Development of chitosan lipid nanoparticles to alleviate the pharmacological activity of piperine in the management of cognitive deficit in diabetic rats.

The aim of the present study was to prepare and evaluate Piperine (PP) loaded chitosan lipid nanoparticles (PP-CLNPs) to evaluate its biological activity alone or in combination with the antidiabetic drug Metformin (MET) in the management of cognitive deficit in diabetic rats. Piperine was successfully loaded on CLNPs prepared using chitosan, stearic acid, Tween 80 and Tripolyphosphate (TPP) at different concentrations. The developed CLNPs exhibited high entrapment efficiency that ranged from 85.12 to 97.41%, a particle size in the range of 59.56-414 nm and a negatively charged zeta potential values (- 20.1 to - 43.9 mV). In vitro release study revealed enhanced PP release from CLNPs compared to that from free PP suspensions for up to 24 h. In vivo studies revealed that treatment with the optimized PP-CLNPs formulation (F2) exerted a cognitive enhancing effect and ameliorated the oxidative stress associated with diabetes. PP-CLNPs acted as an effective bio-enhancer which increased the potency of metformin in protecting brain tissue from diabetes-induced neuroinflammation and memory deterioration. These results suggested that CLNPs could be a promising drug delivery system for encapsulating PP and thus can be used as an adjuvant therapy in the management of high-risk diabetic cognitive impairment conditions.

Copper-doped magnesium phosphate nanopowders for critical size calvarial bone defect intervention.

Calvarial defects of bone present difficult clinical situations, and their restoration using biocompatible materials requires special treatments that enable bone regeneration. Magnesium phosphate (MgP) is known as an osteoinductive biomaterial because it contains Mg2+ ions and P ions that enhance the activity of osteoplast cells and help in bone regeneration. In this study, MgP and CuO-doped MgP were fabricated and characterized for their physicomechanical properties, particle size, morphology, surface area, antibacterial test, and in vitro bioactivity evaluation using the following techniques: X-rays diffraction, Fourier-transformer infrared, TEM, and Brunauer, Emmett and Teller (BET) surface area, X-rays photoelectron spectroscopy (XPS), and Scanning electron microscopy (SEM). Furthermore, these nanopowders were implanted in adult inbred male Wistar rats and studied after two periods (28 and 56 days). The results demonstrated that the obtained semiamorphous powders are in nanoscale (≤ 50 nm). XPS analysis ensured the preparation of MgP as mono MgP and CuO were incorporated in the structure as Cu2+ . The bioactivity was supported by the observation of calcium phosphate layer on the nanopowders' surface. The in vivo study demonstrated success of MgP nanopowders especially those doped with CuO in restoration of calvarial defect bone. Therefore, fabricated biomaterials are of great potential in restoration of bone calvarial defects.

Plant-mediated green synthesis of gold nanoparticles using an aqueous extract of Passiflora ligularis, optimization, characterizations, and their neuroprotective effect on propionic acid-induced autism in Wistar rats.

The current study was conducted to examine an innovative method for synthesizing gold nanoparticles (AuNPs) from an aqueous sweet granadilla (Passiflora ligularis Juss) P. ligularis. Furthermore, the synthesized AuNPs were used to explore their potential neuroprotective impact against propionic acid (PPA)-induced autism. A sweet granadilla extract was used to achieve the synthesis of AuNPs. The structural and dimensional dispersion of AuNPs were confirmed by different techniques, including UV-Vis spectrophotometer (UV-Vis), X-ray Diffraction (XRD) Pattern, Energy Dispersive X-ray (EDX), Zeta potential, and High-Resolution Transmission Electron Microscopy (HRTEM) analysis. The AuNPs mediated by P. ligularis adopt a spherical shape morphology and the particle size was distributed in the range of 8.43-13 nm without aggregation. Moreover, in vivo, the anti-autistic effects of AuNPs administration were higher than those of P. ligularis extract per second. In addition, the reduced anxiety and neurobehavioral deficits of AuNPs were observed in autistic rats which halted the brain oxidative stress, reduced inflammatory cytokines, ameliorated neurotransmitters, and neurochemical release, and suppressed apoptotic genes (p < 0.05). The alleviated antiapoptotic gene expression and histopathological analysis confirmed that the treatment of AuNPs showed significant neural pathways that aid in reducing tissue damage and necrosis. The results emphasize that the biomedical activity was increased by using the green source synthesis P. ligularis -AuNPs. Additionally, the formulation of AuNPs demonstrates strong neuroprotective effects against PPA-induced autism that were arbitrated by a range of different mechanisms, such as anti-inflammatory, antioxidant, neuromodulator, and antiapoptotic effects.

Natural Polyphenols-Resveratrol, Quercetin, Magnolol, and ß-Catechin-Block Certain Aspects of Heroin Addiction and Modulate Striatal IL-6 and TNF-α.

We have examined the effects of four different polyphenols in attenuating heroin addiction using a conditioned place preference (CPP) paradigm. Adult male Sprague Dawley rats received heroin (alternating with saline) in escalating doses starting from 10 mg/kg, i.p. up to 80 mg/kg/d for 14 consecutive days. The rats were treated with distilled water (1 mL), quercetin (50 mg/kg/d), ß-catechin (100 mg/kg/d), resveratrol (30 mg/kg/d), or magnolol (50 mg/kg/d) through oral gavage for 7 consecutive days, 30 min before heroin administration, starting on day 8. Heroin withdrawal manifestations were assessed 24 h post last heroin administration following the administration of naloxone (1 mg/kg i.p). Heroin CPP reinstatement was tested following a single dose of heroin (10 mg/kg i.p.) administration. Striatal interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) were quantified (ELISA) after naloxone-precipitated heroin withdrawal. Compared to the vehicle, the heroin-administered rats spent significantly more time in the heroin-paired chamber (p < 0.0001). Concomitant administration of resveratrol and quercetin prevented the acquisition of heroin CPP, while resveratrol, quercetin, and magnolol blocked heroin-triggered reinstatement. Magnolol, quercetin, and ß-catechin blocked naloxone-precipitated heroin withdrawal and increased striatal IL-6 concentration (p < 0.01). Resveratrol administration was associated with significantly higher withdrawal scores compared to those of the control animals (p < 0.0001). The results of this study show that different polyphenols target specific behavioral domains of heroin addiction in a CPP model and modulate the increase in striatal inflammatory cytokines TNF-α and IL-6 observed during naloxone-precipitated heroin withdrawal. Further research is needed to study the clinical utility of polyphenols and to investigate the intriguing finding that resveratrol enhances, rather than attenuates naloxone-precipitated heroin withdrawal.

Zinc oxide calcium silicate composite attenuates acute tramadol toxicity in mice.

BACKGROUND: Seizures are considered to be the most common symptom encountered in emergency- rushed tramadol-poisoned patients; accounting for 8% of the drug-induced seizure cases. Although, diazepam clears these seizures, the risk of central respiratory depression cannot be overlooked. Henceforth, three adsorbing composites were examined in a tramadol acute intoxication mouse model. METHODS: Calcium Silicate (Wollastonite) either non-doped or wet doped with iron oxide (3%Fe2O3) or zinc oxide (30% ZnO) were prepared. The composites' adsorption capacity for tramadol was determined in vitro. Tramadol intoxication was induced in Swiss albino mice by a parenteral dose of 120 mg/kg. Proposed treatments were administered within 1 min at 5 increasing doses, i.p. The next 30 min, seizures were monitored as an intoxication symptom. Plasma tramadol concentration was recorded after two hours of administration. RESULTS: The 3% Fe2O3-containing composite (CSFe3), was found to be composed of mainly wollastonite with very little alpha-hematite. On the other hand, hardystonite and wellimite were developed in the 30%ZnO-containing composite (CSZn3). Micro-round and irregular nano-sized microstructures were established (The particle size of CS was 56 nm, CSFe3 was 49 nm, and CSZn3 was 42 nm). The CSZn3 adsorption capacity reached 1497 mg of tramadol for each gram. Tramadol concentration was reduced in plasma and seizures were inhibited after its administration to mice at three doses. CONCLUSION: The calcium silicate composite doped with ZnO presented a good resolution of tramadol-induced seizures accompanied by detoxification of blood, indicating its potential for application in such cases. Further studies are required.

Antidepressant-like effects of aqueous extracts of miswak (Salvadora persica) and date palm (Phoenix dactylifera) on depression-like behaviors using CUMS model in male rats.

This study aimed to evaluate the antidepressant-like effects of aqueous extracts of miswak (Salvadora persica) and date palm (Phoenix dactylifera) and their combination on depression-like behaviors using a chronic unpredictable mild stress (CUMS) rat model of depression and to investigate the underlying possible mechanisms. Results showed that CUMS induced depression-like behaviors and anxiety in male rats, as determined by behavioral tests (FST, EPM, and OFT). CUMS significantly increased the levels of plasma malondialdehyde (MDA), cortisol, and pro-inflammatory cytokines (TNF-α and IL-6), in addition to enhancing acetylcholinesterase (ACHE) activity while plasma total antioxidant capacity and serotonin level were reduced. In the prefrontal cortex, CUMS decreased the expression of CREB and BDNF mRNA. However, aqueous extracts of miswak and date palm and their combination effectively ameliorated depressive-like behaviors, body weight loss, and oxidative stress induced by CUMS and restored serotonin and cortisol secretion to normal levels. Furthermore, the studied extracts improved the levels of plasma pro-inflammatory cytokines and CREB and BDNF mRNA expression in the prefrontal cortex. In conclusion, aqueous extracts of miswak and date palm have significant antidepressant-like effects on depression-like behaviors in CUMS model in rats. Moreover, their combination has higher antidepressant-like effects than either extract alone, suggesting that it may be an effective treatment for stress-induced depression-like behaviors acting through modulating pro-inflammatory cytokines and CREB/BDNF signaling pathway in the prefrontal cortex. PRACTICAL APPLICATIONS: Chronic stress is a major contributor to the development of depression. In recent years, there has been a significant increase in the use of herbal remedies for the treatment of a variety of diseases, particularly mood disorders. Because of the side effects encountered by antidepressant drugs such as anxiety, sexual dysfunction, loss of appetite, and inadequate response or developing tolerance to these medications, there is a need for more efficient and convenient antidepressant treatments. According to this study, aqueous extracts of miswak and date palm are effective treatments for stress-induced depression-like behaviors.

Sensory Metabolite Profiling in a Date Pit Based Coffee Substitute and in Response to Roasting as Analyzed via Mass Spectrometry Based Metabolomics.

Interest in developing coffee substitutes is on the rise, to minimizing its health side effects. In the Middle East, date palm (Phoenix dactylifera L.) pits are often used as a coffee substitute post roasting. In this study, commercially-roasted date pit products, along with unroasted and home-prepared roasted date pits, were subjected to analyses for their metabolite composition, and neuropharmacological evaluation in mice. Headspace SPME-GCMS and GCMS post silylation were employed for characterizing its volatile and non-volatile metabolite profile. For comparison to roasted coffee, coffee product was also included. There is evidence that some commercial date pit products appear to contain undeclared additives. SPME headspace analysis revealed the abundance of furans, pyrans, terpenoids and sulfur compounds in roasted date pits, whereas pyrroles and caffeine were absent. GCMS-post silylation employed for primary metabolite profiling revealed fatty acids' enrichment in roasted pits versus sugars' abundance in coffee. Biological investigations affirmed that date pit showed safer margin than coffee from its LD50, albeit it exhibits no CNS stimulant properties. This study provides the first insight into the roasting impact on the date pit through its metabolome and its neuropharmacological aspects to rationalize its use as a coffee substitute.

Novel, cost-effective, Cu-doped calcium silicate nanoparticles for bone fracture intervention: Inherent bioactivity and in vivo performance.

Copper (Cu)-doped calcium silicate nanoparticles were synthesized by a wet precipitation method as economical bone fracture filler. The aim was to improve the overall physicochemical properties, bioactivity, and biological performance of the bone fracture filler prepared herein. The synthesized nanoparticles were evaluated using X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), and transmission electron microscopy (TEM). The bioactivity of the prepared nanoparticles was investigated after immersion in simulated body fluid (SBF) by means of inductively coupled plasma (ICP), SEM coupled with energy dispersive X-rays (EDX), and FTIR. The size and bioactivity of the prepared nanoparticles after 15 days of immersion in SBF was dependent on the Cu concentrations. The fracture healing ability of the fabricated nanoparticles on adult aged male Wistar rats was enhanced by the presence of copper. All the obtained results are of high relevance for fabricating improved Cu-doped calcium silicate nanoparticles (∼50 nm) as low cost bone fracture filler. In addition, the in vivo study presented complete healing of the tibiae bone with normal architecture of bone tissue specifically calcium silicate nanoparticles doped with 3% and 5% Cu. Hence, the presence of copper is a promising tactic for improving the biological properties of calcium silicate. Therefore, the designed nanoparticles have huge potential for the treatment of bone fractures. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 107B: 388-399, 2019.

Novel polysaccharide hybrid scaffold loaded with hydroxyapatite: Fabrication, bioactivity, and in vivo study.

The main goal of this study was to produce a novel porous scaffold for rapid in vivo bone healing behavior. Lyophilization technique was used to produce this highly porous hybrid scaffold from Na-alginate (S) and hydroxyethylcellulose (HEC) impregnated with different concentration of hydroxyapatite (HA). After cross-linking the scaffolds, their incubation was carried out in simulated body fluid (SBF) for 4 weeks at 37 °C to investigate their bioactivity. A number of techniques were employed (e.g., XRD, FTIR, SEM, EDX, and texture analyzer) to characterize the designed scaffolds. It was observed that the mechanical properties of the scaffolds increase deformation energy (182 ±â€¯16 J/m3) and rigidity gradient (19.44 ±â€¯0.85 Pa) after loading with HA. Furthermore, the scaffolds were implanted in femur critical size defects (2 mm) of adult male Wistar rats for 6 weeks. In vitro and in vivo analyses demonstrated impressive bioactivity and biocompatibility for the prepared scaffolds, especially those containing HA. Based on the obtained results we conclude that the designed scaffolds are promising solutions for bone regeneration applications.

Newly developed controlled release subcutaneous formulation for tramadol hydrochloride.

This study presents a drug delivery system of poly (Ɛ-caprolactone) (PCL) ribbons to optimize the pharmaceutical action of tramadol for the first time according to our knowledge. PCL ribbons were fabricated and loaded with tramadol HCl. Ribbons were prepared by slip casting technique and coated with dipping technique with ß-cyclodextrin. The chemical integrity and surface morphology of the ribbons were confirmed using FTIR and SEM coupled with EDX. In addition, thermodynamic behavior of the fabricated ribbons was investigated using DSC/TGA. Tramadol loading into PCL ribbons, biodegradation of ribbons and tramadol release kinetics were studied in PBS.The results revealed that the formulated composition did not affect the chemical integrity of the drug. Furthermore, SEM/EDX confirmed the inclusion of tramadol into the PCL matrix in homogenous distribution pattern without any observation of porous structure. The particle size of loaded tramadol was found to be in the range of (2-4 nm). The formulated composition did not affect the chemical integrity of the drug and should be further investigated for bioavailability. Tramadol exhibited controlled release behavior from PCL ribbons up to 45 days governed mainly by diffusion mechanism. The fabricated ribbons have a great potentiality to be implemented in the long term subcutaneous delivery of tramadol.

Determination of delta-9-tetrahydrocannabinol content of cannabis seizures in Egypt.

OBJECTIVE: To determine the delta-9-tetrahydrocannabinol (THC) content of cannabis seizures in Egypt. METHODS: Unheated and heated extracts of cannabis seizures were prepared from the dried flowering tops and leaves (marijuana) or from the resin (hashish) and subjected to analysis using high performance liquid chromatography (HPLC). RESULTS: The heated resin extract had the peak of THC in a relative ratio of 31.34%, while extracting the resin directly without heating contained only 18.34% of THC. On the other hand, marijuana showed minimum percentage of THC at 11.188% on heating and 9.55% without heating. CONCLUSIONS: These results indicate the high potency of the abused cannabis plant in the illicit Egyptian market.

Enhanced oral bioavailability and sustained delivery of glimepiride via niosomal encapsulation: in-vitro characterization and in-vivo evaluation.

This study was designed to investigate the potency of niosomes, for glimepiride (GLM) encapsulation, aiming at enhancing its oral bioavailability and hypoglycemic efficacy. Niosomes containing nonionic surfactants (NIS) were prepared by thin film hydration technique and characterized. In-vitro release study was performed using a dialysis technique. In-vivo pharmacodynamic studies, as well as pharmacokinetic evaluation were performed on alloxan-induced diabetic rats. GLM niosomes exhibited high-entrapment efficiency percentages (E.E. %) up to 98.70% and a particle size diameter ranging from 186.8 ± 18.69 to 797.7 ± 12.45 nm, with negatively charged zeta potential (ZP). Different GLM niosomal formulation showed retarded in vitro release, compared to free drug. In-vivo studies revealed the superiority of GLM niosomes in lowering blood glucose level (BGL) and in maintaining a therapeutic level of GLM for a longer period of time, as compared to free drug and market product. There was no significant difference between mean plasma AUC0-48 hr of GLM-loaded niosomes and that of market product. GLM-loaded niosomes exhibited seven-fold enhancement in relative bioavailability in comparison with free drug. These findings reinforce the potential use of niosomes for enhancing the oral bioavailability and prolonged delivery of GLM via oral administration.

Nanofiber-expanded stem cells mitigate liver fibrosis: Experimental study.

OBJECTIVES: This study examines a pretreatment strategy to strengthen the hepatic lineage divergence of mesenchymal stem cells (MSCs). DESIGN AND METHODS: BMSCs were expanded in the presence or absence of nanofiber (NF) and treated with growth factors (GF) prior to transplantation. Thioacetamide (TA) was used for liver fibrosis induction and transplantation of NF-expanded BMSCs was compared biochemically and histologically to the cells expanded without NF scaffold. RESULTS: The ultraweb NF caused better proliferation and characterization of MSCs. MSCs transplantation significantly improved liver functions, increased hepatic HGF and Bcl-2 levels, whereas decreased serum fibronectin, hepatic TNF-α and TGF-ß1 levels. Hepatic HNF4α, FOXa2, CYP7a1 genes expression were enhanced while ß-5-Tub and AFP genes expression were depressed. Histological study documented these results. Differentiated NF-MSCs showed pronounced enhancement of the aforementioned parameters as compared to differentiated MSCs in the absence of NF. CONCLUSION: pretreatment with growth factors in the presence of NF augment homing, repopulation and hepatic differentiation abilities of MSCs and proves to be a promising approach for the treatment of liver fibrosis.

Neuroprotective effects of bee venom acupuncture therapy against rotenone-induced oxidative stress and apoptosis.

Parkinson's disease (PD), the most common neurodegenerative movement disorder, is characterized by dopaminergic neurodegeneration, mitochondrial impairment, and oxidative stress. Exposure of animals to rotenone induces a range of responses characteristic of PD, including reactive oxygen species production and dopaminergic cell death. Although l-dopa is the drug of choice for improving core symptoms of PD, it is associated with involuntary movements. The current study was directed to evaluate the neuroprotective effect of bee venom acupuncture therapy (BVA) against rotenone-induced oxidative stress, neuroinflammation, and apoptosis in PD mouse model. Forty male Swiss mice were divided into four groups: (1) received saline solution orally and served as normal control, (2) received rotenone (1.5 mg/kg, s.c. every other day for 6 doses), (3) received rotenone concomitantly with l-dopa (25 mg/kg, daily, p.o. for 6 days), and finally (4) received rotenone concomitantly with BVA (0.02 ml once every 3 days for two weeks). Rotenone-treated mice showed impairment in locomotor behavior and a significant reduction in brain dopamine, serotonin, norepinephrine, GSH levels, and paraoxonase activity, whereas a significant increase was observed in brain malondialdehyde, tumor necrosis factor-α, interleukin-ß levels besides DNA damage, and over-expression of caspase-3, Bax, and Bcl-2 genes. Significant improvement of the aforementioned parameters was demonstrated after BVA compared to l-dopa therapy. In conclusion, bee venom normalized all the neuroinflammatory and apoptotic markers and restored brain neurochemistry after rotenone injury. Therefore, BVA is a promising neuroprotective therapy for PD.