons between the studied groups using the OPLS-DA model in addition to univariate analysis identified several discriminatory metabolites belonged to various chemical classes including amino acids, organic acids and fatty acids that were perturbed between the studied groups. Interestingly, bevacizumab treatment was able to partially restore some of the cancer-induced metabolic disturbances, indicating its potential therapeutic efficacy via improving the tumor vasculature and nutrient delivery. Besides, pathway analysis of the differential metabolites identified key metabolic pathways affected by bevacizumab, which included valine, leucine and isoleucine metabolism, pyruvate metabolism and butanoate metabolism. However, little effects were observed on lipid metabolites such as palmitic acid and stearic acid and consequently their related metabolic pathways such as fatty acid biosynthesis metabolism suggesting that bevacizumab has more prominent effect on energy and amino acid metabolisms as compared to fatty acid metabolism in colon cancer rats. Overall, our study provided novel insights into the metabolic mechanisms underlying the therapeutic effects of bevacizumab in colon cancer rats via the use of a comprehensive GC-MS metabolomics approach., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation leading to joint damage and systemic complications. Angiogenesis promotes inflammation and contributes to RA progression. This study evaluated potential anti-angiogenic effects of several compounds including small-molecule kinase inhibitors, such as sunitinib (pan-kinase inhibitor), tofacitinib (JAK-inhibitor), NIKi (NF-κB-inducing kinase inhibitor), and the integrin-targeting peptide fluciclatide, using a scratch assay and 3D spheroid-based models of angiogenesis. For all drugs tested in the low micromolar range (1-25 μM), sunitinib (as positive anti-angiogenetic control) showed marked inhibition of endothelial cell (EC) migration and sprouting, effectively reducing both scratch closure and sprout formation. Tofacitinib exhibited marginal effectiveness in the scratch assay, but performed better in the 3D models (55% inhibition), whereas NIKi showed around 50% anti-angiogenic effects in both models. Fluciclatide changed EC morphology rather than migration, and only when stimulated with synovial fluid in spheroid model did it show inhibitory effects (at ≥2.5 µM), with none below this dosage. These results highlight the potential of NIKi and tofacitinib for angiogenesis inhibition and of fluciclatide for safe diagnostic targeting of microdose in RA, as well as the need for advanced screening models that mimic RA's complex inflammatory pro-angiogenic environment.

Autophagic dysfunction-induced deterioration of the retinal microenvironment drives the progression of wet age-related macular degeneration (wAMD). The efficacy of single-target anti-VEGF antibodies in treating wAMD has long been suboptimal due to the intricate interplay between autophagy dysfunction, oxidative stress, and angiogenesis. Here, we introduce an intravitreal hydrogel depot, named Rab&Rapa-M@G, consisting of rapamycin-loaded microemulsion (Rapa-M, an mTOR inhibitor), ranibizumab (anti-VEGF antibody), and a thermosensitive hydrogel matrix. A single intravitreal injection of Rab&Rapa-M@G can sustainably deliver Rapa-M and ranibizumab to the retinal pigment epithelium for at least 14 days. This formulation significantly improves retinal autophagic flux homeostasis and reduces oxidative stress injury in wAMD mice by modulating the AMPK/mTOR/HIF-1α/VEGF and AMPK/ROS/HO-1/VEGF pathways. Consequently, it synergistically disrupts the "autophagic dysfunction-oxidative stress-angiogenesis" loop, leading to a remarkable reduction in choroidal neovascularization area and retinal damage compared to ranibizumab alone. Notably, the sequential administration of ranibizumab and Rab&Rapa-M@G further enhances the overall anti-wAMD efficacy, achieved through sequential delivery of Rab and Rapa, allowing for a more precise grasp of the treatment window. In conclusion, this hydrogel depot design, with its sequential and sustained delivery of mTOR inhibitors and anti-VEGF antibodies, offers a promising strategy for multi-target synergistic therapy in wAMD., Competing Interests: Declaration of competing interest No potential conflict of interest was reported by the authors., (Copyright © 2024. Published by Elsevier B.V.)

Background: Angiogenesis is essential for pannus formation and maintenance in rheumatoid arthritis (RA). Heat shock protein 70 kDa (HSP70) can induce angiogenesis by being released extracellularly through exosomes. Geniposide (GE) is the primary pharmacological component of the fruit of Gardenia jasminoides Ellis (GJ). In vivo, we have found that GE is able to reduce HSP70 levels in the synovium and serum of CIA-S and has anti-angiogenic effects. However, the mechanism by which GE inhibits HSP70 to improve angiogenesis is still unclear. This study aims to explore how GE inhibits the extracellular release of HSP70 and its impact on angiogenesis in human umbilical vein endothelial cells (HUVECs)., Methods: HUVECs' exosomes were extracted using ultracentrifugation and characterized through transmission electron microscope, nanoparticle tracer technology, nano-flow cytometry and Western blotting. The proliferative ability of HUVECs was assessed by EdU and CCK8 assay. Transwell and wound healing assays were used to measure the migration ability of HUVECs, while tube formation assay was employed to evaluate their tube-forming ability. The TNF-α-induced HSP70 release model in HUVECs was established, with extracellular HSP70 levels serving as an evaluation index. Immunofluorescence and co-immunoprecipitation assay were used to analyze the interaction between HSP70 and the lipid raft marker Caveolin-1 (Cav-1). Western blotting was employed to investigate the expression of SphK1/S1P/S1PRs/Gαi pathway-related proteins, and ELISA was utilized to detect extracellular S1P and HSP70 levels., Results: The exosomes of HUVECs contained HSP70. HUVECs were stimulated by extracellular HSP70, which enhanced their proliferation, migration, and tube-forming abilities. TNF-α (10 ng/mL) significantly increased the release of HSP70, which was inhibited by GE (25 µM-100 µM) in a concentration-dependent manner. GE reduced HSP70 in lipid rafts without affecting Cav-1. GE (100 µM) inhibited proteins in the SphK1/S1P/S1PRs/Gαi pathway, preventing HSP70 release and improving HUVECs' functions compared to the K6PC-5 (SphK1-specific agonist) and TNF-α groups., Conclusion: This study found that GE inhibited the extracellular release of HSP70 by suppressing the SphK1/S1P/S1PRs/Gαi pathway, thereby producing anti-angiogenic effects in vitro. This provides a novel direction and strategy for anti-angiogenesis therapy for RA., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Epigenetic therapy has gained interest in treating cardiovascular diseases, but preclinical studies often encounter challenges with cell-type-specific effects or batch-to-batch variation, which have limited identification of novel drug candidates targeting angiogenesis. To address these limitations and improve the reproducibility of epigenetic drug screening, we redesigned a 3D in vitro fibrin bead assay to utilize immortalized human aortic endothelial cells (TeloHAECs) and screened a focused compound library with 105 agents. Compared to the established model using primary human umbilical vein endothelial cells, TeloHAECs needed a higher-density fibrin gel for optimal sprouting, successfully forming sprouts under both normoxic and hypoxic cell culture conditions. We identified two epigenetic enzyme inhibitors as novel regulators of sprouting angiogenesis: A196, a selective SUV4-20H1/H2 inhibitor, demonstrated pro-angiogenic effects through increased H4K20me1 levels and upregulation of cell cycle associated genes, including MCM2 and CDK4. In contrast TMP-269, a selective class IIa HDAC inhibitor, exhibited anti-angiogenic effects by downregulating angiogenesis-related proteins and upregulating pro-inflammatory signaling. These findings highlight the suitability of the modified TeloHAEC fibrin bead assay for drug screening purposes and reveal both pro-angiogenic and anti-angiogenic drug candidates with therapeutic potential., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Tumors and angiogenesis are connected through a complex interplay. VEGF165, generated from both tumor and vascular endothelial cells, serves as a mutual benefit for both cell types. Therapeutic approaches modulating VEGF165 have been proposed as promising antitumor therapies. PROTACs are bifunctional molecules that exploit the intracellular ubiquitin-proteasome system to degrade specific proteins. To date, there are no targeted PROTACs designed to degrade VEGF165 in both tumor and vascular endothelial cells. The aptamer AS1411 is notable for its ability to selectively recognize and enter both tumor and vascular endothelial cells by targeting the cell surface nucleolin (NCL). Moreover, AS1411 has also been repurposed as an intracellular recruiter of E3 ligase MDM2 via leveraging NCL as a molecular bridge. In this study, we conjugated AS1411 with a VEGF165-specific aptamer V7t1, creating hybrid aptamers-engineered PROTACs. The PROTACs demonstrate remarkable selectivity for both tumor and vascular endothelial cells and facilitate the ubiquitination and proteasomal degradation of VEGF165. The PROTACs inhibit the growth of tumor cells and also impede angiogenesis, without causing toxicity to normal tissues. The hybrid aptamers-engineered PROTACs provide an avenue for disrupting the tumor-angiogenesis interplay through modulation of VEGF165 in both tumor and vascular endothelial cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Angiogenesis describes the sprouting of blood vessels from existing vasculatures and it plays a pivotal role in disease progress such as diabetes, age-related macular degeneration and cancer. However, the most widely used anti-angiogenic agents targeting vascular endothelial growth factor (VEGF) pathway still lacked of specificity and therapeutic efficacy. To establish a method suitable for high-throughput drug screening and faithfully recapitulate the feature of in vivo angiogenesis, we generated a PECAM1-mRuby3-secNluc; ACTA2-EGFP dual reporter human pluripotent stem cell (hPSC) line and utilizing the cell line to establish a visualized and quantifiable in vitro angiogenesis model with stem cell-derived vascular organoid. Using this method, we evaluated the anti-angiogenic effect of VEGFR inhibitor and efficiently identified several potential candidates of pro- and anti-angiogenic therapy via bioluminescence-based quantification. Overall, our study provides a valuable platform for in vitro drug screenings., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Supplementary Information: The online version contains supplementary material available., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Chondroitin sulfate (CS), a class of glycosaminoglycans covalently attached to proteins to form proteoglycans, is widely distributed in the extracellular matrix and cell surface of animal tissues. In our previous study, CS was used as a template for the synthesis of seleno-chondroitin sulfate (SeCS) through the redox reaction of ascorbic acid (Vc) and sodium selenite (Na 2 SeO 3 ) and we found that SeCS could inhibit tumor cell proliferation and invasion. However, its effect on angiogenesis and its underlying mechanism are unknown. In this study, we analyzed the effect of SeCS on tube formation in vitro, based on the inhibition of tube formation and migration of human umbilical vein endothelial cells (HUVECs), and evaluated the in vivo angiogenic effect of SeCS using the chick embryo chorioallantoic membrane (CAM) assay. The results showed that SeCS significantly inhibited the angiogenesis of chicken embryo urothelium. Further mechanism analysis showed that SeCS had a strong inhibitory effect on VEGFR2 expression and its downstream PI3K/Akt signaling pathway, which contributed to its anti-angiogenic effects. In summary, SeCS showed good anti-angiogenic effects in an HUVEC cell model and a CAM model, suggesting that it may be a potential angiogenesis inhibitor.

Objective: Anti-angiogenic therapy and immune checkpoint blockade therapy are currently important treatments for non-small cell lung cancer. However, the combined use of the two therapies is controversial, and few studies have investigated the effects of different time sequences of the two therapies on treatment outcomes., Methods: The tumor-bearing mouse model was established and the mice were divided into four groups, including AA-ICB sequence group, ICB-AA sequence group, synchronization group and the control group. Immunohistochemistry was used to assess tumor microvessels and PD-L1 expression. Selected immune cell populations were evaluated using flow cytometry. Meta-analysis and clinical information were used to elucidate the clinical effects of administration sequence., Results: We found that anti-PD-L1 treatment followed by anti-VEGFR2 therapy exerts the best inhibitory effect on tumor growth. Different sequences of anti-angiogenic therapy and immune checkpoint blockade therapy resulted in different proportions of tumor microvessels and immune cell populations in the tumor microenvironment. We further revealed that the administration of anti-PD-L1 before anti-VEGFR brought more normalized tumor blood vessels and CD8 + T cell infiltration and reduced immunosuppressive cells in the tumor microenvironment. Subsequent re-transplantation experiments confirmed the long-term benefits of this treatment strategy. The meta-analysis reinforced that immunotherapy prior to anti-angiogenic therapy or combination therapy have better therapeutic effects in advanced non-small cell lung cancer., Conclusion: Our study demonstrated that the therapeutic effect of anti-angiogenic treatment after immune checkpoint therapy was superior to that of concurrent therapy, whereas anti-angiogenic therapy followed by immunotherapy did not bring more significant clinical benefits than independent monotherapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

In this study, a marine medicinal brown alga Sargassum cristaefolium-derived fungal strain Scytalidium lignicola SC228 has been isolated and identified. Column chromatography of the extracts from liquid-fermented products of the fungal strain was carried out, and led to the purification of eight compounds. Their structures were characterized by spectroscopic analysis, and the absolute configurations were further established by single X-ray diffraction analysis and modified Mosher's method as four previously undescribed compounds, namely scytabenzofurans A-C (1-3), and (3S,4S)-5-chloro-3,4-dihydro-4,6,8-trihydroxy-3-methyl-1H-2-benzopyran-1-one (4), along with four known compounds 5-8. All the isolates were subjected to anti-inflammatory and anti-angiogenic assays. Compounds 1-4, 7, and 8 showed moderate nitric oxide production inhibitory activities in lipopolysaccharide-activated BV-2 microglial cells with IC 50 in the range of 19.6 ± 0.1 to 49.0 ± 1.2 μM in comparison with that of curcumin (IC 50  = 2.7 ± 0.3 μM). Compounds 5-7 exhibited moderate to potent inhibitory effects on EPCs growth with IC 50 in the range of 0.5 ± 0.1 to 42.7 ± 0.9 μM as compared to sorafenib (IC 50  = 5.50 ± 1.50 μM)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Abnormal ocular angiogenesis is a major cause of visual impairment and vision loss in neovascularization-related diseases. Currently, anti-vascular endothelial growth factor (VEGF) drugs are used to treat ocular neovascularization, but repeated injections are needed to maintain their therapeutic effects. However, repeated injection of anti-VEGF drugs may affect the retinal blood vessel phenotype and diminish therapeutic effects. In this study, we aimed to investigate the phenotypic changes in endothelial cells and pericytes caused by the repeated interruption of the VEGF receptor signaling pathway in neonatal rats. KRN633 (10 mg/kg), a VEGF receptor tyrosine kinase inhibitor, was subcutaneously administered on postnatal day (P)-7 and P8 (first round), P14 and P15 (second round), and P21 and P22 (third round). The rat eyes were collected on P7, P9, P14, P16, P21, P23, P28, and P35. Using retinal flat-mount specimens stained with specific markers for vascular endothelial cells, basement membranes, and pericytes, the arteriolar tortuosity, capillary area density, and distribution of pericytes were evaluated. Significant loss of capillaries was observed the day after the first round of KRN633 treatment, after which aggressive angiogenesis occurred, leading to the formation of tortuous arterioles. Rats that completed second and third rounds of KRN633 treatment showed more severe abnormalities in the retinal vasculature than those that only completed first round treatment. Repeated treatment with KRN633 decreased the anti-angiogenic effects but increased the immunoreactivity of α-smooth muscle actin in the pericytes on veins and capillaries. α-Smooth muscle actin expression was inversely correlated to anti-angiogenic effects. Overall, these results revealed that repeated interruption of VEGF receptor signaling pathway altered the phenotypes of endothelial cells and pericytes and induced anti-VEGF drug resistance. Therefore, careful follow-up is necessary when using anti-VEGF drugs to treat abnormal angiogenesis-associated ocular diseases., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: To evaluate the duration of vascular endothelial growth factor (VEGF) suppression in the aqueous humor of macaque eyes after intravitreal faricimab (IVF) injection. Methods: Faricimab (6 mg/50 µL) was injected into the vitreous cavity of the right eye of 6 macaques. Aqueous humor samples (150 μL) were collected from both eyes immediately before injection and on days 1, 3, 7, 14, 21, 28, 42, 56, 84, and 112 after injection. The VEGF concentrations in the aqueous humor were measured using an enzyme-linked immunosorbent assay. Results: The VEGF was undetectable until 4 weeks after IVF injection in 4 eyes and until 6 weeks in the remaining 2 eyes. The mean duration of complete VEGF suppression was 4.7 weeks (range, 4-6 weeks). The VEGF concentration did not decrease in the aqueous humor of the non-injected fellow eyes. Conclusions: Faricimab effectively suppressed the VEGF concentrations in the aqueous humor of macaques for an average of 4.7 weeks after a single intravitreal injection. It did not reduce the VEGF concentrations in the aqueous humor of the fellow eyes.

Developing novel anti‑angiogenic agents with minimal toxicity is notably challenging for cancer therapeutics. The discovery and development of peptides, whether derived from natural sources or synthesized, has potential for developing anti‑angiogenic agents characterized by their ability to penetrate cancer cells, high specificity and low toxicity. The present study identified a Bryopsis plumose ‑derived anticancer and anti‑angiogenesis marine‑derived peptide 06 (MP06). A 22‑amino acid peptide was synthesized and conjugated with fluorescein isothiocyanate (FITC‑MP06) for intracellular localization in H1299 non‑small cell lung cancer cells. Regulatory effects of this peptide on the viability, migration and self‑renewal of lung cancer cells was assessed. Furthermore, anti‑angiogenic effect of MP06 was investigated by monitoring vascular tube formation in human umbilical vein endothelial cells and a zebrafish model. Aquaporin (AQP)3, a membrane channel in various tissues, is involved in regulating stemness, epithelial‑mesenchymal transition (EMT) and angiogenesis. MP06 downregulated AQP3 expression. Consistently, AQP3 knockdown by RNA silencing downregulated its gene expression, leading to a decrease in stemness, EMT and angiogenesis properties in H1299 cells. MP06 could thus serve as a novel therapeutic target with anticancer and angiogenesis properties for non‑small cell lung cancer.

Increasing evidence underscores the pivotal role of tumor angiogenesis for tumorigenesis and tumor metastasis. Inhibiting the tumor angiogenesis process is a promising therapeutic approach for cancer. In order to search for natural angiogenic inhibitors, the chemical constitutes of a marine-derived fungus Eutypella sp. F0219 were investigated, leading to the isolation and identification of twelve new ent-eudesmane sesquiterpenoids named eutypenes A-L (1-12). Their structures including absolute configurations were determined by extensive spectroscopic investigations, single crystal X-ray diffraction analyses, modified Mosher's method, and ECD calculations. Notably, eutypene A (1) represents a rare rearranged ent-eudesmane sesquiterpenoid with 5/7 fused ring system. Tube formation assay was performed to evaluate the antiangiogenic effect of all compounds. The results showed that compounds 4, 6, 7, 9, and 10 obviously suppressed the tube formation of human microvascular endothelial cell line (HMEC-1) cells in a dose-dependent manner. Moreover, the most bioactive and less toxic compound 9 displayed significant antiangiogenic effect in vitro and ex vivo. Further mechanistic investigation revealed that compound 9 restrained tumor angiogenesis by reducing the VEGF-A level and suppressing the VEGF-A/VEGFR2 signaling pathway. Our findings give insight into the application of marine ent-eudesmane sesquiterpenoids as potential angiogenesis inhibitor., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

The cascade of events leading to tumor formation includes induction of a tumor supporting neovasculature, as a primary hallmark of cancer. Developing vasculature is difficult to evaluate in vivo but can be captured using microfluidic chip technology and patient derived cells. Herein, we established an on chip approach to investigate the mechanisms promoting tumor vascularization and vascular targeted therapies via co-culture of cancer spheroids and endothelial cells in a three dimensional environment. Methods: We investigated both, tumor neovascularization and therapy, via co-culture of human derived endothelial cells and adjacently localized metastatic renal cell carcinoma spheroids on a commercially available microfluidic chip system. Metastatic renal cell carcinoma spheroids adjacent to primary vessels model tumor, and induce vessels to sprout neovasculature towards the tumor. We monitored real time changes in vessel formation, probed the interactions of tumor and endothelial cells, and evaluated the role of important effectors in tumor vasculature. In addition to wild type endothelial cells, we evaluated endothelial cells that overexpress Prostate Specific Membrane Antigen (PSMA), that has emerged as a marker of tumor associated neovasculature. We characterized the process of neovascularization on the microfluidic chip stimulated by enhanced culture medium and the investigated metastatic renal cell carcinomas, and assessed endothelial cells responses to vascular targeted therapy with bevacizumab via confocal microscopy imaging. To emphasize the potential clinical relevance of metastatic renal cell carcinomas on chip , we compared therapy with bevacizumab on chip with an in vivo model of the same tumor. Results: Our model permitted real-time, high-resolution observation and assessment of tumor-induced angiogenesis, where endothelial cells sprouted towards the tumor and mimicked a vascular network. Bevacizumab, an antiangiogenic agent, disrupted interactions between vessels and tumors, destroying the vascular network. The on chip approach enabled assessment of endothelial cell biology, vessel's functionality, drug delivery, and molecular expression of PSMA. Conclusion: Observations in the vascularized tumor on chip permitted direct and conclusive quantification of vascular targeted therapies in weeks as opposed to months in a comparable animal model, and bridged the gap between in vitro and in vivo models., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

The development of efficient platforms for the evaluation of anti-angiogenic agents is critical in advancing cancer therapeutics. In this study, we exploited an ultrabright semiconducting polymer dots (Pdots) integrating with a three-dimensional (3D) near-infrared-II (NIR-II) fluorescence imaging system designed to assess the efficacy of potent anti-angiogenic agents PX-478 and BPR0C261 in an oral squamous cell carcinoma (OSCC) tumour model, which depends on angiogenesis for dissemination. PX-478, a hypoxia-inducible factor-1α (HIF-1α) inhibitor, and BPR0C261, a microtubule-disrupting agent, were administrated into tumour-bearing mice established using murine MTCQ1 tongue cancer cells through intraperitoneal injection and oral gavage, respectively. Our findings showed that PX-478 and BPR0C261 significantly inhibited tumour growth and extended the life span of tumour-bearing mice without decreasing the body weights. The Pdots-based NIR-II vascular imaging demonstrated that the tumour vascularity was suppressed by PX-478 and BPRC0261. Accordingly, the excised tumours treated with anti-angiogenic agents showed less blood vessels than that treated with vehicles. The expression of endothelial markers CD31 was also found to be reduced in tumours treated with PX-478 and BPRC0261 using immunohistochemical (IHC) staining and Western blot analysis. Furthermore, PX-478 could suppress the expression of HIF-1α and vascular endothelial growth factor-A (VEGF-A), but BPRC0261 only suppressed VEGF-A. Taken together, this innovative 3D NIR-II imaging system combining the biocompatible Pdots with unique optical specificity enables non-invasive, real-time monitoring the efficacy of anti-angiogenic compounds., (© 2025 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Low-dose antiangiogenic therapies have demonstrated the ability to enhance normalization of tumor vessels, consequently improving hypoxia levels, drug delivery, and promoting anticancer immune responses. Mast cells have been identified as contributors to resistance against antiangiogenic therapy and facilitators of abnormal neoangiogenesis. In this study, we demonstrate that by simultaneously targeting intratumoral mast cells with Imatinib and administering low-dose anti-VEGFR2 therapy, antitumor efficacy can be enhanced in preclinical models. Thus, combinatory treatment overcomes therapy resistance, while concurrently promoting tumor vessel normalization. Notably, histomorphometric analysis of tumor sections revealed that vessel perfusion could be improved through mast cell inhibition and, despite a significantly reduced microvessel density, the combination treatment did not result in elevated tumor hypoxia levels compared to anti-VEGFR2 therapy alone. Short-term Imatinib application effectively increased antitumor efficacy, and by prolonging the application of Imatinib tumor vessel normalization was additionally improved. The combination of mast cell depletion and antiangiogenic treatments has not been investigated in detail and promises to help overcoming therapy resistance. Further studies will be required to explore their impact on other treatment approaches, and subsequently to validate these findings in a clinical setting., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Nowadays, the use of monoclonal antibodies to target angiogenic signalling pathways is common, but, unfortunately, the clinical activity of these agents is limited. Thus, the development of approaches targeting multiple pathways for anti-angiogenic effect will lead to increase the clinical benefit. For this purpose, oleuropein, hesperidin, piperine, proanthocyanidins and retinoic acid, which have previously been proven to be bioactive components, anti-angiogenic performances were experimentally tested in retinal pigment epithelial cells. Bioactive ingredients were applied to retinal pigment epithelial cells at varying doses for 48 h, and then IC 50 doses were calculated by MTT analysis. VEGFA and VEGFR1 protein levels were measured by ELISA analysis. Using the RT-PCR technique, the mRNA expression levels of EGF, EGFR, PDGF, PDGFR-β and HIF1A were analysed. Among all bioactive compounds, the bevacizumab group showed the best anti-VEGF activity, followed by the proanthocyanidins and piperine groups. Piperine group showed EGF, PDGF and HIF1A expressions; proanthocyanidins, on the other hand, reduced EGFR, PDGF and HIF1A expressions. Retinoic acid showed an angiogenic effect by increasing VEGFA protein levels and EGF and PDGFR-β expressions. Although hesperidin increased VEGFA protein levels, it decreased EGF, PDGF, PFGFR-β and HIF1A expression levels. Among the bioactive components stated in previous studies to have anti-angiogenic properties, only proanthocyanidins and piperin had anti-VEGF properties. Considering that angiogenesis does not proceed only through VEGF, this study investigated and reported for the first time the effects of relevant bioactive components on angiogenesis through different mechanisms in retinal pigment epithelial cells., (© 2025 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

The search for effective strategies to target tumour angiogenesis remains a critical goal of cancer research. We present a pioneering approach using alternating electric fields to inhibit tumour angiogenesis and enhance the therapeutic efficacy of bevacizumab. Chicken chorioallantoic membrane, cell viability and in vitro endothelial tube formation assays revealed that electric fields with a frequency of 1000 kHz and an electric intensity of 0.6 V/cm inhibited the growth of vascular endothelial cells and suppressed tumour-induced angiogenesis. In an animal U87MG glioma model, 1000 kHz electric fields inhibited tumour angiogenesis and suppressed tumour growth. As demonstrated by 3D vessel analysis, tumour vasculature in the control group was a stout, interwoven network. However, electric fields transformed it into slim, parallel capillaries that were strictly perpendicular to the electric field direction. This architectural transformation was accompanied by apoptosis of vascular endothelial cells and a notable reduction in tumour vessel number. Additionally, we found that the anti-angiogenesis and tumour-suppression effects of electric fields synergised with bevacizumab. The anti-angiogenic mechanisms of electric fields include disrupting spindle formation during endothelial cell division and downregulating environmental angiogenesis-related cytokines, such as interleukin-6, CXCL-1, 2, 3, 5 and 8, and matrix metalloproteinases. In summary, our findings demonstrate the potential of alternating electric fields (AEFs) as a therapeutic modality to impede angiogenesis and restrain cancer growth., (© 2024 The Author(s). Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.)

Purpose: Angiogenesis is a crucial step in tumorigenesis of glioblastoma (GBM). Bevacizumab, an anti-vascular endothelial growth factor drug, is approved for second-line therapy for GBM. Glioma stem cells, presumably the cell of origin of GBM, take an active role in angiogenesis. The subventricular zone (SVZ) is the brain's largest reservoir of neural stem cells, and GBM near this region (SVZ GBM) is associated with a poor prognosis. This study aims to evaluate the potential impact of second-line bevacizumab treatment on survival in patients with SVZ GBM., Methods: The electronic medical records of adult patients with newly diagnosed SVZ GDM under treated between 1/2011 and 12/2021 were retrospectively reviewed. Clinical, surgical, radiological, and outcome parameters were compared between patients treated with bevacizumab after first relapse to patients without such treatment., Results: The cohort included 67 patients. 45 (67.1%) were treated with bevacizumab after the first relapse while 22 (32.9%) were not. The only statistically significant difference between groups was the rate of re-surgery, which was higher in the non-bevacizumab group (40.9% vs. 15.6%; p = 0.023), indicating that the groups were quite homogenous. In general, bevacizumab as a second-line treatment did not affect OS in SVZ GBM cases. However, it significantly prolongs survival time from 1st relapse by an average of more than 4 months, including after adjustment to re-surgery variable (HR = 0.57, 95% CI 0.34-0.94, p = 0.028 and HR = 0.57, 95%CI = 0.34-0.97, PV = 0.038; respectively). Furthermore, when adjusting to time from diagnosis to 1st relapse, bevacizumab treatment was also associated with prolonged OS (HR = 0.58; p = 0.043). In a subgroup analysis, comparing patients treated with both re-surgery and bevacizumab to patients treated in any other way, patients with the combined treatment had the longest mean OS of the entire cohort (22.16 ± 7.81 m vs. 13.60 ± 6.86, p = 0.049; HR = 0.361 95%CI 0.108-1.209, p = 0.085)., Conclusions: The use of bevacizumab as a second-line therapy in SVZ GBM cases may positively affect survival after relapse, even when given as a monotherapy. Additionally, in certain yet-to-be-identified sub-populations, bevacizumab may even extend overall survival. Further research is required to accurately identify SVZ GBM patients who would benefit most from anti-angiogenic therapy., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Introduction: The treatment of advanced cervical cancer is continuously developing. There is a critical need to explore new treatment options to improve cure rates and make treatment more affordable. Despite efforts in prevention, cervical cancer remains the fourth most common cancer worldwide in terms of both incidence and mortality., Areas Covered: This article offers an updated and critical analysis of angiogenesis inhibitors used in the treatment of advanced cervical cancer. It should be noted that this is not a systematic review., Expert Opinion: Bevacizumab is currently the primary antiangiogenic agent used alongside chemotherapy and has become the standard of care for advanced cervical cancer. However, there are still uncertainties regarding the molecular mechanisms and associations in cervical cancer that could help in optimizing the use of Bevacizumab. Factors such as cost, toxicity, and methodological issues in the GOG-240 trial must be considered.

Objective: Angiogenesis is the process of forming new blood vessels from pre-existing vessels and occurs during development, wound healing, and tumor growth. In this review, we aimed to present a comprehensive view of various factors contributing to angiogenesis during carcinogenesis. Anti-angiogenesis agents prevent or slow down cancer growth by interrupting the nutrients and blood supply to the tumor cells, and thus can prove beneficial for treatment., Method: The discovery of several novel angiogenic inhibitors has helped to reduce both morbidity and mortality from several life-threatening diseases, such as carcinomas. There is an urgent need for a new comprehensive treatment strategy combining novel anti-angiogenic agents for the control of cancer. The article contains details of various angiogenic inhibitors that have been adopted by scientists to formulate and optimize such systems in order to make them suitable for cancer., Results: The results of several researches have been summarized in the article and all of the data support the claim that anti-angiogenic agent is beneficial for cancer treatment., Conclusion: This review focuses on novel antiangiogenic agents that play a crucial role in controlling carcinogenesis., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Purpose: Antiangiogenesis therapy has become a hot field in cancer research. Given that tumor blood vessels often express specific markers related to angiogenesis, the study of these heterogeneous molecules in different tumor vessels holds promise for advancing anti-angiogenic therapy. Previously using phage display technology, we identified a targeting peptide named GX1 homing to gastric cancer vessels for the first time. However, GX1 also showed some non-specific binding with normal gastric vessels, which can lead to toxic side effects on normal endothelial cells. Therefore, we urgently need to adopt new screening strategies to avoid non-specific binding to normal vessels and obtain gastric cancer vascular targeting peptides with higher specificity., Methods: In this study, we designed a new strategy which combined "positive screening" in vivo and "negative screening" in vitro for the first time. An in vivo positive screening was conducted using tumor bearing nude mice to identify peptides that were specifically enriched within the vasculature of gastric cancer. Concurrently, an in vitro negative screening process was conducted on normal vasculature endothelial cells, including human umbilical vein endothelial cells (HUVECs) and human microvascular endothelial cells (HMVECs), to eliminate peptides binding to normal vasculature. After four rounds of iterative screening, a targeting peptide specifically targeting gastric cancer vasculature was obtained. In addition, an in vitro co-culture model by culturing HUVEC in tumor conditioned medium (Co-HUVEC) was established to investigate the affinity of these peptides. The targeting peptide was labeled with fluorescein isothiocyanate (FITC) for competitive and inhibitory assays., Results: Blood vessel density analysis confirmed redundant capillary vessels in the xenografts, indicating that the mouse model was suitable for positive screening. Following four rounds of panning, a significant enrichment for phages specifically binding to gastric cancer vasculature was observed, with minimal binding to normal endothelial cells. The peptide CNTGSPYEC exhibited the highest reproducibility. In vitro immunofluorescence staining confirmed that the peptide CNTGSPYEC could specifically enrich in Co-HUVECs while showing no binding to normal vascular endothelial cells. In vivo immunofluorescence staining revealed that the peptide CNTGSPYEC could only bind to vascular endothelial cells specifically in gastric cancer but show no non-specific binding with normal tissue. Competitive and inhibitory assay also verified the targeting characteristics of the peptide with the fluorescence intensity of 17.13. As the concentration increases, the competitive inhibition rate can be incrementally raised to 93% (p < 0.05). Endothelial tube formation assay indicated that the peptide could suppress neovascularization, with the microvessel count reducing by 40% (p < 0.05). Furthermore, Cell Counting Kit-8 assay (CCK8) showed that the targeting peptide could partly inhibit cell proliferation of Co-HUVEC (61.7%)., Conclusion: Our novel strategy of the combined in vitro and in vivo screening outperforms previous methods that relied solely on negative/positive screening. In vivo and in vitro test confirmed the high targeting characteristic of the new peptide. Therefore, the peptide CNTGSPYEC may be a potential candidate in diagnosis and anti-angiogenesis therapy of gastric cancer. Our further exploration employs it as a vehicle for mediating drug accumulation in gastric cancer tissue., Competing Interests: Declarations. Ethics approval and consent to participate: All animals were maintained within specific pathogen-free facilities at the Laboratory Animal Center of Nanfang Hospital. All animal protocols were approved by the Animal Care and Use Committee of Nanfang Hospital (permit and approval number: 202105A028) and performed in accordance with the institutional guidelines of Nanfang Hospital. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Systemic therapy for unresectable hepatocellular carcinoma (HCC) has progressed with the development of multiple kinases, such as vascular endothelial growth factor (VEGF) signaling, targeting cancer growth and angiogenesis. Additionally, the efficacy of sorafenib, regorafenib, lenvatinib, ramucirumab, and cabozantinib has been demonstrated in various clinical trials, and they are now widely used in clinical practice. Furthermore, the development of effective immune checkpoint inhibitors has progressed in systemic therapy for unresectable HCC, and atezolizumab + bevacizumab (atezo/bev) therapy and durvalumab + tremelimumab therapy are now recommended as first-line treatment. Atezo/bev therapy, which combines an anti-programmed cell death 1 ligand 1 antibody with an anti-VEGF antibody, is the first cancer immunotherapy to demonstrate efficacy against unresectable HCC. With the increasing popularity of these treatments, VEGF inhibition is attracting attention from the perspective of its anti-angiogenic effects and impact on the cancer-immune cycle. In this review, we outline the role of VEGF in the tumor immune microenvironment and cancer immune cycle in HCC and outline the potential immune regulatory mechanisms of VEGF. Furthermore, we consider the potential significance of the dual inhibition of angiogenesis and immune-related molecules by VEGF, and ultimately aim to clarify the latest treatment strategies that maximizes efficacy.

Three novel copper(II)-based complexes Cu-1, Cu-2, and Cu-3 containing sulfamethoxazole or sulfamethazine ligand were obtained, and their single structures were characterized. Both Cu-1 and Cu-3 show a broad spectrum of cytotoxicity than Cu-2, and Cu-1 is more cytotoxic than Cu-3. What's interesting is that Cu-1 can exhibit obvious inhibitory effect on the growth of human triple-negative breast cancer in vivo and vitro through anti-proliferative, anti-angiogenic, anti-inflammatory, pro-apoptotic and cuproptotic synergistic effects. Though Cu-3 shows no significant cytotoxicity against MDA-MB-231 cells, it can significantly inhibit the growth of SKOV3 cells in vitro by down-regulating the expression of some key proteins in the VEGF/VEGFR2 signaling pathway and the expression of some pro-inflammatory cytokines, and by disrupting the balance of intracellular reactive oxygen species levels., Competing Interests: Declaration of competing interest Titled“Syntheses, crystal structures of copper (II)-based complexes of sulfonamide derivatives and their anticancer effects through the synergistic effect of anti-angiogenesis, anti-inflammation, pro-apoptosis and cuproptosis” This manuscript has not been published or presented elsewhere in part or in entirety and is not under consideration by another journal. All authors have read and understood your journal's policies, and we believe that neither the manuscript nor the study violates any of these. There are no conflicts of interest to declare., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

The strategy of inhibiting angiogenesis, specifically by targeting vascular endothelial growth factor receptor 2 (VEGFR-2), has been proven effective in tumor treatment. In this study, we designed several VEGFR-2 kinase inhibitors based on an indazole scaffold. Among them, the most potent compound, 30, inhibits VEGFR-2 (IC 50  = 1.24 nM) with subtle selectivity over other kinases. It demonstrates significant inhibitory activity against HUVEC angiogenesis and inhibits cell migration in a dose-dependent manner. Additionally, it exhibits low acute toxicity in mice. In vivo studies, compound 30 demonstrates favorable pharmacokinetic profiles. It suppresses tumor angiogenesis in the zebrafish subintestinal vessel model, indicating that it may be a potential angiogenesis inhibitor for further development., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

The response rates to immunotherapy vary widely depending on the type of cancer and the specific treatment used and can be disappointingly low for many solid tumors. Fortunately, due to their complementary mechanisms of action, immunotherapy and anti-angiogenic therapy have synergistic effects in cancer treatment. By normalizing the tumor vasculature, anti-angiogenic therapy can improve blood flow and oxygenation to facilitate better immune cell infiltration into the tumor and enhance the effectiveness of immunotherapy. It also reduces immunosuppressive factors and enhances immune activation, to create a more favorable environment for immune cells to attack the tumor. Their combination leverages the strengths of both therapies to enhance anti-tumor effects and improve patient outcomes. This review discusses the vasculature-immunity crosstalk in the tumor microenvironment and summarizes the latest advances in combining anti-angiogenic therapy and immune checkpoint inhibitors to treat digestive system tumors., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Xu and Shao.)

Background: A prenylated flavonoid, broussoflavonol F (BFF), was isolated from Macaranga genus with cytotoxicities against various cancer cells, though its underlying mechanisms have not been fully elucidated., Hypothesis: This study aimed to investigate the anti-tumor and anti-angiogenesis activities of BFF and its underlying mechanisms in colon cancer., Method: In the in vitro study, the cytotoxic effects of BFF in human colon cancer HCT-116 and LoVo cells were examined using MTT assay, BrdU assay and colony formation assay. The anti-proliferative effects of BFF in these cells were assessed via cell apoptosis and cell cycle analysis using flow cytometry. The anti-angiogenesis effects of BFF in human endothelial HEMC-1 cells were also detected using scratch wound healing assay and tube formation assay. While the in vivo effects of BFF in colon cancer were further examined in zebrafish embryos and HCT116 tumor-bearing mice. The underlying mechanisms of BFF were predicted using network pharmacology analysis, and Western blotting was performed to validate both in vitro and in vivo results., Results: BFF exhibited cytotoxicities on 5 colon cancer cell lines, as well as anti-proliferative activities via inducing apoptosis and cell cycle arrest at the G0/G1 phase in HCT116 and LoVo cells. BFF at 1.25-5 µM also suppressed cell proliferation in these two colon cancer cell lines by downregulating HER2, RAS, p-BRAF, p-MEK and p-Erk protein expressions. In addition, BFF at 2.5-5 µM could significantly decrease the length of subintestinal vessels of zebrafish embryos through decreasing mRNA expressions of NRP1a, PDGFba, PDGFRb, KDR, FLT1 and VEGRaa. Besides, BFF exhibited anti-angiogenesis activity via inhibiting cell proliferation, motility and tube formation in HMEC-1 cells. Furthermore, intraperitoneal administration of BFF (10 mg/kg) suppressed tumor growth and decreased the expression of tumor proliferation marker Ki-67 and angiogenesis marker CD31 in the tumor tissues in HCT116 tumor-bearing mice. BFF treatment could also significantly decrease expressions of RAS, p-BRAF, p-MEK and p-Erk in the tumor section, which are consistent with the in vitro results., Conclusions: This study revealed the anti-tumor and anti-angiogenesis effects of BFF in colon cancer. This is the first report of the in vitro and in vivo anti-proliferative activity of BFF in colon cancer through regulating the HER2-RAS-MEK-ERK pathway. These findings further support the research development of BFF as an anti-cancer agent in colon cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier GmbH.)

Three new acylphloroglucinols were isolated from the branches and leaves of Hypericum perforatum L., named as hyperipersions A-C ( 1-3 ), together with three known compounds which were identified as elegaphenone ( 4 ), 2,6-dihydroxy-3,4-dimethylbenzoic acid methyl ester ( 5 ) and 2,3-methylenedioxyxanthone ( 6 ), respectively. The structures of isolated compounds were determined by UV, IR, HR-ESI-MS, NMR analysis. Their antiangiogenic activities were studied against HUVECs. The IC 50 value of compound 3 was 2.39 ± 0.21  μ M against HUVECs, which was stronger than vatalanib, and other compounds had moderate antiangiogenic activity.

Purpose: This study aimed to investigate the effects of subconjunctival injection of aflibercept, a soluble protein decoy for VEGFR-1 and VEGFR-2, on corneal angiogenesis and VEGFR-expressing CD11b + cells in a mouse model of suture-induced corneal neovascularization., Methods: Corneal neovascularization was induced in BALB/c mice by placing three sutures on the cornea. Immediately after surgery, either 200 µg aflibercept (5 µL) or an equal volume of phosphate-buffered saline (PBS) was administered into the subconjunctival space. Seven days after later, corneal new vessels were quantified through clinical examination and measurement of the CD31-stained area in corneal flat mounts. The levels of pro-angiogenic and inflammatory markers in the cornea were evaluated using RT-qPCR. The percentages of VEGFR-2 + CD11b + cells and VEGFR-3 + CD11b + cells were analyzed in the cornea, blood, and draining cervical lymph nodes (DLNs) using flow cytometry., Results: Subconjunctival injection of aflibercept significantly reduced the growth of corneal new vessels compared to subconjunctival PBS injection. The mRNA levels of Cd31, vascular growth factors (Vegfc and Angpt1), and pro-angiogenic/inflammatory markers (Tek/Tie2, Mrc1, Mrc2, and Il6) in the cornea were downregulated by subconjunctival aflibercept. Also, the percentage of VEGFR-3 + CD11b + cells in the cornea, blood, and DLNs was decreased by aflibercept, whereas that of VEGFR-2 + CD11b + cells was unaffected., Conclusion: Subconjunctival aflibercept administration inhibits inflammatory angiogenesis in the cornea and reduces the numbers of cornea-infiltrating and circulating VEGFR-3 + CD11b + cells., Competing Interests: Declarations. Ethical approval: The experimental protocol was approved from the Institutional Animal Care and Use Committee of Seoul National University Hospital Biomedical Research Institute (Seoul, Korea) and followed the guidelines stated by ARVO for ophthalmic and vision research. Conflict of interest: The authors have no relevant financial or non-financial interests to disclose., (© 2024. The Author(s).)

Background: Pazopanib is part of the therapeutic armamentarium for the treatment of patients with advanced non-adipocytic soft tissue sarcomas (STS) who have received prior chemotherapy, but its optimal use in STS histologies is still left to be further defined., Design and Methods: Data on STS patients treated with pazopanib in Italy have been prospectively collected from July 2013 to December 2019 through a drug monitoring registry managed by the Italian Medicines Agency (AIFA). This nationwide observational cohort study included patients with advanced STS who received pazopanib. Clinicians were mandatorily requested to fill in the AIFA monitoring registry in order to prescribe pazopanib. Patients were recorded on the basis of their clinical characteristics, histological subtype captured at the time of treatment start, and clinical outcome. Primary outcome was time to treatment discontinuation (TTD). Secondary outcomes recorded were frequency of dose reduction and time to first dose reduction., Results: We analyzed data from 1964 sarcoma patients. The most represented histological subtypes were leiomyosarcoma (44.7%), undifferentiated sarcomas/not otherwise specified (11.5%), and synovial sarcoma (8.1%). Overall, the median TTD was 106 days. The variables significantly associated to shorter TTD were Eastern Cooperative Oncology Group performance status (1-2 versus 0), the number of previous lines of treatment (2-4 versus 0-1) and prescribed dose (200 mg or 400 mg versus 800 mg, all once daily). Among the most represented (>20 patients) histological subtypes, we also observed longer TTD in patients with histological diagnosis of malignant solitary fibrous tumor if compared with undifferentiated sarcoma not otherwise specified., Conclusions: In this nationwide observational real-world study, the outcomes are similar to those reported in the pivotal trial (PALETTE study). Our study includes a significant number of patients with rare/ultra-rare sarcoma subtypes and underlines possible differences in treatment duration among these histologies., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Angiogenesis plays an important role in cancer growth and metastasis, and it is considered a therapeutic target to control tumour growth following anti-angiogenic therapy. However, it is still unclear when tissues initiate angiogenesis during malignant transformation from premalignant condition and whether this premalignant condition could be a therapeutic target of anti-angiogenic therapy. In this study, we aimed to analyse the onset of angiogenesis by evaluating morphological and functional alterations of microvessels during oral multistep carcinogenesis using a 4-nitroquinoline 1-oxide (4NQO)-induced oral carcinogenesis mouse model. In the study, we initially confirmed that with the use of 4NQO, oral lesions develop in a stepwise manner from normal mucosa through oral epithelial dysplasia (OED) to oral squamous cell carcinoma (OSCC). Evaluation of CD31-immunostained specimens revealed that microvessel density (MVD) increases in a stepwise manner from OEDs. Histological and functional analyses revealed the structural abnormalities and leakage of blood vessels had already taken place in OED. Then we evaluated the expression profiles of Hif1a and Vegfa along with hypoxic status and found that OED exhibited increased Vegfa expression under hypoxic conditions. Finally, we tested the possibility of OEDs as a target of anti-angiogenic therapy and found that anti-VEGFR2 neutralising antibody in OED slowed the disease progression from OED to OSCC. These data indicate that an angiogenic switch occurs at the premalignant stage and morphological, and functional alterations of microvessels already exist in OED. These findings also elucidate the tumour microenvironment, which gradually develops along with carcinogenic processes, and highlight usefulness of the 4NQO-induced carcinogenesis model in the study of epithelial and stromal components, which will support epithelial carcinogenesis. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland., (© 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.)

The intricate cooperation between cancer cells and nontumor stromal cells within melanoma microenvironment (MME) enables tumor progression and metastasis. We previously demonstrated that the interplay between tumor-associated macrophages (TAMs) and melanoma cells can be disrupted by using long-circulating liposomes (LCLs) encapsulating prednisolone phosphate (PLP) (LCL-PLP) that inhibited tumor angiogenesis coordinated by TAMs. In this study, our goal was to improve LCL specificity for protumor macrophages (M2-like (i.e., TAMs) macrophages) and to induce a more precise accumulation at tumor site by loading PLP into IL-13-conjugated liposomes (IL-13-LCL-PLP), since IL-13 receptor is overexpressed in this type of macrophages. The IL-13-LCL-PLP liposomal formulation was obtained by covalent attachment of thiolated IL-13 to maleimide-functionalized LCL-PLP. C57BL/6 mice bearing B16.F10  s.c melanoma tumors were used to investigate the antitumor action of LCL-PLP and IL-13-LCL-PLP. Our results showed that IL-13-LCL-PLP formulation remained stable in biological fluids after 24h and it was preferentially taken up by M2 polarized macrophages. IL-13-LCL-PLP induced strong tumor growth inhibition compared to nonfunctionalized LCL-PLP at the same dose, by altering TAMs-mediated angiogenesis and oxidative stress, limiting resistance to apoptosis and invasive features in MME. These findings suggest IL-13-LCL-PLP might become a promising delivery platform for chemotherapeutic agents in melanoma.

Malignant tumors represent an important cause of mortality within the global population. Tumor angiogenesis, recognized as one of the key hallmarks of malignant tumors, is crucial for supplying essential nutrients and oxygen for tumor growth. Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) are key drivers of tumor angiogenesis. Targeted therapeutic interventions not only effectively inhibit tumor growth by specifically blocking tumor angiogenesis but have also made breakthroughs in the treatment of malignant tumors. Fruquintinib, an anti-angiogenic small molecule drug developed independently in China, functions as a potent tyrosine kinase inhibitor with high selectivity. It effectively curtails tumor growth by binding to and inhibiting VEGFR-1, VEGFR-2, and VEGFR-3. Additionally, fruquintinib offers several advantages including minimal off-target toxicity, robust resistance profiles, and commendable efficacy. This agent can be used alone or in combination with other treatments. It has shown high effectiveness and survival benefits across various malignant tumors such as colorectal cancer, gastric cancer, non-small cell lung cancer, breast cancer, and other malignant tumors. Therefore, this article conducts a systematic review encompassing the mechanism of action, pharmacokinetics, clinical efficacy, and safety profile of fruquintinib. Through this review, we aimed to offer a reference for the clinical application and subsequent development of fruquintinib., Competing Interests: Declarations. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests. Conflict of interest: The authors declare that they have no conflict of interest. Ethical approval: Not applicable., (© 2024. The Author(s).)

Introduction: Diabetic retinopathy, a significant trigger for blindness among working age individuals with diabetes, poses a substantial global health challenge. Understanding its underlying mechanisms is pivotal for developing effective treatments. Current treatment options, such as anti-VEGF agents, corticosteroids, laser photocoagulation, and vitreous surgery, have their limitations, prompting the exploration of innovative approaches like nanocapsules based drug-delivery systems. Nanoparticles provide promising solutions to improve drug delivery in ocular medicine, overcoming the complexities of ocular anatomy and existing treatment constraints., Areas Covered: This review explored advanced therapeutic strategies for diabetic retinopathy, focusing on current medications with their limitations, drug delivery methods, device innovations, and overcoming associated barriers. Through comprehensive review, it aimed to contribute to the discovery of more efficient management strategies for diabetic retinopathy in the future., Expert Opinion: In the next five to ten years, we expect a revolutionary shift in how diabetic retinopathy is treated. As we deepen our understanding of oxidative stress and metabolic dysfunction, antioxidants with specialised delivery matrices are poised to take center stage in prevention and treatment strategies. Our vision is to create a more integrated approach to diabetic retinopathy management that not only improves patient outcomes but also reduces the risks associated to traditional therapies.

Over the past few decades, VEGF-targeted antiangiogenic therapy for cancers has gained increasing attention. Nevertheless, there are still several limitations such as the potential resistance mechanisms arising in cancer cells against these therapies and their potential adverse effects. These limitations highlight the need for novel anti-angiogenesis molecules and better understanding of the mechanisms of tumor angiogenesis. In the present study, we investigated the antiangiogenic properties of a novel 14-mer antiangiogenic peptide (14-MAP) derived from N-terminal 14 kDa buffalo prolactin and characterized its mode of action. 14-MAP at the picomolar concentration inhibited VEGF- and bradykinin (an autacoid peptide expressed in vascular tissues in pathophysiology, BK)-stimulated endothelial nitric oxide (eNO) production, cell migration, and proliferation in endothelial cells and vessel development in the chick embryo. Although this peptide inhibited both VEGF- and BK-dependent angiogenic processes, its action was more pronounced in the latter. Moreover, the interference of 14-MAP with the eNO synthase (eNOS)-cyclic GMP pathway was also identified. A combination of a low dose of Avastin, a widely used drug targeting VEGF-dependent angiogenesis, and 14-MAP significantly reduced tumor size in an in vivo model of human colon cancer. Taken together, our results suggest that 14-MAP, a BK- and eNOS-dependent antiangiogenic peptide, might be useful for overcoming the limitation of VEGF-targeted antiangiogenic therapy in cancer patients. However, further studies will be required to further characterize its mode of action and therapeutic potential., (© 2024 The Author(s). FEBS Open Bio published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)