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Distant ischemic post‑conditioning alleviates ischemia/reperfusion‑induced digestive tract damage via the ERK signaling pathway‑mediated RAGE/HMGB axis.
All the results suggest that the indoline derivatives might be a class of novel tubulin inhibitors with potential anticancer activity and is worthy of further study.Skin wound repair represents an important topic for the therapeutic challenges. Many molecules are commonly used as active principles of topical devices to induce the correct tissue regeneration. Among these molecules, mesoglycan, a mixture of glycosaminoglycans, and the lactoferrin have recently aroused interest. Here, for the first time, we used mesoglycan/lactoferrin to treat the cell populations mainly involved in wound healing. We showed that human keratinocytes, fibroblasts and endothelial cells migrate and invade more rapidly when treated with the association. Moreover, we found that mesoglycan/lactoferrin, are able to trigger the differentiation process of keratinocytes, the switch of the fibroblasts into myofibroblasts, the acquisition of a mesenchymal phenotype for the endothelial cells which, in this way, start to form the capillary-like structures. Additionally, we proved that the well known antimicrobial behavior of lactoferrin encourages the inhibition of S. aureus and P. aeruginosa biofilm formation by the whole association, providing an appealing feature for this formulation. Finally, by the in vivo analysis, we showed that the mesoglycan/lactoferrin favors the closure of skin wounds performed on the mice back. Beside the decrease of the lesion diameters, by a confocal analysis of mice biopsies we found that the use of the association strongly promote cell activation underlying the correct tissue regeneration. These results encourage to further investigation aiming the development of a new topical patch that includes this association.Solid lipid nanoparticles and nanostructured lipid carriers showed promising results for enhancement of ocular bioavailability of drugs with poor corneal permeability. One of these drugs is methazolamide, which is an orally administered carbonic anhydrase inhibitor for glaucoma treatment. However, sterilization by autoclaving may result in loss of the physical properties of lipid nanoparticles such as particle size and surface charge. Here, we evaluated gamma radiation as an alternative sterilization method. Methazolamide loaded nanostructured lipid carriers were optimized using 23 factorial design. Optimized formulations contained 6% lipid (85% solid lipid (Cetostearyl alcohol and glyceryl behenate) and 15% oil either medium chain triglycerides or isopropyl myristate) stabilized by 2% polysorbate 80 and 0.15% stearylamine. Nanoparticles were cationic, smaller than 500 nm, and had an entrapment efficiency of about 30%. They released methazolamide within 8 hours and showed a 5-fold enhanced reduction in intraocular pressure compared to methazolamide solution. Gamma sterilization was superior to autoclaving in preserving entrapped methazolamide, size, and surface charge of lipid nanoparticles. These findings demonstrate that gamma radiation is a viable alternative to autoclaving for sterilizing lipid nanoparticles. Moreover, this proves that nanostructured lipid carriers enhance pharmacological response of topically administered methazolamide for treating glaucoma.In order to exploit the advantages to the full of multidrug salification strategy in amending the pharmaceutical properties of drugs both in vitro and in vivo, and further to open up a new way for its applications in bacteria-virus mixed cross-infection drugs, a novel dual-drug crystalline molecular salt hybridizing antibacterial drug sulfamethoxazole (SFM) with antiviral ingredient amantadine (ATE), namely SFM-ATE, is successfully designed and synthesized via multidrug salification strategy oriented by proton exchange reaction. The crystal structure of the firstly obtained molecular salt is precisely identified by employing single-crystal X-ray diffraction and multiple other techniques. The results show that, in the crystal lattice of molecular salt SFM-ATE, the classical hydrogen bonds together with charge-assisted hydrogen bonds contribute to two- dimensional networks, between which the hydrophobic interaction plays an important role. The relevant in vitro/vivo pharmaceutical properties of the dual-drug mo with viral-bacterial coinfection even other complex diseases by drugs' hybridization at the molecular level.Intravesical instillation of a poloxamer 407 (PLX)-based hydrogel offers advantages such as thermo-sensitivity and sol-to-gel transition, but its utility is limited by urinary obstruction and insufficient bladder residence time. To overcome these obstacles, a floating PLX-hydrogel (FPH) was developed using sodium bicarbonate (BC) as a floating agent and hyaluronic acid (HA) as a gel strength modulator. The FPH composition was optimized using the Box-Behnken design with three independent variables X1 [PLX concentration, 23.91%], X2 [BC concentration, 5.15%], and X3 [HA concentration, 3.49%]. The quadratic model was the best fit (desirability function, 0.623), resulting in response parameters of Y1 [floating time, 53.7 s], Y2 [gelation temperature gap, 20.3°C], and Y3 [duration time of gel, 396.7 min]. RU.521 manufacturer Rheological observations revealed the mechanical rigidity (storage modulus > loss modulus at elevated temperature) of the optimized FPH (phase transition temperature, 15.08°C). Gel erosion and drug release studies were performed using the gravimetric method; the remaining FPH fraction decreased exponentially with time, and gemcitabine release was biphasic and surface erosion-controlled. In vivo buoyancy was evaluated in rats using ultrasonography; these results were similar to those of the in vitro floating behavior. Thus, optimized FPH for intravesical instillation is a prospective option for bladder cancer treatment.
Current guidelines advocate reviewing peri-procedural anticoagulation on individual case basis for transvenous lead extraction (TLE). We investigated the safety of TLE on uninterrupted warfarin with therapeutic INR.

Retrospective registry of consecutive patients undergoing TLE on uninterrupted warfarin (Warfarin Group) across two centres. Age and sex matched controls not on anticoagulation (No-Warfarin Group) and undergoing TLE over the same time-period were included. Both groups were compared over one-year.

121 TLEs over 18-months. 22 patients on uninterrupted anticoagulation were compared to 22 controls. Groups were well matched for baseline demographics other than INR. Warfarin group had mean INR of 2.2±0.6 (range 2-3.5). Primary end point was procedural safety and efficacy. Amongst cases, 43/45 (96%) leads were removed in their entirety compared to 37/40 (93%) in controls (p=0.66). In the cases, these included 44% defibrillator, 47% pace-sense and 9% CS leads of average duration 7yrs. There was no reported tamponade, haemothorax or procedural mortality in either group. One patient amongst cases required inotropic support while two patients amongst controls had device-site haematomas. No significant difference reported in Hb drop post-procedure or overall complication rate between the groups (p=0.11,0.32). Cox regression showed a significant association between procedural success and device infection, number of leads extracted, serum creatinine (p=0.03, 0.04, 0.02). Over a 1-year follow-up, there was lead displacement in one case and one control had infection of the re-implanted device.

TLE can be carried out safely in anticoagulated patients with therapeutic INRs. Larger multicentre studies are required to confirm these findings.
TLE can be carried out safely in anticoagulated patients with therapeutic INRs. Larger multicentre studies are required to confirm these findings.Persistence of the left superior caval vein is the most commonly reported thoracic venous anomaly. The vein usually drains into the right atrium through the coronary sinus, reflecting its developmental origin. We describe an unusual variant, in which the vein drained directly into the right atrium.Clinical studies have postulated that β-endorphin deficiency generates excessive alcohol consumption, and it has been shown that the reduction of β-endorphin neurons increases alcohol intake in animal models. The β-endorphin produce their rewarding effect when they act mainly on the μ-opioid receptors (MOR) located in mesolimbic structures. Thus, it is possible that individual differences in these components of the endogenous opioid system are related to different levels of alcohol consumption. The present study thus examines the relation between two levels of alcohol consumption and intrinsic characteristics of the components of the opioid system in outbred Wistar rats that were not genetically selected. We analyzed the number of β-endorphin-positive neurons in the arcuate nucleus (ArN) and the expression of μ-opioid receptors (MOR) in regions of the reward system, such as the nucleus accumbens (NAc), amygdala (Amy), and ventral tegmental area (VTA) in outbred rats with low (LC) or high (HC) voluntary alcohol consumption. Findings showed that the HC rats had a lower number of β-endorphin-positive neurons in the hypothalamic ArN and a higher expression of MOR in the NAc and VTA, compared to the LC rats. No changes in the expression of MOR in the Amy were observed between the two groups. Results suggest that intrinsic variability in the number of β-endorphin neurons and in the expression of MOR in the LC and HC rats could explain their different patterns for alcohol intake.Diethylene glycol (DEG) intoxication results in metabolic acidosis, renal and hepatic dysfunction, and late-stage neurotoxicity. Though the renal and hepatic toxicity of DEG and its metabolites 2-hydroxyethoxyacetic acid (2-HEAA) and diglycolic acid (DGA) have been well characterized, the resultant neurotoxicity has not. SH-SY5Y neuroblastoma cells were incubated with all 3 compounds at increasing concentrations for 24, 48, or 120 h. At all 3 time points, 50 mmol/L DGA and 100 mmol/L DEG showed significant Annexin V and propidium iodide (PI) staining with additional concentrations showing similar staining patterns at 24 h (100 mmol/L DGA) and 48 h (50 mmol/L DEG, 100 mmol/L DGA). Only the 200 mmol/L 2-HEAA concentration induced SH-SY5Y cell death. Interestingly at 24 and 48 h, 100 mmol/L DEG induced significant increases in apoptotic cell death markers, which progressed to necrosis at 120 h. Similar to DEG, 50 mmol/L DGA induced significant increases in SH-SY5Y cell apoptosis and necrosis markers at both 24 and 48 h. As expected, high DGA concentrations (100 mmol/L) at 120 h induced significant SH-SY5Y cell necrosis with no apoptosis detected. However, at 120 h lower DGA concentrations (20 mmol/L) significantly increased oligonucleosome formation alone and in combination with 2-HEAA or DEG. Taken together, these results indicate that DGA and DEG at threshold concentrations induce neurotoxicity in SH-SY5Y cells.The potential developmental toxicity and mode-of-action of fume condensate extracts of bitumen and oxidized asphalt were evaluated in the aryl hydrocarbon receptor (AhR) CALUX assay, the zebrafish embryotoxicity test (ZET), and the mouse embryonic stem cell test (mEST). In the AhR CALUX assay, both fume condensate extracts showed a concentration-dependent AhR induction following 6-h of exposure, but this activity was substantially reduced after 24-h, indicating a transient AhR activation. The main effect observed in the ZET was early embryonic lethality that occurred mostly in the 24 h-post-fertilization (hpf). This typically reflects non-specific toxicity rather than in vitro developmental toxicity of the fume condensate extracts tested since this effect was not seen as a result of the whole cumulative exposure period in the ZET (up to 96 hpf). No malformations were seen in any zebrafish embryo exposed to these fume condensate extracts, although some developed pericardial and/or yolk-sac edemas. Furthermore, both fume condensate extracts tested negative in the mEST.
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