Search Results (180)

Sunitinib, a tyrosine kinase inhibitor (TKI) targeting vascular endothelial growth factor receptors (VEGFRs) and platelet-derived growth factor receptors (PDGFRs), is widely used in renal cell carcinoma. A broad spectrum of thyroid dysfunctions has been observed during TKI therapy, yet their mechanisms and clinical progression remain only partially explained. A longitudinal case analysis of a woman with metastatic clear-cell renal cell carcinoma treated with cyclical sunitinib therapy (4 weeks on, 2 weeks off) was performed. Thyroid function tests, clinical symptoms, and ultrasound imaging findings were evaluated over time and compared with treatment exposure and dose adjustments. Baseline thyroid function was normal. During the third cycle, thyroid-stimulating hormone (TSH) increased markedly (33.44–41.26 mIU/L), with free thyroid hormones initially remaining within reference limits. TSH fluctuations corresponded to treatment intervals before stabilising into persistent hypothyroidism requiring levothyroxine replacement. Thyroid ultrasound revealed progressive parenchymal destruction and a reduction in gland volume from 18 mL to approximately 2 mL over three years. Endocrine management enabled maintenance of biochemical euthyroidism, and systemic oncological treatment continued without interruption. Sunitinib treatment may lead to progressive destructive hypothyroidism. Routine surveillance of thyroid function is essential, and timely levothyroxine therapy facilitates continued anticancer treatment and symptom control. Full article

Colon cancer (CC) is a common malignancy characterized by poor prognostic outcomes and considerable mortality. Oxaliplatin (OXP) is commonly used in the treatment of CC; however, its efficacy may be limited by side effects and the development of resistance. β-sitosterol (β-Sit), a phytosterol derived from plants, has been documented to be effective in the treatment of tumors. This study aimed to investigate the potential of β-Sit to enhance the antitumor efficacy of OXP in COLO-205 cells, focusing on apoptosis induction and suppression of the vascular endothelial growth factor A (VEGF-A)/survival pathway. Molecular docking studies were performed to assess the binding affinity of β-Sit with the target proteins B-cell lymphoma 2 (Bcl-2), phosphoinositide 3-kinase (PI3K), and VEGF receptor-2 (VEGFR-2). COLO-205 cells were treated with OXP, β-Sit, or a combination of OXP + β-Sit for 48 h. The combination treatment substantially lowered the IC₅₀ achieved with 3.24 µM of OXP and 36.01 µM of β-Sit, compared to 25.64 µM for OXP alone and 275.9 µM for β-Sit alone, demonstrating a pronounced synergistic impact. The combined therapy altered the cell cycle distribution by decreasing the number of cells in the G0/G, S, and G2/M phases, coupled with an increase in the Sub-G1 population. Furthermore, apoptosis was augmented by a shift in cell death from necrosis to late apoptosis, as indicated by an increased BAX/BCL2 ratio relative to each treatment alone. Moreover, the inhibitory effect on angiogenesis was enhanced via the reduction of VEGF-A, and β-catenin and nuclear factor κB (NF-κB-p65) were suppressed, thereby preventing the growth and survival of resistant cancer cells. Additionally, molecular docking supported high binding affinities of β-Sit to Bcl-2, PI3K, and VEGFR-2. This study highlights the potential of β-Sit to enhance the anti-cancer efficacy of OXP in CC. Full article

Background/Objectives: Type 2 diabetes mellitus (T2DM) is a chronic and multifactorial metabolic disorder associated with genetic and environmental factors. Vascular endothelial growth factor (VEGF) plays a crucial role in angiogenesis and vascular homeostasis, and genetic polymorphisms in the VEGF signaling pathway have been linked to the T2DM development, progression, and complications. This scoping review investigated the association between VEGF gene and VEGF receptors single-nucleotide polymorphisms (SNPs) and susceptibility to T2DM and vascular complications. Methods: A thorough systematic review was performed utilizing scientific databases (PubMed, Web of Science, and Scopus) in March 2025. From an initial pool of 796 records, 59 relevant articles were selected for inclusion in the analysis. Results: The most frequently studied SNPs were rs2010963 (31/59), rs699947 (16/59), rs3025039 (15/59), rs833061 (11/59), rs1570360 (7/59) in the VEGFA gene and rs2071559(6/59) in VEGFR2. The studies include a diverse range of ethnic groups, including Asian, European and Middle Eastern populations. The main complications associated with these SNPs were microvascular conditions such as diabetic retinopathy (DR) (49/59), diabetic neuropathy (DPN) (6/59), diabetic nephropathy (DNP) (2/59), and as well as macrovascular complications including diabetic foot ulcers (DFU) (10/59). The results revealed that these polymorphisms, particularly rs3025039 and rs2010963, were more consistently associated with microvascular complications such as DR rather than with T2DM itself. The C allele of rs2010963 was associated with increased risk of DR in Indian populations, while no such association was observed in European. Similarly, the T allele of rs3025039 conferred protection against DPN in a Chinese population but was associated with higher DR risk in an Indian study, suggesting that the same allele may play distinct roles depending on ethnic background and clinical phenotype. Conclusions: VEGF signaling pathway genetic polymorphisms demonstrate potential as biomarkers for diabetic complications, especially microvascular outcomes. The findings suggest a genetic basis for differences in complications of T2DM. Future studies should investigate relevant SNPs across diverse ethnic groups to better understand genetic risks associated with the disease and its vascular complications. Full article

Overexpression of growth factor receptors and immunosuppressive molecules is a hallmark of many tumour cells, distinguishing them from normal tissue. This co-expression enables tumours both to exploit proliferative signalling and to evade immune surveillance. Here, we propose a strategy that employs a combination of monoclonal antibodies (mAbs) targeting two distinct antigens (Ags) at sub-cytotoxic doses. This approach aims to achieve a threshold cytotoxic density of immune complexes selectively on malignant cells expressing both target Ags, while sparing normal cells that express only one. Typically, the first target Ag may be a growth factor receptor, such as epidermal growth factor receptor (EGFR and HER1), epidermal growth factor receptor 2 (HER2), or vascular endothelial growth factor receptor 2 (VEGFR2), and the second, an immunoinhibitory molecule, such as programmed death-ligand 1 (PD-L1). Selective mAb-mediated tumour destruction is expected to enhance neoantigen (NeoAg) presentation to the immune system, while the blockade of PD-1/PD-L1 interactions should further stimulate anti-tumour immune responses. Notably, this strategy can be implemented using clinically approved therapeutic mAbs, potentially enabling rapid translation into clinical practice without extensive regulatory hurdles. Full article

Background: Chronic wounds pose a significant public health challenge due to high treatment costs and the limited efficacy of current therapies. This study aims to evaluate the in vitro wound-healing activity and in silico interactions of two antimicrobial cationic peptides, derived from Galleria mellonella cecropin D, whose receptors are involved in tissue healing. Methods: Two peptides were tested: a long peptide (∆M2, 39 amino acids) and a short peptide (CAMP-CecD, 18 amino acids). Their cytotoxicity, as well as their effects on fibroblast proliferation and migration, were assessed using Detroit 551 cells. In parallel, molecular docking studies were conducted with AutoDock Vina to predict the binding affinities of these peptides to the key receptors involved in wound healing: the epidermal growth factor receptor (EGFR), the transforming growth factor beta receptor (TGFRβ2), and the vascular endothelial growth factor receptor (VEGFR). Results: In vitro assays showed that the short peptide exhibited lower cytotoxicity and significantly enhanced cell proliferation and migration, leading to a greater percentage of gap closure compared to the long peptide. A docking analysis revealed binding affinities of −6.7, −7.2, and −5.6 kcal/mol for VEGFR, EGFR, and TGFRβ2, respectively, with the RMSD values below 2 Å, indicating stable binding interactions. Conclusions: These findings suggest that the structure and cationic charge of the short peptide facilitate robust interactions with growth factor receptors, enhancing re-epithelialization and tissue regeneration. Consequently, this peptide is a promising candidate ligand for the treatment of chronic wounds and associated infections. Full article

Background: Cabozantinib is a Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor (VEGFR-TKI). These drugs are employed as therapy for several malignancies. In detail, Cabozantinib has demonstrated its efficacy against several malignancies. On the other hand, Cabozantinib and other VEGFR-TKIs can be responsible for various adverse events (AEs), in particular hepatic and dermatological AEs. Methods: To date, limited data are available in the literature regarding ocular AEs due to therapy with these drugs. In this regard, one case of corneal perforation during treatment with a VEGFR-TKI, Regorafenib, has been reported, while there are no data about Cabozantinib. In this paper, we present another clinical case of corneal perforation in a patient affected by advanced RCC and treated with Cabozantinib as a second-line therapy. The patient started Cabozantinib at the dosage of 60 mg/die although it was necessary to apply some dose reductions because of grade 2 AEs (according to CTCAE v6.0), such as asthenia, diarrhea, dysgeusia, and loss of appetite. Results: After approximately 15 months of treatment, the patient began to experience pain and vision loss in the right eye. A diagnosis of corneal perforation was made, followed by medical and surgical treatment. As regards the etiology of this pathology, all other possible causes were excluded, including a history of ocular disease, contact trauma, exposure to damaging agents (e.g., chemical agents and prolonged use of drugs such as topical NSAIDs), infections, or dry eye. Therefore, we hypothesized a correlation with Cabozantinib’s mechanisms of action and paused its administration. Conclusions: Cabozantinib may alter the ocular environment due to a lack of or imbalance in growth factors in the tear film, with a reduction in corneal epithelium proliferation. This condition might cause dry eye and a delay in corneal healing. Therefore, particular importance should be placed on ophthalmologic surveillance during treatment with these drugs in patients who develop ocular symptoms. Further in vitro and in vivo studies are necessary to deepen the knowledge about VEGFR-TKI-mediated ocular AEs. Full article

The synthesis of (E)-1-(1-benzyl-5-methyl-1H-1,2,3-triazol-4-yl)-3-phenyl-2-propen-1-one derivatives was carried out in two steps, using benzylic chloride derivatives as starting material. The structural determination of intermediates and final products was performed by spectroscopic methods: infrared spectroscopy, nuclear magnetic resonance spectroscopy and mass spectrometry (IR, NMR, and MS). In vitro evaluation of cytotoxic activity on adherent and non-adherent cells showed that triazole chalcones exhibited significant activity against three of the five cell lines studied: non-Hodgkin lymphoma U937, glioblastoma multiform tumor T98G, and gallbladder cancer cells Gb-d1. In contrast, the cytotoxic activity observed for cervical cancer HeLa and gallbladder adenocarcinoma G-415 was considerably lower. Additionally, in the cell lines where activity was observed, some compounds demonstrated an In vitro inhibitory effect superior to that of the control, paclitaxel. Molecular docking studies revealed specific interactions between the synthesized ligands and therapeutic targets in various cell lines. In U937 cells, compounds 4a and 4c exhibited significant inhibition of vascular endothelial growth factor receptor (VEGFR) kinase, correlating with their biological activity. This effect was attributed to favorable interactions with key residues in the binding site. In T98G cells, compounds 4r and 4w showed affinity for transglutaminase 2 (TG2) protein, driven by their ability to form hydrophobic interactions. In Gb-d1 cells, compounds 4l and 4p exhibited favorable interactions with mitogen-activated protein kinase (MEK) protein, similar to those observed with the known inhibitor selumetinib. In HeLa cells, compounds 4h and 4g showed activity against dihydrofolate reductase (DHFR) protein, driven by hydrogen bonding interactions and favorable aromatic ring orientations. On the other hand, compounds 4b and 4t exhibited no activity, likely due to unfavorable interactions related to halogen substitutions in the aromatic rings. Full article

This study aimed to evaluate the effects of CD146, a surface antigen of mesenchymal stem cells from human exfoliated deciduous teeth (SHEDs), on angiogenic potential. SHEDs were isolated from patients’ deciduous teeth and sorted into CD146-positive (CD146 + SHED) and CD146-negative (CD146 − SHED) populations. Three groups—non-sorted SHED, CD146 + SHED, and CD146 − SHED—were compared. Angiogenic potential was assessed by co-culturing each group with human umbilical vein endothelial cells (HUVECs) and evaluating lumen formation using an endothelial tube formation assay. The gene and protein expression levels of angiogenic markers, including vascular endothelial growth factor (VEGF), VEGF receptor 2 (VEGFR2), cluster of differentiation 31 (CD31), and basic fibroblast growth factor (bFGF), were analyzed using a real-time polymerase chain reaction and enzyme-linked immunosorbent assay. The tube formation assay revealed significantly enhanced angiogenic potential in CD146 + SHED and non-sorted SHED compared to CD146 − SHED. The gene and protein expression levels of VEGF, VEGFR2, CD31, and bFGF were significantly upregulated in CD146 + SHED and non-sorted SHED, highlighting superior angiogenic capabilities in CD146 + SHED. CD146 + SHED demonstrated enhanced angiogenic potential compared to CD146 − SHED, supporting their use in regenerative therapies targeting angiogenesis. Full article

Diabetic kidney disease (DKD) is a leading cause of chronic kidney disease (CKD) and end-stage renal disease worldwide, affecting approximately 40% of individuals with type 2 diabetes (T2DM) and 30% of those with type 1 diabetes (T1DM). As the prevalence of diabetes continues to rise, the burden of DKD is expected to grow correspondingly. This review explores the roles of key molecular pathways, including the apelinergic system, vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) axis, and nitric oxide (NO)/nitric oxide synthase (NOS) signaling, in DKD pathogenesis and potential therapeutic applications. The apelinergic system, involving apelin and its receptor (APLNR), influences endothelial function, glucose metabolism, and renal health. Preclinical studies highlight its dual role in renal protection and injury through anti-inflammatory and antioxidant pathways, while other evidence suggests that it may exacerbate DKD through podocyte damage and angiogenesis. Similarly, the VEGF/VEGFR axis demonstrates a complex contribution to DKD, where VEGF-A promotes pathological angiogenesis and glomerular damage, but its inhibition requires careful modulation to prevent adverse effects. The NO/NOS system, integral to vascular and renal homeostasis, also exhibits altered activity in DKD, with reduced bioavailability linked to oxidative stress and inflammation. This review underscores the intricate interplay between these pathways in DKD, revealing both challenges and opportunities in their therapeutic targeting. Further research is essential to refine strategies and develop effective interventions for DKD management. Full article

Peptide Lv is a small endogenous secretory peptide with ~40 amino acids and is highly conserved among certain several species. While it was first discovered that it augments L-type voltage-gated calcium channels (LTCCs) in neurons, thus it was named peptide “Lv”, it can bind to vascular endothelial growth factor receptor 2 (VEGFR2) and has VEGF-like activities, including eliciting vasodilation and promoting angiogenesis. Not only does peptide Lv augment LTCCs in neurons and cardiomyocytes, but it also promotes the expression of intermediate-conductance K_Ca channels (K_Ca3.1) in vascular endothelial cells. Peptide Lv is upregulated in the retinas of patients with early proliferative diabetic retinopathy, a disease involving pathological angiogenesis. This review will provide an overview of peptide Lv, its known bioactivities in vitro and in vivo, and its clinical relevance, with a focus on its role in angiogenesis. As there is more about peptide Lv to be explored, this article serves as a foundation for possible future developments of peptide Lv-related therapeutics to treat or prevent diseases. Full article

The vascular endothelial growth factor receptor 2 (VEGFR2) and the hepatocyte growth factor receptor (C-Met) are critical receptors for signaling pathways controlling crucial cellular processes such as cell growth, angiogenesis and tissue regeneration. However, dysregulation of these proteins has been reported in different diseases, particularly cancer, where these proteins promote tumour growth, invasiveness, metastasis and resistance to conventional therapies. The identification of dual inhibitors targeting both VEGFR-2 and c-Met has emerged as a strategic therapeutic approach to overcome the limitations and resistance mechanisms associated with single-target therapies in clinical settings. Through molecular dynamics simulations and comparative docking analysis, we tested the inhibitory potential of 2,016 Food and Drug Administration (FDA)-approved drugs targeting VEGFR-2 and/or c-Met receptors. The results revealed that entacapone and telmisartan are potent and selective inhibitors for c-Met and VEGFR-2, respectively. Interestingly, triamterene was identified as a promising dual inhibitor, demonstrating specific and significant binding affinity to both proteins. Molecular dynamics simulations revealed key interactions between the identified compounds and critical residues in the catalytic domains of both VEGFR-2 (e.g., Lys868, Asp1028, Asp1046) and c-Met (e.g., Asp1204, His1202, Asp1222), providing insights into their mechanism of action. These findings underscore the therapeutic potential of triamterene in targeting multiple signaling pathways involved in cancer progression, metastasis and poor prognosis in patients. Our study provides a foundational framework for the development of novel anticancer compounds able to target multiple pathways in cancer. Further preclinical and clinical investigations are needed to validate the efficacy of these compounds in clinical settings and to test their ability to overcome resistance and improve patient outcome. Full article

Vascular endothelial growth factor receptor 2 (VEGFR-2) is a crucial mediator of angiogenesis, playing a pivotal role in both normal physiological processes and cancer progression. Tumors harness VEGFR-2 signaling to promote abnormal blood vessel growth, which is a key step in the metastasis process, making it a valuable target for anticancer drug development. While there are VEGFR-2 inhibitors approved for therapeutic use, they face challenges like drug resistance, off-target effects, and adverse side effects, limiting their effectiveness. The quest for new drug candidates with VEGFR-2 inhibitory activity often starts with the selection of key structural motifs present in molecules currently used in clinical practice, expanding the chemical space by generating novel derivatives bearing one or more of these moieties. This review provides an overview of recent advances in the development of novel VEGFR-2 inhibitors, focusing on the synthesis of new drug candidates with promising antiproliferative and VEGFR-2 inhibition activities, organizing them by relevant structural features. Full article

The prevalence of small multi-target drugs containing a fluorinated aromatic moiety among approved drugs in the market is due to the unique properties of this halogen atom. With the aim to develop potent antidiabetic agents, a series of phenylsulfonic esters based on the conjugation of the 5-substituted 2-hydroxy-3-nitroacetophenones 1a–d with phenylsulfonyl chloride derivatives substituted with a fluorine atom or fluorine-containing (-CF₃ or -OCF₃) group were prepared. Their structures were characterized using a combination of spectroscopic techniques complemented with a single-crystal X-ray diffraction (XRD) analysis on a representative example. The compounds were, in turn, assayed for inhibitory effect against α-glucosidase, α-amylase, protein tyrosine phosphatase 1 B (PTP1B) and the vascular endothelial growth factor receptor-2 (VEGFR-2) all of which are associated with the pathogenesis and progression of type 2 diabetes mellitus (T2DM). The antigrowth effect of selected compounds was evaluated on the human breast (MCF-7) and lung (A549) cancer cell lines. The compounds were also evaluated for cytotoxicity against the African Green Monkey kidney (Vero) cell line. The results of an in vitro enzymatic study were augmented by molecular docking (in silico) analysis. Their ADME (absorption, distribution, metabolism and excretion) properties have been evaluated on the most active compounds against α-glucosidase and/or α-amylase to predict their drug likeness. Full article

The vascular endothelium, a specialized monolayer of endothelial cells (ECs), is crucial for maintaining vascular homeostasis by controlling the passage of substances and cells. In the tumor microenvironment, Vascular Endothelial Growth Factor A (VEGF-A) drives tumor angiogenesis, leading to endothelial anergy and vascular immunosuppression—a state where ECs resist cytotoxic CD8⁺ T cell infiltration, hindering immune surveillance. Immunotherapies have shown clinical promise. However, their effectiveness is significantly reduced by tumor EC anergy. Anti-angiogenic treatments aim to normalize tumor vessels and improve immune cell infiltration. Despite their potential, these therapies often cause significant systemic toxicities, necessitating new treatments. The small GTPase Rap1B emerges as a critical regulator of Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) signaling in ECs. Our studies using EC-specific Rap1B knockout mice show that the absence of Rap1B impairs tumor growth, alters vessel morphology, and increases CD8⁺ T cell infiltration and activation. This indicates that Rap1B mediates VEGF-A’s immunosuppressive effects, making it a promising target for overcoming vascular immunosuppression in cancer. Rap1B shares structural and functional similarities with RAS oncogenes. We propose that targeting Rap1B could enhance therapies’ efficacy while minimizing adverse effects by reversing endothelial anergy. We briefly discuss strategies successfully developed for targeting RAS as a model for developing anti-Rap1 therapies. Full article

Renal cell carcinoma (RCC) accounts for nearly 2% of cancers diagnosed worldwide. For metastatic RCC, targeted therapy is one of the most common treatment methods. It can include approaches that target vascular endothelial growth factor (VEGFR) or rely on immune checkpoint inhibitors or mTOR inhibitors. Adenosine A2A receptor (A2AR) is a type of widely distributed G-protein-coupled receptor (GPCR). Recently, an increasing number of studies suggest that the activation of A2AR can downregulate anti-tumor immune responses and prevent tumor growth. Currently, the data on A2AR antagonists in RCC treatment are still limited. Therefore, in this article, we further investigate the clinical trials investigating A2AR drugs in RCC. We also describe the epidemiology and current treatment of RCC, along with the physiological role of A2AR, and the types of A2AR drugs that are associated with tumor treatment. Full article