PRIN LEVANTE 2020: Levulinic acid valorization through advanced novel technologies

The project LEVANTE deals with the development of new catalytic processes for the valorization of levulinic acid and its esters towards three classes of compounds: levulinic ketals, diphenolic acid and γ-valerolactone together with other reduction products

Integrated Cascade Process for the Catalytic Conversion of 5-Hydroxymethylfurfural to Furanic and TetrahydrofuranicDiethers as Potential Biofuels

The depletion of fossil resources is driving the research towards alternative renewable ones. Under this perspective, 5-hydroxymethylfurfural (HMF) represents a key molecule deriving from biomass characterized by remarkable potential as platform chemical. In this work, for the first time, the hydrogenation of HMF in ethanol was selectively addressed towards 2,5-bis(hydroxymethyl)furan (BHMF) or 2,5-bis(hydroxymethyl)tetrahydrofuran (BHMTHF) by properly tuning the reaction conditions in the presence of the same commercial catalyst (Ru/C), reaching the highest yields of 80 and 93 mol%, respectively. These diols represent not only interesting monomers but strategic precursors for two scarcely investigated ethoxylated biofuels, 2,5-bis(ethoxymethyl)furan (BEMF) and 2,5-bis(ethoxymethyl)tetrahydrofuran (BEMTHF). Therefore, the etherification with ethanol of pure BHMF and BHMTHF and of crude BHMF, as obtained from hydrogenation step, substrates scarcely investigated in the literature, was performed with several commercial heterogeneous acid catalysts. Among them, the zeolite HZSM-5 (Si/Al=25) was the most promising system, achieving the highest BEMF yield of 74 mol%. In particular, for the first time, the synthesis of the fully hydrogenated diether BEMTHF was thoroughly studied, and a novel cascade process for the tailored conversion of HMF to the diethyl ethers BEMF and BEMTHF was proposed

Electro-oxidative depolymerisation of technical lignin in water using platinum, nickel oxide hydroxide and graphite electrodes

In order to improve the lignin exploitation to added-value bioproducts, a mild chemical conversion route based on electrochemistry was investigated. For the first time, soda lignin Protobind™ 1000 (technical lignin from the pulp & paper industry) was studied by cyclic voltammetry to preliminarily investigate the effect of the main reaction parameters, such as the type of electrode material (platinum, nickel oxide hydroxide, graphite), the pH (12, 13, 14), the scan rate (10, 50, 100, 250 mV s-1), the substrate concentration (2, 20 g L-1) and the oxidation/reduction potential (from -0.8 to +0.8 V). Under the optimal reaction conditions among those tested (NiOOH electrode, pH 14, lignin 20 g L-1, 0.4 V), the electro-oxidative depolymerisation of lignin by electrolysis was performed in a divided cell. The reaction products were identified and quantified by ultra-pressure liquid chromatography coupled with mass spectrometry. The main products were sinapic acid, vanillin, vanillic acid, and acetovanillone. The obtained preliminary results demonstrated the potential feasibility of this innovative electrochemical route for lignin valorisation for the production of bio-aromatic chemicals

Plasma Kallikrein Mediates Retinal Vascular Dysfunction and Induces Retinal Thickening in Diabetic Rats

Objective: Plasma kallikrein (PK) has been identified in vitreous fluid obtained from individuals with diabetic retinopathy and has been implicated in contributing to retinal vascular dysfunction. In this report, we examined the effects of PK on retinal vascular functions and thickness in diabetic rats. Research Design and Methods: We investigated the effects of a selective PK inhibitor, ASP-440, and C1 inhibitor (C1-INH), the primary physiological inhibitor of PK, on retinal vascular permeability (RVP) and hemodynamics in rats with streptozotocin-induced diabetes. The effect of intravitreal PK injection on retinal thickness was examined by spectral domain optical coherence tomography. Results: Systemic continuous administration of ASP-440 for 4 weeks initiated at the time of diabetes onset inhibited RVP by 42% (P = 0.013) and 83% (P < 0.001) at doses of 0.25 and 0.6 mg/kg per day, respectively. Administration of ASP-440 initiated 2 weeks after the onset of diabetes ameliorated both RVP and retinal blood flow abnormalities in diabetic rats measured at 4 weeks’ diabetes duration. Intravitreal injection of C1-INH similarly decreased impaired RVP in rats with 2 weeks’ diabetes duration. Intravitreal injection of PK increased both acute RVP and sustained focal RVP (24 h postinjection) to a greater extent in diabetic rats compared with nondiabetic control rats. Intravitreal injection of PK increased retinal thickness compared with baseline to a greater extent (P = 0.017) in diabetic rats (from 193 $\pm$ 10 $\mu$m to 223 $\pm$ 13 $\mu$m) compared with nondiabetic rats (from 182 $\pm$ 8 $\mu$m to 193 $\pm$ 9 $\mu$m). Conclusions: These results show that PK contributes to retinal vascular dysfunctions in diabetic rats and that the combination of diabetes and intravitreal injection of PK in rats induces retinal thickening

Whole genome assessment of the retinal response to diabetes reveals a progressive neurovascular inflammatory response

<p>Abstract</p> <p>Background</p> <p>Despite advances in the understanding of diabetic retinopathy, the nature and time course of molecular changes in the retina with diabetes are incompletely described. This study characterized the functional and molecular phenotype of the retina with increasing durations of diabetes.</p> <p>Results</p> <p>Using the streptozotocin-induced rat model of diabetes, levels of retinal permeability, caspase activity, and gene expression were examined after 1 and 3 months of diabetes. Gene expression changes were identified by whole genome microarray and confirmed by qPCR in the same set of animals as used in the microarray analyses and subsequently validated in independent sets of animals. Increased levels of vascular permeability and caspase-3 activity were observed at 3 months of diabetes, but not 1 month. Significantly more and larger magnitude gene expression changes were observed after 3 months than after 1 month of diabetes. Quantitative PCR validation of selected genes related to inflammation, microvasculature and neuronal function confirmed gene expression changes in multiple independent sets of animals.</p> <p>Conclusion</p> <p>These changes in permeability, apoptosis, and gene expression provide further evidence of progressive retinal malfunction with increasing duration of diabetes. The specific gene expression changes confirmed in multiple sets of animals indicate that pro-inflammatory, anti-vascular barrier, and neurodegenerative changes occur in tandem with functional increases in apoptosis and vascular permeability. These responses are shared with the clinically documented inflammatory response in diabetic retinopathy suggesting that this model may be used to test anti-inflammatory therapeutics.</p

Transcriptomic comparison of the retina in two mouse models of diabetes

Mouse models of type I diabetes offer the potential to combine genetic approaches with other pharmacological or physiological manipulations to investigate the pathophysiology and treatment of diabetic retinopathy. Type I diabetes is induced in mice through chemical toxins or can arise spontaneously from genetic mutations. Both models are associated with retinal vascular and neuronal changes. Retinal transcriptomic responses in C57BL/6J mice treated with streptozotocin and Ins2Akita/+ were compared after 3 months of hyperglycemia. Specific gene expression changes suggest a neurovascular inflammatory response in diabetic retinopathy. Genes common to the two models may represent the response of the retina to hyperglycemia, while changes unique to each model may represent time-dependent disease progression differences in the various models. Further investigation of the commonalities and differences between mouse models of type I diabetes may define cause and effect events in early diabetic retinopathy disease progression

Betacellulin Induces Increased Retinal Vascular Permeability in Mice

BACKGROUND: Diabetic maculopathy, the leading cause of vision loss in patients with type 2 diabetes, is characterized by hyper-permeability of retinal blood vessels with subsequent formation of macular edema and hard exudates. The degree of hyperglycemia and duration of diabetes have been suggested to be good predictors of retinal complications. Intervention studies have determined that while intensive treatment of diabetes reduced the development of proliferative diabetic retinopathy it was associated with a two to three-fold increased risk of severe hypoglycemia. Thus we hypothesized the need to identify downstream glycemic targets, which induce retinal vascular permeability that could be targeted therapeutically without the additional risks associated with intensive treatment of the hyperglycemia. Betacellulin is a 32 kD member of the epidermal growth factor family with mitogenic properties for the retinal pigment epithelial cells. This led us to hypothesize a role for betacellulin in the retinal vascular complications associated with diabetes. METHODS AND FINDINGS: In this study, using a mouse model of diabetes, we demonstrate that diabetic mice have accentuated retinal vascular permeability with a concomitant increased expression of a cleaved soluble form of betacellulin (s-Btc) in the retina. Intravitreal injection of soluble betacellulin induced retinal vascular permeability in normoglycemic and hyperglycemic mice. Western blot analysis of retinas from patients with diabetic retinopathy showed an increase in the active soluble form of betacellulin. In addition, an increase in the levels of A disintegrin and metalloproteinase (ADAM)-10 which plays a role in the cleavage of betacellulin was seen in the retinas of diabetic mice and humans. CONCLUSIONS: These results suggest that excessive amounts of betacellulin in the retina may contribute to the pathogenesis of diabetic macular edema

The effect of a preoperative subconjuntival injection of dexamethasone on blood–retinal barrier breakdown following scleral buckling retinal detachment surgery: a prospective randomized placebo-controlled double blind clinical trial

textabstractBackground: Blood-retinal barrier breakdown secondary to retinal detachment and retinal detachment repair is a factor in the pathogenesis of proliferative vitreoretinopathy (PVR). We wished to investigate whether an estimated 700 to 1000 ng/ml subretinal dexamethasone concentration at the time of surgery would decrease the blood-retinal barrier breakdown postoperatively. Methods: Prospective, placebo-controlled, double blind clinical trial. In 34 patients with rhegmatogenous retinal detachment scheduled for conventional scleral buckling retinal detachment surgery, a subconjunctival injection of 0.5 ml dexamethasone diphosphate (10 mg) or 0.5 ml placebo was given 5-6 hours before surgery. Differences in laser flare photometry (KOWA) measurements taken 1, 3 and 6 weeks after randomisation between dexamethasone and placebo were analysed using mixed model ANOVA, while correcting for the preoperative flare measurement. Results: Six patients did not complete the study, one because of recurrent detachment within 1 week, and five because they missed their postoperative laser flare visits. The use of dexamethasone resulted in a statistically significant decrease in laser flare measurements at the 1-week postoperative visit. Conclusion: The use of a preoperative subconjunctival injection of dexamethasone decreased 1-week postoperative blood-retina barrier breakdown in patients undergoing conventional scleral buckling retinal detachment surgery. This steroid priming could be useful as a part of a peri-operative regime that would aim at decreasing the incidence of PVR

Placenta Growth Factor-1 Exerts Time-Dependent Stabilization of Adherens Junctions Following VEGF-Induced Vascular Permeability

Increased vascular permeability is an early event characteristic of tissue ischemia and angiogenesis. Although VEGF family members are potent promoters of endothelial permeability the role of placental growth factor (PlGF) is hotly debated. Here we investigated PlGF isoforms 1 and 2 and present in vitro and in vivo evidence that PlGF-1, but not PlGF-2, can inhibit VEGF-induced permeability but only during a critical window post-VEGF exposure. PlGF-1 promotes VE-cadherin expression via the trans-activating Sp1 and Sp3 interaction with the VE-cadherin promoter and subsequently stabilizes transendothelial junctions, but only after activation of endothelial cells by VEGF. PlGF-1 regulates vascular permeability associated with the rapid localization of VE-cadherin to the plasma membrane and dephosphorylation of tyrosine residues that precedes changes observed in claudin 5 tyrosine phosphorylation and membrane localization. The critical window during which PlGF-1 exerts its effect on VEGF-induced permeability highlights the importance of the translational significance of this work in that PLGF-1 likely serves as an endogenous anti-permeability factor whose effectiveness is limited to a precise time point following vascular injury. Clinical approaches that would pattern nature's approach would thus limit treatments to precise intervals following injury and bring attention to use of agents only during therapeutic windows