The anatomy and physiology of the eye strongly limit the bioavailability of locally administered drugs. The entrapment of therapeutics into nanocarriers represents an effective strategy for the ...topical treatment of several ocular disorders, as they may protect the embedded molecules, enabling drug residence on the ocular surface and/or its penetration into different ocular compartments. The present work shows the activity of hyaluronan-cholesterol nanogels (NHs) as ocular permeation enhancers. Thanks to their bioadhesive properties, NHs firmly interact with the superficial corneal epithelium, without penetrating the stroma, thus modifying the transcorneal penetration of loaded therapeutics. Ex vivo transcorneal permeation experiments show that the permeation of hydrophilic drugs (i.e., tobramycin and diclofenac sodium salt), loaded in NHs, is significantly enhanced when compared to the free drug solutions. On the other side, the permeation of hydrophobic drugs (i.e., dexamethasone and piroxicam) is strongly dependent on the water solubility of the entrapped molecules. The obtained results suggest that NHs formulations can improve the ocular bioavailability of the instilled drugs by increasing their preocular retention time (hydrophobic drugs) or facilitating their permeation (hydrophilic drugs), thus opening the route for the application of HA-based NHs in the treatment of both anterior and posterior eye segment diseases.
The effects that an increase of environmental pH has on the triple helix of scleroglucan (Sclg) and on the Sclg/borax hydrogel are reported. Rheological experiments show that the hydrogel is less ...sensitive to pH increase than Sclg alone, while at pH = 14 a dramatic viscosity decrease takes place for both systems. This effect is evidenced also by the reduced water uptake and anisotropic elongation detected, at pH = 14, by the swelling behaviour of tablets prepared with the Sclg/borax system. On the opposite, a different behaviour was observed with guar gum and locust bean gum tablets, tested as reference polysaccharides. The effect of pH on the structure of Sclg and Sclg/borax was investigated also by means of spectroscopic approaches based on the interaction between Congo red (CR) and the Sclg triple helix. Obtained results indicated that the CR absorbance maximum is shifted as a function of pH and by the presence of borax. Principal component analysis allowed very precise identification of the pH value at which the Sclg helix collapses. Molecular dynamics simulations of the Sclg/borax-CR complex indicated that, at physiological pH, only a few ordered configurations are populated, according to the induced circular dichroism (CD) spectrum evidence.
The novel amphiphilic polyacrylate grafted with cholesterol moieties, PAAbCH, previously synthesized, was deeply characterized and investigated in the lab and on a pre-industrial scale. Solid-state ...NMR analysis confirmed the polymer structure, and several water-based pharmaceutical and cosmetic products were developed. In particular, stable oil/water emulsions with vegetable oils, squalene, and ceramides were prepared, as well as hydrophilic medicated films loaded with diclofenac, providing a prolonged drug release. PAAbCH also formed polyelectrolyte hydrogel complexes with chitosan, both at the macro- and nano-scale. The results demonstrate that this polymer has promising potential as an innovative excipient, acting as a solubility enhancer, viscosity enhancer, and emulsifying agent with an easy scale-up transfer process.
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•Amphiphilic polyacrylate by cholesterol grafting on polymer backbone.•High increase in the viscosity of aqueous solutions.•Mucoadhesive physical hydrogel formation.•Improved ...properties as solubility enhancer, emulsifier, skin permeation enhancer.•Useful in hydrophobic molecules formulation for pharmaceutical and cosmetic applications.
Polyacrylic acid (PAA), the synthetic homopolymer of acrylic acid, plays a key role in both pharmaceutical and cosmetic fields, for its rheological and mucoadhesive properties. These features may be enhanced and tuned by means of chemical or modifications, leading to new derivatives such as block copolymers, cross-linked gels, and amphiphilic polymers. The first two kinds of derivatives were already widely studied, while only few examples are described in literature of chemical derivatizations post-polymerization of PAA for the preparation of amphiphilic derivatives. In this study the preparation and the characterization of an innovative polymer for potential biomedical, cosmetic and pharmaceutical applications is reported. The new water-soluble polymer showed amphiphilic properties, due to the functionalization with cholesterol moieties. Furthermore, the new polymer is able to significantly improve the solubility of poorly water-soluble drug molecules.
In the present study, we aimed at assessing the influence of breed and feeding system on the bovine milk profile of betaines and carnitines and milk capacity in counteracting the inflammatory ...endothelial cell (EC) damage induced by interleukin (IL)-6. In the first experimental design, two breeds were chosen (Holstein vs. Modicana) to investigate the biomolecule content and antioxidant capacity in milk and dairy products. In the second experimental design, two feeding systems (pasture vs. total mixed ratio) were tested only in Holstein to evaluate the possible effect on the functional profile of milk and dairy products. Finally, the bulk milk from the two experimental designs was used to evaluate the efficacy of preventing IL-6-induced endothelial inflammatory damage. Results showed that Modicana milk and whey had higher biomolecule content and antioxidant activity compared to Holstein milk (p < 0.01). Milk from Holstein fed TMR showed higher concentration of γ-butyrobetaine, δ-valerobetaine (p < 0.01), and l-carnitine (p < 0.05). Similarly, whey from Holstein fed TMR also showed higher content of δ-valerobetaine, glycine betaine, l-carnitine, and acetyl-l-carnitine (p < 0.01) compared to the Holstein fed pasture. Conversely, the antioxidant activity of milk and dairy products was not affected by the feeding system. In ECs, all milk samples reduced the IL-6-induced cytokine release, as well as the accumulation of reactive oxygen species (ROS) and the induction of cell death, with the most robust effect elicited by Modicana milk (p < 0.01). Overall, Modicana milk showed a higher content of biomolecules and antioxidant activity compared to Holstein, suggesting that the breed, more than the feeding system, can positively affect the health-promoting profile of dairy cattle milk.
Climate change is leading to an increase in the intensity, duration, and frequency of severe droughts, especially in southern and southeastern Europe, thus aggravating water scarcity problems. Water ...deficit stress harms the growth, physiology, and yield of crops like durum wheat. Hence, studying ancient wheat varieties’ stress responses could help identify genetic traits to enhance crop tolerance to environmental stresses. In this background, this study aimed to investigate the effects of PEG 6000-stimulated drought stress in the ancient wheat variety Saragolla and the modern one Svevo by analyzing various biochemical and molecular parameters that can especially condition the stomatal movement. Our data revealed that drought stress caused a significant increase in the levels of total soluble sugars, ABA, and IAA in both selected cultivars to a greater extent in the Saragolla than in the Svevo. We demonstrated that, under water deficit stress, calcium dynamics as well as the expression of ERF109, MAPK3/6, MYB60, and TaTPC1, involved in the activation of drought-related calcium-sensitive pathways, display significant differences between the two varieties. Therefore, our study provided further evidence regarding the ability of the ancient wheat variety Saragolla to better cope with drought stress compared to the modern variety Svevo.
The present investigation exposes the main results raised from an active collaboration started in 2018 with the San Pio Hospital (Benevento, Southern Italy), aiming at a detailed mineralogical ...investigation of urinary stones of patients from the Campania region. Forty-nine uroliths (both bladder and kidney stones) have been surgically collected from patients admitted between 2018 and 2020 at the Department of Urology of the San Pio Hospital and characterized for clinical purposes and environmental biomonitoring from a mineralogical point of view. Possible causes and environmental implications were inferred according to the morpho-constitutional classification of the uroliths carried out by means of a conventional analytical approach. The mineralogical frequency distribution of uroliths from the Campanian region can be discussed as a function of dietary, socio-demographic, and environmental risk factors. Whewellite CaC2O4·H2O and weddellite CaC2O4·(2+x)H2O, along with anhydrous calcium oxalate, represent the main mineralogical phases forming the biominerals examined here. Worth to note is that the percentage of oxalates in the Campanian region (ca. 51%) is quite comparable to those of other Mediterranean areas. Frequent uricite C5H4N4O3 (ca. 33%), mainly observed in bladder stones of older male patients, could be related to an incorrect lifestyle and dietary habits. Occurrence of lower percentages of phosphate (i.e., brushite CaHPO4·2(H2O) and carbonated apatite Ca10(PO4CO3)6(OH)8) and mixed stones (such as, for example, a mixture of ammonium urate NH4C5H3N4O3 and calcium oxalates) indicates specific etiopathogenetic mechanisms, suggesting proper therapeutical approaches.
Durum wheat is widely cultivated in the Mediterranean, where it is the basis for the production of high added-value food derivatives such as pasta. In the next few years, the detrimental effects of ...global climate change will represent a serious challenge to crop yields. For durum wheat, the threat of climate change is worsened by the fact that cultivation relies on a few genetically uniform, elite varieties, better suited to intensive cultivation than "traditional" ones but less resistant to environmental stress. Hence, the renewed interest in "ancient" traditional varieties are expected to be more tolerant to environmental stress as a source of genetic resources to be exploited for the selection of useful agronomic traits such as drought tolerance. The aim of this study was to perform a comparative analysis of the effect and response of roots from the seedlings of two durum wheat cultivars: Svevo, a widely cultivated elite variety, and Saragolla, a traditional variety appreciated for its organoleptic characteristics, to Polyethylene glycol-simulated drought stress. The effect of water stress on root growth was analyzed and related to biochemical data such as hydrogen peroxide production, electrolyte leakage, membrane lipid peroxidation, proline synthesis, as well as to molecular data such as qRT-PCR analysis of drought responsive genes and proteomic analysis of changes in the protein repertoire of roots from the two cultivars.
Nanohydrogels based on natural polymers, such as polysaccharides, are gaining interest as vehicles for therapeutic agents, as they can modify the pharmacokinetics and pharmacodynamics of the carried ...drugs. In this work, hyaluronan-riboflavin nanohydrogels were tested in vivo in healthy rats highlighting their lack of toxicity, even at high doses, and their different biodistribution with respect to that of native hyaluronan. They were also exploited as carriers of a hydrophobic model drug, the anti-inflammatory piroxicam, that was physically embedded within the nanohydrogels by an autoclave treatment. The nanoformulation was tested by intravenous administration showing an improvement of the pharmacokinetic parameters of the molecule. The obtained results indicate that hyaluronan-based self-assembled nanohydrogels are suitable systems for low-soluble drug administration, by increasing the dose as well as the circulation time of poorly available therapeutic agents.
Quercetin (Qc) inhibits cell proliferation and induces apoptosis in a variety of cancer cells. The molecular mechanism of action has not been fully elucidated; however, interplay with some miRNAs has ...been reported, specifically with miR-27a, an onco-miRNA overexpressed in several malignancies. Here, we show that Qc reduces cell viability and induces apoptosis in HCT116 and HT-29 colon cancer cells, by upregulating negative modulators of proliferation pathways such as Sprouty2, PTEN and SFRP1. These are targets of miR-27a whose high expression is reduced by Qc. Moreover, miR-23a, and miR-24-2, the two other components of the unique gene cluster, and the pri-miRNA transcript are reduced, evoking a transcriptional regulation of the entire cluster by Sp1. Mechanistically, we show that Qc is rapidly internalized and localizes in the nucleus, where it likely interacts with Sp1, inducing its proteasomal degradation. Sp1 is further repressed by ZBTB10, an Sp1 competitor for DNA binding that is an miR-27a target and whose levels increase following Qc. SP1 mRNA is also reduced, supporting the regulation of its own gene transcription. Finally, Sp1 knockdown elicits the impaired transcription of the entire cluster and the upregulation of the miR-27a targets, phenocopying the effects of Qc. Through this dual mode of action, Qc counteracts the protumoral Sp1-miR-27a axis, opening the way for novel therapies based on its association as neoadjuvant with known anticancer treatments.
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