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Galectins are ten family members of carbohydrate-binding proteins with a high affinity for β galactose-containing oligosaccharides. Galectin-1 (Gal-1) is the first protein discovered in the family, expressed in many sites under normal and pathological conditions. In the first part of the review article, we described recent advances in the Gal-1 modulatory role on wound healing, by focusing on the different phases triggered by Gal-1, such as inflammation, proliferation, tissue repair and re-epithelialization. On the contrary, Gal-1 persistent over-expression enhances angiogenesis and extracellular matrix (ECM) production via PI3K/Akt pathway activation and leads to keloid tissue. Therefore, the targeted Gal-1 modulation should be considered a method of choice to treat wound healing and avoid keloid formation. In the second part of the review article, we discuss studies clarifying the role of Gal-1 in the pathogenesis of proliferative diabetic retinopathy, liver, renal, pancreatic and pulmonary fibrosis. This evidence suggests that Gal-1 may become a biomarker for the diagnosis and prognosis of tissue fibrosis and a promising molecular target for the development of new and original therapeutic tools to treat fibrosis in different chronic diseases.

The role of the hydroxycarboxylic acid receptor 2 (HCA2) in the retinal damage induced by diabetes has never been explored. In this context, the present study highlights an upregulation of retinal HCA2 receptors in diabetic C57BL6J mice. Moreover, we illustrate that HCA2 receptors exert an anti-inflammatory effect on the retinal damage induced by diabetes when activated by the endogenous ligand β-hydroxybutyrate. Seven-to-10-week-old C57BL6J mice were rendered diabetic by a single intraperitoneal injection of streptozotocin (75 mg/kg of body weight) and monitored intermittently over a 10-week period extending from the initial diabetes assessment. Mice with a fasting blood glucose level higher than 250 mg/dl for 2 consecutive weeks after streptozotocin injection were treated twice a week with intraperitoneal injections of 25-50-100 mg/kg β-hydroxybutyrate. Interestingly, while the retinal endoplasmic reticulum stress markers (pPERK, pIRE1, ATF-6α) were elevated in diabetic C57BL6J mice, their levels were significantly reduced by the systemic intraperitoneal treatment with 50 mg/kg and 100 mg/kg β-hydroxybutyrate. These mice also exhibited high NLRP3 inflammasome activity and proinflammatory cytokine levels. In fact, the elevated levels of retinal NLRP3 inflammasome activation markers (NLRP3, ASC, caspase-1) and of the relative proinflammatory cytokines (IL-1β, IL-18) were significantly reduced by 50 mg/kg and 100 mg/kg β-hydroxybutyrate treatment. These doses also reduced the high apoptotic cell number exhibited by the diabetic mice in the retinal outer nuclear layer (ONL) and increased the ONL low connexin 43 expression, leading to an improvement in retinal permeability and homeostasis. These data suggest that the systemic treatment of diabetic C57BL6J mice with BHB activates retinal HCA2 and inhibits local damage.

Hydrogel-based dressings exhibit suitable features for successful wound healing, including flexibility, high water-vapor permeability and moisture retention, and exudate absorption capacity. Moreover, enriching the hydrogel matrix with additional therapeutic components has the potential to generate synergistic results. Thus, the present study centered on diabetic wound healing using a Matrigel-enriched alginate hydrogel embedded with polylactic acid (PLA) microspheres containing hydrogen peroxide (H2O2). The synthesis and physicochemical characterization of the samples, performed to evidence their compositional and microstructural features, swelling, and oxygen-entrapping capacity, were reported. For investigating the three-fold goal of the designed dressings (i.e., releasing oxygen at the wound site and maintaining a moist environment for faster healing, ensuring the absorption of a significant amount of exudate, and providing biocompatibility), in vivo biological tests on wounds of diabetic mice were approached. Evaluating multiple aspects during the healing process, the obtained composite material proved its efficiency for wound dressing applications by accelerating wound healing and promoting angiogenesis in diabetic skin injuries.

Breast cancer and melanoma are among the most frequent cancer types leading to brain metastases. Despite the unquestionable clinical significance, important aspects of the development of secondary tumours of the central nervous system are largely uncharacterized, including extravasation of metastatic cells through the blood‐brain barrier. By using transmission electron microscopy, here we followed interactions of cancer cells and brain endothelial cells during the adhesion, intercalation/incorporation and transendothelial migration steps. We observed that brain endothelial cells were actively involved in the initial phases of the extravasation by extending filopodia‐like membrane protrusions towards the tumour cells. Melanoma cells tended to intercalate between endothelial cells and to transmigrate by utilizing the paracellular route. On the other hand, breast cancer cells were frequently incorporated into the endothelium and were able to migrate through the transcellular way from the apical to the basolateral side of brain endothelial cells. When co‐culturing melanoma cells with cerebral endothelial cells, we observed N‐cadherin enrichment at melanoma‐melanoma and melanoma‐endothelial cell borders. However, for breast cancer cells N‐cadherin proved to be dispensable for the transendothelial migration both in vitro and in vivo. Our results indicate that breast cancer cells are more effective in the transcellular type of migration than melanoma cells.

Introduction: Cardiac fibrosis is strongly induced by diabetic conditions. Both chrysin (CHR) and calixarene OTX008, a specific inhibitor of galectin 1 (Gal-1), seem able to reduce transforming growth factor beta (TGF-β)/SMAD pro-fibrotic pathways, but their use is limited to their low solubility. Therefore, we formulated a dual-action supramolecular system, combining CHR with sulfobutylated β-cyclodextrin (SBECD) and OTX008 (SBECD + OTX + CHR). Here we aimed to test the anti-fibrotic effects of SBECD + OTX + CHR in hyperglycemic H9c2 cardiomyocytes and in a mouse model of chronic diabetes. Methods: H9c2 cardiomyocytes were exposed to normal (NG, 5.5 mM) or high glucose (HG, 33 mM) for 48 h, then treated with SBECD + OTX + CHR (containing OTX008 0.75–1.25–2.5 µM) or the single compounds for 6 days. TGF-β/SMAD pathways, Mitogen-Activated Protein Kinases (MAPKs) and Gal-1 levels were assayed by Enzyme-Linked Immunosorbent Assays (ELISAs) or Real-Time Quantitative Reverse Transcription Polymerase chain reaction (qRT-PCR). Adult CD1 male mice received a single intraperitoneal (i.p.) administration of streptozotocin (STZ) at a dosage of 102 mg/kg body weight. From the second week of diabetes, mice received 2 times/week the following i.p. treatments: OTX (5 mg/kg)-SBECD; OTX (5 mg/kg)-SBECD-CHR, SBECD-CHR, SBECD. After a 22-week period of diabetes, mice were euthanized and cardiac tissue used for tissue staining, ELISA, qRT-PCR aimed to analyse TGF-β/SMAD, extracellular matrix (ECM) components and Gal-1. Results: In H9c2 cells exposed to HG, SBECD + OTX + CHR significantly ameliorated the damaged morphology and reduced TGF-β1, its receptors (TGFβR1 and TGFβR2), SMAD2/4, MAPKs and Gal-1. Accordingly, these markers were reduced also in cardiac tissue from chronic diabetes, in which an amelioration of cardiac remodeling and ECM was evident. In both settings, SBECD + OTX + CHR was the most effective treatment compared to the other ones. Conclusion: The CHR-based supramolecular SBECD-calixarene drug delivery system, by enhancing the solubility and the bioavailability of both CHR and calixarene OTX008, and by combining their effects, showed a strong anti-fibrotic activity in rat cardiomyocytes and in cardiac tissue from mice with chronic diabetes. Also an improved cardiac tissue remodeling was evident. Therefore, new drug delivery system, which could be considered as a novel putative therapeutic strategy for the treatment of diabetes-induced cardiac fibrosis.

This study aimed to investigate the interactions between fingolimod, a sphingosine 1-phosphate receptor (S1PR) agonist, and melanocortin receptors 1 and 5 (MCR1, MCR5). In particular, we investigated the effects of fingolimod, a drug approved to treat relapsing-remitting multiple sclerosis, on retinal angiogenesis in a mouse model of diabetic retinopathy (DR). We showed, by a molecular modeling approach, that fingolimod can bind with good-predicted affinity to MC1R and MC5R. Thereafter, we investigated the fingolimod actions on retinal MC1Rs/MC5Rs in C57BL/6J mice. Diabetes was induced in C57BL/6J mice through streptozotocin injection. Diabetic and control C57BL/6J mice received fingolimod, by oral route, for 12 weeks and a monthly intravitreally injection of MC1R antagonist (AGRP), MC5R antagonist (PG20N), and the selective S1PR1 antagonist (Ex 26). Diabetic animals treated with fingolimod showed a decrease of retinal vascular endothelial growth factor A (VEGFA) and vascular endothelial growth factor receptors 1 and 2 (VEGFR1 and VEGFR2), compared to diabetic control group. Fingolimod co-treatment with MC1R and MC5R selective antagonists significantly ( p < 0.05) increased retinal VEGFR1, VEGFR2, and VEGFA levels compared to mice treated with fingolimod alone. Diabetic animals treated with fingolimod plus Ex 26 (S1PR1 selective blocker) had VEGFR1, VEGFR2, and VEGFA levels between diabetic mice group and the group of diabetic mice treated with fingolimod alone. This vascular protective effect of fingolimod, through activation of MC1R and MC5R, was evidenced also by fluorescein angiography in mice. Finally, molecular dynamic simulations showed a strong similarity between fingolimod and the MC1R agonist BMS-470539. In conclusion, the anti-angiogenic activity exerted by fingolimod in DR seems to be mediated not only through S1P1R, but also by melanocortin receptors.

Liver fibrosis can develop on the background of hyperglycemia in diabetes mellitus. However, xenobiotic-related factors may accelerate diabetes-associated liver fibrosis. In this study, we aimed to assess the antfibrotic effect of ADSC and HGF therapy and to establish the cellular and molecular mechanisms through in vitro and in vivo experiments. In vitro, TGF-β1-activated hepatic stellate cells (HSCs) were cocultured with ADSCs or HGF, and the expression of several fibrosis markers was investigated. The antifibrotic effect of the ADSCs, HGF, and ADSCs supplemented with HGF was further assessed in vivo on diabetic mice with liver fibrosis experimentally induced. In vitro results showed the inhibition of HSC proliferation and decrease in fibrogenesis markers. Coadministration of ADSCs and HGF on diabetic mice with liver fibrosis enhanced antifibrotic effects confirmed by the downregulation of Col I, α-SMA, TGF-β1, and Smad2, while Smad7 was upregulated. Moreover, stem cell therapy supplemented with HGF considerably attenuated inflammation and microvesicular steatosis, decreased collagen deposits, and alleviated liver fibrosis. In conclusion, the HGF-based ADSC therapy might be of interest for the treatment of liver fibrosis in diabetic patients, consecutive aggression exerts by different environmental factors.

This study assessed the distribution of heavy metals in the gills, kidney, and liver, correlated with the severity of histopathological changes, of three fish species with different feeding habitats (Barbus barbus, Squalius cephalus, and Chondrostoma nasus) from the Crișul Negru river, Romania. The levels of copper (Cu), chromium (Cr), cadmium (Cd), lead (Pb), and zinc (Zn) in fish tissues were measured by atomic absorption spectrophotometry. Histopathology and the expressions of TNF-α and proliferation cell nuclear antigen (PCNA) were investigated by immunohistochemistry and Western blot. Our data suggest a significant correlation between the bioconcentration level of metals and structural changes. The carnivorous species was the most affected compared to the omnivorous and herbivorous ones, and the most affected organ was the kidney. Moreover, the correlation of tissue damage with the PCNA and TNF-α expression levels revealed that the herbivorous species presented less extended lesions, likely due to higher activated repair mechanisms and lower levels of inflammation. In conclusion, our data and the subsequent statistical analysis suggest that feeding behavior could be correlated with the histopathological alterations and might be used for a more profound evaluation of aquatic environment safety and analysis of aquatic ecosystems.

In the original publication [...].

In the original publication [...]