Search Results (815)

Background: Pancreatic cystic lesions may be benign and require observation or cancerous, with high mortality, requiring risky surgery. Diagnosis is often difficult, and the search for biomarkers to differentiate pancreatic cancer from other lesions is ongoing. Methods: 60 consecutive patients, operated on due to histopathologically confirmed pancreatic cancer or due to pancreatic cystic lesions, were analyzed. The concentrations of 16 immunological factors (sHER-2neu, sEGFR, sIL-6Ra, follistatin, FGF-basic, sVEGFR-2, PECAM-1, PDGF-AB BB, prolactin, G-CSF, HGF, sTIE-2, SCF, sVEGFR-1, osteopontin, and leptin) were assessed in both serum and cystic fluid and compared between the groups. Results: Lower PDGF-AB/BB and leptin concentrations in serum, as well as lower sTIE-2, osteopontin, and leptin levels, were associated with cancer. In cystic tumors, for some factors, significant differences between cancerous and benign lesions were found when the differences in cystic fluid and serum concentrations were compared. Conclusions: PDGF-AB/BB, leptin, sTIE-2, and osteopontin, as well as the comparison of serum/cystic fluid concentrations of immunological factors, might be useful for pancreatic cystic tumor diagnosis. However, this requires confirmation in a larger study. Full article

Angiogenesis, the formation of new blood vessels from pre-existing ones, is crucial for various physiological and pathological conditions, including embryonic development, wound healing, tissue regeneration and tumor progression. While traditionally attributed to the actions of growth factors and their receptors, emerging evidence highlights the crucial regulatory roles of mitochondria in angiogenesis. This narrative review explores the multifaceted functions of mitochondria in endothelial cells, which are central to blood vessel formation. Beyond their classical role in ATP production, mitochondria contribute to angiogenesis through redox signaling, calcium homeostasis, biosynthetic activity, and reactive oxygen species (ROS) generation. These organelles help regulate key endothelial behaviors such as proliferation, migration, and tube formation through mechanisms that include mitochondrial calcium signaling and ROS-mediated stabilization of hypoxia-inducible factor-1α (HIF-1α), leading to increased vascular endothelial growth factor (VEGF) expression. Additionally, mitochondrial dynamics, dysfunction, and genetic factors are discussed for their influence on angiogenic outcomes. Understanding these complex mitochondrial functions opens new therapeutic avenues for modulating angiogenesis in diseases such as cancer and cardiovascular disorders. Full article

Cardiovascular diseases (CVDs) remain the leading cause of morbidity and mortality in industrialized countries. Coronary artery disease (CAD) represents the most prevalent form of cardiovascular disease and remains a leading cause of morbidity, mortality, and long-term disability worldwide. Therefore, the identification of early biomarkers and clarification of the mechanism of action of pharmacological adjuvants is urgently needed. Nutraceuticals such as Arthrospira platensis (commonly known as spirulina) have emerged as promising modulators for their notable vascular anti-inflammatory properties. In this study, we provide novel evidence of the anti-inflammatory and anti-atherosclerotic potential of Arthrospira platensis toward endothelial cells and immune interactions, combining in vitro assays with bioinformatic profiling. Spirulina treatment significantly attenuated endothelial and angiogenic activation, reducing pro-inflammatory cytokine and VEGFA/VEGFR2 expression. Additionally, it also decreased the activation and adhesion capabilities of THP-1 monocytic cell lines. Through computational analysis of the complex molecular mixture present in Arthrospira platensis, we have identified a subset of compounds exhibiting high structural similarity to CHEMBL3559503, a well-characterized synthetic molecule with dual activity as a TLR9 agonist and anti-angiogenic agent. This represents a novel insight, suggesting that spirulina may serve as a natural source of analogues capable of modulating both immune and angiogenic pathways. These results highlight Arthrospira platensis as a promising candidate nutraceutical for targeting endothelial/immune crosstalk in the context of atherosclerosis prevention, offering both mechanistic insights and translational potential. 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

Zebrafish are model organisms for drug screening owing to their transparent bodies, rapid embryonic development, and genetic similarities with humans. However, using standard polystyrene culture plates can limit the oxygen supply, potentially affecting embryo survival and the reliability of assays conducted in zebrafish. In this study, we evaluated the application of a novel, highly oxygen-permeable culture plate (InnoCell^TM) in zebrafish development and drug screening assays. Under both normal and oxygen-restricted conditions, zebrafish embryos cultured on InnoCell^TM plates exhibited significantly improved developmental parameters, including heart rate and body length, compared with those cultured on conventional polystyrene plates. The InnoCell^TM plate enabled a significant reduction in medium volume without compromising zebrafish embryo viability, thereby demonstrating its advantages, particularly in high-throughput 384-well formats. Drug screening tests using antiangiogenic receptor tyrosine kinase inhibitors (TKIs) revealed enhanced sensitivity and more pronounced biological effects in InnoCell^TM plates, as evidenced by the quantification of intersegmental blood vessels and gene expression analysis of the vascular endothelial growth factor receptor (vegfr, also known as kdrl). These results indicate that the InnoCell^TM highly oxygen-permeable plate markedly improves zebrafish-based drug screening efficiency and assay reliability, highlighting its potential for widespread application in biomedical research. Full article

Natural products, characterized by their structural novelty, multi-target capabilities, and favorable toxicity profiles, represent a prominent reservoir for the discovery of innovative anticancer therapeutics. In the current investigation, we identified ajuforrestin A, a diterpenoid compound extracted from Ajuga lupulina Maxim, as a potent agent against lung cancer. In vitro, this compound markedly curtailed the proliferation of A549 cells. Mechanistic explorations revealed that ajuforrestin A could arrest A549 cells in the G0/G1 phase of the cell cycle, provoke apoptosis in cancer cells, and impede their migration by modulating the STAT3 and FAK signaling cascades. Angiogenesis is indispensable for tumor formation, progression, and metastatic dissemination. Vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 are established as crucial mediators in tumor neovascularization, a process fundamental to both the expansion of tumor cells and the development of new blood vessels within the tumor milieu. Through the combined application of a Tg(fli1:EGFP) zebrafish model and SPR experimentation, we furnished strong evidence for the ability of ajuforrestin A to obstruct tumor angiogenesis via selective engagement with VEGFR-2. Finally, a zebrafish xenograft tumor model demonstrated that ajuforrestin A could effectively restrain tumor growth and metastasis in vivo. Ajuforrestin A therefore shows considerable promise as a lead compound for the future development of therapies against non-small cell lung cancer (NSCLC). Full article

Malignant cutaneous melanoma is among the most aggressive forms of skin cancer, characterized by high metastatic potential and frequent resistance to standard therapies. Hydroxytyrosol, a phenolic compound derived from extra virgin olive oil, has shown promising anticancer properties in various models, yet its effects in 3D melanoma systems remain poorly understood. In this study, we used paired 3D spheroid models of non-tumorigenic (HEMa) and melanoma (C32) to assess the therapeutic potential of hydroxytyrosol. To evaluate the anti-tumoral effect of hydroxytyrosol, we performed cytotoxicity, metastasis, invasiveness, cell cycle arrest, apoptotic, and proteomic assays. Hydroxytyrosol treatment significantly impaired spheroid growth, reduced cell viability, and induced cell cycle arrest and apoptosis in C32 spheroids, with minimal cytotoxicity observed in HEMa models. Proteomic profiling further demonstrated that hydroxytyrosol selectively downregulated a network of oncogenic proteins, including ERBB2, ERBB3, ERBB4, VEGFR-2, and WIF-1, along with suppression of downstream PI3K-Akt and MAPK/ERK signaling pathways. In conclusion, compared to dabrafenib, hydroxytyrosol exerted a broader range of molecular effects and was more selective toward tumor cells. These findings support the use of hydroxytyrosol as a multi-targeted agent capable of attenuating melanoma progression through suppression of kinase signaling and tumor-stromal interactions. Full article

Cancer remains one of the leading causes of death globally, highlighting the urgent need for novel anticancer therapies with higher efficacy and reduced toxicity. Similarly, the rise in multidrug-resistant pathogens and emerging infectious diseases underscores the critical demand for new antimicrobial agents that target resistant infections through unique mechanisms. This study used computational approaches to investigate twenty quinolone–triazole and conazole–triazole hybrid derivatives as antimicrobial and anticancer agents (1–20) with nine reference drugs. By studying their interactions with 6 bacterial DNA gyrase and 10 cancer-inducing target proteins (E. faecalis, M. tuberculosis, S. aureus, E. coli, M. smegmatis, P. aeruginosa and EGFR, MPO, VEGFR, CDK6, MMP1, Bcl-2, LSD1, HDAC6, Aromatase, ALOX15) and comparing them with established drugs such as ampicillin, cefatrizine, fluconazole, gemcitabine, itraconazole, ribavirin, rufinamide, streptomycin, and tazobactam, compounds 15 and 16 emerged as noteworthy antimicrobial and anticancer agents, respectively. In molecular dynamics simulations, compounds 15 and 16 had the strongest binding at −10.6 kcal mol⁻¹ and −12.0 kcal mol⁻¹ with the crucial 5CDQ and 2Z3Y proteins, respectively, exceeded drug-likeness criteria, and displayed extraordinary stability within the enzyme’s pocket over varied temperatures (300–320 K). In addition, we used density functional theory (DFT) to calculate dipole moments and molecular orbital characteristics and analyze the thermodynamic stability of putative antimicrobial and anticancer derivatives. This finding reveals a well-defined, possibly therapeutic relationship, supported by theoretical and future in vitro and in vivo studies. Compounds 15 and 16, thus, emerged as intriguing contenders in the fight against infectious diseases and cancer. Full article

By stimulating living tissues with proper molecules, the angiogenesis and vasculogenesis processes can be observed. Prostaglandin E1 (PGE1), which is a molecule that widens blood vessels and which is used for several medical purposes, such as treating critical limb ischemia, is a typical leading molecule in angiogenesis studies. Nevertheless, its involvement in vasculogenesis and morphogenesis is a more specific subject in the field of developmental biology and therapeutic research. Vasculogenesis is the embryonic phenomenon in which endothelial progenitor cells generate new blood vessels. This phenomenon is distinct and divergent from angiogenesis, which entails the creation of novel blood vessels extending from pre-existing ones. Morphogenesis is the biological phenomenon responsible for the development of an organism or its components into a specific shape. Embryonic development and tissue regeneration are essential components. Current research is investigating the broader consequences of prostaglandins, such as PGE1, in the fields of developmental biology and regenerative medicine. Gaining knowledge about the impact of PGE1 on morphogenesis could provide valuable insights into congenital vascular abnormalities and innovative approaches for tissue repair and regeneration, especially in limb ischemia. In this study, a histologic and morphogenesis study was carried out on Artemia salina napi (first stage of development) by simulating the angiogenesis and morphogenesis processes using PGE1 as the top molecule with vasoactive properties and a series of benopyridyne (3-aminoquinolines, 5-amino quinolines, 8-aminoquinolines, 8-hydroxyquinolines and quinolines, respectively). A series of 30 Artemia salina napi were exposed to the compound listed before. Also, a lot of 30 unexposed Artemia salina napi was taken into account. In total, 210 Artemia salina napi were studied as a model for angionensis and morphogenesis. The study used wet experiments together with imaging reconstruction and graph-generating methodologies. The results show that PGE1 can initiate the shape of the vessel formation. Also, some quinoline series have a pro-mild morphogenetic and angiogenetic effect. Overall, PGE1 plays a significant role in mediating vasculogenesis and morphogenesis through its vasodilatory, anti-inflammatory, and pro-proliferative effects on endothelial cells. PGE1 is involved mainly in increasing the length of the vessel, while the number of vascular branching has an all-simulating general impact. However, the molecules with mild vasculogenic effects tend to develop more complex, limited vascular networks, having a more localized role in the angiogenetic process. Overall imaging and graph analysis showed significant and distinct properties of the vascular network-derived graph. Full article

Preeclampsia (PE) is one of the main causes of obstetric complications and leads to both maternal and neonatal mortality. The maternal innate immune system plays an important role throughout pregnancy by providing protection against pathogens, while simultaneously inducing tolerance to a semi-allogenic developing fetus and placental development. Background/Objectives: To conduct a comparative study of immunological markers in the blood and placenta in preeclampsia. Methods: A total of 35 pregnant women were enrolled in a comparative study with preeclampsia (7) and with physiological pregnancy (28). A study of the immune status in peripheral blood and placenta was conducted with an examination of the subpopulation of lymphocytes profile and intracellular cytokines production by flow cytometry. Results: In the blood of pregnant women with PE, there was a decrease in CD14+ monocytes, as well as a significant increase of natural killers CD16+, CD56+ and activation markers HLA-DR+ and CD95+, as well as a significant rise in production of IL-10, TNF, Perforin, GM-CSF, and IGF. At the same time, in placental tissue in patients with preeclampsia, on the contrary, a significant decrease in regulatory cells CD4+, CD8+, CD14+, CD56+, CD59+, activation markers CD95+, as well as anti-inflammatory cytokine IL-10, growth factors VEGFR and IGF was detected. Conclusions: The maternal–fetal immune profile is crucial for successful fetal development and dysregulation of T-, B-, and NK cells can contribute to inflammation, oxidative stress, and the development of preeclampsia. 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

Novel senotherapeutics are needed to reverse aging-related skin decline. The research question addressed was whether mesoglycan, a clinically approved glycosaminoglycan formulation known to enhance perfusion, angiogenesis, and VEGF-A signaling, possesses therapeutic potential for rejuvenating photo aged human skin. To test this, we treated full-thickness photoaged facial human skin samples (mean age: 72 ± 5 years) from seven women ex vivo. The samples were treated with topical or medium-delivered mesoglycan (100, 200, and 300 µM) for 6 days under serum-free conditions that accelerate skin aging. Biomarkers associated with aging were assessed using quantitative immunohistomorphometry. Mesoglycan treatment improved key skin aging biomarkers at all doses. Compared to vehicle-treated skin, mesoglycan broadly enhanced epidermal structure and function, improved pigmentation-related markers, reduced cellular senescence, boosted mitochondrial performance and antioxidant defenses, and improved dermal matrix structure and microvasculature density. Notably, mesoglycan also upregulated VEGF-A and VEGFR2, promoting skin rejuvenation. Medium-delivered mesoglycan produced stronger overall effects, while rete ridge reappearance was observed exclusively after topical application. Mesoglycan demonstrates senotherapeutic potential in photoaged human skin, acting via complementary pathways, including VEGF-A upregulation. Although medium-delivered mesoglycan yielded the greatest biomarker improvements topical application restored rete ridges, a sign of epidermal reorganization and also significantly enhanced basement membrane structure, pigmentation, mitochondrial function and antioxidant defenses, while avoiding systemic exposure, making it the safer and more feasible route for localized skin anti-aging. Full article

Dermatofibrosarcoma protuberans (DFSP) is a rare sarcoma, characterized by a COL1A1-PDGFB fusion. Imatinib, a multi-target tyrosine kinase inhibitor, is a standard treatment of DFSP. However, resistance emerges in 10–50% of cases. There is an urgent need for predictive biomarkers to refine the patient selection and improve therapeutic outcomes. We aimed to identify predictive biomarkers for imatinib response and explored a pharmacokinomic approach using in vitro assays with patient-derived DFSP cell lines. Four DFSP cell lines that we established were analyzed for tyrosine kinase activities on PamChip, a three-dimensional peptide array, in the presence and absence of imatinib, along with an imatinib-sensitive cell line, GIST-T1, as a positive control. Drug screening was also performed using 60 FDA-approved tyrosine kinase inhibitors, including imatinib. The kinomic profiles were compared with the kinase inhibitor screening results to identify predictive druggable targets. Drug sensitivity was associated with increased activity of PDGFRB, as indicated by the PamChip assay and Western blotting. Furthermore, imatinib sensitivity correlated with the activity of three kinases: FER, ITK, and VEGFR1, suggesting their potential as potential predictive biomarkers. Our cell-based pharmacokinomic approach using patient-derived DFSP cell lines would facilitate the identification of resistant cases to imatinib and guide alternative therapeutic strategies. 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

Background: The aging process is accompanied by changes in the immunological status of a person. Immunosenescence is considered a significant cause of the development of cardiovascular diseases (CVD) in elderly people. However, to date, the relationship between immune/inflammatory processes and diseases associated with age is considered quite complex and is not fully understood. Immunophenotyping and the intracellular production of cytokines involved in the processes of inflammatory aging will allow us to identify biomarkers that are associated with cardiovascular diseases in the elderly. Objectives: To identify immunological markers associated with the process of inflammatory aging in older individuals with cardiovascular diseases. Methods: CD-phenotyping and intracellular cytokine analysis of peripheral blood using the flow cytometry method were conducted in 52 people over 60 years of age (group 1 had CVD and group 2 did not). Blood samples were stained with monoclonal antibodies (mAb) using Becton Dickinson (BD) reagents for the staining and binding of surface receptors CD4+, CD8+, CD14+, CD19+, CD16+, CD56+, CD59+, CD95+, and HLA DR+ and intracellular receptors TNF, IL-10, GM-CSF, VEGFR-2, IGF, and perforin. In addition, the following parameters were studied: questionnaire data (gender, age, alcohol consumption, smoking, physical activity, and marital status), clinical data (blood pressure (BP), heart rate (HR), body mass index (BMI)), comorbid conditions, and cardiovascular diseases (coronary heart disease (CHD), chronic heart failure (CHF), arterial hypertension (AH), previous myocardial infarction (PICS), diabetes mellitus (DM), atrial fibrillation (AF), and stroke). Results: The older patients with cardiovascular pathology had high levels of monocytes CD14+ (p = 0.014), low levels of CD8+ lymphocytes (p = 0.046), and low intracellular production of GM-CSF (p = 0.013) compared to the older people without CVD. Conclusions: The revealed differences in the expression of CD14+ monocytes indicate their role in the development of cardiovascular pathology associated with age-related changes. A decrease in cytotoxic CD8+ lymphocytes and intracellular GM-CSF production leads to an increased risk of developing cardiovascular diseases in older individuals. These observed changes with age will not only expand existing knowledge about the aging of the regulatory link of the immune system but also help to obtain data to predict CVD in older people. Thus, the obtained results support the use of these immunological markers to identify the risk of circulatory disease and a personalized approach in geriatric practice. Full article