This paper deals with the physical and mathematical modelling description of drug release from matrix systems. In the introduction, matrix systems are considered in the wide frame of the controlled ...release systems and the concept of mathematical model is briefly discussed. Then, matrix structure and topology are matched, analysing the characteristics of the three-dimensional network constituting them. In this context, drug release mechanisms are considered with particular emphasis on the key factors ruling the release kinetics, such as matrix swelling, erosion, drug dissolution (re-crystallisation), drug diffusion, drug - polymer interaction, initial drug distribution and particle size distribution (for powdered matrix systems). The mathematical modelling section firstly considers the empirical and semi-empirical models that have the great advantage of showing analytical solutions. Then, the attention is focused on theoretical approaches regarding matrix swelling equilibrium and kinetics, drug dissolution, drug diffusion, drug - polymer interaction, initial drug distribution and matrix erosion. Finally, release kinetics from polydispersed spherical particles is studied. This review points out the fact that the comprehension of the phenomena ruling drug release from matrix systems is appropriate from both the physical and modelling point of view, although further improvements are always possible and desirable.
•Cannflavin A content in threshing residue is affected by variety and air temperature.•Cannabidiol and tetrahydrocannabinol accumulation support late harvesting for multipurpose ...application.•Precipitation level and distribution affect cannabidiol level in threshing residues.
Industrial hemp cultivation in Europe is dual-purpose, with stalks providing fibers and hurds, and seeds being used for food, feed and pharmaceutical applications. Economic sustainability of hemp cultivation should encompass the possibility of recovering non-narcotic secondary metabolites from hemp by-products (leaves, leaflets and bracts) originating from seed harvest and seed cleaning procedures. Surprisingly, no information is currently available on the contents of high added value bioactive compounds (CBD, CBG, cannflavin A, Δ9-THC) in industrial hemp inflorescence and threshing residues. This observation provided a rationale for investigating the issue on three monoecious varieties grown in Northern Italy. The concentration of target compounds was monitored from full-flowering until plant senescence by LC–MS/MS analysis of methanolic extracts of the plant biomass. The anti-inflammatory prenylated flavonoid cannflavin A was present in all varieties at levels mainly affected by genotype and air temperature. Conversely, the concentration of CBD, currently the clinically most promising non-narcotic cannabinoid, correlated to the overall extent and distribution of precipitation during growing cycle. Our findings suggest that postponing harvest after seed maturity increases the CBD contents and increase the CBD/Δ9-THC ratio in harvest threshing.
Epithelial-to-mesenchymal transition (EMT) and the reverse process mesenchymal-to-epithelial transition (MET) are events involved in development, wound healing and stem cell behaviour and contribute ...pathologically to cancer progression. The identification of the molecular mechanisms underlying these phenotypic conversions in hepatocytes are fundamental to design specific therapeutic strategies aimed at optimising liver repair. The role of autophagy in EMT/MET processes of hepatocytes was investigated in liver-specific autophagy-deficient mice (Alb-Cre;ATG7(fl/fl)) and using the nontumorigenic immortalised hepatocytes cell line MMH. Autophagy deficiency in vivo reduces epithelial markers' expression and increases the levels of mesenchymal markers. These alterations are associated with an increased protein level of the EMT master regulator Snail, without transcriptional induction. Interestingly, we found that autophagy degrades Snail in a p62/SQSTM1 (Sequestosome-1)-dependent manner. Moreover, accordingly to a pro-epithelial function, we observed that autophagy stimulation strongly affects EMT progression, whereas it is necessary for MET. Finally, we found that the EMT induced by TGFβ affects the autophagy flux, indicating that these processes regulate each other. Overall, we found that autophagy regulates the phenotype plasticity of hepatocytes promoting their epithelial identity through the inhibition of the mesenchymal programme.
Abstract Aims Growing evidence suggests that renal denervation may reduce elevated blood pressure values in resistant hypertension. More recently a number of studies have assessed the effects of the ...intervention on the dysmetabolic disarray (i.e. insulin resistance, glucose intolerance, and diabetes mellitus) frequently detectable in resistant hypertensive patients. The present viewpoint article critically examines the results obtained so far in this area. Data synthesis The results of the studies performed so far provide evidence that ablation of efferent and afferent sympathetic renal nerves improves glucose metabolism, reducing the incidence of glucose intolerance, fasting hyperglycemia and diabetic state in resistant hypertensive patients. The results, however, cannot be regarded as conclusive, taking into account that limitations in the experimental design of the studies published so far, as well as the frequent lack of specific subgroups data analysis, prevent to draw conclusive information on this issue. Conclusions Although promising, the favorable results of renal denervation on the metabolic disarray frequently detectable in resistant hypertension require to be confirmed in large scale, randomized studies which are currently ongoing.
Introduction Pulse-loading treatment consists in a rapid titration of the pharmacological agent in the first days of treatment. A few studies suggested that this kind of titration with intravenous ...clomipramine could result in a greater and faster response than with a standard titration in obsessive-compulsive disorder (OCD) resistant patients. The aim of this open-label trial was to investigate the effectiveness and tolerability of a citalopram pulse-loading protocol in severe treatment-resistant OCD patients. Methods We enrolled 8 severe treatment-resistant OCD patients. Patients were treated with intravenous citalopram starting with 40 mg for 3 days and increasing the dose up to 80 mg from the fourth day. The patients continued the treatment with 80 mg of intravenous citalopram for 18 days (a total of 21 days of intravenous treatment), then they switched to oral treatment (80 mg of oral citalopram). Results During the pulse-loading treatment no patients showed significant adverse events. No patients showed clinical significant change of the QTc interval and/or of the sodium levels. Five out of eight patients had a partial or full response at the end-point (4 patients had a full response and 1 patient had a partial response) and two of these had remission. Pulse-loading treatment seemed to induce a faster improvement respect to a standard titration, since the responder patients showed a significant improvement already after 3 weeks. Three out of eight patients did not respond. Conclusion Taking into account the very limited sample size, this case series suggests that this treatment approach deserves further controlled studies
Objective The aim of the study was to evaluate decision-making process and probabilistic bias in patients with obsessive-compulsive disorder (OCD). Methods Our sample consisted of 80 subjects (40 ...diagnosed with OCD and 40 healthy controls). To assess the clinical characteristic of the sample we performed a clinical interview and a psychometric assessement using the Barrat Impulsiveness Scale (BIS-11) and the Cloniger's Temperamnt and Character Inventory (TCI-125). To assess decision making processes and probabilistic reasoning we used the Iowa Gambling Task (IGT) and the Beads Task. Results OCD group had a significantly lower IGT final netscore (p 0.032). Moreover, controls showed a significant improvement between netscore 1 and netscore 5 (p 0.014) while patients did not (p 0.700). Patients also showed significantly less draws till decision on the Beads Task (p 0.000). We performed four regression analysis to evaluate the influence of clinical variables (duration of illness, treatment resistance, Y-BOCS Score, presence of tics, Barratt Score) and personality traits (TCI sub-scales) on IGT netscore and Beads Task. The results indicated that the four overall models were not statistically significant. Conclusions Our data show the presence of a decision making and probabilistic reasoning impairment in OCD. These data could be intareptated in a neurocognitive perspective as executive dysfunction and in a neuroeconomic perspective as a reduced loss avoidance and overconfidence during decision making processes.
Reward dysfunction represents a key feature of addiction progression. Although anxiety symptoms are a core feature of obsessive–compulsive disorder (OCD), current literature shows growing evidences ...of a reward dysfunction in OCD, mainly in resistant patients. These data support the hypothesis that addiction and OCD share some common neurobiological dysfunctions and corroborate the idea that OCD starts as an anxiety disorder and becomes a behavioral addiction through the same stages of addiction. A common link between all substance abuse and the addictive behaviors is their rewarding effect. Compulsion is a suffering reducing activity that might step on the border of rewarding experience due to its capacity to reduce anxiety and distress generated by obsessions. In this perspective compulsion could be potentially addictive. In fact, many patients report having a sort of’addiction to compulsions’. From this perspective, it is possible to conceptualize OCD progression as a slow progression to a’compulsions addiction’. In this view, it is also possible to hypothesize a clinical staging of OCD consisting of three main stages. First stage: the endophenotype stage. In this stage the patient present only subtreshold symptoms, but show endophenotypical abnormalities such as motor disinhibition and cognitive inflexibility. Second stage: the alarm stage. In this stage the patient has the OCD onset and the anxiety dimension is prominent. Third stage: the reward dysfunction stage. In this stage the patient becomes addicted to compulsions.
In order to assess the impact of nanoplastics on marine species, polystyrene nanoparticles (PS NPs) have been largely used as model particles. Here we studied the effects of 50 nm amino-modified ...PS-NH
2
on Mediterranean sea urchin Paracentrotus lividus immune system cells (coelomocytes) in the presence of celomic fluid (CF) and at different NP concentrations (1, 5, 10, and 25 μg mL
−1
) and experimental conditions (absence or presence of EDTA). PS-NH
2
acquired a protein corona once incubated with CF, dominated by the toposome precursor protein (TPP). In short-term cultures, a significant concentration- and time-dependent decrease in lysosomal membrane stability and apoptotic-like nuclear alterations were observed in phagocytes upon exposure to PS-NH
2
(10 and 25 µg mL
−1
) in CF but they resulted abolished in the presence of EDTA confirming the role of TPP in triggering PS-NH
2
-coelomocytes interaction and toxicity. PS-NH
2
did not alter MXR phenotype but the observed dose-dependent decrease in calcein accumulation suggests the ability of PS-NH
2
to affect pump's efflux activity. Overall results encourage additional studies on positively charged nanoplastics, since the observed effects on sea urchin coelomocytes as well as the TPP corona formation might represent a first step for addressing their impact on sensitive marine species.
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Small interfering RNAs (siRNAs) have the potential to be of therapeutic value for many human diseases. So far, however, a serious obstacle to their therapeutic use is represented by ...the absence of appropriate delivery systems able to protect them from degradation and to allow an efficient cellular uptake.
In this work we developed a siRNA delivery system based on inulin (Inu), an abundant and natural polysaccharide. Inu was functionalized via the conjugation with diethylenetriamine (DETA) residues to form the complex Inu-DETA. We studied the size, surface charge and the shape of the Inu-DETA/siRNA complexes; additionally, the cytotoxicity, the silencing efficacy and the cell uptake-mechanisms were studied in the human bronchial epithelial cells (16HBE) and in the hepatocellular carcinoma derived cells (JHH6).
The results presented here indicate that Inu-DETA copolymers can effectively bind siRNAs, are highly cytocompatible and, in JHH6, can effectively deliver functional siRNAs. Optimal delivery is observed using a weight ratio Inu-DETA/siRNA of 4 that corresponds to polyplexes with an average size of 600nm and a slightly negative surface charge. Moreover, the uptake and trafficking mechanisms, mainly based on micropinocytosis and clatrin mediated endocytosis, allow the homogeneous diffusion of siRNA within the cytoplasm of JHH6. Notably, in 16 HBE where the trafficking mechanism (caveolae mediated endocytosis) does not allow an even distribution of siRNA within the cell cytoplasm, no significant siRNA activity is observed.
In conclusion, we developed a novel inulin-based siRNA delivery system able to efficiently release siRNA in JHH6 with negligible cytotoxicity thus opening the way for further testing in more complex in vivo models.
This paper presents a new scheme to achieve generalized synchronization（GS） between different discrete-time chaotic（hyperchaotic） systems.The approach is based on a theorem,which assures that GS is ...achieved when a structural condition on the considered class of response systems is satisfied.The method presents some useful features：it enables exact GS to be achieved in finite time（i.e.,dead-beat synchronization）;it is rigorous,systematic,and straightforward in checking GS;it can be applied to a wide class of chaotic maps.Some examples of GS,including the Grassi-Miller map and a recently introduced minimal 2-D quadratic map,are illustrated.
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