Work stress, work-family conflict, and psychological distress among resort employees: a JD-R model and spillover theory perspectives.

The hospitality industry is well-known for its challenging and high-pressure work settings. In this context, employees commonly face a multitude of stressors originating from their roles and job responsibilities, which can significantly impact their psychological wellbeing. Hence, based on the job demands-resources (JD-R) model and the spillover theory, this study aims to empirically explore the direct and indirect effect of work stress (assessed by role overload, ambiguity, and conflict) on psychological distress among frontline employees in 3- and 4-star Egyptian resorts while considering the mediating influence of work-family conflict (WFC). Four hypotheses were put to the test through the application of the PLS-SEM 4.0 version (4.0.9.9). Based on the findings from 563 frontline employees who participated in this research, the study supports the four hypotheses affirming that work-related stressors significantly contributed to employees' psychological distress. Further, the findings highlighted that these stressors significantly spill over into employees' family lives, generating conflicts between work and family roles. In addition, the results emphasized the significance of WFC as a contributing factor to employees' psychological distress. Finally, the study concluded that WFC partially mediates the link between work stress and employees' psychological distress. Based on these findings, some theoretical and practical implications for hospitality scholars, resort management, and policymakers were suggested to enhance the employees' wellbeing and mitigate psychological distress in this vital sector.

Self-Assembling Lecithin-Based Mixed Polymeric Micelles for Nose to Brain Delivery of Clozapine: In-vivo Assessment of Drug Efficacy via Radiobiological Evaluation.

Purpose: The research objective is to design intranasal brain targeted CLZ loaded lecithin based polymeric micelles (CLZ- LbPM) aiming to improve central systemic CLZ bioavailability. Methods: In our study, intranasal CLZ loaded lecithin based polymeric micelles (CLZ- LbPM) were formulated using soya phosphatidyl choline (SPC) and sodium deoxycholate (SDC) with different CLZ:SPC:SDC ratios via thin film hydration technique aiming to enhance drug solubility, bioavailability and nose to brain targeting efficiency. Optimization of the prepared CLZ-LbPM using Design-Expert® software was achieved showing that M6 which composed of (CLZ:SPC: SDC) in respective ratios of 1:3:10 was selected as the optimized formula. The optimized formula was subjected to further evaluation tests as, Differential Scanning Calorimetry (DSC), TEM, in vitro release profile, ex vivo intranasal permeation and in vivo biodistribution. Results: The optimized formula with the highest desirability exhibiting (0.845), small particle size (12.23±4.76 nm), Zeta potential of (-38 mV), percent entrapment efficiency of > 90% and percent drug loading of 6.47%. Ex vivo permeation test showed flux value of 27 µg/cm².h and the enhancement ratio was about 3 when compared to the drug suspension, without any histological alteration. The radioiodinated clozapine ([131I] iodo-CLZ) and radioiodinated optimized formula ([131I] iodo-CLZ-LbPM) were formulated in an excellent radioiodination yield more than 95%. In vivo biodistribution studies of [131I] iodo-CLZ-LbPM showed higher brain uptake (7.8%± 0.1%ID/g) for intranasal administration with rapid onset of action (at 0.25 h) than the intravenous formula. Its pharmacokinetic behavior showed relative bioavailability, direct transport percentage from nose to brain and drug targeting efficiency of 170.59%, 83.42% and 117% respectively. Conclusion: The intranasal self-assembling lecithin based mixed polymeric micelles could be an encouraging way for CLZ brain targeting.

Chitosan Surface-Modified PLGA Nanoparticles Loaded with Cranberry Powder Extract as a Potential Oral Delivery Platform for Targeting Colon Cancer Cells.

Nutraceutical cranberry powder extract (CBPE) has distinct polyphenols inhibiting colon cancer growth and proliferation. However, its oral therapeutic efficacy is hindered because of its low permeability. This study aims to formulate chitosan surface-modified PLGA nanoparticles (CS-PLGA NPs) for encapsulating CBPE and modulating its release rate, permeation, cell targeting, and, therefore, its cytotoxicity. A full 23 factorial design is employed to scrutinize the effect of lactide/glycolide ratio, PLGA weight, and stabilizer concentrations on entrapment efficiency percentage (EE%), particle size (PS), polydispersity index (PDI), and zeta potential (ZP). The optimum formula (F4) shows spherical particles with a relatively high EE% (72.30 ± 2.86%), an appropriate size of 370.10 ± 10.31 nm, PDI; 0.398 ± 0.001, and ZP; -5.40 ± 0.21 mV. Alongside the ATR-FTIR outcomes, the chitosan surface-modified formula (CS-F4) demonstrates a significant increase in particle size (417.67 ± 6.77 nm) and a shift from negative to positive zeta potential (+21.63 ± 2.46 mV), confirming the efficiency of surface modification with chitosan. The intestinal permeability of F4 and CS-F4 is significantly increased by 2.19- and 3.10-fold, respectively, compared to the CBPE solution, with the permeability coefficient (Papp) being 2.05 × 10-4 cm/min and 2.91 × 10-4 cm/min, for F4 and CS-F4, respectively, compared to the CBPE solution, 9.36 × 10-5 cm/min. Moreover, CS-F4 evidences significant caspase-3 protein level expression stimulation and significant inhibition of vascular endothelial growth factor (VEGF) and signal transducer and activator of transcription-3 (STAT-3) protein expression levels, confirming the superiority of CS-F4 for targeting HT-29 cells. Briefly, CS-PLGA NPs could be regarded as a prosperous delivery system of CBPE with enhanced permeation, cell targeting, and antitumor efficacy.

Ocular Drug Delivery: a Comprehensive Review.

The human eye is a sophisticated organ with distinctive anatomy and physiology that hinders the passage of drugs into targeted ophthalmic sites. Effective topical administration is an interest of scientists for many decades. Their difficult mission is to prolong drug residence time and guarantee an appropriate ocular permeation. Several ocular obstacles oppose effective drug delivery such as precorneal, corneal, and blood-corneal barriers. Routes for ocular delivery include topical, intravitreal, intraocular, juxtascleral, subconjunctival, intracameral, and retrobulbar. More than 95% of marketed products exists in liquid state. However, other products could be in semi-solid (ointments and gels), solid state (powder, insert and lens), or mixed (in situ gel). Nowadays, attractiveness to nanotechnology-based carries is resulted from their capabilities to entrap both hydrophilic and lipophilic drugs, enhance ocular permeability, sustain residence time, improve drug stability, and augment bioavailability. Different in vitro, ex vivo, and in vivo characterization approaches help to predict the outcomes of the constructed nanocarriers. This review aims to clarify anatomy of the eye, various ocular diseases, and obstacles to ocular delivery. Moreover, it studies the advantages and drawbacks of different ocular routes of administration and dosage forms. This review also discusses different nanostructured platforms and their characterization approaches. Strategies to enhance ocular bioavailability are also explained. Finally, recent advances in ocular delivery are described.

A comprehensive review on recent nanosystems for enhancing antifungal activity of fenticonazole nitrate from different routes of administration.

This review aims to comprehensively highlight the recent nanosystems enclosing Fenticonazole nitrate (FTN) and to compare between them regarding preparation techniques, studied factors and responses. Moreover, the optimum formulae were compared in terms of in vitro, ex vivo and in vivo studies in order to detect the best formula. FTN is a potent antifungal imidazole compound that had been used for treatment of many dangerous fungal infections affecting eye, skin or vagina. FTN had been incorporated in various innovative nanosystems in the recent years in order to achieve significant recovery such as olaminosomes, novasomes, cerosomes, terpesomes and trans-novasomes. These nanosystems were formulated by various techniques (ethanol injection or thin film hydration) utilizing different statistical designs (Box-Behnken, central composite, full factorial and D-optimal). Different factors were studied in each nanosystem regarding its composition as surfactant concentrations, surfactant type, amount of oleic acid, cholesterol, oleylamine, ceramide, sodium deoxycholate, terpene concentration and ethanol concentration. Numerous responses were studied such as percent entrapment efficiency (EE%), particle size (PS), poly-dispersity index (PDI), zeta potential (ZP), and in vitro drug release. Selection of the optimum formula was based on numerical optimization accomplished by Design-Expert® software taking in consideration the largest EE %, ZP (as absolute value) and in vitro drug release and lowest PS and PDI. In vitro comparisons were done employing different techniques such as Transmission electron microscopy, pH determination, effect of gamma sterilization, elasticity evaluation and docking study. In addition to, ex vivo permeation, in vivo irritancy test, histopathological, antifungal activity and Kinetic study.

Pronounced capping effect of olaminosomes as nanostructured platforms in ocular candidiasis management.

The aim of this study was to formulate and boost ocular targeting of Fenticonazole Nitrate (FTN)-loaded olaminosomes in order to improve drug corneal permeation and candidiasis treatment. Olaminosomes were formulated by ethanol injection technique applying a central composite design. The independent variables were: span 80 amount (mg) (A), oleylamine concentration (mg%) (B) and oleic acid: drug ratio (C). The dependent responses were: percent entrapment efficiency (EE %), particle size (PS), poly-dispersity index (PDI), zeta potential (ZP) and in vitro drug release after 10 hours (Q10h). Numerical optimization by Design-Expert® software was adopted to select the optimum formula. This formula was chosen based on highest EE %, ZP (as absolute value) and Q10h and lowest PS and PDI. The optimum formula was subjected to further in vitro characterization via Differential scanning calorimetry, Transmission electron microscopy, Fourier transform infrared spectroscopy, pH determination, effect of storage, influence of terminal sterilization, detection of Minimal Inhibitory Concentration and ex vivo corneal penetration analysis. Safety and antifungal activity of the optimum formula were tested through various in vivo studies like ocular irritancy, corneal tolerance, corneal uptake and susceptibility test. The optimum formula with the maximum desirability value (0.972) revealed EE% (84.24%), PS (117.55 nm), ZP (-74.85 mV) and Q10h (91.26%) respectively. The optimum formula demonstrated ocular tolerance with enhanced corneal penetration behavior (428.66 µg/cm2) and boosted antifungal activity (56.13%) compared to FTN suspension (174.66 µg/cm2 and 30.83%). The previous results ensured the ability of olaminosomes to enhance the corneal penetration and antifungal efficacy of Fenticonazole Nitrate.

Corneal targeted fenticonazole nitrate-loaded novasomes for the management of ocular candidiasis: Preparation, in vitro characterization, ex vivo and in vivo assessments.

The purpose of this manuscript was to develop and optimize Fenticonazole Nitrate (FTN)-loaded novasomes aiming to enhance drug corneal penetration and to improve its antifungal activity. Ethanol injection was used to formulate FTN-loaded novasomes adopting a central composite design. The researched factors were: stearic acid concentration (g%) (A), span 80: drug ratio (B) and cholesterol amount (mg) (C), and their effects on percent entrapment efficiency (EE%), particle size (PS), poly-dispersity index (PDI), zeta potential (ZP), and in vitro drug release after 8 hours (Q8h) were studied. Numerical optimization by Design-Expert® software was employed to select the optimum formula in respect to highest EE%, ZP (as absolute value), and Q8h >80% and lowest PS and PDI. Additional evaluation of the optimum formula was accomplished by short term stability study, effect of gamma sterilization, determination of Minimal Inhibitory Concentration and ex vivo corneal permeation study. The in vivo evaluation of the optimum formula was done to ensure its safety via in vivo ocular irritancy and in vivo corneal tolerance studies. Also, the efficacy was confirmed through in vivo corneal uptake study and susceptibility test. The optimum formula with the highest desirability value (0.738) showed EE% (94.31%), PS (197.05 nm), ZP (-66.95 mV) and Q8h (85.33%). It revealed to be safe, with augmented corneal permeation (527.98 µg/cm2) that leads to higher antifungal activity. The above results confirmed the validity of novasomes to improve the corneal permeation and antifungal activity of Fenticonazole Nitrate.

Protective effect of rutin and ß-cyclodextrin against hepatotoxicity and nephrotoxicity induced by lambda-cyhalothrin in Wistar rats: biochemical, pathological indices and molecular analysis.

BACKGROUND: This study aimed to assess hepatotoxicity and nephrotoxicity of Lambda-cyhalothrin (LCT) and the protective effect of rutin alone and in combination with ß-cyclodextrin (ß-CD). MATERIALS AND METHODS: Male Wistar rats were divided into five groups: Group 1: was used as a control and received a standard diet and water. Group 2, 3, 4 and 5 were orally administered with LCT (7.6 mg/kg body weight), rutin (200 mg/kg body weight) LCT and rutin (at the same doses as in Group 2 and Group 3), and LCT and a mixture of rutin with ß-CD (400 mg/kg body weight), respectively. All experimental animals were orally gavaged 5 days/week for 60 days. RESULTS: Our data revealed that LCT-induced liver and kidney injuries were related to the up-regulated expression of TNF-α and down-regulated expression of NRF-2 genes mRNA, whereas these effects were reversed with rutin treatment. LCT-induced oxidative stress altered the histological picture, and the hematological and biochemical parameters. CONCLUSION: Treatment with a rutin-ß-CD complex had preventive potential against LCT via suppression of oxidative stress and augmentation of the antioxidant defense system.

"TPGS surface modified bilosomes as boosting cytotoxic oral delivery systems of curcumin against doxorubicin resistant MCF-7 breast cancer cells".

The goal of this work was to design nude bilosomes (Bil) and D-alpha-tocopheryl polyethylene glycol succinate (TPGS) surface coated bilosomes as an oral delivery platform for improving the antitumor activity and poor oral permeability of Curcumin (CUR). Twelve different formulae were acquired from 31.22 factorial analysis considering different independent variables: bile salt type; Sodium taurocholate (STC) or Sodium cholate (SC) and weight percent; 1% or 5 % W/W, both at 2 levels respectively, while Span 60:Cholesterol ratio at 3 levels (1:1, 5:1, 9:1). Following optimization, the selected optimum formula was picked up based on the favorable minimum particle size (187.2 ± 2.2 nm), maximum zeta potential value (-41.3 ± 2.2 mV) and maximum entrapment efficiency (93.4 ± 5.1%) which was further coated with TPGS. The mean fluorescence intensity (MFI) of CUR permeated from the optimum TPGS-F7 and CUR-Bil (F7) formulae exhibited 6.6 and 3.4 folds increase respectively adopting ex-vivo duodenal permeation assay relative to that of CUR suspension. Moreover, the cellular uptake efficiency via the established Caco-2 cells revealed that the uptake of CUR was 61.9 ± 5.3% and 34.76 ± 0.61% from TPGS-F7 and CUR-Bil (F7) relative to the uptake efficiency of CUR suspension (7.4 ± 2.12%). Coherently, TPGS-CUR-Bil showed excellent response expressed in dominant reduction in IC50 value (2.8 ± 0.07 µg/ml) against multidrug resistant (MDR) tumors following 48 h incubation of Doxorubicin Resistant Breast Cancer (MCF-7/ADR) cell lines.

Predictors and effectiveness of different biopsy techniques in spotting invasion in the clinically diagnosed breast ductal carcinoma in situ / Factores predictivos y efectividad de diferentes técnicas de biopsia en la detección de focos infiltrantes en carcinomas in situ diagnosticados clínicamente

Objectives: To study the management of patients with ductal carcinoma in situ (DCIS) and detect the predictors of recurrence and of missing an invasive component in the preoperative biopsy, aiming at guiding tailored treatment of these cases.Materials and methods: A total of 123 cases of DCIS, pure/with invasion, were retrieved from the database of a tertiary cancer hospital in the period from February 2007 to February 2018. Clinical, radiologic & pathologic characteristics and its impact on the surgical management were analyzed.Results: The mean age of the patients was 50.5±12.4 years. The commonest presentation was a palpable mass in 82.9% of the cases. Conservative breast surgery was successfully performed in 15 cases and mastectomy in 108 cases. Recurrence was reported in 11 cases. The underestimation rate in core needle biopsy was 48.9% missing invasive component within diagnosed malignant lesions and 19.6% missing the diagnosis of malignancy. On the other hand, overtreatment was noted as regard surgical procedure and adjuvant therapies.Conclusions: Mastectomy still the most common surgical treatment of DCIS and unfortunately sentinel lymph node biopsy is still underused. Underestimation of invasive component can occur in at least 1/4 of the patients, complexing the treatment plan. Overtreatment with axillary surgery, chemotherapy or radiotherapy needs governance. (AU)

Objetivos: Estudiar el manejo de pacientes con carcinoma ductal in situ (CDIS) y detectar los predictores de recaída y de ausencia de un componente invasivo en la biopsia preoperatoria, con el objetivo de orientar el tratamiento a medida de estos casos.Materiales y métodos: Se recuperó un total de 123 casos de CDIS, puro/con invasión de la base de datos de un hospital de cáncer terciario en el período de febrero de 2007 a febrero de 2018. Se analizaron las características clínicas, radiológicas y patológicas, así como su impacto en el manejo quirúrgico.Resultados: La edad media fue de 50,5 ± 12,4 años. La presentación más común fue masa palpable en el 82,9% de los casos. Se realizó cirugía de mama conservadora con éxito en 15 casos y mastectomía en 108 casos. Se informó de recaída en 11 casos. La tasa de subestimación en la biopsia con aguja fue de 48,9% sin componente invasivo en lesiones malignas diagnosticadas y 19,6% sin diagnóstico de malignidad. Por otra parte, se observó un exceso de tratamiento con relación al procedimiento quirúrgico y las terapias adyuvantes.Conclusiones: La mastectomía sigue siendo el tratamiento quirúrgico más común del CDIS y desafortunadamente no se utiliza aún la biopsia de ganglio linfático centinela. La subestimación del componente invasivo puede ocurrir en al menos el 25% de los pacientes, complejizando el plan de tratamiento. Debe gestionarse el sobretratamiento con cirugía axilar, quimioterapia o radioterapia. (AU)

Digenic inheritance of IL-36RA and SEC61A1 mutations underlies generalized pustular psoriasis with hypogammaglobulinemia.

We report a female patient presenting with generalized pustular psoriasis and hypogammaglobulinemia due to digenic mutations in IL-36RA and SEC61A1. The patient presented with recurrent fevers, elevated inflammatory markers, hepatosplenomegaly, and recurrent sinopulmonary infections in the context of hypogammaglobulinemia which improved on immunoglobulin replacement. This report demonstrates how digenic inheritance leads to complex phenotypes, and illustrates the importance of following an unbiased approach to identifying variants, especially in patients with atypical clinical presentations.

Thymol ameliorates 5-fluorouracil-induced intestinal mucositis: Evidence of down-regulatory effect on TGF-ß/MAPK pathways through NF-κB.

5-Fluorouracil (5-FU) is a front-line cytotoxic therapy. However, intestinal mucositis is a well-known adverse event of 5-FU, which limits its therapeutic use. Indeed, thymol, which is a monoterpene component of the essential oil derived from thymus, has a potential anti-inflammatory and immunomodulatory activity. Therefore, this study aimed to investigate the potential chemoprotective effect of thymol against 5-FU-induced intestinal mucositis. Rats were either exposed to two doses of 5-FU (150 mg/kg, ip) and/or treated with thymol (60 or 120 mg/kg). Oxidative stress and inflammatory markers, as well as pathological changes, were assessed. 5-FU-induced severe intestinal damages as were evidenced by histopathological changes as well as oxidative and inflammatory responses. Thymol pretreatment inhibited 5-FU-induced oxidative stress by reducing lipid peroxidation and increasing intestinal levels of antioxidant systems. Moreover, inflammatory response markers, such as interleukin-6, prostaglandin E2, and COX-2 were also improved. The immunoblotting analysis also showed that thymol significantly inhibited the 5-FU-induced expression of nuclear factor-κB, tumor necrosis factor-α, and transforming growth factor ß-1 (TGF-ß1), in addition to the suppression of p38 and phosphorylated c-Jun N-terminal kinases (p-JNK) mitogen-activated protein kinase proteins' expressions. Our study is the first to demonstrate the promising protective effect of thymol against 5-FU-induced intestinal mucositis through inhibition of oxidative, inflammatory pathways, and suppression of TGF-ß/p38/p-JNK signaling.

Brain targeting efficiency of intranasal clozapine-loaded mixed micelles following radio labeling with Technetium-99m.

The research objective is to design intranasal (IN) brain targeted CLZ-loaded polymeric nanomicellar systems (PNMS) aiming to improve central systemic CLZ bioavailability. Direct equilibrium method was used to prepare CLZ-PNMS using two hydrophobic poloxamines; Tetronic® 904 (T904) and Tetronic® 701 (T701) and one hydrophilic poloxamer; Synperonic® PE/F127 (F127). Optimization is based on higher percent transmittance, solubilizing efficiency, and in vitro release after 24 h with smaller particle size was achieved using Design-Expert® software. The optimized formula was further evaluated via TEM, ex vivo nasal permeation in addition to in vivo biodistribution using radiolabeling technique of the optimized formula by Technetium-99m (99mTc). The optimized formula M5 has small size (217 nm) with relative high percentage of transmittance (97.72%) and high solubilization efficacy of 60.15-fold following 92.79% of CLZ released after 24 h. Ex vivo nasal permeation showed higher flux of 36.62 µg/cm2.h compared to 7.324 µg/cm2.h for CLZ suspension with no histological irritation. In vivo biodistribution results showed higher values of radioactivity percentage of the labeled optimized formula (99mTc-M5) in brain and brain/blood ratio following IN administration of 99mTc-M5 complex which were greater than their corresponding values following intravenous route. It is obvious that nasal delivery of CLZ-PNMS could be a promising way to improve central systemic CLZ bioavailability.

Therapeutic effect of mesenchymal stem cells on histopathological, immunohistochemical, and molecular analysis in second-grade burn model.

BACKGROUND AND AIM: Deleterious cutaneous tissue damages could result from exposure to thermal trauma, which could be ameliorated structurally and functionally through therapy via the most multipotent progenitor bone marrow mesenchymal stem cells (BM-MSCs). This study aimed to induce burns and examine the effect of BM-MSCs during a short and long period of therapy. MATERIAL AND METHODS: Ninety albino rats were divided into three groups: group I (control); group II (burn model), the animals were exposed to the preheated aluminum bar at 100°C for 15 s; and group III (the burned animals subcutaneously injected with BM-MSCs (2×106 cells/ ml)); they were clinically observed and sacrificed at different short and long time intervals, and skin samples were collected for histopathological and immunohistochemical examination and analysis of different wound healing mediators via quantitative polymerase chain reaction (qPCR). RESULTS: Subcutaneous injection of BM-MSCs resulted in the decrease of the wound contraction rate; the wound having a pinpoint appearance and regular arrangement of the epidermal layer with thin stratum corneum; decrease in the area percentages of ADAMs10 expression; significant downregulation of transforming growth factor-ß (TGF-ß), interleukin-6 (IL-6), tumor necrotic factor-α (TNF-α), metalloproteinase-9 (MMP-9), and microRNA-21; and marked upregulation of heat shock protein-90α (HSP-90α) especially in late stages. CONCLUSION: BM-MSCs exhibited a powerful healing property through regulating the mediators of wound healing and restoring the normal skin structures, reducing the scar formation and the wound size.

Trimetazidine Dihydrochloride Pulsatile-Release Tablets for the Treatment of Morning Anginal Symptoms: Dual Optimization, Characterization and Pharmacokinetic Evaluation.

OBJECTIVE: This research work aimed to target the early morning peak symptoms of chronic stable angina through formulating antianginal drug, Trimetazidine (TMZ) in a pulsatile-release tablet. METHODS: The core formulae were optimized using 22 .31 factorial design to minimize disintegration time (DT) and maximize drug release after 5 minutes (Q5min). Different ratios of Eudragit S100 and Eudragit L100 were used as a coating mixture for the selected core with or without a second coating layer of hydroxypropyl methylcellulose (HPMC E50). The different formulation variables were statistically optimized for their effect on lag time and drug release after 7 hours (Q7h) using BoxBehnken design. The optimized formula (PO) was subjected to stability study and pharmacokinetic assessment on New Zealand rabbits. RESULTS: The optimal core (F8) was found to have 1.76 min disintegration time and 61.45% Q5min PO showed a lag time of 6.17 h with 94.80% Q7h and retained good stability over three months. The pharmacokinetics study confirmed the pulsatile-release pattern with Cmax of 206.19 ng/ml at 5.33 h (Tmax) and 95.85% relative bioavailability compared to TMZ solution. CONCLUSION: Overall pulsatile-release tablets of TMZ successfully released the drug after a desirable lag time, providing a promising approach for early morning anginal symptoms relief.

Cubogel as potential platform for glaucoma management.

The aim of this work is to survey the potential of cubogel as an ocular dosage form to boost the corneal permeability of Dorzolamide Hydrochloride DZ; an antiglaucomal drug. DZ-loaded cubosomal dispersions were prepared according to Box-Behnken design, where the effect of independent variables; Monoolein MO concentration (2.5, 5 and 7.5%w/w), Pluronic® F127 concentration (0.25, 0.5 and 0.75%w/w) and magnetic stirrer speed of (400, 800 and 1200 rpm) was studied on PS (nm), Zp (-mV) and Q 2 h (%) respectively. The prepared formulae were characterized via drug content DC (%), particle size PS (nm), polydispersity index PDI, zeta potential Zp (-mV), in-vitro drug release (Q 2 h%) and finally TEM. The optimized formulation composed of: 6.13% w/w of MO, 0.75% w/w of F127 and prepared at 1200 rpm stirring speed was chosen based on the criteria of minimum PS (nm), maximum Zp (-mV) and minimum Q 2 h (%). Results revealed that the optimum formula showed PS of 153.3 ± 8.4 n, Zp of 32 ± 3 -mV and 37.78 ± 1.3% released after 2 h. Carbopol 934 (1% w/v) as gelling agent was used to prepare the optimum cubogel, which was further evaluated by DSC, ex-vivo permeation and stability studies at 4 °C for three months. Moreover, in vivo studies of the optimized cubogel include; draize test, histological examination, confocal laser scanning microscopy (CLSM) and intraocular pressure (IOP) measurement. Results revealed that the optimized cubogel was considerably safe, stable and competent to corneal delivery as assured by draize and histological examination. CLSM showed a deeper penetration of more than 2.5-fold. A higher bioavailability (288.24 mg. h/ml) was attained from cubogel compared to the market product Trusopt® eye drops (115.40 mg. h/ml) following IOP measurement. Therefore, DZ-loaded cubogel could be considered as promising delivery system to boost the transcorneal permeation hence corneal bioavailability of DZ as antiglaucomal drug.

Comparative study between human mesenchymal stem cells and etanercept as immunomodulatory agents in rat model of rheumatoid arthritis.

To compare human adipose tissue mesenchymal stem cells (AT-MSCs) and etanercept as immunomodulatory agents for collagen-induced arthritis (CIA). CIA was induced by rats' immunization with collagen type II (CII) in complete Freund's adjuvant in days 0 and 7. Before the onset of CIA, prevention group received five doses of AT-MSCS intraperitoneally. After establishment of arthritis, rats received either five doses of AT-MSCs or phosphate-buffered saline (PBS) intraperitoneally or six doses of etanercept subcutaneously. Clinical and histopathological evaluation were performed in all groups; serum levels of tumor necrosis factor-α (TNF-α), interleukin-10 (IL-10), and anti-collagen II were assessed by enzyme-linked immunosorbent assay (ELISA). A total percent of autoreactive T and regulatory T (Treg) cells were quantified using spleen immune histochemical analysis. AT-MSCs were able to delay the onset of CIA, suppress the ongoing clinical and histopathological signs, decrease serum levels of TNF-α and anti-collagen type II, and downregulate the autoreactive T cells as etanercept. AT-MSCs were more potent in Treg cells upregulation, producing high serum levels of IL10. AT-MSCs might have a therapeutic effect in CIA via their potency in immune cell education, representing an effective new promising approach in rheumatoid arthritis in human.

Stabilized oral nanostructured lipid carriers of Adefovir Dipivoxil as a potential liver targeting: Estimation of liver function panel and uptake following intravenous injection of radioiodinated indicator.

PURPOSE: Adefovir dipivoxil (AD), a nucleoside reverse transcriptase inhibitor is effective against Hepatitis B virus. Its poor oral bioavailability leads to frequent administration causing severe adverse effects. Thereby the entrapment of AD within lipid nanoparticulate systems is a way of increasing AD oral bioavailability as a result of improving intestinal permeability with efficient liver-targeted delivery together with higher drug stability during storage. METHODS: AD-loaded nanostructured lipid carriers (AD-NLCs) were prepared via solvent emulsification diffusion technique adopting 24 full factorial design to study the effect of lipid percentage, presence of egg yolk lecithin, surfactant type and percentage on entrapment efficiency (E.E.%), particle size and percent in-vitro drug released after 8 h (Q8hrs). RESULTS: Formula (F12) showed E.E.% of 90.5 ± 0.2%, vesicle size of 240.2 ± 2.5 nm and Q8hrs of 58.55 ± 9.4% was selected as the optimum formula with desirability value of 0.757 based on highest EE%, lowest P.S. and Q8hrs. Further evaluation of the optimized formula using radioiodinated rose bengal (RIRB) in thioacetamide induced liver damage in Swiss Albino mice revealed a higher liver uptake of 22 ± 0.01% ID/g (percent injected dose/g organ) and liver uptake/Blood (T/B) ratio of 2.22 ± 0.067 post 2 h of I.V injection of RIRB compared to 9 ± 0.01% ID/g and 0.64 ± 0.017 in untreated group, respectively. CONCLUSION: NLCs could be successfully used as oral drug delivery carriers of the antiviral drug Adefovir Dipivoxil to the liver with higher stability and oral bioavailability. Graphical abstract.

Biotin, coenzyme Q10, and their combination ameliorate aluminium chloride-induced Alzheimer's disease via attenuating neuroinflammation and improving brain insulin signaling.

Insulin is important for brain function and neuronal survival. Insulin signaling is initiated by the phosphorylation of insulin receptor substrate-1 (IRS-1) at tyrosine (pTyr) residue. However, IRS-1 is inhibited by phosphorylation at serine (pSer). In Alzheimer's disease (AD), oxidative stress and accumulation of amyloid beta (Aß) induce neuroinflammation, which augments pSer-IRS-1 and reduces pTyr-IRS-1 disturbing insulin signaling pathway. Coenzyme Q10 (CoQ10) and biotin possess antioxidant and anti-inflammatory properties, and, in this study, their impact on insulin signaling is investigated in an aluminium chloride (AlCl3 ) model of AD. AD was induced by oral administration of AlCl3 (75 mg/kg) for 60 days. Biotin (2 mg/kg), CoQ10 (10 mg/kg), and their combination were supplemented concomitantly with AlCl3 for 60 days. Memory test and histological examination were performed. Brain levels of lipid peroxides, antioxidants (reduced glutathione and superoxide dismutase), inflammatory markers (tumor necrosis factor-α, interleukin-6 [IL-6], IL-1, and nuclear factor κB), and phosphorylated Akt (survival kinase) as well as protein levels of Aß, IRS-1 (pTyr and pSer), and caspase-3 (apoptotic marker) were determined. AlCl3 resulted in impaired memory, significant increase in Aß, lipid peroxides, inflammatory markers, caspase-3, and pSer-IRS-1, with significant reduction of the antioxidants, pTyr-IRS-1, and p-Akt reflecting Aß-induced inflammation and defective insulin signaling. Histological examination revealed focal aggregations of inflammatory cells and neuronal degeneration. The biochemical deviations and histological changes were attenuated by the concomitant treatment with biotin and, to greater extent, with CoQ10 and the combination. In conclusion, biotin and CoQ10 could protect against AD via attenuating inflammatory response and enhancing insulin signaling.

Effect of Formulation Variables and Gamma Sterilization on Transcorneal Permeation and Stability of Proniosomal Gels as Ocular Platforms for Antiglaucomal Drug.

This study aims to evaluate the effect of different formulation variables (surfactant type and HLB value) adopting full factorial design (51. 21) using coacervation phase technique on in vitro characterization of dorzolamide hydrochloride (DZ)-loaded proniosomal gels, namely, entrapment efficiency percentage (EE%), vesicle size distribution, polydispersion index (PDI), and in vitro DZ release. The optimum formula F2 with a desirability value of 0.937 composed of 40 mg DZ, 500 mg span 60, 500 mg of L-α-Lethicin, and 55.5 mg cholesterol showing EE% of 84.5 ± 1.5%, PS of 189.5 ± 35.76 nm with PDI 0.8 ± 0.28 and 58.51% ± 1.00 of DZ released after 8 h was further evaluated using differential scanning calorimetry (DSC) and transmission electron microscopy (TEM). The effect of gamma sterilization on transcorneal permeation and stability of DZ from the selected formulation (F2) revealed that F2 was significantly tolerable, stable, and competent to corneal permeation confirmed by histological examination, confocal laser microscopy, and intraocular pressure (IOP) measurement. Significant corneal bioavailability was attained from formula F2 (370.6 mg. h/m) compared to the market product Trusopt® eye drops (92.59 mg. h/ml) following IOP measurement, thereby proniosomal gels could be considered as tolerable and competent ocular platforms for improving the transcorneal permeation of DZ.