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Los empresarios y la Administración italiana han llevado a cabo, a lo largo de los últimos años, objetivos comunes para la descontaminación de las áreas industriales de Piombino. La realización de una plataforma multifuncional permite tratar y descontaminar sitios de interés nacional y tiene como meta la valoración de las áreas descontaminadas, la gestión racional y la recuperación de los residuos siderúrgicos en una planta de producción de conglomerados hidráulicos (CIC).

Peripheral nerve injury treatment is a relevant problem because of nerve lesion high incidence and because of unsatisfactory regeneration after severe injuries, thus resulting in a reduced patient’s life quality. To repair severe nerve injuries characterized by substance loss and to improve the regeneration outcome at both motor and sensory level, different strategies have been investigated. Although autograft remains the gold standard technique, a growing number of research articles concerning nerve conduit use has been reported in the last years. Nerve conduits aim to overcome autograft disadvantages, but they must satisfy some requirements to be suitable for nerve repair. A universal ideal conduit does not exist, since conduit properties have to be evaluated case by case; nevertheless, because of their high biocompatibility and biodegradability, natural-based biomaterials have great potentiality to be used to produce nerve guides. Although they share many characteristics with synthetic biomaterials, natural-based biomaterials should also be preferable because of their extraction sources; indeed, these biomaterials are obtained from different renewable sources or food waste, thus reducing environmental impact and enhancing sustainability in comparison to synthetic ones. This review reports the strengths and weaknesses of natural-based biomaterials used for manufacturing peripheral nerve conduits, analyzing the interactions between natural-based biomaterials and biological environment. Particular attention was paid to the description of the preclinical outcome of nerve regeneration in injury repaired with the different natural-based conduits.

Conduits for the repair of peripheral nerve gaps are a good alternative to autografts as they provide a protected environment and a physical guide for axonal re-growth. Conduits require colonization by cells involved in nerve regeneration (Schwann cells, fibroblasts, endothelial cells, macrophages) while in the autograft many cells are resident and just need to be activated. Since it is known that soluble Neuregulin1 (sNRG1) is released after injury and plays an important role activating Schwann cell dedifferentiation, its expression level was investigated in early regeneration steps (7, 14, 28 days) inside a 10 mm chitosan conduit used to repair median nerve gaps in Wistar rats. In vivo data show that sNRG1, mainly the isoform α, is highly expressed in the conduit, together with a fibroblast marker, while Schwann cell markers, including NRG1 receptors, were not. Primary culture analysis shows that nerve fibroblasts, unlike Schwann cells, express high NRG1α levels, while both express NRG1β. These data suggest that sNRG1 might be mainly expressed by fibroblasts colonizing nerve conduit before Schwann cells. Immunohistochemistry analysis confirmed NRG1 and fibroblast marker co-localization. These results suggest that fibroblasts, releasing sNRG1, might promote Schwann cell dedifferentiation to a “repair” phenotype, contributing to peripheral nerve regeneration.

Peripheral nerves are characterised by the ability to regenerate after injury. Schwann cell activity is fundamental for all steps of peripheral nerve regeneration: immediately after injury they de-differentiate, remove myelin debris, proliferate and repopulate the injured nerve. Soluble Neuregulin1 (NRG1) is a growth factor that is strongly up-regulated and released by Schwann cells immediately after nerve injury. To identify the genes regulated in Schwann cells by soluble NRG1, we performed deep RNA sequencing to generate a transcriptome database and identify all the genes regulated following 6 h stimulation of primary adult rat Schwann cells with soluble recombinant NRG1. Interestingly, the gene ontology analysis of the transcriptome reveals that NRG1 regulates genes belonging to categories that are regulated in the peripheral nerve immediately after an injury. In particular, NRG1 strongly inhibits the expression of genes involved in myelination and in glial cell differentiation, suggesting that NRG1 might be involved in the de-differentiation (or “trans-differentiation”) process of Schwann cells from a myelinating to a repair phenotype. Moreover, NRG1 inhibits genes involved in the apoptotic process, and up-regulates genes positively regulating the ribosomal RNA processing, thus suggesting that NRG1 might promote cell survival and stimulate new protein expression. This in vitro transcriptome analysis demonstrates that in Schwann cells NRG1 drives the expression of several genes which partially overlap with genes regulated in vivo after peripheral nerve injury, underlying the pivotal role of NRG1 in the first steps of the nerve regeneration process.

Aim: To report a paediatric case of retinopathy-positive cerebral malaria, emphasizing the clinical significance of long-term neurological and ophthalmological follow-up (5,5 years)., Case Report: After a recent journey in Ghana, a 17-month-old African female child was admitted at the Paediatric Emergency Room with fever and vomiting. Blood smear confirmed a Plasmodium Falciparum parasitaemia. Iv quinine was promptly administered, but after a few hours, the child developed generalized seizures, requiring benzodiazepine therapy and assisted ventilation for severe desaturation. Brain imaging (CT and MRI), lumbar puncture and several electroencephalograms showed data compatible with cerebral involvement of malaria. Schepens ophthalmoscopy and Ret-Cam pictures acquisition revealed macular haemorrhages in the left eye with central whitening and bilateral capillary abnormalities, typical signs of malarial retinopathy. Antimalarial therapy and iv Levetiracetam allowed neurological improvement. Eleven days after the admission, the child was discharged, showing no neurological symptoms and with an improved EEG signal, a normalized fundus oculi and brain imaging. Neurological and ophthalmological long-term follow-up were conducted: EEG controls didn't reveal abnormalities and the complete ophthalmological assessment showed a regular visual acuity and fundus oculi, as well as a normal SD-OCT and electrophysiologic testing., Conclusion: Cerebral malaria is a severe complication, characterized by a high fatality rate and challenging diagnosis. A helpful instrument for diagnostic and prognostic evaluation is the ophthalmological detection of malarial retinopathy and its monitoring over time. In our patient the long term visual follow-up didn't reveal any adverse outcome., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

(1) Background: Obesity, a complex metabolic disease resulting from an imbalance between food consumption and energy expenditure, leads to an increase in adipocytes and chronic inflammatory conditions. The aim of this paper was to synthesize a small series of carvacrol derivatives ( CD1-3 ) that are able to reduce both adipogenesis and the inflammatory status often associated with the progression of the obesity disease. (2) Methods: The synthesis of CD1-3 was performed using classical procedures in a solution phase. Biological studies were performed on three cell lines: 3T3-L1, WJ-MSCs, and THP-1. The anti-adipogenic properties of CD1-3 were evaluated using western blotting and densitometric analysis by assessing the expression of obesity-related proteins, such as ChREBP. The anti-inflammatory effect was estimated by measuring the reduction in TNF-α expression in CD1-3 -treated THP-1 cells. (3) Results: CD1-3 -obtained through a direct linkage between the carboxylic moiety of anti-inflammatory drugs (Ibuprofen, Flurbiprofen, and Naproxen) and the hydroxyl group of carvacrol-have an inhibitory effect on the accumulation of lipids in both 3T3-L1 and WJ-MSCs cell cultures and an anti-inflammatory effect by reducing TNF- α levels in THP-1 cells. (4) Conclusions: Considering the physicochemical properties, stability, and biological data, the CD3 derivative-obtained by a direct linkage between carvacrol and naproxen-resulted in the best candidate, displaying anti-obesity and anti-inflammatory effects in vitro.

The avalanche of genomic data generated from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus requires the development of tools to detect and monitor its mutations across the world. Here, we present a webtool, coronapp, dedicated to easily processing user-provided SARS-CoV-2 genomic sequences and visualizing the current worldwide status of SARS-CoV-2 mutations. The webtool allows users to highlight mutations and categorize them by frequency, country, genomic location and effect on protein sequences, and to monitor their presence in the population over time. The tool is available at http://giorgilab.unibo.it/coronannotator/ for the annotation of user-provided sequences. The full code is freely shared at https://github.com/federicogiorgi/giorgilab/tree/master/coronannotator., (© 2020 Wiley Periodicals LLC.)

So far, there is no effective disease-modifying therapies for Alzheimer's Disease (AD) in clinical practice. In this context, glycine-L-proline-L-glutamate (GPE) and its analogs may open the way for developing a novel molecule for treating neurodegenerative disorders, including AD. In turn, this study was aimed to investigate the neuroprotective potentials exerted by three novel GPE peptidomimetics (GPE1, GPE2, and GPE3) using an in vitro AD model. Anti-Alzheimer potentials were determined using a wide array of techniques, such as measurements of mitochondrial viability (MTT) and lactate dehydrogenase (LDH) release assays, determination of acetylcholinesterase (AChE), α-secretase and β-secretase activities, comparisons of total antioxidant capacity (TAC) and total oxidative status (TOS) levels, flow cytometric and microscopic detection of apoptotic and necrotic neuronal death, and investigating gene expression responses via PCR arrays involving 64 critical genes related to 10 different pathways. Our analysis showed that GPE peptidomimetics modulate oxidative stress, ACh depletion, α-secretase inactivation, apoptotic, and necrotic cell death. In vitro results suggested that treatments with novel GPE analogs might be promising therapeutic agents for treatment and/or or prevention of AD.

Cyclic dipeptides administered by both parenteral and oral routes are suggested as promising candidates for the treatment of neurodegeneration-related pathologies. In this study, we tested Cyclo (His-Pro) isomers (cHP1-4) for their anti-Alzheimer potential using a differentiated human neuroblastoma cell line (SH-SY5Y) as an Alzheimer's disease (AD) experimental model. The SH-SY5Y cell line was differentiated by the application of all-trans retinoic acid (RA) to obtain mature neuron-like cells. Amyloid-beta 1-42 ( Aβ 1-42 ) peptides, the main effector in AD, were administered to the differentiated cell cultures to constitute the in vitro disease model. Next, we performed cell viability analyses 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) release assays) to investigate the neuroprotective concentrations of cyclodipeptides using the in vitro AD model. We evaluated acetylcholinesterase (AChE), α- and β-secretase activities (TACE and BACE1), antioxidant potency, and apoptotic/necrotic properties and performed global gene expression analysis to understand the main mechanism behind the neuroprotective features of cHP1-4. Moreover, we conducted sister chromatid exchange (SCE), micronucleus (MN), and 8-hydroxy-2'-deoxyguanosine (8-OHdG) analyses to evaluate the genotoxic damage potential after applications with cHP1-4 on cultured human lymphocytes. Our results revealed that cHP1-4 isomers provide a different degree of neuroprotection against Aβ 1-42 -induced cell death on the in vitro AD model. The applications with cHP1-4 isomers altered the activity of AChE but not the activity of TACE and BACE1. Our analysis indicated that the cHP1-4 increased the total antioxidant capacity without altering total oxidative status levels in the cellular AD model and that cHP1-4 modulated the alterations of gene expressions by Aβ 1-42 exposure. We also observed that cHP1-4 exhibited noncytotoxic and non-genotoxic features in cultured human whole blood cells. In conclusion, cHP1-4 isomers, especially cHP4, have been explored as novel promising therapeutics against AD.

Purpose: To evaluate the efficacy and safety of bimanual, low-energy femtosecond laser-assisted cataract surgery with 1.4-mm microincisions compared to standard bimanual phacoemulsification (bimanual microincision cataract surgery)., Design: Prospective, non-randomized comparative case series., Methods: Bimanual femtosecond laser-assisted cataract surgery with microincisions was performed on 80 eyes (Group A) with the low-energy Ziemer LDV Z8; a matched case-control series of 80 eyes performed with standard bimanual microincision cataract surgery technique was selected for comparison (Group B). All interventions were performed by the same experienced surgeon. Intraoperative parameters were recorded as well as intra- and postoperative complications. Best corrected visual acuity, surgically induced astigmatism, central corneal thickness and endothelial cell count were evaluated before surgery and at 1 and 3 months post intervention., Results: The mean effective phaco times were 3.79 ± 2.19 s (Group A) and 4.49 ± 1.84 s (Group B) (p = 0.041). No major intra- or postoperative complications occurred. An overall significant mean best corrected visual acuity improvement was noted at 3 months, but was not statistically different between the groups. No significant changes were observed for surgically induced astigmatism or corneal pachymetry. A significant loss of endothelial cell count in both groups was detected at 3 months, with Group A reporting a significantly lower endothelial cell count loss compared to Group B (p = 0.009)., Conclusion: Bimanual, low-energy femtosecond laser-assisted cataract surgery with 1.4-mm microincisions by an expert surgeon was proven to be safe and effective in this study. This technique has advantages compared with standard bimanual microincision cataract surgery in terms of endothelial preservation.

Carvacrol (CAR), a natural monoterpene particularly abundant in plants belonging to the Lamiaceae family, has recently attracted much attention for its many biological properties (antioxidant, anti-inflammatory, neuroprotective, antitumour, antibacterial, and several others). However, CAR has poor chemical-physical properties (low water solubility and high volatility), which hamper its potential pharmacological uses. In this paper, the synthesis and antimicrobial evaluation of 23 carvacrol derivatives (WSCP1-23) against a panel of selected gram-positive and gram-negative bacteria are reported. Using the prodrug approach, CAR hydrophilic (WSCP1-17) and lipophilic prodrugs (WSCP18-23) were prepared. Notably, CAR water solubility was increased by using polar neutral groups (such as natural amino acids) with the aim of improving oral drug delivery. On the other hand, CAR lipophilic prodrugs, obtained by prenylation of CAR hydroxyl group, were designed to promote membrane permeation and oral absorption. Our results revealed that WSCP1-3, showing the highest water solubility (>1700-fold compared to that of CAR), possessed good antibacterial activity against gram-negative bacteria with MIC values comparable to those of CAR and antifungal properties against different species of Candida. WSCP18-19 were the most promising prodrugs, showing good antibacterial profiles against gram-positive bacteria by interfering with the biofilm formation of Staphylococcus aureus and Staphylococcus epidermidis. Moreover, WSCP18-19 resulted more stable in simulated fluids and human plasma than WSCP1-3. Toxicity studies performed on human erythrocytes and HaCaT cells revealed that all WSCPs were not toxic at the tested concentrations., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Background: To evaluate macular pigment optical density (MPOD) after bimanual femtosecond laser-assisted cataract surgery (FLACS) compared to standard bimanual phacoemulsification (B-MICS). Methods: A prospective, case matched, comparative cohort study conducted at the Institute of Ophthalmology, University of Modena and Reggio Emilia (Italy); 30 eyes underwent bimanual FLACS with low-energy Ziemer LDV Z8 (FLACS) and 30 underwent B-MICS standard technique (B-MICS). All interventions were conducted by the same expert surgeon. MPOD using the Macular Pigment Screener II (MPS II) was evaluated at baseline, 7 and 30 days after surgery. As secondary outcomes, we considered best corrected visual acuity (BCVA) and central macular thickness (CMT) obtained using optical coherence tomography. Results: In all cases, a BunnyLens AF IOL was safely implanted in the capsular bag through a 1.4 mm incision. We found a significant reduction in MPOD in both groups at 7 and 30 days; 0.16±0.14 and 0.10±0.12 (FLACS) and 0.18±0.13 and 0.15±0.14 (B-MICS), respectively ( P <0.05). However, there was no significant difference between the two groups at either 7 ( P =0.52) or 30 days ( P =0.18). BCVA improved significantly in both groups and CMT increased in both groups ( P <0.001, P <0.001, respectively). BCVA and CMT were similar between the groups with a significant difference in CMT in favor of the FLACS group at 30 days ( P =0.017). Conclusions: MPOD was reduced in both groups without any significant difference between the FLACS and B-MICS cataract interventions. FLACS is associated with a significantly higher increase of macular thickness at 30 days compared to B-MICS., Competing Interests: The authors report no conflicts of interest in this work.

This study investigated the anti-inflammatory effects of novel pseudotripeptides (GPE 1-3) as potential candidates to counteract neuroinflammation processes in Alzheimer's disease. GPE 1-3 pseudotripeptides are synthetic derivatives of Gly-l-Pro-l-Glu (GPE), the N-terminal tripeptide of IGF-1, obtained through the introduction of isosteres of the amidic bond (aminomethylene unit) to increase the metabolic stability of the native tripeptide. The results showed that all synthetic derivatives possessed higher half-lives (t 1/2  > 4 h) than GPE (t 1/2  = 30 min) in human plasma and had good water solubility. The biological results demonstrated that GPE 1-3 had protective properties in several experimental models of treated THP-1 cells. Notably, the novel pseudotripeptides influenced inflammatory cytokine expression (IL-1β, IL-18, and TNF-α) in Aβ 25-35 -, PMA-, and LPS-treated THP-1 cells. In PMA-differentiated THP-1 macrophages, both GPE 1 and GPE 3 reduced the expression levels of all selected cyto-chemokines, even though GPE 3 showed the best neuroprotective properties., (Copyright © 2018. Published by Elsevier Ltd.)

Purpose: To describe the intraoperative complications and the learning curve of microincision cataract surgery assisted by femtosecond laser (FLACS) with bimanual technique performed by an experienced surgeon., Methods: It is a prospective, observational, comparative case series. A total of 120 eyes which underwent bimanual FLACS by the same experienced surgeon during his first experience were included in the study; we considered the first 60 cases as Group A and the second 60 cases as Group B. In both groups, only nuclear sclerosis of grade 2 or 3 was included; an intraocular lens was implanted through a 1.4-mm incision. Best-corrected visual acuity (BCVA), surgically induced astigmatism (SIA), central corneal thickness and endothelial cell loss (ECL) were evaluated before and at 1 and 3 months after surgery. Intraoperative parameters, and intra- and post-operative complications were recorded., Results: In Group A, we had femtosecond laser-related minor complications in 11 cases (18.3%) and post-operative complications in 2 cases (3.3%); in Group B, we recorded 2 cases (3.3%) of femtosecond laser-related minor complications with no post-operative complications. Mean effective phaco time (EPT) was 5.32 ± 3.68 s in Group A and 4.34 ± 2.39 s in Group B with a significant difference (p = 0.046). We recorded a significant mean BCVA improvement at 3 months in both groups (p < 0.05) and no significant SIA nor corneal pachymetry changes in the two groups during the follow-up (p > 0.05). Finally, we found significant ECL in both groups with a significant difference between the two groups (p = 0.042)., Conclusions: FLACS with bimanual technique and low-energy LDV Z8 is associated with a necessary initial learning curve. After the first adjustments in the surgical technique, this technology seems to be safe and effective with rapid visual recovery and it helps surgeons to standardize the crucial steps of cataract surgery.

Purpose: We describe the clinicopathological and ultrastructural features of an opaque single-piece hydrophilic acrylic intraocular lens (IOL) explanted from a patient., Method: The main outcome of this report is the documentation of calcium deposits confirmed by surface analysis. The decrease in visual acuity was due to the opacification of the IOL. The opacification involved both the optic plate and the haptics., Results: The analysis at the scansion electron microscope revealed that the opacity was caused by the deposition of calcium and phosphate within the lens optic and haptics., Conclusion: This is the first case about the opacification of an Oculentis L-313. The opacification was characterized by calcium and phosphate deposition probably due to a morphological alteration of the posterior surface of the IOL.

Purpose: Comparative evaluation of morphological features of anterior capsules and apoptosis induction in epithelial cells after femtosecond laser-assisted cataract surgery (FLACS) and standard phacoemulsification surgery., Methods: Group 1: 30 FLACS anterior capsulotomies and Group 2: 30 manual anterior continuous curvilinear capsulorhexes. All patients were operated on by the same experienced surgeon. Morphological features of the anterior capsules and apoptosis induction in epithelial cells were evaluated., Results: All patients revealed a significant mean best-corrected visual acuity (BCVA) improvement 3 months after surgery, and no major intraoperative nor postoperative complications occurred. The capsular epithelium appeared to be preserved in both groups. Scanning electron microscopy analysis revealed irregular saw-tooth shaped edges in capsules from Group 1 whereas capsules from Group 2 showed regular and smooth edges. A statistically significant higher expression of the downstream apoptotic effector cleaved caspase 3 was observed in Group 1., Conclusions: The saw-tooth appearance was likely due to the progressive sequence of laser pulses on the capsule. The low energy/high frequency properties of the laser pulse, combined with an overlapped pulse pattern, resulted in highly continuous morphology of capsule edges. The higher apoptosis induction in FLACS group might be due to photodisruption-dependent plasma generation and formation of cavitation bubbles.

In this study, effects of LA-GPE (R-α-Lipoyl-Gly-l-Pro-l-Glu dimethyl ester) and GPE (Gly-L-Pro-L-Glu) on the cytotoxic action of Aβ 1-42 were tested with differentiated human neuroblastoma SH-SY5Y cells as cellular Alzheimer model via measurements of mitochondrial viability (MTT assay) and lactate dehydrogenase release (LDH assay). Effects of LA-GPE and GPE on acetylcholinesterase (AChE) activity, total antioxidant capacity (TAC) and total oxidative status (TOS) levels, and neural cell apoptosis and necrosis were also determined. In addition, biological safety of these novel formulations was evaluated in human blood cells using different cytotoxicity and genotoxicity assays. Our results indicated that both compounds could block Aβ 1-42 induced cell death. LA-GPE reduced Aβ-induced AChE activity and oxidative stress, suggesting it as a multifunctional compound potentially valuable for the treatment of Alzheimer's disease (AD)., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Aim: To analyze the visual outcomes and the posterior capsule opacification (PCO) with the new Incise ® MJ14 intraocular lens (IOL) implanted through a 1.4 mm clear corneal incision (CCI) in patients who underwent bimanual microincision cataract surgery (B-MICS)., Methods: Eighty eyes which underwent cataract surgery using B-MICS technique performed by the same experienced surgeon were included in the study: 40 eyes were implanted with an Incise ® MJ14 IOL through a 1.4 mm CCI (group A) without enlargement of the main CCI, while 40 eyes were implanted with an Akreos ® MI60 IOL with enlargement of the main CCI to 1.8 mm (group B). Best corrected visual acuity (BCVA), astigmatism and endothelial cell loss were evaluated before and after surgery at 7, 30d and 6mo. Anterior segment-optical coherence tomography (AS-OCT) of CCI was performed at 1, 3, 7, 30d, 6 and 18mo. PCO incidence was evaluated at 18mo using EPCO 2000 Software., Results: Mean BCVA improvement and endothelial cell loss were statistically significant at 18mo in both groups with no difference between the two groups; no statistically significant difference in surgically induced astigmatism (SIA) was noticed in the two groups. At AS-OCT the only significant alterations in the CCI were endothelial gaping and local detachment of Descemet's membrane at 1 and 7d after surgery; no statistically significant alterations were found at 1, 6 and 18mo. PCO score at 18mo was 0.03±0.07 for group A and 0.08±0.18 for group B ( P =0.11) with no sign of central optic plate invasion in both groups., Conclusion: The implant of the new Incise ® MJ14 IOL through a 1.4 mm CCI and B-MICS technique appeared to be a safe and effective procedure with rapid visual recovery. PCO rate resulted very low and the CCI presented few morphological alterations which were only detectable in the first days postoperatively and achieved fast corneal healing during the long-term follow-up.

Glioblastoma is one of the most aggressive malignant primary brain cancer in adults. To date, surgery, radiotherapy and current pharmacological treatments are not sufficient to manage this pathology that has a high mortality rate (median survival 12-15months). Recently, anticancer multi-targeted compounds have attracted much attention with the aim to obtain new drugs able to hit different biological targets that are involved in the onset and progression of the disease. Here, we report the synthesis of novel memantine-derived drugs (MP1-10) and their potential antitumor activities in human U87MG glioblastoma cell line. MP1-10 were synthetized joining memantine, which is a NMDA antagonist, to different histone deacetylase inhibitors to obtain one molecule with improved therapeutic efficacy. Biological results indicated that MP1 and MP2 possessed more potent anti-proliferative effects on U87MG cells than MP3-10 in a dose-dependent manner. MP1 and MP2 induced significant cell death by apoptosis characterized by apoptotic morphological changes in Hoechst staining. Both drugs also exhibited non-genotoxic and only mild cytotoxic effects in human whole blood cells. However, only MP1, showing good chemico-physical properties (solubility, LogP) and enzymatic stabilities in gastric and intestinal fluids, can be considered a suitable candidate for in vivo pharmacokinetic studies., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Medicinal chemistry methodologies are presently used to develop multifunctional molecules which simultaneously reduce oxidative stress, excitotoxicity, metal dyshomeostasis, and neuroinflammation that characterize neuropathological conditions, such as Alzheimer's Disease., Results: Memantine (MEM) derivatives 1-6 were designed and synthesized as novel multifunctional entities with antioxidant and neuroprotective capabilities to manage neurodegenerative diseases, such as Alzheimer's Disease. In vitro neuroprotective studies were performed by using astroglial GL15 cell line to assess antioxidant capability of MEM derivatives 1-6., Conclusion: Our outcomes showed that compounds 1 and 5 (at the concentration of 10 μM), containing as antioxidant portion residues of N-acetyl-Cys-OH and N-acetyl-Cys(Allyl)-OH, respectively, revealed a significant neuroprotective activity against oxidative stress, as assessed by NBT assays., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Background: MRJF4, a novel haloperidol metabolite II prodrug, was obtained through the esterification of the secondary hydroxyl group of haloperidol metabolite II with 4-phenylbutyric acid. The activities of (±)-MRJF4 and its two enantiomers [(+)-MRJF4 and (-)-MRJF4] as tumor specific inducers of pro-apoptotic genes were evaluated on malignant C6 glioma cells. In particular, changes in Nf-κB signaling pathway, activity of nitric oxide synthases (NOS), metalloproteinases (MMPs), and membrane adhesion proteins were investigated., Results: IκBα reduced phosphorylation and iNOS lowered activity could be correlated with the previously demonstrated decreased proliferation and tumor progression of C6 cells upon 24 h of treatment with all the three compounds. Integrin β1 decreased expression, at the same experimental time, seems to support lower C6 cells migrative capability and the consequent reduced invasiveness of these cells upon treatment with (±)-MRJF4 and its enantiomers., Conclusion: These results suggest that this multi-target prodrug and its two enantiomers might be a valuable clinical tool for the treatment of metastatic glioblastoma., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Introduction: The failure of many molecules as CNS bioactive compounds is due to many restrictions: poor water solubility, intestinal absorption, in vivo stability, bioavailability, therapeutic effectiveness, side effects, plasma fluctuations, and difficulty crossing physiological barriers, like the brain blood barrier (BBB), to deliver the drug directly to the site of action., Area Covered: Nanotechnology-based approaches with the employment of liposomes, micelles, dendrimers, and solid lipid nanoparticles (SLN) as drug delivery systems, are used to overcome the above reported limitations. Here, we focus on the delivery of drugs based on SLN formulation to treat neurodegenerative diseases. Notably, SLN have the ability to protect drugs from chemical and enzymatic degradation, direct the active compound towards the target site with a substantial reduction of toxicity for the adjacent tissues, and pass physiological barriers increasing bioavailability without resorting to high dosage forms., Expert Opinion: We believe that SLN could represent a suitable tool to pass the BBB and permit drugs to reach damaged areas of the CNS in patients affected by neurodegenerative pathologies, such as Alzheimer's and Parkinson's diseases.

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been suggested for the potential treatment of neurodegenerative diseases, such as Alzheimer's disease (AD). Prolonged use of NSAIDs, however, produces gastrointestinal (GI) toxicity. To overcome this serious limitation, the aim of this study was to develop novel NSAID-derived drug conjugates (Anti-inflammatory-Lipoyl derivatives, AL4-9) that preserve the beneficial effects of NSAIDS without causing GI problems. As such, we conjugated selected well-known NSAIDs, such as (S)-naproxen and (R)-flurbiprofen, with (R)-α-lipoic acid (LA) through alkylene diamine linkers. The selection of the antioxidant LA was based on the proposed role of oxidative stress in the development and/or progression of AD. Our exploratory studies revealed that AL7 containing the diaminoethylene linker between (R)-flurbiprofen and LA had the most favorable chemical and in vitro enzymatic stability profiles among the synthesized compounds. Upon pretreatment, this compound exhibited excellent antioxidant activity in phorbol 12-miristate 13-acetate (PMA)-stimulated U937 cells (lymphoblast lung from human) and Aβ(25-35)-treated THP-1 cells (leukemic monocytes). Furthermore, AL7 also modulated the expression of COX-2, IL-1β and TNF-α in these cell lines, suggesting anti-inflammatory activity. Taken together, AL7 has emerged as a potential lead worthy of further characterization and testing in suitable in vivo models of AD.

In staphylococci, quorum sensing regulates both biofilm formation and toxin production, moreover it has been demonstrated to be inhibited by RNAIII inhibiting peptide (RIP). Aim our study was to evaluate the in vitro activity and its in vivo efficacy of the combined administration of FS10, a novel RIP derivative, and tigecycline in an animal model of methicillin-resistant (MR) and methicillin-sensitive (MS) Staphylococcus aureus wound infection. Using a 1.x2 cm template, one full thickness wound was established through the panniculus carnosus on the back subcutaneous tissue of each animal. Infection was determined by inoculation of 5x107 CFU/ml of bacteria, that produced an abscess within 24 h, after this, treatment was initiated. The study included, for each strain, a control group without infection, a control infected group that did not receive any treatment and a control infected group with drug-free foam dressing, and three infected groups treated, respectively, with: FS10-soaked foam dressing (containing 20 μg FS10), daily intraperitoneal tigecycline (7 mg/Kg), FS10-soaked foam dressing (containing 20 μg FS10) and daily intraperitoneal injections of tigecycline (7 mg/Kg). The main outcome measures were quantitative culture and histological examination of tissue repair. The highest inhibition of infection was achieved in the group that received FS10-soaked and parenteral tigecycline reducing the bacterial load from 107 CFU/ml to about 103 CFU/g for MSSA and to about 104 CFU/g for MRSA. The group treated with FS10-soaked foam dressing associated with parenteral tigecycline showed, histologically, better overall healing with epithelialization and collagen scores significantly higher than those of the other groups in both strains. In conclusion, the combined use of topical FS10 with i.p. tigecycline induced positive interaction in vivo, resulting in an enhanced therapeutic benefit versus staphylococcal infections in murine wound models.

Herein is described the synthesis of novel glycine-α-methyl-proline-containing tripeptides (GP(Me)X tripeptides namely GP(Me)R, GP(Me)K, and GP(Me)H) with the aim of obtaining derivatives highly stable in human plasma and able to counteract neuroinflammatory processes that are distinctive of neurodegenerative pathologies. The syntheses of GP(Me)R, GP(Me)K, and GP(Me)H were all achieved both by introducing the Pro(Me) residue into the Gly-Pro-Arg (GPR) sequence in place of the native Pro in P2 position and replacing the basic amino acid Arg in P3 position by Lys or His. Results showed that all novel GP(Me)X tripeptides are stable in human plasma (t1/2 > 51 h) and that GP(Me)H - generating stable intramolecular H-bond in a C11-turn by interaction of His imidazole ring and Gly carbonyl group - restored physiological levels of nitric oxide deriving from neuronal NOS (nNOS) activity, thus preventing the inflammatory response by suppression of the NF-kB activity and, consequently, the expression of inflammatory genes such as inducibile NOS (iNOS). Therefore, GP(Me)H could be a lead compound for further development of peptidomimetics able to contrast neuroinflammatory processes., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Solid lipid nanoparticles (SLNs) are considered very attractive drug-delivery systems (DDS) able to enhance the efficacy of some therapeutic agents in several pathologies difficult to treat in a conventional way. Starting from these evidences, this study describes the preparation, physicochemical characterization, release, and in vitro cytotoxicity of stealth SLNs as innovative approach to improve solubility and absorption through the gastrointestinal tract of lipoyl-memantine (LA-MEM), a potential anti-Alzheimer codrug. Physico-chemical properties of LA-MEM loaded SLNs have been intensively investigated. Differential scanning calorimetry (DSC) was used to clarify the state and crystalline structure of the formulation. The results obtained from particles size analysis, polydispersity (PDI), and zeta potential measurements allowed the identification of the optimized formulation, which was characterized by a drug-lipid ratio 1:5, an average intensity diameter of 170nm, a PDI of 0.072, a zeta potential of -33.8mV, and an entrapment efficiency of 88%. Moreover, in vitro stability and release studies in both simulated gastric fluid (SGF) and simulated intestinal fluid (SIF), and preliminary in vitro cytotoxicity studies revealed that LA-MEM loaded SLNs could represent potential candidate for an in vivo investigation as DDS for the brain since it resulted devoid of citotoxicity and able to release the free codrug., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Objective: The increasing prevalence of antibiotic-resistant bacterial infections led to identify alternative strategies for a novel therapeutic approach. In this study, we synthesized ten carvacrol codrugs - obtained linking the carvacrol hydroxyl group to the carboxyl moiety of sulphur-containing amino acids via an ester bond - to develop novel compounds with improved antimicrobial and antibiofilm activities and reduced toxicity respect to carvacrol alone., Method: All carvacrol codrugs were screened against a representative panel of Gram positive (S. aureus and S. epidermidis), Gram negative (E. coli and P. aeruginosa) bacterial strains and C. albicans, using broth microdilution assays., Findings: Results showed that carvacrol codrug 4 possesses the most notable enhancement in the anti-bacterial activity displaying MIC and MBC values equal to 2.5 mg/mL for all bacterial strains, except for P. aeruginosa ATCC 9027 (MIC and MBC values equal to 5 mg/mL and 10 mg/mL, respectively). All carvacrol codrugs 1-10 revealed good antifungal activity against C. albicans ATCC 10231. The cytotoxicity assay showed that the novel carvacrol codrugs did not produce human blood hemolysis at their MIC values except for codrugs 8 and 9. In particular, deepened experiments performed on carvacrol codrug 4 showed an interesting antimicrobial effect on the mature biofilm produced by E. coli ATCC 8739, respect to the carvacrol alone. The antimicrobial effects of carvacrol codrug 4 were also analyzed by TEM evidencing morphological modifications in S. aureus, E. coli, and C. albicans., Conclusion: The current study presents an insight into the use of codrug strategy for developing carvacrol derivatives with antibacterial and antibiofilm potentials, and reduced cytotoxicity.

A novel cyclic prodrug of S-allyl-glutathione (CP11), obtained by using an acyloxy-alkoxy linker, was estimated for its pharmacokinetic and biological properties. The stability of CP11 was evaluated at pH 1.2, 7.4, in simulated fluids with different concentrations of enzymes, and in human plasma. The anti-inflammatory ability of CP11 was assessed in U937 cells, an immortalized human monocyte cell line. Results showed that CP11 is stable at acidic pH showing a possible advantage for oral delivery due to the longer permanence in the stomach. Having a permeability coefficient of 2.49 × 10(-6) cm s(-1), it was classified as discrete BBB-permeable compound. Biological studies revealed that CP11 is able to modulate inflammation mediated by LPS in U937 cells preventing the increase of ROS intracellular levels through interaction with the MAPK pathway.

Children with cerebral palsy (CP) and quadriplegia or severe diplegia suffer from highly reduced mobility and consequent constipation. Clinicians recommend standing frames to exercise the support reaction in this population, sharing the opinion that the upright position may facilitate intestinal transit, although no evidence supports this assumption. We conducted this study to determine the effects of the standing frame on spontaneous evacuation in children with CP. Moreover, we studied its effects on the frequency of induction of evacuation, the characteristics of the stool and the pain suffered by the child due to constipation and/or evacuation. We implemented a single-subject research design in one chronically constipated child with CP and quadriplegia, Gross Motor Function Classification System Level V. To monitor the effects of the standing frame, we measured the outcome of interest throughout the study using a daily diary and the Bristol Stool Scale. This study was approved by the local Ethics Committee. This study has several limitation; primarily, the use of a single-subject research design only makes possible the visual analysis of data obtained from a unique patient. So, by themselves, data obtained do not allow us any generalization for the target population. Future research should verify our results collecting more data and also investigating the effect of the standing-frame on respiratory functions. Although the standing frame did not affect the frequency of evacuations or the characteristics of the stool, its employment reduced the inductions of evacuation and the related pain suffered by the child. However, this study has several limitations, such as the lack of generalization due to the fact that we studied a unique patient and the overall brevity of the study due to external circumstances. Therefore, we suggest future research to verify our results, also investigating the effect of the standing frame on respiratory functions. Relevance to clinical practice. The standing frame may positively influence the management of constipation of these children, possibly improving their quality of life., (Copyright © 2014 John Wiley & Sons, Ltd.)

Many neurological and neurodegenerative diseases are associated with oxidative stress and glial inflammation, all related to endoplasmic reticulum stress. Cyclo(His-Pro) is an endogenous cyclic dipeptide that exerts cytoprotection by interfering with the Nrf2-NF-κB systems, the former presiding the antioxidant and the latter the pro-inflammatory cellular response. Here we investigated whether the cyclic dipeptide inhibits glial inflammation thus reducing the detrimental effect of inflammatory neurotoxins on neurons. We found that systemic administration of cyclo(His-Pro) exerts in vivo anti-inflammatory effects in the central nervous system by down-regulating hepatic and cerebral TNFα expression thereby counteracting LPS-induced gliosis. Mechanistic studies indicated that the cyclic dipeptide-mediated effects are achieved through the activation of Nrf2-driven antioxidant response and the inhibition of the pro-inflammatory NF-κB pathway. Moreover, by up-regulating Bip, cyclo(His-Pro) increases the ER stress sensitivity and triggers the unfolded protein response to alleviate the ER stress. These results unveil a novel potential therapeutic use of cyclo(His-Pro) against neuroinflammatory-related diseases and we might now consider its potential anti-inflammatory role in other neuropathological conditions., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Metal-ion dysregulation and oxidative stress have been linked to the progressive neurological decline associated with neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. Herein we report the synthesis and chelating, antioxidant, and in vitro neuroprotective activities of a novel derivative of glutathione, GS(HQ)H, endowed with an 8-hydroxyquinoline group as a metal-chelating moiety. In vitro results showed that GS(HQ)H may be stable enough to be absorbed unmodified and arrive intact to the blood-brain barrier, that it may be able to remove Cu(II) and Zn(II) from the Aβ peptide without causing any copper or zinc depletion in vivo, and that it protects SHSY-5Y human neuroblastoma cells against H2 O2 - and 6-OHDA-induced damage. Together, these findings suggest that GS(HQ)H could be a potential neuroprotective agent for the treatment of neurodegenerative diseases in which a lack of metal homeostasis has been reported as a key factor., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

We investigated the efficacy of tigecycline and FS8, alone or combined, in preventing prosthesis biofilm in a rat model of staphylococcal vascular graft infection. Graft infections were established in the back subcutaneous tissue of adult male Wistar rats by implantation of Dacron prostheses followed by topical inoculation with 2 x 107 colony-forming units of Staphylococcus aureus, strain Smith diffuse. The study included a control group, a contaminated group that did not receive any antibiotic prophylaxis, and three contaminated groups that received: (i) intraperitoneal tigecycline, (ii) FS8-soaked graft, and (iii) tigecycline plus FS8-soaked graft, respectively. Each group included 15 animals. The infection burden was evaluated by using sonication and quantitative agar culture. Moreover, an in vitro binding-study was performed to quantify the how much FS8 was coated to the surface of the prosthesis. Tigecycline, combined with FS8, against the adherent bacteria showed MICs (2.00 mg/L) and MBCs (4.00 mg/L) four-fold lower with respect to tigecycline alone in in vitro studies. The rat groups treated with tigecycline showed the lowest bacterial numbers (4.4 x 104 ± 1.2 x 104 CFU/mL). The FS8-treated group showed a good activity and significant differences compared to control group with bacterial numbers of 6.8 x 104 ± 2.0 x 104 CFU/mL. A stronger inhibition of bacterial growth was observed in rats treated with a combined FS8 and tigecycline therapy than in those that were singly treated with bacterial numbers of 101 CFU/mL graft. In conclusion, the ability to affect biofilm formation as well, its property to be an antibiotic enhancer suggests FS8 as alternative or additional agent to use in conjunction with conventional antimicrobial for prevention of staphylococcal biofilm related infection.

The aim of the study was to investigate the efficacy of the quorum sensing inhibitor FS3 and daptomycin in preventing prosthesis biofilm in a rat model of staphylococcal vascular graft infection. Graft infections were established in the back subcutaneous tissue of adult male Wistar rats by implantation of Dacron prostheses followed by topical inoculation with 2×10(7) colony-forming units of Staphylococcus aureus, strain Smith diffuse. The study included a control group, a contaminated group that did not receive any antibiotic prophylaxis and three contaminated groups that received: (i) intraperitoneal daptomycin, (ii) FS3-soacked graft, and (iii) daptomycin plus FS3-soaked graft, respectively. Each group included 15 animals. The infection burden was evaluated by using sonication and quantitative agar culture. Moreover, an in vitro binding-study was performed to quantify the how much FS3 was coated to the surface of the prosthesis. The in vitro studies showed, that minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values for daptomycin were lower in presence of FS3. In in vivo studies, when tested alone, daptomycin and FS3 showed good efficacies. Their combination showed efficacies significantly higher than that of each single compound. Daptomycin is an important candidate for prevention of staphylococcal biofilm related infection and FS3 could serve as an interesting anti-staphylococcal antibiotic enhancer., (Copyright © 2012 Elsevier Inc. All rights reserved.)