Floating Ricobendazole Delivery Systems: A 3D Printing Method by Co-Extrusion of Sodium Alginate and Calcium Chloride

At present, the use of benzimidazole drugs in veterinary medicine is strongly limited by both pharmacokinetics and formulative issues. In this research, the possibility of applying an innovative semi-solid extrusion 3D printing process in a co-axial configuration was speculated, with the aim of producing a new gastro-retentive dosage form loaded with ricobendazole. To obtain the drug delivery system (DDS), the ionotropic gelation of alginate in combination with a divalent cation during the extrusion was exploited. Two feeds were optimized in accordance with the printing requirements and the drug chemical properties: the crosslinking ink, i.e., a water ethanol mixture containing CaCl₂ at two different ratios 0.05 M and 0.1 M, hydroxyethyl cellulose 2% w/v, Tween 85 0.1% v/v and Ricobendazole 5% w/v; and alginate ink, i.e., a sodium alginate solution at 6% w/v. The characterization of the dried DDS obtained from the extrusion of gels containing different amounts of calcium chloride showed a limited effect on the ink extrudability of the crosslinking agent, which on the contrary strongly influenced the final properties of the DDS, with a difference in the polymeric matrix toughness and resulting effects on floating time and drug release.     

Promising Strategies for Preserving Adult Endothelium Health and Reversing Its Dysfunction: From Liquid Biopsy to New Omics Technologies and Noninvasive Circulating Biomarkers

The endothelium has multiple functions, ranging from maintaining vascular homeostasis and providing nutrition and oxygen to tissues to evocating inflammation under adverse conditions and determining endothelial barrier disruption, resulting in dysfunction. Endothelial dysfunction represents a common condition associated with the pathogenesis of all diseases of the cardiovascular system, as well as of diseases of all of the other systems of the human body, including sepsis, acute respiratory distress syndrome, and COVID-19 respiratory distress. Such evidence is leading to the identification of potential biomarkers and therapeutic targets for preserving, reverting, or restoring endothelium integrity and functionality by promptly treating its dysfunction. Here, some strategies for achieving these goals are explored, despite the diverse challenges that exist, necessitating significant bench work associated with an increased number of clinical studies.     

Tracking Prostate Carcinogenesis over Time through Urine Proteome Profiling in an Animal Model: An Exploratory Approach

Prostate cancer (PCa) is one of the most lethal diseases in men, which justifies the search for new diagnostic tools. The aim of the present study was to gain new insights into the progression of prostate carcinogenesis by analyzing the urine proteome. To this end, urine from healthy animals and animals with prostate adenocarcinoma was analyzed at two time points: 27 and 54 weeks. After 54 weeks, the incidence of pre-neoplastic and neoplastic lesions in the PCa animals was 100%. GeLC-MS/MS and subsequent bioinformatics analyses revealed several proteins involved in prostate carcinogenesis. Increased levels of retinol-binding protein 4 and decreased levels of cadherin-2 appear to be characteristic of early stages of the disease, whereas increased levels of enolase-1 and T-kininogen 2 and decreased levels of isocitrate dehydrogenase 2 describe more advanced stages. With increasing age, urinary levels of clusterin and corticosteroid-binding globulin increased and neprilysin levels decreased, all of which appear to play a role in prostate hyperplasia or carcinogenesis. The present exploratory analysis can be considered as a starting point for studies targeting specific human urine proteins for early detection of age-related maladaptive changes in the prostate that may lead to cancer.     

Small Vessel Disease: Ancient Description,Novel Biomarkers

Small vessel disease (SVD) is one of the most frequent pathological conditions which lead to dementia. Biochemical and neuroimaging might help correctly identify the clinical diagnosis of this relevant brain disease. The microvascular alterations which underlie SVD have common origins, similar cognitive outcomes, and common vascular risk factors. Nevertheless, the arteriolosclerosis process, which underlines SVD development, is based on different mechanisms, not all completely understood, which start from a chronic hypoperfusion state and pass through a chronic brain inflammatory condition, inducing a significant endothelium activation and a consequent tissue remodeling action. In a recent review, we focused on the pathophysiology of SVD, which is complex, involving genetic conditions and different co-morbidities (i.e., diabetes, chronic hypoxia condition, and obesity). Currently, many points still remain unclear and discordant. In this paper, we wanted to focus on new biomarkers, which can be the expression of the endothelial dysfunction, or of the oxidative damage, which could be employed as markers of disease progression or for future targets of therapies. Therefore, we described the altered response to the endothelium-derived nitric oxide-vasodilators (ENOV), prostacyclin, C-reactive proteins, and endothelium-derived hyperpolarizing factors (EDHF). At the same time, due to the concomitant endothelial activation and chronic neuroinflammatory status, we described hypoxia-endothelial-related markers, such as HIF 1 alpha, VEGFR2, and neuroglobin, and MMPs. We also described blood–brain barrier disruption biomarkers and imaging techniques, which can also describe perivascular spaces enlargement and dysfunction. More studies should be necessary, in order to implement these results and give them a clinical benefit.     

Smart Lipid–Polysaccharide Nanoparticles for Targeted Delivery of Doxorubicin to Breast Cancer Cells

In this study, actively-targeted (CD44-receptors) and dual stimuli (pH/redox)-responsive lipid–polymer nanoparticles were proposed as a delivery vehicle of doxorubicin hydrochloride in triple negative breast cancer cell lines. A phosphatidylcholine lipid film was hydrated with a solution of oxidized hyaluronic acid and doxorubicin, chosen as model drug, followed by a crosslinking reaction with cystamine hydrochloride. The obtained spherical nanoparticles (mean diameter of 30 nm) were found to be efficiently internalized in cancer cells by a receptor-mediated endocytosis process, and to modulate the drug release depending on the pH and redox potential of the surrounding medium. In vitro cytotoxicity assays demonstrated the safety and efficacy of the nanoparticles in enhancing the cytotoxic effect of the free anticancer drug, with the IC₅₀ values being reduced by two and three times in MDA-MB-468 and MDA-MB-231, respectively. The combination of self-assembled phospholipid molecules with a polysaccharide counterpart acting as receptor ligand, and stimuli-responsive chemical moieties, was carried out on smart multifunctional nanoparticles able to actively target breast cancer cells and improve the in vitro anticancer activity of doxorubicin.     

Enzymatic Formation of Rufoschweinitzin,a Binaphthalene from the Basidiomycete Cortinarius rufoolivaceus

Dimeric polyketides are widespread fungal secondary metabolites. They occur in both ascomycetes and basidiomycetes and, therefore, across fungal phyla. Here we report the isolation of a new binaphthalene, named rufoschweinitzin, from the basidiomycete Cortinarius rufoolivaceus. Rufoschweinitzin consists of two symmetrically 4,4′-coupled torachrysone-8-O-methyl ether moieties. Furthermore, we have identified a binaphthalene biosynthetic gene cluster in an unrelated fungus, the ascomycete Xylaria schweinitzii. Heterologous expression of the encoded cytochrome P450 enzyme verified its coupling activity: dimerization of torachrysone-8-O-methyl ether led to the formation of rufoschweinitzin alongside a hitherto unknown regioisomer, now named alloschweinitzin. We have thus demonstrated enzymatic formation of the basidiomycete's metabolite rufoschweinitzin and made the regiochemistry of alloschweinitzin accessible with an ascomycete-derived enzyme.     

Controlled‐Release LCST‐Type Nonwoven Depots via Squeezing‐Out Thermal Response

A novel thermoresponsive fibrous matrix as controlled release depots upon heating is described. The matrix is composed of electrospun fibers of a lower critical solution temperature (LCST)‐type poly(methacrylamide‐co‐N‐tert‐butylacrylamide‐co‐4‐acryloylbenzophenone) P(MAAm‐NtbAAm‐ABP) copolymer. Spherical particles, simulating depots of drugs, are embedded with liquid‐filled inter‐fiber spaces (pores). On heating above 25 °C up to 45 °C, the nanofibers undergo a contraction of about 40%. This solid deformation is attributed to the LCST transition. Fibrous matrix contraction drives expulsion of depots and water solution stored in the pores of the matrix, as evidenced by in situ observations. The liquid flow in the deformable porous medium demonstrates liquid drainage from the matrix as a function of temperature. Experimental results reveal that 70% of the particles are expelled from the matrix upon heating to 45 °C from room temperature. The presented particles encapsulation and release model system using LCST‐type fibrous matrix can be used as a transdermal patch.     

Drug Repurposing in Rare Diseases: An Integrative Study of Drug Screening and Transcriptomic Analysis in Nephropathic Cystinosis

Diagnosis and cure for rare diseases represent a great challenge for the scientific community who often comes up against the complexity and heterogeneity of clinical picture associated to a high cost and time-consuming drug development processes. Here we show a drug repurposing strategy applied to nephropathic cystinosis, a rare inherited disorder belonging to the lysosomal storage diseases. This approach consists in combining mechanism-based and cell-based screenings, coupled with an affordable computational analysis, which could result very useful to predict therapeutic responses at both molecular and system levels. Then, we identified potential drugs and metabolic pathways relevant for the pathophysiology of nephropathic cystinosis by comparing gene-expression signature of drugs that share common mechanisms of action or that involve similar pathways with the disease gene-expression signature achieved with RNA-seq.     

Theory of organic field effect transistors

Field effect transistors with an organic material as active layer are at present essentially used to determine the mobilities in these materials. Until now, in analysing the measured current characteristics, only the simplest (Shockley) model has been used which accounts neither for this type of thin film transistor (TFT), which operates in depletion and accumulation, nor for the nature of the carriers. Starting from two-dimensional simulations for the analogous silicon TFT, we have developed an analytical model for the TFT that accounts for several peculiarities of the current characteristics of this type of transistor. In addition, a first modification has been developed which describes the situation when the charged states are polarons and bipolarons, as is the case in organic materials. Applications to published experimental current characteristics show that a general reanalysis is needed. Copyright © 1998 John Wiley & Sons, Ltd.