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Two mixtures of polyaminoazides were synthesized by a nucleophilic displacement strategy providing no separation of the components. The mixtures were adequately characterized by means of combined HR-ESIMS, FTIR and NMR techniques and, despite their complexity, they were successfully used to accomplish the subsequent preparation of pH-sensitive calixarene hyper-reticulated nanosponge materials. The desired responsivity to pH variations of the nanosponges obtained was verified by means of absorption tests on a set of organic pollutant model molecules.

Objective To determine the effect of the Klox fluorescence biomodulation system (Phovia) on the healing of surgical wounds. Study design Prospective, blinded, controlled clinical trial. Sample population Healthy dogs undergoing orthopedic surgery (n = 10). Methods Half of the length of each surgical wound was treated with Phovia, and the remaining 50% was treated with saline solution on the first day after surgery and every 3 days until day 13. Wound healing of treated and control areas within each wound was evaluated via macroscopic assessment and histological and immunohistochemical analysis of treated and control wounds. Results The areas treated with Phovia achieved lower histology scores (P = .001), consistent with complete re-epithelialization, less inflammation of the dermal layer, and greater and more regular deposition of collagen. According to immunohistochemistry, expression of factor VIII, epidural growth factor, decorin, collagen III, and Ki67 was increased in treated compared with untreated tissues. Conclusion Phovia therapy improved re-epithelialization, decreased dermal inflammation, and improved matrix formation in uncomplicated cutaneous incisional wounds by regulating the expression of key biological mediators. Clinical significance Phovia may be a beneficial adjunct to promote the healing of incisional wounds.

nflammation can be the leading cause of several diseases, including cancer, diabetes, and ulcerative colitis; however, the existing anti-inflammatory drugs cause side effects. For these reasons, it is necessary to find new supportive therapeutic agents. In recent years, plant-derived extracellular vesicles (PDEVs) are gaining increasing interest in the scientific community as they have been found to possess a variety of biological properties; among those, the anti-inflammatory effects have been described by different groups that evaluated the effects of PDEVs in in vitro and in vivo models. We successfully isolated and characterized extracellular vesicles from Citrus limon juice (LEVs) and we studied their anti-inflammatory properties on in vitro and ex-vivo models: murine macrophages (RAW264.7) and immune cells isolated from healthy donors. LEVs were isolated by differential centrifugation followed by a final ultracentrifugation step. Further, biophysical analyses confirmed the size and morphology of LEVs. Also, through metabolomics analysis by means of HPLCESI-Q-ToF-MS, we characterized flavonoids, limonoids and lipids contained in the LEVs. Comparing the vesicle content with the total juice and LEVs-deprived juice, we observed an enrichment in the lipid component for LEVs. We then tested the toxicity of LEVs on target cells at different doses and time points and we observed that LEVs did not affect RAW and primary immune cell growth. To assess the role of EVs on inflammatory stimuli, we pre-treated both cell types for 24h with LEVs and subsequently stimulated them with LPS. Through RTPCR, ELISA and FACS analysis, we saw that the pre-treatment with LEVs decreased the gene and protein expression levels of the pro-inflammatory cytokines IL-6, IL-1β, and TNFα. Besides, we observed a reduction in the gene expression of prostaglandin COX-2, compared to LPS alone. Similarly, pretreatment with LEVs followed by stimulation with LPS in human monocytes, down-regulated TNFα levels compared to LPS alone. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) is a key pro-inflammatory pathway that can be activated by the ERK 1/2 signalling cascade. By confocal analysis and western blot, we observed that the pre-treatment with LEVs reduced the nuclear translocation of NF-kB in RAW stimulated with LPS as well as its phosphorylation. NF-kB modulation is associated with the decrease of ERK phosphorylation. In conclusion, LEVs showed promising anti-inflammatory properties, both in vitro and ex vivo, by reducing the production of pro-inflammatory cytokines through the ERK/NF-kB pathway

Six recently synthesized alkyl (Z)-2-(2-oxopyrrolidin-3-ylidene)acetates were evaluated for their potential as cytotoxic and anticancer agents. All compounds were tested in the ERα positive MCF-7, triple negative MDA-MB-231, and Her2+ SKBR-3 breast cancer cell lines. The most lipophilic derivatives, bearing the 4-isopropylphenyl (2) or 4-tert-butylphenyl (3) group at the γ-lactam nitrogen, proved to be cytotoxic against all the cancer cell lines tested (IC50 values ranging from 18 to 63 μM), exerting their greatest activity in SKBR-3 cells, with IC50 values of 33 and 18 μM, respectively. Biological studies showed that the cytotoxic effects of 2 and 3 are accompanied by apoptotic death in breast cancer cells, and both compounds showed no significant toxicity on healthy cells (e.g., MCF-10A) and red blood cells. An in-depth mechanistic study based on molecular biology, immunoblotting analysis and in silico docking calculations suggested that α,β-unsaturated γ-lactam derivatives could interfere with the functioning of PI3K and PDK-1, two key enzymes in the PI3K/AKT signaling pathway, whose overactivation is related to the regulation of cell growth and survival in several malignancies.

Neurodegenerative diseases (NDs) are one of major public health problems and their impact is continuously growing. Curcumin has been proposed for the treatment of several of these pathologies, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) due to the ability of this molecule to reduce inflammation and aggregation of involved proteins. Nevertheless, the poor metabolic stability and bioavailability of curcumin reduce the possibilities of its practical use. For these reasons, many curcumin derivatives were synthetized in order to overcome some limitations. In this review will be highlighted recent results on modification of curcumin scaffold in the search of new effective therapeutic agents against NDs, with particular emphasis on AD.

The first determination of presence and biodistribution of PFOA in ninety specimens of sea urchin Paracentrotus lividus from two differently contaminated sites along Palermo’s coastline (Sicily) is reported. Analyses were performed on the sea urchins’ coelomic fluids, coelomocytes, gonads or mixed organs, as well as on seawater and Posidonia oceanica leaves samples from the collection sites. PFOA concentration ranged between 1 and 13 ng/L in seawater and between 0 and 794 ng/g in P. oceanica. The analyses carried out on individuals of P. lividus from the least polluted site (A) showed PFOA median values equal to 0 in all the matrices (coelomic fluid, coelomocytes and gonads). Conversely, individuals collected from the most polluted site (B) showed median PFOA concentrations of 21 ng/g in coelomic fluid, 153 ng/g in coelomocytes, and 195 ng/g in gonads. Calculated bioconcentration factors of log10BCF > 3.7 confirmed the very bioaccumulative nature of PFOA. Significant correlations were found between the PFOA concentration of the coelomic fluid versus the total PFOA concentration of the entire sea urchin. PERMANOVA (p = 0.001) end Welch's t-test (p P. lividus as sentinel species for PFOA biomonitoring.

The maturation of coronavirus SARS-CoV-2, which is the etiological agent at the origin of the COVID-19 pandemic, requires a main protease Mpro to cleave the virus-encoded polyproteins. Despite a wealth of experimental information already available, there is wide disagreement about the Mpro monomer-dimer equilibrium dissociation constant. Since the functional unit of Mpro is a homodimer, the detailed knowledge of the thermodynamics of this equilibrium is a key piece of information for possible therapeutic intervention, with small molecules interfering with dimerization being potential broad-spectrum antiviral drug leads. In the present study, we exploit Small Angle X-ray Scattering (SAXS) to investigate the structural features of SARS-CoV-2 Mpro in solution as a function of protein concentration and temperature. A detailed thermodynamic picture of the monomer-dimer equilibrium is derived, together with the temperature-dependent value of the dissociation constant. SAXS is also used to study how the Mpro dissociation process is affected by small inhibitors selected by virtual screening. We find that these inhibitors affect dimerization and enzymatic activity to a different extent and sometimes in an opposite way, likely due to the different molecular mechanisms underlying the two processes. The Mpro residues that emerge as key to optimize both dissociation and enzymatic activity inhibition are discussed.

During the monitoring of Caretta caretta nests on the island of Linosa, 30 unhatched eggs from four nests were collected to study the presence of phthalates in their three components (shell, yolk, and albumen). Four phthalates, namely diethyl (DEP), dibutyl (DBP), di-(2-ethylhexyl) (DEHP), and dioctyl (DOTP) phthalic acid esters (PAE), which are widely used as additives in plastics, were detected in all egg components. The most frequently found phthalate was DBP, followed by DEHP in eggshell and yolk. Dimethyl- (DMP) and butylbenzyl-phthalate (BBP) were below the limits of detection for all samples. The high total phthalate recorded in the yolk suggests that contamination could arise by vitellogenesis. PERMANOVA analysis (p = 0.01) confirmed significant differences in the PAEs contamination profiles in the eggs from the four nests. This study confirms the negative impact of plastic related compounds posing questions about the potential adverse effects on organisms and their conservation status.

The iodolactonization of 3-alkynylthiophene-2-carboxylic acids and 3-alkynylpicolinic acids has been investigated. Using I2 as the iodine source and NaHCO3 as the base in MeCN, the process took place smoothly to afford thienopyranones and pyranopyridinones, respectively, from 6-endo-dig cyclization. The method also worked nicely for the transformation of 2-(phenylethynyl)thiophene-3-carboxylic acid and 3-(phenylethynyl) isonicotinic acid into 7-iodo-6-phenyl-4H-thieno[3,2-c]- pyran-4-one and 4-iodo-3-phenyl-1H-pyrano[4,3-c]pyridin-1- one, respectively. Although with some 3-alkynylpicolinic acids the process led to a mixture of the 6-endo-dig and 5-exo-dig products, it could be still made selective toward the pyranopyridinone compound working in 1-ethyl-3-methylimidazolium ethyl sulfate as the solvent. On the other hand, the exclusive formation of the 5-exo-dig product was observed in N-ethyl-Nmethylmorpholinium dicyanamide starting from 3-(3,3-dimethylbut- 1-yn-1-yl)picolinic acid. Some representative iodinated thienopyridinone products were successfully used as substrates for Pd-catalyzed Suzuki and Sonogashira reactions.

The present invention relates to novel small molecules of Formulas I, II, III, IIIa, IIIb, and IV and pharmaceutically acceptable salts thereof, as well as the preparation and the use thereof.

The pathological aggregation and accumulation of tau, a microtubule-associated protein, is a common feature amongst more than 18 different neurodegenerative diseases that are collectively known as tauopathies. Recently, it has been demonstrated that the soluble and hydrophobic tau oligomers are highly toxic in vitro due to their capacity towards seeding tau misfolding, thereby propagating the tau pathology seen across different neurodegenerative diseases. Modulating the aggregation state of tau oligomers through the use of small molecules could be a useful therapeutic strategy to target their toxicity, regardless of other factors involved in their formation. In this study, we screened and tested a small library of newly synthesized curcumin derivatives against preformed recombinant tau oligomers. Our results show that the curcumin derivatives affect and modulate the tau oligomer aggregation pathways, converting to a more aggregated non-toxic state as assessed in the human neuroblastoma SH-SY5Y cell line and primary cortical neuron cultures. These results provide insight into tau aggregation and may become a basis for the discovery of new therapeutic agents, as well as advance the diagnostic field for the detection of toxic tau oligomers.

3-Pentadecafluoroheptyl,5-perfluorophenyl-1,2,4-oxadiazole (FOX) molecules were attached onto a graphene oxide (GO) via a facile aromatic substitution in alkaline environment. This approach allows achieving high degree of functionalization under mild conditions. The covalent attachment of perfluoromoieties onto GO lamellae was confirmed by spectroscopic analyses. The performance of these nanoplatforms (GOF) as oxygen reservoirs was assessed at different concentrations and temperature. The results revealed that under physiologic conditions GO and FOX synergistically operate for increasing oxygen uptake and release, either from a thermodynamic and a kinetic point of view. Even at low concentrations, GOF showed values in terms of oxygen content at saturation and diffusion rate higher than those of other materials currently proposed as O2-reservoirs in tissue engineering, for cell oxygenation during the regeneration of vascularized tissues. Furthermore, GOF displayed a high cytocompatibility. These findings open new, intriguing scenarios for a further application field of graphene-derived materials.

Simple Summary Small rodents and, in particular, rabbits require special attention during anaesthesia since they develop a high level of stress following painful procedures or manipulations. The transversus abdominis plane (TAP) block is a locoregional technique that has been shown to provide good perioperative analgesia for abdominal surgery, reducing the stress during recovery from anaesthesia and the need for systemic analgesic drugs. The aim of this cadaveric study was to describe a US-guided lateral TAP block technique in rabbits and evaluate the spread of the dye administered by a single injection. Our results showed that this US-guided block is applicable and easy to perform in rabbits. However, a single injection of local anaesthetic may fail to cover the sensory component of the entire abdomen. It would be interesting to evaluate the same technique in vivo but using a double injection point, as recently described in other species. Abstract The aims of the study were to describe the ultrasonographic-guided lateral TAP block in rabbit cadavers and evaluate the spread of a lidocaine/methylene blue solution through a single fascial infiltration. The US-guided block and anatomical dissections were performed in 17 New Zealand rabbit cadavers. The probe was placed perpendicular to the column, one centimetre ventrally to the transverse processes, halfway between the iliac crest and the costal margin. External oblique (EO), internal oblique (IO), and transversus abdominis (TA) muscles were visualised, and 1 mL/kg of lidocaine 2% plus methylene blue 1% was injected. After dissection, the branches of spinal nerves stained were measured. Moreover, the percentage of length and height of the area marked were calculated. A good visualisation of the TAP was obtained in all 34 hemiabdomens. T11 nerve eminence was successfully stained in 52% of cases. T12, L1, and L2 were stained in 75%, 95%, and 100% of cases, respectively. L3 and L4 were stained in 60% and 40% of cases, respectively. The lateral TAP block with a single point of injection can be easily performed in rabbits, but it is not sufficient to cover the nerve eminences of the cranial abdomen. The two-point TAP block (lateral and subcostal) could represent a better option, particularly when large surgical incisions are required.

The purpose of this study was to estimate the safety, feasibility, and efficacy of the intra-articular treatment of autologous microfragmented adipose tissue in dogs with spontaneous osteoarthritis (OA) in comparison with hyaluronic acid (HA), the standard intra-articular treatment. Specifically, it clinically evaluated pain and lameness, the radiographic progression of osteoarthritis, and synovial fluid inflammation. This was a prospective, single-center, parallel-group, randomized, controlled, in vivo clinical study. Participants (n = 40) received either a single intra-articular injection of microfragmented adipose tissue or a single intra-articular injection of HA (1:1). Clinical outcomes were determined using a specialistic clinician assessment obtained by the completion of a specific clinical form based on the Vesseur modified lameness classification system, a pain evaluation using the Visual Analogue Scale (VAS), the measurement of the range of motion (ROM) of the affected joint, limb circumference, and the owners’ score evaluation using the Canine Brief Pain Inventory (CBPI) for up to 6 months after the time of injection. Patients underwent a radiographic examination to establish the degree of OA in the affected joint, and synovial fluid samples were collected to assess the biochemical environment of the joint and evaluate and quantify the cellular population and the presence of three specific inflammation biomarkers for up to 60 days. The results of this study suggest that microfragmented autologous adipose tissue is safe and can effectively relieve pain and improve function in dogs with spontaneous articular OA. This one-step procedure is simple, timesaving, cost-effective, minimally invasive, and eliminates the need for complex and time-intensive cell culture processing. Furthermore, the clinical evidence and cytological results suggest better long-term pain control, resulting in an improvement in joint function, compared to HA treatment. The canine spontaneous OA model could play a key role in developing successful treatments for human medicine.

The synthesis and characterization of a new class of 1,2,4-oxadiazolylpyridinium as a cationic scaffold for fluorinated ionic liquid crystals is herein described. A series of 12 fluorinated heterocyclic salts based on a 1,2,4-oxadiazole moiety, connected through its C(5) or C(3) to an N-alkylpyridinium unit and a perfluoroheptyl chain, differing in the length of the alkyl chain and counterions, has been synthesized. As counterions iodide, bromide and bis(trifluoromethane)sulfonimide have been considered. The synthesis, structure, and liquid crystalline properties of these compounds are discussed on the basis of the tuned structural variables. The thermotropic properties of this series of salts have been investigated by differential scanning calorimetry and polarized optical microscopy. The results showed the existence of an enantiotropic mesomorphic smectic liquid crystalline phase for six bis(trifluoromethane)sulfonimide salts.

The maturation of coronavirus SARS-CoV-2, which is the etiological agent at the origin of the COVID-19 pandemic, requires a main protease Mpro to cleave the virus-encoded polyproteins. Despite a wealth of experimental information already available, there is wide disagreement about the Mpro monomer-dimer equilibrium dissociation constant. Since the functional unit of Mpro is a homodimer, the detailed knowledge of the thermodynamics of this equilibrium is a key piece of information for possible therapeutic intervention, with small molecules interfering with dimerization being potential broad-spectrum antiviral drug leads. In the present study, we exploit small angle x-ray scattering (SAXS) to investigate the structural features of the SARS-CoV-2 Mpro monomer-dimer equilibrium, by revealing the corresponding equilibrium dissociation constant and the associated thermodynamic parameters. SAXS is also used to study how the Mpro dissociation process is affected by small inhibitors selected through combinatorial design. Our results show that a clear picture connecting the ability of inhibitors to disrupt the Mpro dimerization with the loss of catalytic activity cannot be provided, thus highlighting the possible role of allosteric effects for the regulation of Mpro functionality.

In Europe, approximatively 100 000 to 500 000 tendon repairs are performed every year. These procedures are associated with a considerable rate of postoperative complications (from 6% to 11%). Autologous micro‐grafts (AAMG) and stromal vascular fraction (SVF) have been shown to improve tendon healing in 60% to 70% of treated rodents. The purpose of this study was to evaluate the effects of AAMG in a sheep model with tendinopathy. We used sheep models because, as a large animal, they are more comparable to humans. The hypothesis was that SVF injection would improve tendon healing compared with the control group, reducing inflammatory and matrix degrading, while increasing anti‐inflammatory expression and collagen synthesis in the early stage of tendon injury. Sixteen Apennine sheep aged 2 to 5 years underwent 500 UI type I collagenase injection into both common calcaneal tendons (CCT) to induce tendinopathy. After 15 days (T0), one CCT in every ovine underwent randomly to 2.5 mL of AAMG obtained by mechanical disruption and the contralateral CCTs received no treatment. Clinical, ecographic, and sonographic evaluations were performed after 4 weeks (T1) and 8 weeks (T2). Histological, immunohistochemical, real‐time polymerase chain reaction (RT‐PCR), and biomechanical evaluations were performed at T2. At T2, the treated group showed a final tendon diameter (9.1 ± 1.4 mm) and a hardness expression (62%) that were similar to the original healthy tendon (8.1 ± 1.1 mm; 100%), with a significant recovery compared with the control group (9.5 ± 1.7 mm; 39%). Moreover, histological analysis of the treated group revealed an improvement in the fiber orientation score, fiber edema score, infiltrative‐inflammatory process, and necrosis score (4.3 ± 3.3) compared with control group (8.8 ± 2.9). Immunohistochemically, the treated group showed high expression of collagen 1, Factor VIII and significantly low expression of collagen 3. These data were confirmed by RT‐PCR analysis. The study findings suggested that AAMGs obtained through mechanical disruption present a safe, efficient, and reliable technique, enhancing tendon healing., The group treated with stromal vascular fraction showed a final tendon diameter and a percentage hardness expression that were similar to the original healthy tendon.

Background: Pantarsal arthrodesis is a salvage procedure carried out for the treatment of tarsal joint disease, including severe osteoarthritis with intractable pain in the tarsocrural joint, tarsal fractures, shearing injuries, tarsocrural joint instability, and failure of the common calcaneal tendon. Although medial plating is preferable, the high incidence of post-surgery complications is possible. Using thin, pre-contouring or easy contouring, locking plates might reduce the incidence of such complications. However, to date, there are no pre-contouring and dedicated locking plates forpantarsal arthrodesis with medial placement.Case Description: The case of an 18-month-old female stray European cat has been referred because of a severe tibiotarsal injury improperly treated with an intramedullary pin. The patient was submitted for medial pantarsal arthrodesis, performed with the Compact UniLock 2.0™ locking plate systema (DePuy Synthes, Oberdorf, Switzerland). The authors hypothesized that this particularly innovative osteosynthesis system could present advantages compared to the systems already in use for medial pantarsal arthrodesis and therefore reduce the risk of complications.Conclusion: This innovative titanium locking system, because of its versatile contour function and thinness, allowed the good functional recovery of the limb and showed numerous advantages over traditional systems.

The purpose of this report was to describe an uncommon congenital anomaly in a dog. An 8-year-old, mixed-breed, male dog, was referred because of progressive difficulties on defecation. A complete diagnostic work-up (hematological analysis, radiology, ultrasound, and computed tomography), followed by surgery and histopathology, allowed us to diagnose the condition as unilateral urogenital disontogeny. The disorder was characterized by unilateral anomalies of the urinary tract (ectopic and dilated hydroureter, hydronephrosis, and renal dysplasia) associated with ipsilateral anomalies of the genital system (partial permanence of the duct of Wolff evolved into an epididymal-like structure and testicular agenesis). En bloc surgical excision of the complex of urogenital anomalies was performed with no complications during or after surgery. Surgery was considered to be effective in this dog since he no longer showed clinical signs of illness.