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Asmaa A Ashour,1 Amal H El-Kamel,1 Doaa A Abdelmonsif,2,3 Hoda M Khalifa,4 Alyaa A Ramadan1 1Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt; 2Department of Medical Biochemistry, Faculty of Medicine, Alexandria University, Alexandria, 21131, Egypt; 3Center of Excellence for Research in Regenerative Medicine and Applications (CERRMA), Faculty of Medicine, Alexandria University, Alexandria, 21131, Egypt; 4Department of Histology, Faculty of Medicine, Alexandria University, Alexandria, 21131, EgyptCorrespondence: Amal H El-KamelDepartment of Pharmaceutics, Faculty of Pharmacy, Alexandria University, 1 Khartoum Square, Azarita, Messalla Post Office PO Box 21521, Alexandria, EgyptTel +20 10-0508-0510Fax +20 3 4873273Email amalelkamel@yahoo.comIntroduction: Liver fibrosis represents a serious global disease with no approved treatment. Tanshinone IIA (TSIIA) is a phytomedicine with documented activity in treating many hepatic disorders. TSIIA has been reported to have potent anti-inflammatory and antioxidant properties. It can also induce apoptosis for activated hepatic stellate cells, and is thereby considered as a promising herbal remedy for treating fibrotic liver. However, its poor aqueous solubility, short half-life, exposure to the first-pass effect, and low concentration reaching targeted cells constitute the major barriers hindering its effective therapeutic potential. Therefore, this work aimed at enhancing TSIIA systemic bioavailability together with achieving active targeting potential to fibrotic liver via its incorporation into novel modified lipid nanocapsules (LNCs).Methods: Blank and TSIIA-loaded LNCs modified with either hyaluronate sodium or phosphatidyl serine were successfully prepared, optimized, and characterized both in vitro and in vivo.Results: The developed LNCs showed good colloidal properties (size ≤ 100 nm and PDI ≤ 0.2), high drug-entrapment efficiency (> 97%) with sustained-release profile for 24 hours, high storage stability up to 6 months, and good in vitro serum stability. After a single intraperitoneal injection, the administered LNCs exhibited a 2.4-fold significant increase in AUC0–∞ compared with the TSIIA suspension (p≤ 0.01). Biodistribution-study results proved the liver-targeting ability of the prepared modified LNCs, with a significant ∼ 1.5-fold increase in hepatic accumulation compared with the unmodified formulation (p≤ 0.05). Moreover, the modified formulations had an improved antifibrotic effect compared with both unmodified LNCs and TSIIA suspension, as evidenced by the results of biochemical and histopathological evaluation.Conclusion: The modified TSIIA-LNCs could be regarded as promising novel targeted nanomedicines for effective management of liver fibrosis.Keywords: phytomedicine, hyaluronic acid, phosphatidyl serine, antifibrotic activity

Mohyeldin SM, Samy WM, Ragab D, Abdelmonsif DA, Aly RG, Elgindy NA. Int J Nanomed. 2021;16:2013–2044 The authors have advised that Figure 10A on page 2041 is incorrect owing to an inadvertent error during the preparation of representative images for Figure 10. The corrected version of Figure 10 is shown below. Figure 10 Photomicrograph of representative tissues within normal histologic limits of the brain (A,F and K), intestinal mucosa (B,G and L), gastric mucosa (C,H and M), kidney (D,I and N) and liver (E,J and O) in the negative control, blank, and SUL-LPS, respectively, ×200, H&E.Abbreviations: H&E, hematoxylin and eosin; SUL-LPS, sulpiride-loaded lipospheres. The authors sincerely apologize for this error and affirm that it does not affect the data interpretation and the conclusion of the study.

Hala M Helal,1 Wael M Samy,1 Elbadawy A Kamoun,2,3 Esmail M El-Fakharany,4 Doaa A Abdelmonsif,5,6 Rania G Aly,7 Sana M Mortada,1 Marwa A Sallam1 1Department of Industrial Pharmacy, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt; 2Polymeric Materials Research Dep., Advanced Technology and New Materials Research Institute (ATNMRI), City of Scientific Research and Technological Applications (SRTA-City), New Borg Al-Arab City, Alexandria, 21934, Egypt; 3Nanotechnology Research Center (NTRC), The British University in Egypt (BUE), El- Sherouk City, Cairo, 11837, Egypt; 4Proteins Research Dep., Genetic Engineering and Biotechnology Research Institute (GEBRI), City of Scientific Research and Technological Applications (SRTA-City), New Borg Al-Arab City, Alexandria, 21934, Egypt; 5Department of Medical Biochemistry, Faculty of Medicine, Alexandria University, Alexandria, 21521, Egypt; 6Center of Excellence for Research in Regenerative Medicine and Applications (CERRMA), Faculty of Medicine, Alexandria University, Alexandria, 21521, Egypt; 7Department of Surgical Pathology, Faculty of Medicine, Alexandria University, Alexandria, 21521, EgyptCorrespondence: Marwa A SallamDepartment of Industrial Pharmacy, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, EgyptTel +20 3 4868256Fax +20 3 4871668Email marwa.sallam@alexu.edu.egElbadawy A KamounPolymeric Materials Research Dep., Advanced Technology and New Materials Research Institute (ATNMRI), City of Scientific Research and Technological Applications (SRTA-City), New Borg Al-Arab City, Alexandria, 21934, EgyptTel +20 1283320302Email e-b.kamoun@tu-bs.deBackground: Tacrolimus (TAC) is a powerful immunosuppressive agent whose therapeutic applicability is confined owing to its systemic side effects.Objective: Herein, we harnessed a natural polymer based bioconjugate composed of maltodextrin and α-tocopherol (MD-α-TOC) to encapsulate TAC as an attempt to overcome its biological limitations while enhancing its therapeutic anti-rheumatic efficacy.Methods: The designed TAC loaded maltodextrin-α-tocopherol nano-micelles (TAC@MD-α-TOC) were assessed for their physical properties, safety, toxicological behavior, their ability to combat arthritis and assist bone/cartilage formation.Results: In vitro cell viability assay revealed enhanced safety profile of optimized TAC@MD-α-TOC with 1.6- to 2-fold increase in Vero cells viability compared with free TAC. Subacute toxicity study demonstrated a diminished nephro- and hepato-toxicity accompanied with optimized TAC@MD-α-TOC. TAC@MD-α-TOC also showed significantly enhanced anti-arthritic activity compared with free TAC, as reflected by improved clinical scores and decreased IL-6 and TNF-α levels in serum and synovial fluids. Unique bone formation criteria were proved with TAC@MD-α-TOC by elevated serum and synovial fluid levels of osteocalcin and osteopontin mRNA and proteins expression. Chondrogenic differentiation abilities of TAC@MD-α-TOC were proved by increased serum and synovial fluid levels of SOX9 mRNA and protein expression.Conclusion: Overall, our designed bioconjugate micelles offered an excellent approach for improved TAC safety profile with enhanced anti-arthritic activity and unique bone formation characteristics.Keywords: polymeric micelles, vitamin E, osteopontin, SOX9, rheumatoid

Salma M Mohyeldin,1 Wael M Samy,1 Doaa Ragab,1 Doaa A Abdelmonsif,2,3 Rania G Aly,4 Nazik A Elgindy1,5 1Department of Industrial Pharmacy, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt; 2Department of Medical Biochemistry, Faculty of Medicine, Alexandria University, Alexandria, Egypt; 3Centre of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria, Egypt; 4Department of Surgical Pathology, Faculty of Medicine, Alexandria University, Alexandria, Egypt; 5Department of Industrial Pharmacy, College of Pharmacy, Arab Academy for Science, Technology and Maritime Transport, Alexandria, EgyptCorrespondence: Salma M MohyeldinDepartment of Industrial Pharmacy, Faculty of Pharmacy, Alexandria University, 1-Azarita Square, Alexandria, EgyptTel +20 1008024214Fax +20 3 4873273Email salma.eldin@alexu.edu.egBackground: Sulpiride (SUL), is a selective antidopaminergic drug that had extensive biological activities. However, its sparingly aqueous solubility and limited gastrointestinal permeability lead to scanty oral bioavailability which hinders its clinical efficacy.Objective: SUL-loaded lipospheres (SUL-LPS) were designed to serve as an oral biocompatible nanovector for improving SUL permeability as well as conquering its low oral absorption and then in turn enhancing its antidepressant action.Methods: SUL-LPS were fabricated via two processing techniques namely, melt emulsification and solvent evaporation. The impact of different lipid cores, phospholipid shells together with various surfactant concentrations and types on the lipospheres properties were screened. Detailed physicochemical elucidations were performed followed by ex vivo permeation appraisal using the non-everted intestine model. The pharmacokinetic parameters of SUL-LPS, free SUL and marketed product were assessed following oral administration to healthy rats. Reserpine-induced depression rat model was used to assess the antidepressant action of SUL-LPS on which full behavioural and biochemical analysis was conducted. Safety attributes of nanoencapsulated SUL on the brain and other internal organs were evaluated.Results: The optimum LPS revealed an excellent nanosize with a narrow PdI, negative zeta potential and acceptable entrapment efficiency of 68.62 nm, 0.242, − 30.4 mV and 84.12%, respectively. SUL-LPS showed a sustained release pattern and 2.1-fold enhancement in the intestinal permeation parameters with low mucin interaction. Oral pharmacokinetic appraisal exhibited that LPS provided 3.4-fold improvement in SUL oral bioavailability together with long-circulating properties, relative to the free drug. Pharmacodynamic study confirmed the superior antidepressant action of SUL-LPS as evident by 1.6 and 1.25-fold elevation in the serotonin and dopamine expressions, respectively. Meanwhile, nanotoxicological appraisal proved the biocompatibility of SUL-LPS upon repetitive oral administration.Conclusion: Rationally designed lipospheres hold promising in vitro and in vivo characteristics for efficient delivery of SUL with high oral bioavailability, antidepressant activity together with a good safety profile.Keywords: sulpiride, lipospheres, ex vivo permeation, bioavailability, depression, toxicity

Noha Khalifa Abo Aasy,1 Doaa Ragab,1,2 Marwa Ahmed Sallam,1,3 Doaa A Abdelmonsif,4,5 Rania G Aly,6 Kadria A Elkhodairy1 1Department of Industrial Pharmacy, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt; 2Department of Chemical and Biochemical Engineering, Faculty of Engineering, University of Western Ontario, London, Ontario, Canada; 3John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA; 4Department of Medical Biochemistry, Faculty of Medicine, Alexandria University, Alexandria, Egypt; 5Molecular Biology and Nanomedicine Labs, Centre of Excellence for Regenerative Medicine Research & Applications, University of Alexandria, Alexandria, Egypt; 6Department of Surgical Pathology, Faculty of Medicine, Alexandria University, Alexandria, EgyptCorrespondence: Noha Khalifa Abo AasyDepartment of Industrial Pharmacy, Faculty of Pharmacy, Alexandria University, 1-Azarita Square, Alexandria, EgyptTel +20 122 710 1058Fax +20 3 487 3273Email drnohakhalifa@yahoo.comIntroduction: This study was conducted to elucidate the chemopreventive potential, cytotoxic, and suppression of cellular metastatic activity of etodolac (ETD)-loaded nanocarriers.Methods: To esteem the effect of charge and composition of the nanovectors on their performance, four types of vectors namely, negative lipid nanovesicles; phosalosomes (N-Phsoms), positive phosalosomes (P-Phsoms), nanostructured lipid carriers (NLCs) and polymeric alginate polymer (AlgNPs) were prepared and compared. ETD was used as a model cyclo-oxygenase-2 (COX-2) inhibitor to evaluate the potency of these nanovectors to increase ETD permeation and retention through human skin and cytotoxicity against squamous cell carcinoma cell line (SCC). Moreover, the chemopreventive activity of ETD nanovector on mice skin cancer model was evaluated.Results: Among the utilized nanovectors, ETD-loaded N-Phsoms depicted spherical vesicles with the smallest particle size (202.96±2.37 nm) and a high zeta potential of −24.8±4.16 mV. N-Phsoms exhibited 1.5, and 3.6 folds increase in the ETD amount deposited in stratum corneum, epidermis and dermis. Moreover, cytotoxicity studies revealed a significant cytotoxic potential of such nanovector with IC50=181.76 compared to free ETD (IC50=982.75), correlated to enhanced cellular internalization. Its efficacy extended to a reduction in the relative tumor weight with 1.70 and 1.51-fold compared to positive control and free ETD, that manifested by a 1.72-fold reduction in both COX-2 and proliferating cell nuclear antigen mRNA (PCNA-mRNA) levels and 2.63-fold elevation in caspase-3 level in skin tumors relative to the positive control group with no hepato-and nephrotoxicity.Conclusion: Encapsulation of ETD in nanovector enhances its in-vitro and in-vivo anti-tumor activity and opens the door for encapsulation of more relevant drugs.Keywords: COX-2, confocal laser microscopy, skin cancer, metastasis, cytotoxicity, chemoprevention

May S Freag,1 Yosra SR Elnaggar,1,2 Doaa A Abdelmonsif,3 Ossama Y Abdallah1 1Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, 2Department of Pharmaceutics, Faculty of Pharmacy and Drug Manufacturing, Pharos University in Alexandria, 3Department of Medical Biochemistry, Faculty of Medicine, Alexandria University, Alexandria, Egypt Abstract: Recently, research has progressively highlighted on clues from conventional use of herbal medicines to introduce new anticancer drugs. Aloe-emodin (AE) is a herbal drug with promising anticancer activity. Nevertheless, its clinical utility is handicapped by its low solubility. For the first time, this study aims to the fabrication of surface-functionalized polyethylene glycol liquid crystalline nanoparticles (PEG-LCNPs) of AE to enhance its water solubility and enable its anticancer use. Developed AE-PEG-LCNPs were optimized via particle size and zeta potential measurements. Phase behavior, solid state characteristics, hemocompatibility, and serum stability of LCNPs were assessed. Sterile formulations were developed using various sterilization technologies. Furthermore, the potential of the formulations was investigated using cell culture, pharmacokinetics, biodistribution, and toxicity studies. AE-PEG-LCNPs showed particle size of 190 nm and zeta potential of -49.9, and PEGylation approach reduced the monoolein hemolytic tendency to 3% and increased the serum stability of the nanoparticles. Sterilization of liquid and lyophilized AE-PEG-LCNPs via autoclaving and γ-radiations, respectively, insignificantly affected the physicochemical properties of the nanoparticles. Half maximal inhibitory concentration of AE-PEG-LCNPs was 3.6-fold lower than free AE after 48 hours and their cellular uptake was threefold higher than free AE after 24-hour incubation. AE-PEG-LCNPs presented 5.4-fold increase in t1/2 compared with free AE. Biodistribution and toxicity studies showed reduced AE-PEG-LCNP uptake by reticuloendothelial system organs and good safety profile. PEGylated LCNPs could serve as a promising nanocarrier for efficient delivery of AE to cancerous cells. Keywords: aloe-emodin, anticancer, breast cancer cell line, liquid crystalline nanoparticles, monoolein, pharmacokinetics

Yosra SR Elnaggar,1 Samar M Etman,1 Doaa A Abdelmonsif,2 Ossama Y Abdallah1 1Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt; 2Department of Medical Biochemistry, Faculty of Medicine, Alexandria University, Alexandria, Egypt Abstract: Alzheimer’s disease (AD) is one of the most patient devastating central nervous system diseases with no curative therapy. An effective oral therapy with brain-targeting potential is required that is hampered by blood–brain barrier. Piperine (PIP) is a natural alkaloid with memory enhancing potentials. Oral PIP delivery suffers from its hydrophobicity and first-pass metabolism. In this study, novel Tween-modified monoolein cubosomes (T-cubs) were elaborated as bioactive nanocarriers for brain-targeted oral delivery of PIP. Seven liquid crystalline nanoparticles (cubosomes) were prepared testing different bioactive surfactants (Tween 80, poloxamer, and Cremophor). Full in vitro characterization was carried out based on particle size, zeta potential, polydispersity index, entrapment efficiency, and in vitro release. Morphological examination and structure elucidation were performed using transmission and polarizing microscopes. Sporadic dementia of Alzheimer’s type was induced in 42 male Wistar rats on which full behavioral and biochemical testing was conducted. Brain toxicity was assessed based on Caspase-3 assay for apoptosis and tumor necrosis factor-α for inflammation. Liver and kidney toxicity studies were conducted as well. Among others, T-cubs exhibited optimum particle size (167.00±10.49 nm), polydispersity index (0.18±0.01), and zeta potential (-34.60±0.47 mv) with high entrapment efficiency (86.67%±0.62%). Cubs could significantly sustain PIP in vitro release. In vivo studies revealed T-cubs potential to significantly enhance PIP cognitive effect and even restore cognitive function to the normal level. Superiority of T-cubs over others suggested brain-targeting effect of Tween. Toxicological studies contended safety of cubs on kidney, liver, and even brain. T-cubs exhibited potential anti-inflammatory and anti-apoptotic activity of loaded PIP, indicating potential to stop AD progression that was first suggested in this article. Novel oral nanoparticles elaborated possess promising in vitro and in vivo characteristics with high safety for effective chronic treatment of AD. Keywords: piperine, monoolein, cubosome, nanoparticles, Alzheimer’s disease, liquid crystalline

This study was executed to mitigate imiquimod (IMQ)-side effects and promote its anticancer potential against skin cancer via encapsulation in hyaluronic acid-coated lipid nanocapsules (HA-LNCs) for targeted topical delivery. The LNCs were prepared using the phase inversion technique. Optimized LNCs formulation was gained following 2 2 factorial design experiment to adjust the IMQ and CTAB concentrations. The two variables were found to significantly influence the dependent responses. The encapsulation efficiency of IMQ exceeded 97 %. HA coating provided a sustained release of IMQ from LNCs, with 63.81 ± 2.45 % of IMQ released after 24 h. Moreover, the ex-vivo human skin permeation study showed that 7.9-fold more IMQ was localized in all skin layers than that permeated. In vitro anticancer activity indicated that IMQ-HA-LNCs had higher cytotoxicity (IC 50  = 22.39 μg/mL) compared to free IMQ (IC 50  = 97.94 μg/mL). Further, in vivo studies revealed that encapsulation of IMQ in HA-LNCs enhanced its immunostimulatory potential and promoted its anti-tumor activity in competing skin cancer even in low doses compared to the untreated group and group treated with a brand product with no topical or systemic toxicity. The present study suggested that HA-LNCs with their mixed polymeric/lipophilic nature epitomize a promising strategy for safe topical delivery of poorly water-soluble candidates., Competing Interests: Declaration of competing interest The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Chronic stress induces changes in the prefrontal cortex and hippocampus. Selenium nanoparticles (SeNPs) showed promising results in several neurological animal models. The implementation of SeNPs in chronic restraint stress (CRS) remains to be elucidated. This study was done to determine the possible protective effects of selenium nanoparticles on behavioral changes and brain oxidative stress markers in a rat model of CRS. 50 rats were divided into three groups; control group (n = 10), untreated CRS group (n = 10) and CRS-SeNPs treated group (n = 30). Restraint stress was performed 6 h./day for 21 days. Rats of CRS-SeNPs treated group received 1, 2.5 or 5 mg/kg SeNPs (10 rats each) by oral gavage for 21 days. Rats were subjected to behavioral assessments and then sacrificed for biochemical and histological analysis of the prefrontal cortex and hippocampus. Prefrontal cortical and hippocampal serotonin levels, oxidative stress markers including malondialdehyde (MDA), reduced glutathione (GSH) and glutathione peroxidase (GPx), tumor necrosis factor alpha (TNF-α) and caspase-3 were assessed. Accordingly, different doses of SeNPs showed variable effectiveness in ameliorating disease parameters, with 2.5 mg/kg dose of SeNPs showing the best improving results in all studied parameters. The present study exhibited the neuroprotective role of SeNPs in rats subjected to CRS and proposed their antioxidant, anti-inflammatory and anti-apoptotic effects as the possible mechanism for increased prefrontal cortical and hippocampal serotonin level, ameliorated anxiety-like and depressive-like behaviors and improved prefrontal cortical and hippocampal histological architecture., Competing Interests: Declarations. Ethics Approval: The study protocol was approved by the institutional Medical Ethics Committee, Faculty of Medicine (IRB NO: 00012098; FWA NO: 00018699; approval NO: 0106414). Consent to Participate: Not applicable. Consent for Publication: Not applicable. Competing Interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Spermidine is a natural biologically active substance that has widespread influences on the body., Objective: This study aims to enhance our understanding of the potential effect of spermidine on long non-coding RNA MALAT1 and explore the underlying mechanism in the rotenone-induced rat model of Parkinson's disease., Methods: Rats were sacrificed after locomotor behavioral testing. Striatal tissues were used to assess the expression of MALAT1, oxidative stress markers, and autophagy markers., Results: Our study found that treatment with spermidine for 2 weeks during the induction of the model significantly improved behavioral assessment, dopamine levels, and attenuated the histopathological changes that occurred in PD in comparison to the non-treated group., Conclusion: Our preliminary study supports the protective effect of spermidine on the activation of autophagy and its antioxidant properties. Part of the antioxidant activity is due to the inhibition of MALAT1. However, MALAT1 does not correlate with the spermidine-induced autophagy pathway., (© 2024 Société Française de Pharmacologie et de Thérapeutique. Published by John Wiley & Sons Ltd.)

Resveratrol is known to exhibit neuroprotective effects in many neurological disorders via autophagy modulation. However, controversial results have been reported about the therapeutic potential of resveratrol and the implication of autophagy in demyelinating diseases. This study aimed to evaluate the autophagic changes in cuprizone-intoxicated C57Bl/6 mice and explore the effect of autophagy activation by resveratrol on the demyelination and remyelination processes. Mice were fed with chow containing 0.2% cuprizone for 5 weeks, followed by a cuprizone-free diet for 2 weeks. Resveratrol (250 mg/kg/day) and/or chloroquine (an autophagy inhibitor; 10 mg/kg/day) were given for 5 weeks starting from the third week. At the end of the experiment, animals were tested on rotarod and then sacrificed for biochemical assessment, luxol fast blue (LFB) staining, and transmission electron microscopy (TEM) imaging of the corpus callosum. We observed that cuprizone-induced demyelination was associated with impaired degradation of autophagic cargo, induction of apoptosis, and manifest neurobehavioral disturbances. Oral treatment with resveratrol promoted motor coordination and improved remyelination with regular compacted myelin in most axons without a significant impact on myelin basic protein (MBP) mRNA expression. These effects are mediated, at least in part, via activating autophagic pathways that may involve SIRT1/FoxO1 activation. This study verified that resveratrol dampens cuprizone-induced demyelination, and partially enhances myelin repair through modulation of the autophagic flux, since interruption of the autophagic machinery by chloroquine reversed the therapeutic potential of resveratrol., (© 2023. The Author(s).)

Background: Impaired inflammation and vascularization are common reasons for delayed diabetic wound healing. Nanoparticles (NPs)-in-nanofibers composites can manage diabetic wounds. A multifunctional scaffold was developed based on tadalafil (TDF)-loaded NPs incorporated into polyvinyl alcohol/ Withania somnifera extract nanofibers. Materials & methods: TDF-loaded NPs were prepared and fully characterized in terms of their physicochemical properties. Extract of ashwagandha was prepared and a blend composed of TDF-loaded NPs, herbal extract and polyvinyl alcohol was used to prepare the whole composite. Results: The whole composite exhibited improved wound closure in a diabetic rat model in terms of reduced inflammation and enhanced angiogenesis. Conclusion: Results suggest that this multifunctional composite could serve as a promising diabetic wound dressing.

Background: Melanocytic neoplasms range from banal nevi to malignant melanomas. The genetic background has been extensively studied in the Caucasian population. BRAF mutations were reported among the early driver mutations in nevogenesis. Nevertheless, the pathogenesis in the Egyptian population has not been elucidated., Aim and Methods: The present study was carried out to assess the sensitivity and specificity of immunohistochemistry (IHC) using the RM-08 clone in reference to allele-specific real-time PCR (CAST-PCR) for the detection of the BRAF V600E mutation in 50 formalin-fixed paraffin-embedded blocks of melanocytic neoplasms with prior bleaching using hydrogen peroxide in Tris-HCL and Bovine Serum Albumin respectively., Results: IHC staining was interpreted using staining reaction (positive versus negative) and staining pattern (negative and heterogeneous versus homogenous). Using the staining pattern, the specificity increased from 73.3 to 88.2%, the negative predictive value increased from 73.3 to 100%, the diagnostic accuracy increased from 71.4 to 90.48% and the overall accuracy increased from 69.9 to 77.3%. The sensitivity and positive predictive value remained unchanged. The K-agreement coefficient increased from 0.364 (fair agreement) to 0.741 (good agreement) and was statistically significant (p = 0.00). Next-generation sequencing was performed in 11 cases, 8 cases with IHC-positive and BRAF wild type in addition to 3 cases that failed PCR analysis and revealed no BRAF V600E . No statistically significant difference was found in the clinicopathological parameters between BRAF V600E and BRAF wild-type melanomas., Conclusions: These findings suggest that IHC staining homogeneity may be more accurate in predicting BRAF V600E mutational status. However, IHC cannot replace molecular methods., (© 2023. The Author(s).)

Wound healing is a complicated cellular process with overlapping phases. Naringin (NAR); a flavanone glycoside, possesses numerous pharmacological effects such as anti-inflammatory, antioxidant and anti-apoptotic effects. In the current study, Arabic gum (AG)/pectin hydrogel was utilized to encapsulate NAR. Drug-loaded AG/pectin hydrogel exhibited excellent EE% of about 99.88 ± 0.096 and high DL% of about 16.64 ± 0.013. The formulated drug-loaded hydrogel was characterized using Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), scanning electron microscopy (SEM) and Zetasizer analyzer, besides determination of equilibrium degree of swelling (EDS%). Afterwards, wound healing potential of NAR-loaded AG/pectin hydrogel was evaluated in an in vivo animal model. Results manifested that NAR-loaded AG/pectin hydrogel was able to accelerate wound healing in terms of enhanced angiogenesis, re-epithelialization and collagen deposition. Furthermore, it significantly (P < 0.001) down-regulated the mRNA expression of inflammatory mediators (TNF-α) and apoptosis (BAX). In addition, NAR-loaded AG/pectin hydrogel was found to possess potent antioxidant activity as it enhanced the levels of SOD and GSH, besides decreasing the levels of MPO, MDA and nitrite. These data suggest that NAR-loaded AG/pectin hydrogel could be utilized in wound healing applications., Competing Interests: Declaration of competing interest This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Aims: Pulmonary fibrosis (PF) is considered as an end stage for many lung diseases. Mesenchymal stem cells (MSC) as regenerative therapy have become a remarkably valuable therapeutic strategy in different diseases. Hydrogen sulfide has been recently introduced into the medical field for its antifibrotic properties in addition to enhancement of MSC stemness and function. The aim of the present study was to investigate the ability of BM-MSC in combination with NaHS to attenuate Bleomycin induced pulmonary fibrosis was studied in rats. A special emphasis was given to miR-21 and GAS5 as important players in the development of PF., Main Methods: PF was induced in 32 Wistar male rats by single endotracheal injection of bleomycin, those were randomly divided into four groups (8 rats each): (untreated PF group) - (PF + MSC) treated group- (PF + NaHS treated group) - PF + combined (NAHS + MSC) treated group., Key Findings: Induction of PF was associated with increased miR-21 and decreased lncRNA-GAS5 expression. Treatment with either NaHS or BM-MSC leads to an inhibitory effect on pulmonary fibrosis as evidenced by improvement of histopathological studies, pulmonary function tests, reduction of inflammatory and fibrotic markers like Hydroxyproline, TNF α, TGF-β and caspase -3 together with downregulation miR-21 and increase lncRNA-GAS5 expression., Significance: The current work revealed the inhibitory effect of combined NaHS and BM-MSC on pulmonary fibrosis with concomitant modulation of miR-21 and lncRNA-GAS5 expression., Competing Interests: Declaration of competing interest None of the authors have potential conflicts of interest to be disclosed., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Recent studies have suggested that irisin may act as a potential neurokine. Exercise and L-carnosine supplementation showed neuroprotective effects in Alzheimer's disease (AD)-like conditions. However, the regulation of irisin in the hippocampus of streptozotocin (STZ)-induced memory impairment and its relation to insulin signalling remain to be investigated. This study was designed to compare the effect of swimming exercise and L-carnosine intake on serum, CSF and hippocampal irisin in rats received intracerebroventricular (ICV) injection of STZ. Rats were recruited in swimming paradigm, received oral carnosine (100 mg/kg/day) or vehicle treated. After 5 weeks, rats were sacrificed after neurobehavioural testing. CSF and serum irisin were determined. Hippocampal tissues were used to assess expression of FNDC5/irisin, BDNF and proteins related to insulin signalling, in addition to β-amyloid peptide and phosphorylated tau protein levels. We observed decreased hippocampal, but not CSF or serum, irisin in ICV-STZ-injected rats. Exercise and carnosine intake almost normalized hippocampal FNDC5/irisin expression which was associated with reduced soluble β-amyloid peptide and phosphorylated tau protein, improved BDNF and insulin signalling proteins, with corresponding mitigated cognitive impairments. However, hippocampal FNDC5/irisin was not correlated with serum or CSF irisin levels. Histologically, both interventions ameliorated the hippocampal damage in STZ-injected rats. The current study reveals that carnosine is equivalent to exercise in reversing cognitive decline and Alzheimer's biomarkers. In both interventions, enhancement of hippocampal FNDC5/irisin and insulin signalling may be involved in mediating these neuroprotective effects., (© 2021. University of Navarra.)

Aim: Contradiction overwhelms chemerin link to feeding behavior. Neither the chemerin central role on appetite regulation nor its relation to hypothalamic histamine and AMPK is verified., Main Methods: Food intake, body weight and hypothalamic biochemical changes were assessed after a single intra-cerebroventricular or intraperitoneal injection (ip) (1 μg/kg or 16 μg/kg, respectively) or chronic ip administration (8 μg/kg/day) of chemerin for 14 or 28 days. Hypothalamic neurobiochemical changes in chemerin/histamine/AMPK induced by either 8-week high fat diet (HFD) or food restriction were also investigated. To confirm chemerin-histamine crosstalk, these neurobiochemical changes were assessed under settings of H 1 -receptor agonism and/or antagonism by betahistine and/or olanzapine, respectively for 3 weeks., Key Findings: Chemerin-injected rats exhibited anorexigenic behavior in both acute and chronic studies that was associated with a decreased AMPK activity in the arcuate nucleus (ARC). However, with long-term administration, chemerin anorexigenic effect gradually ceased. Contrarily to food restriction, 8-week HFD increased ARC expression of chemerin and its receptor CMKLR1, reducing food intake via an interplay of H 1 -receptors and AMPK activity. Blockage of H 1 -receptors by olanzapine disrupted chemerin signaling pathway with an increased AMPK activity, augmenting food intake. These changes were reversed to normal by betahistine coadministration., Significance: Chemerin is an anorexigenic adipokine, whose dysregulation is implicated in diet, and olanzapine-induced obesity through a histamine/AMPK axis in the ARC. Hypothalamic chemerin/CMKLR1 expression is a dynamic time-dependent response to changes in body weight and/or food intake. Targeting chemerin as a novel therapeutic approach against antipsychotic- or diet-induced obesity is worth to be further delineated., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Sulpiride (SUL), a benzamide derivative, acts as a multitarget drug with extensive biological properties. However, being a P-glycoprotein efflux substrate with a limited oral bioavailability imposes a challenge to its clinical efficacy. The current research explores the impact of tailored hybrid lipid-polysaccharide nanocomposites in augmenting the biological performance of SUL. Chitosan-graft-tocopherol polyethylene glycol 1000 succinate (TPGS) copolymers were synthesized and integrated as a polysaccharide shell into a SUL-loaded lipid nanocore. The optimized nanohybrids revealed a nanocore-shell structure with 110.1 nm particle size, 23.7 mV zeta potential, 85.42% encapsulation efficiency, a pH-dependent-release profile, and an acceptable mucoadhesive tendency. Employing TPGS into the chitosan backbone alleviated the cellular internalization of nanohybrids into the Caco-2 intestinal cells and hence increased the intestinal permeation and the oral bioavailability of SUL by 3.3, and 8.7-folds, respectively. Reserpine-induced depression rat model confirmed the superior antidepressant activity of nanohybrids, compared with free SUL and a marketed product. The nanohybrids exhibited 1.87- and 1.47-folds enhancement in both serotonin and dopamine levels, respectively. Additionally, nanohybrids were shown to attenuate brain oxidative stress state and SUL irritant effect on different body tissues. Overall, the newly tailored nanohybrids pave the way for an advance in the field of oral drug delivery., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Targeted delivery of cytotoxic drugs has shown great potential in cancer therapy. In this light, vitamin D3 (vit.D3)-coated micelles were fabricated to encapsulate the cytotoxic drug; etoposide (ETP). Sodium caseinate micelles were first utilized to encapsulate vit.D3 and ETP within their hydrophobic core, then drug-loaded micelles were further decorated with an envelope of vit.D3/ phospholipid complex to enhance the active targeting potency of fabricated micelles via exploiting vit.D3 receptors (VDRs) overexpressed on the outer surface of breast cancer cells. In vitro cytotoxicity studies showed that fabricated micelles exhibited improved anticancer effect on MDA MB-231 and MCF-7 human breast cancer cell lines in comparison to free vit.D3 + ETP without any significant toxicity on normal human lung fibroblast (Wi-38) cells. In vivo biodistribution and efficacy studies in Ehrlich ascites tumor animal model revealed that fabricated micelles manifested improved accumulation in tumor tissue due to active targeting potential of vit.D3 without any remarkable toxicity. More importantly, fabricated micelles resulted in enhanced tumor apoptosis, reduced angiogenesis, invasion and autophagy, besides a decline in the tumor expression levels of both miR-21 and miR-192. Therefore, vit.D3/ETP micelles could serve as a favorable actively targeted anticancer delivery system having a superior effect over the free combination., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Chemotherapy induces an irreversible premature ovarian dysfunction (POD). Amniotic fluid mesenchymal stem cells (AFMSCs) can rescue fertility; however, the notion that stem cells can rejuvenate follicles is highly controversial due to the predetermined ovarian reserve. This study aims to isolate AFMSC-derived extracellular vesicles (EVs) and investigate their abundancy for the anti-apoptotic miRNA-21 as a means of ovarian restoration. Female rats were divided into healthy controls and POD-induced groups. The POD induced groups were subdivided into three groups according to the therapies they received: placebo-treated POD, AFMSC and EVs groups. Rats were assessed for serum anti-Müllerian hormone (AMH) levels, ovarian caspase 3 and PTEN protein levels in the ovarian lysate. Total follicular counts (TFCs) were estimated from stained ovarian sections. Functional recovery was investigated through daily vaginal smears and mating trials. In vitro chemical transfection of the AFMSCs with selective miRNA-21 mimics/inhibitors followed by isolation of EVs for therapy was conducted in two additional groups. At the interval points studied, treatment with AFMSCs and EVs equally restored TFC, AMH levels, regular estrous cycles and fruitful conception, while it both diminished caspase 3 and PTEN levels. EVs carrying miRNA-21 mimics recapitulated the short-term effects. Placebo-treated POD or EVs carrying miRNA-21 inhibitors showed augmented ovarian follicular damage demonstrated the low AMH levels, TFC and high levels of PTEN and caspase 3. miRNA-21 allowed regeneration by modulating PTEN and caspase 3 apoptotic pathways. Our findings exemplify that EVs could serve as an innovative cell-free therapeutic tool functioning through their miRNA content and that miRNA-21 has a chief regenerative role through modulating PTEN and caspase 3 apoptotic pathways., (© The Author(s) 2020. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Alzheimer's disease (AD) is neurological disorder characterized by dementia which causes severe problems with behavior, thinking and memory. Systemic administration of therapeutics to the central nervous system (CNS) is usually associated with very low efficiency due to presence of blood brain barrier (BBB), which only allows permeation of few types of molecules from the circulation to the CNS. As an alternative, naturally amphiphilic micelles can be utilized to enhance targeted drug delivery to the brain. In this sense, lactoferrin (LF) was covalently attached to conjugated linoleic acid (CLA) via carbodiimide coupling reaction to form a new micellar nanoplatform with particle size of about 53 nm. Afterwards, fabricated micelles were further loaded once again with CLA to enhance its delivery to the CNS. In vitro drug release study revealed that CLA exhibited sustained release at pH 6.8, associated with good hemocompatibility without any remarkable in vivo toxicity in terms of liver and kidney functions. Moreover, in vivo studies showed that the fabricated micelles manifested enhanced in vivo biodistrbution in brain tissue due to the active targeting potential of LF. Additionally, drug-loaded LF-CLA micelles exhibited enhanced cognitive capabilities, reduced brain oxidative stress, inflammation, apoptosis and acetylcholine esterase activity, besides a decline in the deposition of amyloid β peptide1-42 in aluminum chloride Alzheimer's-induced animal model. CLA-based micelles could be a promising CNS actively targeted delivery system with a sophisticated potential to reduce AD symptoms., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Tanshinone IIA (TSIIA) is a promising phytomedicine that has been extensively studied due to its numerous biological activities, especially as an anticancer drug. However, it suffers from poor oral bioavailability owing to low aqueous solubility, poor permeability and exposure to first-pass metabolism. This study endeavored to improve TSIIA oral bioavailability by encapsulation into lipid nanocapsules (LNCs) for the first time. A previously reported phase-inversion method was used to prepare Tanshinone II A loaded LNCs (TSIIA-LNCs) with slight modifications based on a constructed phase diagram. They were then in-vitro characterized and their oral pharmacokinetics were studied in rats. TSIIA-LNCs showed excellent colloidal properties (size; 70 nm, PDI < 0.2 and zeta-potential; -13.5 mV), a high percent entrapment efficiency (98%) and a good drug payload (2.6 mg/g). Furthermore, the in-vivo pharmacokinetic study revealed a significant enhancement in both the rate and extent of absorption of TSIIA-LNCs compared with TSIIA suspension with about 3.6-fold increase in AUC 0-inf value (p ≤ 0.01). Additionally, a significant increase in both half-life and mean residence time was exhibited by TSIIA-LNCs (p ≤ 0.01), confirming their long circulating properties. Therefore, the elaborated LNCs could be addressed as a promising nanoplatform permitting higher TSIIA oral bioavailability., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Body weight is subjected to genetic and epigenetic modifiers that might affect the success of weight loss interventions. Because of its possible complications and disparity in patients' response, identification of predictors to the outcome of bariatric surgery is indispensable., Objectives: This prospective study aims to investigate serpin peptidase inhibitor type 1 (SERPINE-1) protein and gene methylation as molecular predictors to the outcome of bariatric surgery., Patients and Methods: One hundred participants were enrolled and divided to control group (n = 50) and obese patients who underwent laparoscopic sleeve gastrectomy (LSG) (n = 50). Anthropometric measurements were assessed and blood samples were collected preoperatively and 6 months postoperatively for assessment of SERPINE-1 protein and gene methylation, C-reactive protein (CRP), and homeostatic model assessment of insulin resistance (HOMA-IR). Moreover, subjects were followed for 2 years for weight loss parameters., Results: Patients with obesity showed high baseline SERPINE-1 protein and gene hypermethylation where LSG was followed by a drop in SERPINE-1 protein level but not gene hypermethylation. Baseline SERPINE-1 gene methylation was negatively related to postoperative weight loss and was the independent predictor to weight loss after LSG. Likewise, postoperative SERPINE-1 protein was negatively related to weight loss with independent expression from its gene methylation state. Furthermore, postoperative SERPINE-1 gene methylation correlated to CRP and HOMA-IR., Conclusion: Baseline SERPINE-1 gene methylation might be a predictor of weight loss after LSG. Meanwhile, postoperative SERPINE-1 protein could be a predictor to weight loss maintenance after LSG. Lastly, postoperative SERPINE-1 gene methylation might serve as an index to postoperative changes in obesity-related comorbidities.

This study aims at improving the bioavailability of a poorly soluble phosphodiesterase-5 inhibitor; tadalafil (TD) via developing intranasal (IN) nanoemulsions (NEs). Optimum NE ingredients were selected based on solubility studies, emulsification tests, and phase diagram construction. Both o/w and w/o NEs were selected based on their drug loading capacity. Optimum formulations were subjected to physicochemical characterization and were assessed for nasal toxicity through biochemical analysis of tumor necrosis factor-α (TNF-α) and caspase-3 in rat nasal tissues. Pharmacodynamic study was performed via biochemical analysis of cyclic guanosine monophosphate (cGMP) in rat penis 2-h post-treatment and compared with oral suspension of Cialis® tablets. Optimum o/w and w/o NEs were successfully prepared using different ratios of Capmul-MCM-EP, Labrasol:Transcutol-HP (1:1) and water. Optimized formulations exhibited more than 4000-fold increase in TD solubility compared with its aqueous solubility. Both formulations were optically isotropic with the majority of globules in the nanometric-size range. Nasal toxicity study revealed no significant difference in values of TNF-α and caspase-3 between the NE-treated groups and the control group. Both TD-NEs succeeded to achieve a significant enhancement in cGMP levels. Our findings suggested that IN administration of the developed TD-NEs could provide a safe and effective alternative to TD oral delivery.

Aim: The current work highlighted preparation of highly penetrating liquid crystalline nanoparticulates (LCNPs) reservoir of a solubility modified berberine oleate (Brb-OL) complex for effective psoriasis management. Materials & methods: Brb-OL-loaded LCNPs (Brb-OL-LCNPs) were prepared using hydrotrope method., Results: The proposed Brb-OL-LCNPs showed a particle size of 137 ± 3.7 nm and negative ζ-potential (-38 ± -5.85 mV). Brb-OL-LCNPs showed a threefold increase in the drug accumulated within rat skin and around tenfold increase in the drug permeation compared with crude Brb. In vivo studies revealed that topical application of Brb-OL-LCNPs hydrogel significantly alleviated psoriasis symptoms and reduced the levels of psoriatic inflammatory cytokines., Conclusion: Formulating Brb-OL in the LCNPs controlled the release, retention and permeation of the drug across skin layers, which are of prime importance for psoriasis management.

Multiple sclerosis is among the most common causes of neurological disabilities in young adults. Over the past decade, several therapeutic strategies have emerged as having potential neuroprotective and neuroregenerative properties. We investigated the effect of intranasal administration of LINGO-1-directed siRNA-loaded chitosan nanoparticles on demyelination and remyelination processes in a rat model of demyelination. Adult male Wistar rats were randomly assigned to one of 6 groups (n = 10 each) and subjected to intrapontine stereotaxic injection of ethidium bromide (EB) to induce demyelination. EB-treated rats were either left untreated or received intranasal LINGO-1-directed siRNA-chitosan nanoparticles from day 1 to day 7 (demyelination group) or from day 7 to day 21 (remyelination group) after EB injection. Chitosan nanoparticle (50 μl) was given alone after EB stereotaxic injection for both demyelination and remyelination groups. Two additional groups received 10 μl of saline by stereotaxic injection, followed by intranasal saline as controls for demyelination and remyelination groups (n = 10/group). Behavioural testing was conducted for all rats, as well as terminal biochemical assays and pathological examination of pontine tissues were done. After EB injection, rats had compromised motor performance and coordination. Pathological evidence of demyelination was observed in pontine tissue and higher levels of caspase-3 activity were detected compared to control rats. With LINGO-1-directed siRNA-chitosan nanoparticle treatment, animals performed better than controls. Remyelination-treated group showed better motor performance than demyelination group. LINGO-1 downregulation was associated with signs of repair in histopathological sections, higher expression of pontine myelin basic protein (MBP) mRNA and protein and lower levels of caspase-3 activity indicating neuroprotection and remyelination enhancement.

Alzheimer's disease (AD) is a neurodegenerative disorder that has no cure till now. Piperine (PIP) is an alkaloid characterized by memory-enhancing properties but challenging oral delivery obstacles. The objectives of this study are as follows: preparation of microemulsion (ME) as a proposed oral PIP nanocarrier for treatment of Alzheimer's disease and testing its safety on the brain and other internal organs. This study employs bioactive surfactants in the common safe doses to improve PIP targeting to the brain. Selected ME systems encompassed Caproyl 90 (oil)/Tween 80/Cremophor RH 40 (surfactant) and Transcutol HP (co-surfactant). The particle size of the prepared formulations was less than 150 nm with negative zeta potential. The in vivo results showed a superior effect of ME over free PIP. Colchicine-induced brain toxicity results showed the safety of ME on brain cells. Nevertheless, toxicological results showed a potential ME nephrotoxicity. Oral microemulsion increased PIP efficacy and enhanced its delivery to the brain resulting in better therapeutic outcome compared to the free drug. However, the toxicity of this nanosystem should be carefully taken into consideration on chronic use.

Aims: Cerium oxide nanoparticles (CeO 2 NPs) have been recently introduced into the medical field for their antioxidant properties. The ability of CeO 2 NPs alone or in combination with spironolactone (SP) to attenuate monocrotaline (MCT)-induced pulmonary hypertension and associated right ventricular hypertrophy was studied in rats. A special emphasis was given to endothelin-1 pathway., Materials and Methods: Pulmonary hypertension was induced in albino rats by a single subcutaneous injection of MCT (60 mg/kg). Rats received either single CeO 2 NPs therapy or combined therapy with SP for 2 weeks., Key Findings: CeO 2 NPs improved pulmonary function tests with concomitant decrease in serum endothelin-1 and pulmonary expression of endothelin-1 and its receptor ETAR. Besides, CeO 2 NPs diminished MCT-induced right ventricular hypertrophy and reduced cardiac oxidative stress and apoptosis., Significance: CeO 2 NPs could improve pulmonary hypertension and associated right ventricular hypertrophy with no additive value for SP. Besides being an antioxidant, CeO 2 NPs work through endothelin-1 pathway to improve pulmonary hypertension., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Hepatocellular carcinoma (HCC) is an expanding health problem with a great impact on morbidity and mortality, both in Egypt and worldwide. Recently, metformin and aspirin showed a potential anticancer effect on HCC, although the mechanism of this effect is not fully elucidated., Objective: The current work aimed to investigate the possibility of targeting AMP-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), and β-catenin proteins through combined metformin/aspirin treatment in the HepG2 cell line, and to explore such molecular targets in Egyptian HCC patients., Materials and Methods: HepG2 cells were exposed to increasing concentrations of metformin, aspirin and combined treatment, and an MTT assay was performed to determine half maximal inhibitory concentration (IC 50 ). Caspase-3 activity, cell cycle analysis, and protein expression of AMPK, phosphorylated AMPK (pAMPK) and mTOR proteins were assessed. Furthermore, the expression and localization of β-catenin protein was assessed by immunocytochemistry, and protein expression of pAMPK, mTOR and β-catenin was assessed in Egyptian HCC and cirrhotic tissue specimens., Results: Metformin/aspirin combined treatment had a synergistic effect on cell cycle arrest at the G2/M phase and apoptosis induction in a caspase-dependent manner via downregulation of pAMPK and mTOR protein expression. Additionally, metformin/aspirin combined treatment enhanced cell-cell membrane localization of β-catenin expression in HepG2 cells, which might inhibit the metastatic potential of HepG2 cells. In Egyptian HCC specimens, pAMPK, mTOR and β-catenin proteins showed a significant increased expression compared with cirrhotic controls., Conclusions: Targeting AMPK, mTOR and β-catenin by combined metformin/aspirin treatment could be a promising therapeutic strategy for Egyptian HCC patients, and possibly other HCC patients.

The objectives of this study were to formulate, characterize silymarin-loaded Eudragit nanoparticles (SNPs) and evaluate their hepatoprotective and cytotoxic effects after oral administration. SNPs were prepared by nanoprecipitation technique and were evaluated for particle size, entrapment efficiency, TEM, solid-state characterization, and in vitro drug release. The hepatoprotective activity was evaluated after oral administration of selected SNPs in carbon tetrachloride-intoxicated rats. Potential in vivo acute cytotoxicity study was also assessed. The selected SNPs contained 50 mg silymarin and 50 mg Eudragit polymers (1:1 w/w Eudragit RS 100 & Eudragit LS 100). Morphology of the selected SNPs (particle size of 84.70 nm and entrapment efficiency of 83.45% with 100% drug release after 12 h) revealed spherical and uniformly distributed nanoparticles. DSC and FT-IR studies suggested the presence of silymarin in an amorphous state and absence of chemical interaction. The hepatoprotective evaluation of the selected SNPs in CCl 4 -intoxicated rats revealed significant improvement in the activities of different biochemical parameters (P ≤ 0.01) compared to the marketed product. The histopathological studies suggested that the selected SNPs produced better hepatoprotective effect in CCl 4 -intoxicated rats compared with the commercially marketed product. Toxicity study revealed no evident toxic effect for blank or silymarin-loaded nanoparticles at the dose level of 50 mg/kg body weight. The obtained results suggested that the selected SNPs were safe and potentially offered enhancement in the pharmacological hepatoprotective properties of silymarin.

Background: Cerium oxide nanoparticles (CeO 2 NPs) showed promising effects in neurodegenerative diseases including some animal models of Parkinsonism. However, the implication of CeO 2 NPs in 6-hydroxydopamine (6-OHDA) induced Parkinsonism remains to be investigated., Aim: This study was designed to assess whether CeO 2 NPs treatment could alleviate neurobehavioral and neurobiochemical deficits in 6-OHDA induced neurotoxicity in rats., Material and Methods: 50 rats received left intrastriatal (IS) injection of either saline (control, n = 10) or 6-OHDA (n = 40). At the third week post-lesion, motor dysfunction was verified using neurobehavioral tests. Then diseased rats received intraperitoneal injection of 0.1, 0.5 or 1 mg/kg of CeO 2 NPs or vehicle (10 rats each) for 3 weeks. Rats were subjected to behavioral assessments and then sacrificed for biochemical analyses of the striatum. Striatal dopamine levels, oxidative stress markers including total antioxidant capacity (TAC) and malondialdehyde (MDA), and caspase 3 activity as an apoptotic marker were assessed., Results: Different doses of CeO 2 NPs variably improved motor dysfunctions induced by 6-OHDA injection in open field, Rota Rod and stepping tests. In addition, the neurobiochemical derangements were almost reversed by the 0.5 mg/kg dose of CeO 2 NPs, while 0.1 mg/kg dose was not sufficient to alter biochemical measurements in the striatum. Administration of 1 mg/kg of CeO 2 NPs partially ameliorated striatal dopamine and decreased apoptosis without significant effect on oxidative stress., Conclusion: The present study showed a putative therapeutic role of CeO2NPs in the treatment of 6-OHDA-induced Parkinsonian rats, and suggested their antioxidant and antiapoptotic effects as possible mechanisms for elevated striatal dopamine level and improved motor performance., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The aim of this study was to formulate and evaluate chitosan (CS)/alginate (ALG) nanoparticles (NPs) loaded with furosemide (FSM) in an attempt to enhance its release, permeability and bioavailability. Non-everted gut sac method was used to evaluate the ex vivo permeation of FSM from its suspension and the selected CS/ALG NPs formulation. The pharmacokinetic parameters of FSM subsequent to oral administration of the selected formulation were assessed in rats. In vivo subacute toxicity study of the prepared blank and FSM loaded formulations was evaluated in rats. The selected optimized formulation (F3) showed optimum particle size (PS), polydispersity index (PDI), zeta potential (ZP) and acceptable percentage entrapment efficiency (%EE) of 253.8nm±4.6, 0.25±0.03, -35mV±1 and 96%±1, respectively. The release profile of FSM from the selected formulation was characterized by initial burst effect in 0.1N HCl. Scanning electron microscope (SEM) demonstrated a smooth surface and spherical shape for the lyophilized optimized NPs. Selected CS/ALG NPs (F3) presented a significant enhancement (p≤0.01) in permeation parameters of FSM as well as in T max , C max , AUC 0-24 and AUC 0-∞ . Subacute toxicity study results revealed that the selected formulation was safe and nontoxic. The histopathological inspection of the stomach and small intestine tissues of the loaded NPs (F3) and blank groups reflected no obvious signs of cellular toxicity or inflammatory reaction. CS/ALG NPs loaded with FSM enhanced both drug release and mucus-penetrating ability leading to an overall increase in FSM bioavailability. In addition, the in vivo subacute toxicity study results indicated the safety of the prepared NPs for oral drug delivery., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Aim: This work spotlights on fabrication of CD44-tropic, layer-by-layer (LbL) coated, liquid crystalline nanoparticles of rapamycin (Rap-LbL-LCNPs) to enhance its water solubility and enable its anticancer use., Methods: Rap-LCNPs were fabricated using hydrotrope method and then coated using LbL self-assembly technique., Results: LbL coating strategy successfully reduced monoolein-induced hemolysis and increased LCNPs serum stability. Lyophilized Rap-LbL-LCNPs were successfully sterilized using γ-radiations. In CD44-overexpressed MDA-MB-231 cells, Rap-LbL-LCNPs demonstrated superior cytotoxicity compared with the nontargeted formulation. Rap-LbL-LCNPs showed 3.35-fold increase in bioavailability compared with free drug. Rap-LbL-LCNPs significantly inhibited tumor growth, enhanced animal survival and reduced nephrotoxic and hyperglycemic effects of Rap., Conclusion: LbL coating strategy of Rap-LCNPs could serve as a promising approach that facilitates Rap use in cancer therapy.

Piperine (PIP) is a phytopharmaceutical with reported neuroprotective potential in Alzheimer's disease (AD). Oral PIP delivery suffers from its hydrophobicity and pre-systemic metabolism. In this article, mono-disperse intranasal chitosan nanoparticles (CS-NPs) were elaborated for brain targeting of PIP. Formula optimization was based on particle size (PS), zeta potential (ZP), polydispersity index (PDI), % entrapment efficiency (% EE), release studies, and transmission electron microscopy. AD was induced in 48 male Wistar rats on which full behavioral and biochemical testing was conducted. Brain toxicity was assessed based on Caspase-3 assay for apoptosis and tumor necrosis factor for inflammation. Spherical NPs with optimum % EE (81.70), PS (248.50 nm), PDI (0.24), and ZP (+56.30 mV) were elaborated. PIP-NPs could significantly improve cognitive functions as efficient as standard drug (donpezil injection) with additional advantages of dual mechanism (Ach esterase inhibition and antioxidant effect). CS-NPs could significantly alleviate PIP nasal irritation and showed no brain toxicity. This work was the first to report additional mechanism of PIP in AD via anti-apoptosis and anti-inflammatory effects. To conclude, mucoadhesive CS-NPs were successfully tailored for effective, safe, and non-invasive PIP delivery with 20-folds decrease in oral dose, opening a gate for a future with lower AD morbidity., (© 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.)