During the recent years, more attentions have been focused on lipid base drug delivery system to overcome some limitations of conventional formulations. Among these delivery systems solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) are promising delivery systems due to the ease of manufacturing processes, scale up capability, biocompatibility, and also biodegradability of formulation constituents and many other advantages which could be related to specific route of administration or nature of the materials are to be loaded to these delivery systems. The aim of this article is to review the advantages and limitations of these delivery systems based on the route of administration and to emphasis the effectiveness of such formulations.

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Ethanol injection is one of the techniques frequently used to produce liposomes which favors both simplicity and safety. In this process, an ethanolic solution of lipids is rapidly injected into an aqueous medium through a needle, dispersing the phospholipids throughout the medium and promoting the vesicle formation. Being a critical parameter that determines the fate of liposome and its distribution, we studied different factors affecting the particle size of liposomes including different phospholipid (Phosal^® 53 MCT) and cholesterol concentrations and the use of different types of non-ionic surfactants at fixed Phosal^® 53 MCT concentration of 50 mg per formulation. Both Phosal^® 53 MCT and cholesterol concentration had direct effect on liposomes particle size. Non-ionic surfactants produced liposomes of smaller particle size when compared to conventional liposomes formed using Phosal^® 53 MCT 300 mg per formulation only, whereas this effect was diminished when higher Phosal^® 53 MCT to cholesterol ratios were used that obviously increased liposomes size. Smaller liposomes sizes were obtained upon using non-ionic surfactants of lower hydrophilic/hydrophobic balance (HLB) as both Tween 80 and Cremophor RH 40 produced liposomes of smaller particle size compared to Poloxamer 407. The smallest liposomes particle size was successfully obtained in the formulation comprising 300 mg Phosal^® MCT, 150 mg cholesterol and 50 mg Tween 80.

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Rivastigmine hydrogen tartrate (RHT), one of the potential cholinesterase inhibitors, has received great attention as a new drug candidate for the treatment of Alzheimer's disease. However, the bioavailability of RHT from the conventional pharmaceutical forms is low because of the presence of the blood brain barrier. The main aim of the present study was to prepare positively charged Eudragit RL 100 nanoparticles as a model scaffold for providing a sustained release profile for RHT. The formulations were evaluated in terms of particle size, zeta potential, surface morphology, X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), and differential scanning calorimetry (DSC). Drug entrapment efficiency and in vitro release properties of lyophilized nanoparticles were also examined. The resulting formulations were found to be in the size range of 118 nm to 154 nm and zeta potential was positive (+22.5 to 30 mV). Nanoparticles showed the entrapment efficiency from 38.40 ± 8.94 to 62.00 ± 2.78%. An increase in the mean particle size and the entrapment efficiency was observed with an increase in the amount of polymer. The FTIR, XRD, and DSC results ruled out any chemical interaction between the drug and Eudragit RL100 polymer. RHT nanoparticles containing low ratio of polymer to drug (4:1) presented a faster drug release and on the contrary, nanoparticles containing high ratio of polymer to drug (10:1) were able to give a more sustained release of the drug. The study revealed that RHT nanoparticles were capable of releasing the drug in a prolonged period of time and increasing the drug bioavailability.

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The low solubility of the plant-extracted agent like D-limonene in cancer therapy is a critical problem. In this study, we prepared D-limonene-loaded niosomes (D-limonene/Nio) for cancer therapy through in vitro cytotoxicity assay of HepG2, MCF-7, and A549 cell lines. The niosomal formulation was prepared by film hydration technique with Span^® 40: Tween^® 40: cholesterol (35:35:30 molar ratio) and characterized for vesicle distribution size, morphology, entrapment efficiency (EE%), and in vitro release behaviour. The obtained niosomes showed a nanometric size and spherical morphology with EE% about 87 ± 1.8%. Remarkably prolonged release of D-limonene from niosomes compared to free D-limonene observed. The loaded formulation showed significantly enhanced cytotoxic activity with all three cancer cell lines (HepG2, Macf-7 and A549) at the concentration of 20 μM. These results indicated that niosome loaded with phytochemicals can be a promising nano-carrier for cancer therapy applications

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The aim of the current study was to investigate the antioxidative effect of metformin (MTF) on bile duct ligation (BDL)-induced hepatic disorder and histological damage in rats. The rats were divided into 4 groups including sham control (SC), BDL alone (BDL surgery), MTF1 (BDL surgery and administration of 250 mg/kg of MFM) and MTF2 (BDL surgery and administration of 500 mg/kg of MTF). After BDL, the animals treated with MTF by gavage for 10 days. Hematoxylin and eosin staining, biochemical analysis and oxidative stress markers were assayed to determine histological alterations, liver functions, and oxidant/antioxidant status. Hepatotoxicity was verified by remarkable increase in plasma levels of aminotransferases and alkaline phosphatase activity and liver histology 10 days after the BDL surgery. Our finding showed that treatment with MTF markedly reduced plasma alkaline phosphatase and alleviated liver injury indices (P ≤ 0.05). Furthermore, BDL caused a considerable increase in the protein carbonyl and malondialdehyde content (P ≤ 0.05). However, MTF reduces oxidative stress by constraining the protein oxidation and lipid peroxidation, and increases antioxidant reserve by increasing the ferric reducing ability of plasma and reducing glutathione levels. MTF exerts antioxidative effects in the liver fibrosis and may represent a hepato-protective effect when given to rats with BDL-induced hepatic injury.

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Aromatase inhibitors (AIs) as effective candidates have been used in the treatment of hormone-dependent breast cancer. In this study, we have proposed 300 structures as potential AIs and filtered them by Lipinski's rule of five using DrugLito software. Subsequently, they were subjected to docking simulation studies to select the top 20 compounds based on their Gibbs free energy changes and also to perform more studies on the protein-ligand interaction fingerprint by AuposSOM software. In this stage, anastrozole and letrozole were used as positive control to compare their interaction fingerprint patterns with our proposed structures. Finally, based on the binding energy values, one active structure (ligand 15) was selected for molecular dynamic simulation in order to get information for the binding mode of these ligands within the enzyme cavity. The triazole of ligand 15 pointed to HEM group in aromatase active site and coordinated to Fe of HEM through its N4 atom. In addition, two π-cation interactions was also observed, one interaction between triazole and porphyrin of HEM group, and the other was 4-chloro phenyl moiety of this ligand with Arg115 residue.

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In recent years, the use of the antioxidant in reducing heavy metal toxicities has increased worldwide. Curcumin has been reported to have a strong antioxidant activity. In this study, we investigated the protective effects of curcumin on lead acetate-induced testicular damage in rats. The sample used 40 male rats divided into 5 groups: negative control (rats were given daily with corn oil); positive control (rats were given daily with lead acetate 50 mg/kg BW orally once in a day for 35 days); and the treatment group (rats were given the curcumin 100 mg, 200 mg, and 400 mg/kg BW orally once in a day for 40 days, and on the 5^th day, were given lead acetate 50 mg/kg BW one h after the curcumin administration). After 40 days, levels of malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GPx) in testicular tissue, and sperm count, motility and viability in the epididymis were measured in rats. Testis samples were also collected for histopathological studies. Results showed that lead acetate administration significantly decreased the SOD, GPx, and increased MDA levels. Lead acetate also decreased the sperm count, motility, viability, and altered histopathological testis (testicular damage, necrosis of seminiferous tubules and loss of spermatid) compared to the negative control. However, administration of curcumin significantly improved the histopathological in testis, increased the sperm count, motility, viability, and also significantly increased the SOD, GPx, and decreased MDA in testis of lead acetate-treated rats. From the results of this study we concluded that the curcumin could be a potent natural product provide a promising protective effect against lead acetate induced testicular toxicity in rats.

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Type 2 diabetes often leads to dislipidemia and abnormal activity of hepatic enzymes. The purpose of this study was to evaluate the antidiabetic and hypolipidemic properties of Rhus coriaria (R. coriaria) seed extrac on nicotinamide-streptozotocin induced type 2 diabetic mice. In this experimental study, 56 male Naval Medical Research Institute mice (30-35 g) were randomly separated into seven groups: control, diabetic group, diabetic mice treated with glibenclamide (0.25 mg/kg, as standard antidiabetic drug) or R. coriaria seed extract in doses of 200 and 300 mg/kg, and control groups received these two doses of extract orally for 28 days. Induction of diabetes was done by intraperitoneal injection of nicotinamide and streptozotocin. Ultimately, body weight of mice, blood levels of glucose, insulin, hepatic enzymes, leptin, and lipid profile were assayed. After induction of type 2 diabetes, level of glucose, cholesterol, low density lipoprotein, serum glutamic oxaloacetic transaminase, and serum glutamic pyruvic transaminase increased and level of insulin and high density lipoprotein decreased remarkably. Administration of both doses of extract decreased level of glucose and cholesterol significantly in diabetic mice. LDL level decreased in treated group with dose of 300 mg/kg of the extract. Although usage of the extract improved level of other lipid profiles, insulin and hepatic enzymes, changes weren't significant. This study showed R. coriaria seeds administration has a favorable effect in controlling some blood parameters in type 2 diabetes. Therefore it may be beneficial in the treatment of diabetes.

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Colitis is an inflammatory disease of the intestine with unknown etiology involving multiple immune, genetic, and environmental factors. We were interested to examine the effect of total extract from Dracocephalum Kotschyi (D. kotschyi) Boiss. on the experimental colitis. D. kotschyi hydroalcoholic extract (10, 20, and 40 mg/kg) or apigenin (5, 10, and 20 mg/kg) were administered orally 2 h prior to induction of colitis which was induced by intrarectal administration of acetic acid (4%) in rats. Prednisolone (4 m/kg) was used as the standard drug for comparison. Biochemical evaluation of inflamed colon was performed by measuring myeloperoxidase (MPO) activity. After 5 days treatment, mucosal ulceration was evaluated. Intrarectal instillation of acetic acid caused significant inflammatory reactions as indicated by macroscopic and microscopic changes. The activity of MPO increased in vehicle treated groups while recovered to normal level by pretreatment of animals with D. kotschyi extract, apigenin, or prednisolone. D. kotschyi and apigenin-treated groups showed significantly lower score values of macroscopic and microscopic characters when compared with the vehicle-treated negative control group. The beneficial effect of apigenin was comparable with that of prednisolone. This research has shown the anti-inflammatory potential of D. kotschyi extract and apigenin in experimentally induced colitis.

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Inhalable dry powders containing poly lactic-co-glycolic acid (PLGA) nanoparticles (NPs) were developed for the delivery of tadalafil (TAD) for treatment of life-treating pulmonary arterial hypertension. Taguchi design was employed to evaluate the effects of different formulation variables on the physicochemical characteristics of PLGA-NPs prepared using emulsion solvent evaporation method. Inhalable PLGA-NPs of TAD were successfully prepared by co-spray drying the PLGA-NPs with inert carriers. Physicochemical characteristics and in vitro deposition of the aerosolized drug were also evaluated. The optimized formulation was prepared using 7.5 mg of PLGA, 2.5 mg of TAD, sonication time of 6 min and 2% polyvinyl alcohol (PVA) as the stabilizer. The optimized aqueous/oil phase ratio for PLGA-NPs preparation was 10:1. Polymer/drug ratio was the most effective parameter on the release efficiency. Encapsulation efficiency, zeta potential and particle size of PLGA-NPs were more affected by aqueous/organic phase ratio. The spray dried powders containing PLGA-NPs had a mass median aerodynamic diameter (MMAD) in the range of 1.4–2.8 μm that was suitable for TAD delivery to the deep region of lung. The presence of L- leucine in mannitol containing formulations decreased the interparticulate forces between particles and increased significantly the process yield and fine particle fraction (FPF). The results indicated that prepared dry powders containing TAD-loaded PLGA-NPs were suitable for inhalation and has the potential for the treatment of pulmonary arterial hypertension.

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At the present time, utilization of essential oils in food preservation to prevent bacterial and fungal growth and improve shelf life and safety of the food products has notably gained increased interest. The aim of the present study was to improve the antimicrobial efficacy of citral as a natural preservative using nanostructured lipid carriers (NLCs). Formulations of NLCs were characterized using particle size analysis and scanning electron microscopy methods. Possible citral-carrier interaction and citral encapsulation efficiency percent (EE%) were assessed by Fourier transform infrared (FTIR) spectroscopy and gas chromatography techniques, respectively. Antimicrobial activity, minimum inhibitory concentration (MIC), and minimum bactericidal concentration (MBC) of citral-loaded NLCs were evaluated and compared with the conventional citral emulsion against various gram-positive bacteria (Staphylococcus aureus, Bacillus cereus), gram-negative bacteria (Escherichia coli), and fungi (Candida albicans). Citral-loaded NLCs were spherically shaped nanosized (74.8 nm) particles with narrow size distribution, high EE% (99.84%), and appropriate physical stability during 90 days of storage period. FTIR spectra indicated the interaction between citral and formulation ingredients, which justified the obtained high EE% value. The MIC and MBC values of citral-loaded NLCs were lower than those of citral emulsion for all microorganisms. NLCs formulation showed remarkable capability of encapsulating essential oil and increasing antimicrobial properties to offer effective preservation in food industry.

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In the current study, we aimed to develop a novel injectable thermosensitive hydrogel for simultaneous intra-tumoral administration of paclitaxel (PTX) and doxorubicin hydrochloride (DOX). At first, mixed micelles composed of Pluronic F127 and α-tocopheryl polyethylene glycol 1000 succinate (TPGS) was loaded with PTX and their physicochemical properties including particle size, zeta potential, drug loading content, entrapment efficiency, and the drug release were investigated in details. In the second step, the optimized PTX-loaded micelles prepared in the first step were incorporated into the thermosensitive Pluronic F127/hyaluronic acid (PF127/HA) hydrogel containing fixed amount of DOX. Gel formation temperature, rheological properties, injectability, degradation rates of the hydrogel, and the release rate of PTX and DOX from the hydrogel were examined. The mean particle sizes and zeta potentials of the PTX-loaded micelles were 157.5 ± 20.1 nm and -9.6 ± 1.1 mV, respectively. The entrapment efficiency of the formulation was about 51%. The hydrogel containing PTX-loaded micelles and DOX existed as a solution with low viscosity at 4 °C converted to a semisolid upon increasing the temperature to 35 °C. DOX was completely released from the hydrogel within 12 h, while 40-80% of PTX could be released from the different formulations during 3 days. This novel thermosensitive hydrogel prepared in the current study could be efficiently used for co-delivery of PTX and DOX in solid tumor types.

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Cyclophosphamide (CP), as a chemotherapy drug, induces hepatotoxicity through causing oxidative stress. Atorvastatin (ATV) at a low dose has antioxidant and anti-inflammatory properties. The present study was designed to investigate the protective effects of ATV against CP-induced hepatotoxicity in rat. In this experimental study, 32 rats were treated with ATV orally at a dose of 10 mg/kg for 10 consecutive days, 5 days before and 5 days after the administration of a single intraperitoneal injection of CP (150 mg/kg). The hepatoprotective effect of ATV was evaluated by measuring liver function markers, oxidative markers, histological and immunohistochemical assays. The biochemical results showed that administration of CP increased hepatic biomarkers enzymes as aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) levels. CP increased malondialdehyde (MDA), protein carbonyl (PC) and decreased glutathione (GSH) content in rats. Moreover, administration of CP was associated with periportal leucocyte infiltration, dilation sinusoids, hepatocyte vacuolation, congestion and hemorrhage in livers of rats. CP significantly increased immunoreactivity of caspase-3 as a marker of apoptosis in liver tissue. ATV markedly mitigated liver injury through reduction in oxidative stress biomarkers, histopathological findings and apoptosis. The antioxidant and anti-apoptotic activities of ATV are main proposed mechanisms involved in its hepatoprotective effects against CP-induced hepatic injury.

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Chronic liver disease (CLD) affects millions of people and its impact on bone loss has become a subject of interest. Nitric oxide and endogenous opioids are suggested to increase during cholestasis/cirrhosis and may impact bone resorption by different mechanisms. The receptor activator of nuclear factor-κB (RANK)/RANK-ligand (RANKL)/osteoprotegerin (OPG) signaling pathway regulates bone resorption, but its role in metabolic bone disease subsequent to CLD is unknown. We aimed to investigate the involvement of nitrergic and opioidergic systems in bone loss relative to the RANK/RANKL/OPG pathway, in bile duct-ligated (BDL) rats. Eighty BDL/sham-operated (SO) rats received injections of 3 mg/kg/day Nω-Nitro-L-arginine methyl ester ± naltrexone (10 mg/kg/day) or saline for 28 days. Plasma bone turnover markers, OPG, RANK, and RANKL along with mRNA expression levels of the latter three were assessed. Plasma bone turnover markers and OPG level increased, but RANKL decreased in the BDL group compared with their SO controls (both: P ≤ 0.05). Administration of naltrexone reduced bone turnover markers and OPG level while increased RANKL content in comparison to BDL rats (P ≤ 0.05). As compared to untreated BDL rats, nitric oxide inhibition showed no effect on bone turnover marker i.e. OPG, RANK, and RANKL levels. BDL significantly increased RANK mRNA, but had no significant effect on RANKL and OPG mRNA expression. The lack of association between plasma levels and quantitative gene expression of RANKL and OPG suggests an indirect function of these markers in BDL rats. Considering that opioid receptor blockage by naltrexone in BDL animals caused a significant decrease in OPG and an increase in RANKL plasma contents, it could be postulated that the opioidergic system may have a regulatory effect on these bone markers.

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Thymoquinone (TQ) is the main active constituent of Nigella sativa seeds. The objective of this study was to explore the protective effects of TQ on diazinon (DZN)-induced liver toxicity in the mouse model. The animals were divided into five groups of 6 each and treated intraperitoneally. Group 1 received the vehicle, group 2 was given 16 mg/kg DZN, group 3 received 5 mg/kg TQ, and groups 4 and 5 were treated with 1.25 and 5 mg/kg of TQ as well as 16 mg/kg DZN, respectively. Finally, butyrylcholinesterase (BChE), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) serum activity as well as nitric oxide (NO), lipid peroxidation (LPO), total antioxidant capacity (TAC), total thiol molecule (TTM), and histopathological experiments were evaluated in the liver samples. Our findings showed that DZN caused a significant increase in ALT (P < 0.01), AST (P < 0.001), ALP (P < 0.001) serum levels, LPO (P < 0.001) and NO (P < 0.001), the depletion of the TAC (P < 0.05) and TTM (P < 0.001), and structural changes in the liver tissue. Following TQ administration, a significant improvement was observed in the oxidative stress biomarkers in the liver tissue. In addition, our biochemical findings were correlated well to the histopathological examinations. In conclusion, the data from this study indicate that the administration of TQ may prevent liver damage by preventing free radical formation in animals exposed to DZN.

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Several attempts have so far been made in the search of new anticancer agents of plant origin. Some studies have reported that different species of Pine genus possess cytotoxic activities against various cancer cell lines. In the present study, we evaluated the cytotoxic effects of Pinus eldarica bark and leaf extracts or leaf essential oil on HeLa and MCF-7 tumor cell lines. Hydroalcoholic and phenolic extracts and the essential oil of plant were prepared. Total phenolic contents of the extracts were measured using Folin-Ciocalteu reagent. Essential oil components were determined by gas chromatography-mass spectroscopy (GC-MS). Cytotoxic activity of the extracts and essential oil against HeLa and MCF-7 tumor cell lines were assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. The polyphenolic content of hydroalcoholic and phenolic extracts of the bark and hydroalcoholic extract of the leaf were 48.31%, 47.2%, and 8.47%, respectively. According to the GC-MS analysis, the major components of the leaf oil of P. eldarica were: ß -caryophyllene (14.8%), germacrene D (12.9%), α-terpinenyl acetate (8.15%), α -pinene (5.7%), and -α humulene (5.9%). Bark extracts and leaf essential oil of P. eldarica significantly reduced the viability of both HeLa and MCF-7 cells in a concentration dependent manner. However, leaf extract showed less inhibitory effects against both cell lines. The essential oil of P. eldarica was more cytotoxic than its hydroalcoholic and phenolic extracts. The terpenes and phenolic compounds were probably responsible for cytotoxicity of P. eldarica. Therefore, P. eldarica might have a good potential for active anticancer agents.

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Deferoxamine mesylate (DFO) is administered as a slow subcutaneous or intravenous infusion due to its poor oral bioavailability and lack of dose proportionality. The aim of the present study was to prepare and optimize polymeric micelles containing DFO, as an oral drug delivery system for increasing permeability and oral bioavailability. Based on a full factorial design with three variables in two levels, eight polymeric micelle formulations were made using film hydration method. Two polymers including 0.1% of carbomer 934 and Poloxamer^® P 407 and two blends of surfactant + co-surfactant including 1 and 2 fold of critical micelle concentration of Labrafil^® + Labrasol^® and Tween 80 + Span 20 were used to prepare polymeric micelles. The effect of variables on particle size (PS), entrapment efficiency (EE), drug release, thermal behavior, in vitro iron bonding and ex vivo rat intestinal permeability were evaluated. The PS of polymeric micelles was less than 83 nm that showed 80% EE with continuous drug release pattern. The change in type of polymer from carbomer to Ploxamer^® significantly increased drug release. All polymeric micelles increased the iron-bonding ability of DFO compared to control. This could be due to surfactants that can play an important role in this ability. Polymeric micelles increased drug permeability through intestine more than 2.5 folds compared to control mainly affected by polymer type. Optimized polymeric micelle consists of Tween 80 and Span 20 with 1.35 folds of critical micelle concentration and Poloxamer^® demonstrated 97.32% iron bonding and a 3-fold increase in permeation through the rat intestine compared with control.

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Vitamin B6 is a cofactor of various enzymes influencing numerous neurotransmitters in the brain such as norepinephrin, and serotonin. Since these neurotransmitters influence mood, the aim the present work to evaluate the effect of vitamin B6 on depression and obsessive compulsive behavior when coadministred with clomipramine, fluoxetine, or venlafaxine. Male mice weighing 25-30 g were used. The immobility time and latency to immobility was measured in the forced swimming test as a model of despair and the number of marbles buried (MB) in an open field was used as the model of obsessive compulsive behavior in mice. Vitamin B6 (100 mg/kg, i.p.) was injected to animals for six days and on the last day antidepressants were also administered and the tests took place with 30 min intervals. Immobility was reduced in vitamin B6 + clomipramine (141 ± 15 s) or venlafaxine (116 ± 15 s) but it was not significant comparing with the drugs alone. No beneficial response was seen in co-administration of vitamin B6 with fluoxetine compared to fluoxetine alone. Fluoxetine also increased the latency to first immobility. Vitamin B6 + clomipramine or venlafaxine reduced the MB behaviour by 77 ± 12% and 83 ± 7% respectively, while using them alone was less effective. Fluoxetine was very effective in reducing MB behaviour (95 ± 3.4%) thus using vitamin B6 concomitantly was not useful. Therefore vitamin B6 as a harmless agent could be suggested in depression and particularly in obsessive compulsive disorder as an adjuvant for better drug response.

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Increasing multiple drug resistant (MDR) strains of Acinetobacter baumannii has aggravated curiosity in development of alternative therapy. Bacteriophages are often considered as alternative agents for controlling A. baumannii infections. In the present study two lytic phages for MDR A. baumannii were isolated and their efficacy and host ranges were evaluated. The phages were isolated from hospital wastewater. Electron microscopy revealed that IsfAB78 might belong to Myoviridae and IsfAB39 to Podoviridae. Initial characterization of phages showed that they have narrow host range and failed to infect relative and non- relative bacteria. Both phages decreased the A. baumannii turbidity significantly, indicating that these isolated phages may be considered as candidates for phage therapy.

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The use of heat shock protein 90 inhibitors like 17-allylamino-17-demethoxy-geldanamycin (17-AAG) has been recently introduced as an attractive anticancer therapy. It has been shown that 17-AAG may potentiate the inhibitory effects of some classical anticolorectal cancer (CRC) agents. In this study, two panels of colorectal carcinoma cell lines were used to evaluate the effects of 17-AAG in combination with capecitabine and oxaliplatin as double and triple combination therapies on the proliferation of CRC cell lines. HT-29 and all HCT-116 cell lines were seeded in culture media in the presence of different doses of the mentioned drugs in single, double, and triple combinations. Water-soluble tetrazolium-1 (WST-1) assay was used to investigate cell proliferation 24 h after treatments. Then, dose-response curves were plotted using WST-1outputs, and IC₅₀ values were determined. For double and triple combinations respectively 0.5 × IC₅₀ and 0.25 × IC₅₀ were used. Data was analyzed with the software CompuSyn. Drug interactions were analyzed using Chou-Talalay method to calculate the combination index (CI).The data revealed that 17-AAG shows a potent synergistic interaction (CI < 1) with oxaliplatin and capecitabine in double combinations (0.5 × IC₅₀) in both cell lines. In the case of triple combinations, the findings showed an antagonistic interaction (CI > 1) in HT-29 and a synergistic effect (CI < 1) in HCT-116 (0.25 × IC₅₀) cell lines. It was concluded that double combinations of 17-AAG with oxaliplatin or capecitabine might be effective against HCT-116 and HT-29 cell lines. However, in triple combinations, positive results were seen only against HCT-116. Further investigation is suggested to confirm the effectiveness of these combinations in clinical trials.

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Diabetes mellitus is developed by lack of insulin secretion or reduction of tissues sensitivity to insulin, which lead to serious complications. The aim of this study is to evaluate antihyperlipidemic effect of betulinic acid (BA) on streptozotocin-nicotinamide (STZ-NA) induced diabetic mice. In this experimental study, seventy adult male NMRI mice (20-25 g) were divided randomly into seven groups (n = 10) of control, sham, diabetes, diabetes + BA (10, 20 and 40 mg/kg), and diabetes + metformin (200 mg/kg). Diabetes was induced by intraperitoneal (i.p.) injection of a single dose of STZ (50 mg/kg) 15 min after an i.p. administration of nicotinamide (NA) (120 mg/kg). BA and metformin were orally administered and after two weeks blood samples were taken. Blood levels of leptin, adiponectin, lipid profile and liver enzyme were then measured. One day after the last drug administration, liver was removed to evaluate the histological changes. A significant increase (P < 0.05) in the plasma levels of leptin, alanine-aminotransferase (ALT), aspartate-aminotransferase (AST), alkaline phosphatase (ALP), low density lipoprotein cholesterol (LDL-C), cholesterol, and a significant decrease in adiponectin and high density lipoprotein cholesterol (HDL-C) were observed in diabetic mice. The groups treated with BA indicated a significant decrease in leptin, AST, ALT, ALP, TG, cholesterol, LDL-C and an increases in adiponectin and HDL levels, while VLDL did not show significant changes. BA was found to have positive effects on liver injury. BA has an effective role on liver damage induced by diabetes through amelioration of leptin, adiponectin, liver enzyme levels and lipid profile. Since BA has a positive effect on lipid profile, adiponectin and leptin, it may improve metabolic syndrome.

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Oxidative stress (OS) is a main mechanism in organophosphorus poisoning. The effects of calcium channel blockers have been confirmed in decreasing of oxidative stress. In the current study, the effects of amlodipine (AM), as a calcium channel blocker, were evaluated on oxidative damages induced by diazinon (DZN) in hippocampus tissue of Wistar rats. Forty-two rats were divided into six groups and treated intraperitoneally for two weeks. Group 1 served as control received vehicle, group 2 was treated with 9 mg/kg of AM, group 3 (positive control) received DZN (32 mg/kg), Groups 4, 5, and 6 were treated with 3, 6, and 9 mg/kg of AM adjunct with DZN (32 mg/kg), respectively. After 14 days, all the animals were sacrificed under anesthesia and hippocampus tissue and blood samples were collected for biochemical analysis and histopathology experiments. The results showed that DZN caused significant increase in lipid peroxidation (P < 0.001), nitric oxide (P < 0.001) and lactate dehydrogenase (P < 0.001) levels, depletion of total antioxidant capacity (P < 0.01), and structural changes in hippocampus tissues. Following AM administration, a significant improvement was observed in oxidative biomarkers in hippocampus tissues. Additionally, our biochemical findings were related well with histopathological examinations. In conclusion, the data of this study indicated that AM administration may prevent oxidative damages via improving of energy production and preventing of free radical formation in DZN-exposed animals.

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Oxytetracycline is an antibiotic for the treatment of the infections caused by Gram-positive and Gram-negative microorganisms. Among novel formulations applied for damaged skin, hydrogels have shown to be superior as they can provide a moist environment for the wound. The purpose of this study was to prepare and evaluate the hydrogels of oxytetracycline consisted of polyvinyl alcohol (PVA) and chitosan polymers. A study design based on 4 factors and 3 levels was used for the preparation and evaluation of hydrogels formed by freeze-thaw (F-T) cycle using PVA and chitosan as a matrix-based wound dressing system. Furthermore, an experimental design was employed in order to study the effect of independent variables, namely drug amount (X₁, 500-1000 mg), the amount of PVA (X₂, 3.33-7.5%), the amount of chitosan (X₃, 0.5-1%), and F-T cycle (X₄, 3-7 cycles) on the dependent variables, including encapsulation efficiency, swelling index, adsorption of protein onto hydrogel surface, and skin permeation. The interaction of formulation variables had a significant effect on both physicochemical properties and permeation. Hydrogel microbial tests with sequential dilution method in Muller-Hinton broth medium were also carried out. The selected hydrogel (F6) containing 5% PVA, 0.75% chitosan, 1000 mg drug, and 3 F-T cycles was found to have increased encapsulation efficiency, gel strength, and higher skin permeation suitable for faster healing of wounds. Results showed the biological stability of oxytetracycline HCl in the hydrogel formulation with a lower dilution of the pure drug. Thus, oxytetracycline-loaded hydrogel could be a potential candidate to be used as a wound dressing system.

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Multiple sclerosis (MS) is a demyelinating disease that causes chronic inflammation in the central nervous system. The aim of this study was to investigate the effects of apamin administration on myelination process. MS was induced by feeding cuprizone pellets (0.2%) for 6 weeks (demyelination phase) followed by normal feeding for additional 2 weeks (remyelination phase). Briefly, C57BL/6 male mice were randomly divided into six groups. Group 1, received the regular food pellets. Group 2 contained two subgroups of 6 animals each (n = 2 × 6). First group received cuprizone for 6 weeks and the sacrificed while the second group after 6 weeks of cuprizone, received no treatment for additional 2 weeks. Group 3 (co-treatment group) was composed of two subgroups of 6 animals each (n = 2 × 6). Both subgroups received apamin (100 μ/kg) intraperitoneally twice a week for 6 weeks. First subgroup terminated at this time and the second subgroup was fed normal diet for two additional weeks. Group 4 (post-treatment, n = 6) received apamin (100 μ/kg) intraperitoneally twice a week for 2 weeks after cuprizone secession. Groups 5 and 6 (vehicle, n = 6 in each group) received phosphate buffered saline as the vehicle of apamin during demyelination and remyelination phase. At the end of each phase, mice were deeply anesthetized and perfused. Groups 5 and 6 (vehicle) received PBS as the vehicle during both phases. Mice were anesthetized, perfused with PBS through their heart, and their brains were removed. Brain sections stained with luxol fast blue and the images were analyzed. Apamin co-treatment significantly increased the myelin content as compared to the cuprizone group. Also, mild elevation in the myelinated areas was observed with apamin post-treatment in comparison with remyelination phase. Our results revealed that apamin prevents myelin destruction more significantly as compared to remyelination process. This observation explains the possible role of apamin in inhibiting the activation of the microglia cells than stimulation of the oligodendrocytic precursor cells.

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Ionizing radiation causes DNA damage and chromosome abbreviations on normal cells. The radioprotective effect of celecoxib (CLX) was investigated against genotoxicity induced by ionizing radiation in cultured human blood lymphocytes. Peripheral blood samples were collected from human volunteers and were incubated at different concentrations at 1, 5, 10 and 50 μM of CLX for two hours. At each dose point, the whole blood was exposed in vitro to 150 cGy of X-ray, and then the lymphocytes were cultured with mitogenic stimulation to determine the micronucleus frequency in cytokinesis blocked binucleated lymphocytes. Incubation of the whole blood with CLX exhibited a significant decrease in the incidence of micronuclei in lymphocytes induced by ionizing radiation, as compared with similarly irradiated lymphocytes without CLX treatment. The maximum reduction on the frequency of micronuclei was observed at 50 μM of CLX (65% decrease). This data may have an important possible application for the protection of human lymphocytes from the genetic damage induced by ionizing irradiation in human exposed to radiation.

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