Erythrocyte nanovesicles: Biogenesis, biological roles and therapeutic approach Erythrocyte nanovesicles

AbstractNanovesicles (NVs) represent a novel transporter for cell signals to modify functions of target cells. Therefore, NVs play many roles in both physiological and pathological processes. This report highlights biogenesis, composition and biological roles of erythrocytes derived nanovesicles (EDNVs). Furthermore, we address utilization of EDNVs as novel drug delivery cargo as well as therapeutic target. EDNVs are lipid bilayer vesicles rich in phospholipids, proteins, lipid raft, and hemoglobin. In vivo EDNVs biogenesis is triggered by an increase of intracellular calcium levels, ATP depletion and under effect of oxidative stress conditions. However, in vitro production of EDNVs can be achieved via hypotonic treatment and extrusion of erythrocyte. NVs can be used as biomarkers for diagnosis, monitoring of therapy and drug delivery system. Many therapeutic agents are suggested to decrease NVs biogenesis

Influence of pravastatin chitosan nanoparticles on erythrocytes cholesterol and redox homeostasis: An in vitro study

AbstractThe objective of this study was to develop and characterize chitosan nanoparticles (CSNPs) to increase efficacy of pravastatin (PR) on erythrocytes redox status. CSNPs and PR loaded CSNPs (PRCSNPs) were prepared by ionic gelation method. The particle size, zeta potential, scanning electron microscopy (SEM), differential scanning calorimetry (DSC), Fourier-transform infrared (FTIR) and X-ray diffraction (XRD) were used to investigate physicochemical characters of the prepared nanoparticles. The present results revealed that CSNPs and PRCSNPs have nanosize about 90nm with spherical shape, positive zeta potential and prolonged PR release. Moreover, DSC and FTIR indicated no chemical interactions between PR and CS. In vitro studies revealed that, erythrocyte uptake of PR from PRCSNPs was higher than free PR solution. Incubation of erythrocytes in high cholesterol plasma, hypercholesterolemia (HC), increases membrane cholesterol, erythrocyte hemolysis, oxidized glutathione (GSH), protein carbonyl (PCC), and malondialdeyhe (MDA). However, HC significantly decreases PR uptake by erythrocytes, superoxide dismutase (SOD), glutathione peroxidase (GPx) catalase (CAT) activities, reduced GSH and nitrite levels compared to control. By contrast, treatment of HC with PR plus CS as free drug or nanostructure formula keeps the measured parameters at values near that of control. The effect of CSNPs and PRCSNPs on redox status of erythrocytes was more prominent than free drugs. In conclusion, PRCSNPs are promising drug carrier to deliver PR into erythrocytes, moreover, PRCSNPs possess promising characteristics with high biological safety for treatment of HC induced disruption of redox homeostasis

Physical pegylation enhances the cytotoxicity of 5-fluorouracil-loaded PLGA And PCL nanoparticles.

Purpose : The main goal of this study is to evaluate the impact of physical incorporation of polyethylene glycol (PEG) into 5-fluorouracil (5-FU)-loaded polymeric nanoparticles (NPs). METHODS: The 5-FU-loaded NPs were prepared utilizing a simple double emulsion method using polycaprolactone (PCL) and polylactic-co-glycolic acid (PLGA) with or without PEG 6000. The surface charge, particle size, and shape of NPs were evaluated by standard procedures. Both Fourier Transform Infrared Spectroscopy and X-ray diffraction spectra of the 5-FU loaded NPs were compared against the pure 5-FU. The in vitro release profile of 5-FU from the NPs was monitored by the dialysis tubing method. Cell death and apoptosis induction in response to 5-FU NP exposure were measured by MTT and Annexin-V/7-amino-actinomycin D (7-AAD) assays, respectively, in Daoy, HepG2, and HT-29 cancer cell lines. RESULTS: The 5-FU loaded NPs were found to be spherical in shape with size ranging between 176±6.7 and 253.9±8.6 nm. The zeta potential varied between -7.13± 0.13 and -27.06±3.18 mV, and the entrapment efficiency was between 31.96% and 74.09%. The in vitro release of the drug followed a two-phase mode characterized by rapid release in the first 8 hrs followed by a period of slow release up to 72 hrs with composition-based variable extents. Cells exposed to NPs demonstrated a significant cell death which correlated with the ratio of PEG in the formulations in Daoy and HepG2 cells but not in HT-29 cells. Formulations (F1-F3) significantly induced early apoptosis in HT-29 cell lines. CONCLUSION: The physical PEGylation significantly enhanced the entrapment and loading efficiencies of 5-FU into NPs formulated with PLGA and PCL. It also fostered the in vitro cytotoxicity of 5-FU-loaded NPs in both Daoy and HepG2 cells. Induction of early apoptosis was confirmed for some of the formulations

Novel docetaxel chitosan-coated PLGA/PCL nanoparticles with magnified cytotoxicity and bioavailability

In the present study, docetaxel (DTX)-loaded poly(lactic-co-glycolic acid) (PLGA) and polycaprolactone (PCL) nanoparticles were successfully prepared and coated with chitosan (CS). The prepared nanoparticles (NPs) were evaluated for their particle size, zeta potential, particle morphology, drug entrapment efficiency (EE%), and in vitro drug release profile. The anticancer activity of DTX-loaded NPs was assessed in human HT29 colon cancer cell line utilizing MTT assay. The pharmacokinetics of DTX-loaded NPs was monitored in Wistar rats in comparison to DTX solution. The prepared NPs exhibited particle sizes in the range 177.1 ± 8.2-287.6 ± 14.3 nm. CS decorated NPs exhibited a significant increase in particle size and a switch of zeta potential from negative to positive. In addition, high EE% values were obtained for CS coated PCL NPs and PLGA NPs as 67.1 and 76.2%, respectively. Moreover, lowering the rate of DTX in vitro release was achieved within 48 h by using CS coated NPs. Furthermore, a tremendous increase in DTX cytotoxicity was observed by CS-decorated PLGA NPs compared to all other NPs including DTX-free-NPs and pure DTX. The in vivo study revealed significant enhancement in DTX bioavailability from CS-decorated PLGA NPs with more than 4-fold increase in AUC compared to DTX solution. In conclusion, CS-decorated PLGA NPs are a considerable DTX-delivery carrier with magnificent antitumor efficacy

Role of Alternative Lipid Excipients in the Design of Self-Nanoemulsifying Formulations for Fenofibrate: Characterization, in vitro Dispersion, Digestion and ex vivo Gut Permeation Studies

Background: The choice of lipid excipients and their origin are crucial determinant factors in the design of self-nanoemulsifying drug delivery system (SNEDDS).Aim: To investigate the aspects of alternative excipients which can influence the development of efficient SNEDDS and determine the fate of fenofibrate in aqueous media.Methods: SNEDDS of two groups (a and b) were developed using Cremercoor MCT/Capmul MCM and Kollisolv MCT/Imwitor 742 blended oils and water soluble surfactants (to improve lipid polarity) for the model anti-cholesterol drug fenofibrate. Visual assessment was employed and droplet size measurement was taken into initial consideration for optimized SNEDDS. Further SNEDDS optimizations were done on the basis of maximum drug loading by equilibrium solubility studies and maximum solubilized drug upon aqueous dispersion by dynamic dispersion studies. In vitro lipolysis was examined under simulated Fed and Fasted conditions. Intestinal permeability study of the optimal SNEDDS formulation was compared with the raw fenofibrate dispersion using non- everted “intestinal sac technique.”Results: Initial characterization and solubility studies showed that mixed glycerides of Kollisolv MCT/Imwitor 742 (group b) containing formulations generated highly efficient SNEDDS as they are stable and produced lower nanodroplets with higher drug loading (group b) as compared to mixed glycerides of Cremercoor MCT/Capmul MCM (group a). In vitro dispersion and digestion studies confirmed that SNEDDS of group b (polar mixed glycerides) can retain high amount of drug (99% drug in solution for more than 24 h time) in dispersion media and have high recovery after digestion. The results from the permeability assessment confirmed that fenofibrate had 4.3-fold increase with F3b SNEDDS compared with the control.Conclusion: SNEDDS formulations containing alternative excipients (Kollisolv MCT/Imwitor 742 blend) could be a potential oral pharmaceutical product in taking anti-hyperlipidaemic agent fenofibrate to the systemic circulation as solubilized form

Evaluation of Self-Nanoemulsifying Drug Delivery Systems (SNEDDS) for Poorly Water-Soluble Talinolol: Preparation, in vitro and in vivo Assessment

ObjectiveThe aim of this study was to investigate the in vitro and in vivo performance of self-nanoemulsifying drug delivery systems (SNEDDSs) of talinolol (TAL), a poorly water-soluble drug.MethodsSelf-nanoemulsifying drug delivery systems of TAL were prepared using various oils, non-ionic surfactants and/or water-soluble co-solvents and assessed visually/by droplet size measurement. Equilibrium solubility of TAL in the anhydrous and diluted SNEDDS was conducted to achieve the maximum drug loading. The in vitro dissolution experiments and human red blood cells (RBCs) toxicity test, ex vivo gut permeation studies, and bioavailability of SNEDDS in rats were studied to compare the representative formulations with marketed product Cordanum® 50 mg and raw drug.ResultsThe results from the characterization and solubility studies showed that SNEDDS formulations were stable with lower droplet sizes and higher TAL solubility. From the dissolution studies, it was found that the developed SNEDDS provided significantly higher rate of TAL release (>97% in 2.0 h) compared to raw TAL and marketed product Cordanum®. The RBC lysis test suggested negligible toxicity of the formulation to the cells. The ex vivo permeability assessment and in vivo pharmacokinetics study of a selected SNEDDS formulation (F6) showed about four-fold increase in permeability and 1.58-fold enhanced oral bioavailability of TAL in comparison to pure drug, respectively.ConclusionTalinolol loaded SNEDDS formulations could be a potential oral pharmaceutical product with high drug-loading capacity, improved drug dissolution, increased gut permeation, reduced/no human RBC toxicity, and enhanced oral bioavailability

The aesthetics and politics of ‘reading together’ Moroccan novels in Arabic and French

This paper attempts to break down the common practices of reading multilingual Moroccan novels, particularly Moroccan postcolonial novels in Arabic and French. I argue that dominant reading practices are based on binary oppositions marked by a reductionist understanding of language and cultural politics in Morocco. They place the Moroccan novel in Arabic and French in independent traditions with the presupposition that they have no impact on each other, thereby reifying each tradition. They also ignore the similar historical, social and cultural context from which these novels emerge, and tend to reinforce the marginalisation of the Moroccan novel within hegemonic single-language literary systems such as the Francophone or Arabic literary traditions. I advocate ‘reading together’ – or an entangled comparative reading of – postcolonial Moroccan novels in Arabic and French, a reading that privileges the specificity of the literary traditions in Morocco rather than language categorisation, and that considers their mutual historical, cultural, geographical, political, and aesthetic interweaving and implications

Is quadratus lumborum block combined with low dose-spinal anesthesia an effective alternative to general anesthesia in patients undergoing percutaneous nephrolithotomy?

Background: General anesthesia in high-risk patients has many complications and needs long preoperative preparations and postoperative intensive care unit (ICU). Therefore the present study aimed to evaluate the efficacy of combined low-dose spinal anesthesia with quadratus lumborum block (QLB) as an alternative to general anesthesia for patients undergoing percutaneous nephrolithotomy. Patients and methods: A prospective study was conducted at the urology department of Al-Azhar University Hospitals in Cairo, Egypt, from January 2021 to January 2022. The study included 60 patients of ASA ll-lll scheduled for percutaneous nephrolithotomy. All patients received low-dose spinal anesthesia (5 mg bupivacaine) and QLB (QL1-QL2-QL3) approaches. The primary observation parameter was the efficacy of this technique as an alternative to general anesthesia. The secondary parameters measured were evaluation of need for intraoperative narcotics, postoperative pain score (VAS), and patients satisfaction as assessed using a 5-point Likert Scale. Results: None of the patients was given general anesthesia, and intraoperative sedation was given to nineteen patients (32.2%). No hemodynamic changes were observed in all patients. There was a significant correlation between the use of intraoperative sedation and stone site, intraoperative blood loss, and hospital stay. Pain intensity on VAS at rest and movement was low until the 24th postoperative hour. Patient satisfaction score was 3, 4, and 5 in 1 (1.7%), 4 (6.7%), and 55 (91.6%) patients, respectively. Conclusions: Combined low-dose spinal anesthesia with quadratus lumborum block is an effective alternative to general anesthesia in patients undergoing PCNL procedures with good postoperative analgesia. Patients with lower calyceal punctures have a lower incidence of intraoperative sedation requirements

A meta-review of meta-analyses and an updated meta-analysis on the efficacy of chloroquine and hydroxychloroquine in treating COVID19 infection

Objective: To synthesize the findings presented in systematic reviews and meta-analyses as well as to update the evidence using a meta-analysis in evaluating the efficacy and safety of CQ and HCQ with or without Azithromycin for the treatment of COVID19 infection.Methods: The design of this meta-review followed the Preferred Reporting Items for Overviews of Systematic Reviews including harms checklist (PRIO-harms). A comprehensive search included several electronic databases in identifying all systematic reviews and metaanalyses as well as experimental studies which investigated the efficacy and safety of CQ, HCQ with or without antibiotics as COVID19 treatment. Findings from the systematic reviews and meta-analyses were reported using a structured summary including tables and forest plots. The updated meta-analysis of experimental studies was carried out using the distributional assumption-free quality effects model. Risk of bias was assessed using the Assessing the Methodological Quality of Systematic Reviews (AMSTAR) tool for reviews and the MethodologicAl STandard for Epidemiological Research (MASTER) scale for the experimental studies. The main outcome for both the meta-review and the updated meta-analysis was mortality. Secondary outcomes included transfer to the intensive care unit (ICU) or mechanical ventilation, worsening of illness, viral clearance and the occurrence of adverse events. Results: A total of 13 reviews with 40 primary studies comprising 113,000 participants were included. Most of the primary studies were observational (n=27) and the rest were experimental studies. Two meta-analyses reported a high risk of mortality with similar ORs of 2.5 for HCQ with Azithromycin. However, four other meta-analyses reported contradictory results with two reporting a high risk of mortality and the other two reporting no significant association between HCQ with mortality. Most reviews reported that HCQ with or without Azithromycin had no significant effect on virological cure, disease exacerbation or the risk of transfer to the ICU, need for intubation or mechanical ventilation. After exclusion of studies that did not meet the eligibility criteria, the updated meta-analysis contained eight experimental studies (7 RCTs and 1 quasiexperimental trial), with a total of 5279 participants of whom 1856 were on either CQ/HCQ or combined with Azithromycin. CQ/HCQ with or without Azithromycin was significantly associated with a higher risk of adverse events. HCQ was not effective in reducing mortality transfer to the ICU, intubation or need for mechanical ventilation virological cure (RR 1.0, 95%CI 0.9-1.2, I2 =55%, n=5 studies) nor disease exacerbation (RR 1.2, 95%CI 0.3-5.0, I2 =29%, n=3 studies). Conclusion: There is conclusive evidence that CQ and HCQ, with or without Azithromycin are not effective in treating COVID-19 or its exacerbation

National survey of variations in practice in the prevention of surgical site infections in adult cardiac surgery, United Kingdom and Republic of Ireland

Background: Currently no national standards exist for the prevention of surgical site infection (SSI) in cardiac surgery. SSI rates range from 1% to 8% between centres. Aim: The aim of this study was to explore and characterize variation in approaches to SSI prevention in the UK and the Republic of Ireland (ROI). Methods: Cardiac surgery centres were surveyed using electronic web-based questionnaires to identify variation in SSI prevention at the level of both institution and consultant teams. Surveys were developed and undertaken through collaboration between the Cardiothoracic Interdisciplinary Research Network (CIRN), Public Health England (PHE) and the National Cardiac Benchmarking Collaborative (NCBC) to encompass routine pre-, intra- and postoperative practice. Findings: Nineteen of 38 centres who were approached provided data and included responses from 139 consultant teams. There was no missing data from those centres that responded. The results demonstrated substantial variation in over 40 aspects of SSI prevention. These included variation in SSI surveillance, reporting of SSI infection rates to external bodies, utilization of SSI risk prediction tools, and the use of interventions such as sternal support devices and gentamicin impregnated sponges. Conclusion: Measured variation in SSI prevention in cardiac centres across the UK and ROI is evidence of clinical uncertainty as to best practice, and has identified areas for quality improvement as well as knowledge gaps to be addressed by future research