Ellagic acid (EA) is a polyphenolic compound that can be found as a naturally occurring hydrolysis product of ellagitannins in pomegranates, berries, grapes, green tea and nuts. Previous studies have reported the antitumor properties of EA mainly using in vitro models. No data are available about EA influence on bladder cancer cell invasion of the extracellular matrix triggered by vascular endothelial growth factor-A (VEGF-A), an angiogenic factor associated with disease progression and recurrence, and tumor growth in vivo. In this study, we have investigated EA activity against four different human bladder cancer cell lines (i.e., T24, UM-UC-3, 5637 and HT-1376) by in vitro proliferation tests (measuring metabolic and foci forming activity), invasion and chemotactic assays in response to VEGF-A and in vivo preclinical models in nude mice. Results indicate that EA exerts anti-proliferative effects as a single agent and enhances the antitumor activity of mitomycin C, which is commonly used for the treatment of bladder cancer. EA also inhibits tumor invasion and chemotaxis, specifically induced by VEGF-A, and reduces VEGFR-2 expression. Moreover, EA down-regulates the expression of programmed cell death ligand 1 (PD-L1), an immune checkpoint involved in immune escape. EA in vitro activity was confirmed by the results of in vivo studies showing a significant reduction of the growth rate, infiltrative behavior and tumor-associated angiogenesis of human bladder cancer xenografts. In conclusion, these results suggest that EA may have a potential role as an adjunct therapy for bladder cancer.

This pilot study aimed to ascertain whether the local application of ascorbic acid (AA), of T3, and of rat (r) bone marrow mesenchymal stem cells (BMSCs), alone or in all possible combinations, promoted healing after an Achilles tendon injury in a rat model. An Achilles tendon defect was produced in 24 6–8-week-old male inbred Lewis rats. The animals were then randomly divided into eight groups of three rats each. The tendon defect was filled with 50 μL of phosphate-buffered saline (PBS) containing (1) 50 μg/mL AA (AA group), (2) 10−7 M T3 (T3 group), (3) 4 × 106 rBMSCs (rBMSC group), (4) 50 μg/mL AA + 10−7 M T3 (AA + T3 group), (5) 4 × 106 rBMSCs + 50 μg/mL AA (rBMSC + AA group), (6) 4 × 106 rBMSCs + 10−7 M T3 (rBMSC + T3 group), (7) 4 × 106 rBMSCS + 50 μg/mL AA + 10−7 M T3 (rBMSC + AA + T3 group), and (8) PBS only (control group: CTRL). All treatments were administered by local injection immediately after the tendons had been damaged; additionally, AA was injected also on the second and fourth day from the first injection (for groups 1, 4, 5, and 7), and T3 was injected again every day for 4 days (for groups 2, 4, 6, and 7). At 30 days from initial treatment, tendon samples were harvested, and the quality of tendon repair was evaluated using histological and histomorphological analysis. The structure and morphology of the injured Achilles tendons were evaluated using the modified Svensson, Soslowsky, and Cook score, and the collagen type I and III ratio was calculated. The group treated with AA combined with T3 displayed the lowest Svensson, Soslowsky, and Cook total score value of all tissue sections at histopathological examination, with fiber structure close to regular orientation, normal-like tendon vasculature, and no cartilage formation. AA + T3 also showed the highest collagen I and the lowest collagen III values compared to all other treatments including the CTRL. There are potential benefits using a combination of AA and T3 to accelerate tendon healing.

This study aims to develop a reliable and reproducible inflammatory bowel disease (IBD) murine model based on a careful spatial–temporal histological characterization. Secondary aims included extensive preclinical studies focused on the in situ expression of clinically relevant biomarkers and targets involved in IBD. C57BL/6 female mice were used to establish the IBD model. Colitis was induced by the oral administration of 2% Dextran Sulfate Sodium (DSS) for 5 days, followed by 2, 4 or 9 days of water. Histological analysis was performed by sectioning the whole colon into rings of 5 mm each. Immunohistochemical analyses were performed for molecular targets of interest for monitoring disease activity, treatment response and predicting outcome. Data reported here allowed us to develop an original scoring method useful as a tool for the histological assessment of preclinical models of DSS-induced IBD. Immunohistochemical data showed a significant increase in TNF-α, α4β7, VEGFRII, GR-1, CD25, CD3 and IL-12p40 expression in DSS mice if compared to controls. No difference was observed for IL-17, IL-23R, IL-36R or F480. Knowledge of the spatial–temporal pattern distribution of the pathological lesions of a well-characterized disease model lays the foundation for the study of the tissue expression of meaningful predictive biomarkers, thereby improving translational success rates of preclinical studies for a personalized management of IBD patients.

Poly-lactic-co-glycolic acid nanoparticles (PLGA-NPs) were approved by the Food and Drug Administration (FDA) for drug delivery in cancer. The enhanced permeability and retention (EPR) effect drives their accumulation minimizing the side effects of chemotherapeutics. Our aim was to develop a new theranostic tool for cancer diagnosis and therapy based on PLGA-NPs and to evaluate the added value of vascular endothelial growth factor (VEGF) for enhanced tumor targeting. In vitro and in vivo properties of PLGA-NPs were tested and compared with VEGF-PLGA-NPs. Dynamic light scattering (DLS) was performed to evaluate the particle size, polydispersity index (PDI), and zeta potential of both preparations. Spectroscopy was used to confirm the absorption spectra in the near-infrared (NIR). In vivo, in BALB/c mice bearing a syngeneic tumor in the right thigh, intravenously injected PLGA-NPs showed a high target-to-muscle ratio (4.2 T/M at 24 h post-injection) that increased over time, with a maximum uptake at 72 h and a retention of the NPs up to 240 h. VEGF-PLGA-NPs accumulated in tumors 1.75 times more than PLGA-NPs with a tumor-to-muscle ratio of 7.90 ± 1.61 (versus 4.49 ± 0.54 of PLGA-NPs). Our study highlights the tumor-targeting potential of PLGA-NPs for diagnostic and therapeutic applications. Such NPs can be conjugated with proteins such as VEGF to increase accumulation in tumor lesions.