Investigating the Anti-inflammatory Effect of Quinoline Derivative: N1-(5-methyl-5H-indolo[2,3-b]quinolin-11-yl)benzene-1,4-diamine Hydrochloride Loaded Soluble Starch Nanoparticles Against Methotrexate-induced Inflammation in Experimental Model.

BACKGROUND: It is necessary to develop advanced therapies utilizing natural ingredients with anti-inflammatory qualities in order to lessen the negative effects of chemotherapeutics. RESULTS: The bioactive N1-(5-methyl-5H-indolo[2,3-b]quinolin-11-yl)benzene-1,4-diamine hydrochloride (NIQBD) was synthesized. After that, soluble starch nanoparticles (StNPs) was used as a carrier for the synthesized NIQBD with different concentrations (50 mg, 100 mg, and 200 mg). The obtained StNPs loaded with different concentrations of NIQBD were coded as StNPs-1, StNPs-2, and StNPs-3. It was observed that, StNPs-1, StNPs-2, and StNPs-3 exhibited an average size of 246, 300, and 328 nm, respectively. Additionally, they also formed with homogeneity particles as depicted from polydispersity index values (PDI). The PDI values of StNPs-1, StNPs-2, and StNPs-3 are 0.298, 0.177, and 0.262, respectively. In vivo investigation of the potential properties of the different concentrations of StNPs loaded with NIQBD against MTX-induced inflammation in the lung and liver showed a statistically substantial increase in levels of reduced glutathione (GSH) accompanied by a significant decrease in levels of oxidants such as malondialdehyde (MDA), nitric oxide (NO), advanced oxidation protein product (AOPP), matrix metalloproteinase 9/Gelatinase B (MMP-9), and levels of inflammatory mediators including interleukin 1-beta (IL-1ß), nuclear factor kappa-B (NF-κB) in both lung and liver tissues, and a significant decrease in levels of plasma homocysteine (Hcy) compared to the MTX-induced inflammation group. The highly significant results were obtained by treatment with a concentration of 200 mg/mL. Histopathological examination supported these results, where treatment showed minimal inflammatory infiltration and congestion in lung tissue, a mildly congested central vein, and mild activation of Kupffer cells in liver tissues. CONCLUSION: Combining the treatment of MTX with natural antioxidant supplements may help reducing the associated oxidation and inflammation.

Moringa oleifera leaves extract loaded gold nanoparticles offers a promising approach in protecting against experimental nephrotoxicity.

Cisplatin is one of the most important antitumor drugs, however; it has numerous adverse effects like nephrotoxicity which is considered one of cisplatin uses . The study was planned to evaluate the nephroprotective effect of M. oleifera leaves extract loaded gold nanoparticles (Au-NPs) against cisplatin-induced nephrotoxicity in rats. Initially, total phenolic contents (TPC) and the antioxidant activity of the M. oleifera leaves extract were evaluated and recorded 8.50 mg/g and 39.89 % respectively. After that, the dry leaves of M. oleifera were grinded into fine powder and extracted using water extraction system. Then, different volumes (0.5, 1 and 2 mL) of M. Oleifera were blended with constant volume of Au-NPs (1 mL). Both Au-NPs and M. oleifera extract loaded Au-NPs were investigated using transmission electron microscope (TEM) that illustrated the deposition of M. Oleifera onto Au-NPs. The experimental study was performed on seventy male albino rats alienated into seven groups. Group I healthy rats, group II injected with one dose of cisplatin (CisPt), groups from III to VII treated groups received CisPt then received M. Oleifera leaves extract alone and /or Au-NPs with different ratios and concentrations. After the experiment' time, serum urea and creatinine, kidney injury molecule-1 (KIM-1), advanced oxidation protein products (AOPP), monocyte chemoattractant protein-1 (MCP-1), tumor necrotic factor-α (TNF-α), and interleukin-6 (IL-6) were evaluated as markers of renal nephrotoxicity. The kidneys of rats were excised for malondialdehyde (MDA), nitric oxide (NO), and superoxide dismutase (SOD) assessments. Induction of CisPt showed a highly significant disturbance in oxidant/anti-oxidant balance and inducing inflammatory cascades supporting nephrotoxicity, while treatment with M. Oleifera leaves extract, Au-NPs, and the different concentrations of the extract loaded on Au-NPs had a crucial role in attenuating oxidative stress, enhancing antioxidant systems, and reducing inflammatory biomarkers, although the most significant results showed a powerful scavenging activity against nephrotoxicity induced by CisPt was obtained with M. Oleifera leaves extract loaded on Au-NPs with a concentration of 2:1 respectively.

Development of Transdermal Oleogel Containing Olmesartan Medoxomil: Statistical Optimization and Pharmacological Evaluation.

Olmesartan medoxomil (OLM) is a first-line antihypertensive drug with low oral bioavailability (28.6%). This study aimed to develop oleogel formulations to decrease OLM side effects and boost its therapeutic efficacy and bioavailability. OLM oleogel formulations were composed of Tween 20, Aerosil 200, and lavender oil. A central composite response surface design chose the optimized formulation, containing Oil/Surfactant (SAA) ratio of 1:1 and Aerosil % of 10.55%, after showing the lowest firmness and compressibility, and the highest viscosity, adhesiveness, and bioadhesive properties (Fmax and Wad). The optimized oleogel increased OLM release by 4.21 and 4.97 folds than the drug suspension and gel, respectively. The optimized oleogel formulation increased OLM permeation by 5.62 and 7.23 folds than the drug suspension and gel, respectively. The pharmacodynamic study revealed the superiority of the optimized formulation in maintaining normal blood pressure and heart rate for 24 h. The biochemical analysis revealed that the optimized oleogel achieved the best serum electrolyte balance profile, preventing OLM-induced tachycardia. The pharmacokinetic study showed that the optimized oleogel increased OLM's bioavailability by more than 4.5- and 2.5-folds compared to the standard gel and the oral market tablet, respectively. These results confirmed the success of oleogel formulations in the transdermal delivery of OLM.

Enhancement of the antitumor effect of 5-fluorouracil with modulation in drug transporters expression using PI3K inhibitors in colorectal cancer cells.

AIMS: 5-Fluorouracil (5-FU) represents the cornerstone for colorectal cancer therapy. However, resistance to its action is a major hindrance. This study aimed to investigate the effectiveness of suppressing the activity of PI3K/Akt/mTOR signaling pathway on the chemosensitivity of colorectal cancer cells to 5-FU, as well as to delineate the possible underlying cellular mechanisms and the expected modulation in the expression of specific ABC drug transporters. MAIN METHODS: HCT116 and Caco-2 cells were incubated with 5-FU, LY294002, or PI-103 individually or in combination. Cell viability was monitored using MTT assay. The expression of a panel of drug transporters was evaluated by RT-PCR. Immunofluorescence staining was applied to evaluate the expression pattern of phospho-AKT, phospho-mTOR, and ABGG2. HPLC evaluated the enhancement in the 5-FU cellular uptake. Cell apoptosis was detected by flow cytometry, and cell morphological changes following treatment were inspected under a fluorescence microscope. Additionally, the migration ability of cells following our suggested treatment combination was examined by wound healing assay. KEY FINDINGS: The results reveal a notable enhancement in the cytotoxicity of a low dose of 5-FU when combined with a PI3K inhibitor (LY294002 or PI-103). This enhancement was influenced by the significant reduction in the expression of p-AKT and p-mTOR and was also mediated by a significant suppression in the expression of ABCG2 and ABCC5. Consequently, we detected an increase in the cellular uptake and concentration of 5-FU in cells treated with this combination rather than a single 5-FU treatment. Our Suggested combination treatment also induced cell apoptosis and reduced the migration ability of cells. SIGNIFICANCE: Our data provide evidence that survival signaling pathways represent distinctive targets for the enhancement of chemotherapeutic sensitivity. The antitumor efficacy of 5-FU is enhanced when combined with a PI3K inhibitor, and this effect was mediated by alterations in the expression of specific drug transporters.

Eicosapentaenoic acid loaded silica nanoemulsion attenuates hepatic inflammation through the enhancement of cell membrane components.

BACKGROUND: Liver inflammation is a multistep process that is linked with cell membrane fatty acids composition. The effectiveness of eicosapentaenoic acid (EPA) undergoes an irreversible change during processing due to their unsaturated nature; so the formation of nanocarrier for EPA is crucial for improving EPA's bioavailability and pharmacological properties. OBJECTIVE: In this study we aimed to evaluate the efficiency of EPA alone or loaded silica nanoemulsion on the management of hepatic inflammation induced by diethyl nitrosamine (DEN) through the enhancement of the cell membrane structure and functions. METHODS: The new formula of EPA was prepared to modify the properties of EPA. Forty-eight male Wistar albino rats were classified into: control, EPA, EPA loaded silica nanoemulsion (EPA-NE), DEN induced hepatic inflammation; DEN induced hepatic inflammation treated with EPA or EPA -NE groups. Plasma tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1ß), liver hydroxyproline (Hyp) content, and liver oxidant and anti-oxidants were estimated. Urinary 8- hydroxyguanozine (8- OHdG) and erythrocyte membrane fatty acids fractions were estimated by High-performance liquid chromatography (HPLC). Also, histopathology studies were done to verify our hypothesis. RESULTS: It was appeared that administration of EPA, in particular EPA loaded silica nanoemulsion, ameliorated the inflammatory response, increased the activity of the anti-oxidants, reduced levels of oxidants, and improved cell membrane structure compared to hepatic inflammation induced by DEN group. Histopathological examination confirmed these results. CONCLUSION: EPA and notably EPA loaded silica nanoemulsion strongly recommended as a promising supplement in the management of hepatic inflammation.

Preclinical activity of fluvastatin-loaded self-nanoemulsifying delivery system against breast cancer models: Emphasis on apoptosis.

Statins trigger apoptotic cell death in some types of growing tumor cells in a cholesterol-lowering-independent manner. Self-nanoemulsifying delivery systems (SNEDs) are potentially effective for the suppression of breast cancer development. This study aims to investigate the potential anticancer activity of fluvastatin (FLV)-SNEDs in breast cancer while comparing it with FLV in vitro as well as in vivo exploiting/using MDA-MB-231 and Erhlich ascites carcinoma (EAC)-bearing mice, respectively. Biochemical analysis of liver and kidney functions, oxidative stress markers, and histopathological examinations of such tumor tissues were performed showing the potentiality of SNEDs as a nanocarrier for antitumor agents. FLV-SNEDs demonstrated more potent anticancer activity compared to FLV on MDA-MB-231 and hepatocellular carcinoma (HepG2) cells. In vivo experiments on the EAC-bearing mice model indicated that FLV and-to a greater extent-FLV-SNEDs ameliorated EAC-induced hepatotoxicity and nephrotoxicity. FLV or FLV-SNEDs evidently reduced the percent of Ki-67 +ve EAC cells by 57.5% and 86.5% in comparison to the vehicle-treated EAC group. In addition, FLV or FLV-SNEDs decreased Bcl-2 levels in serum and liver specimens. In contrast, FLV or FLV-SNEDs significantly activated the executioner caspase-3. Simultaneously, both FLV and FLV-SNEDs stimulated p53 signaling and modulated Bcl-2 protein levels in treated cells. Collectively, these results support the contribution of apoptotic cell death in mediating the anticancer activities of FLV and FLV-SNEDs against murine EAC model in vivo. This study provides new understandings of how FLV and FLV-SNEDs regulate EAC cell viability via upregulation of p53 signaling, and through modulation of cleaved caspase-3 as well as antiapoptotic Bcl-2 marker.

Prophylactic effect of probiotics fortified with Aloe vera pulp nanoemulsion against ethanol-induced gastric ulcer.

The purpose of this study was designed to evaluate the protective effect of probiotics fortified with Aloe vera pulp nanoemulsion on ethanol-induced gastric ulcer (GU). Freshly harvested Aloe vera pulp nanoemulsion was prepared and subsequently inoculated with 2% of the activated yogurt starter culture of Streptococcus thermophilus and Lactobacillus delbreukii subsp. bulgaricus (1:1). Chemical composition and physicochemical characterization of yogurt and the Aloe vera pulp nanoemulsion were assessed. GU was induced by ethanol. Rats were randomly assigned into control, GU, and four prophylactic groups including probiotics fortified with Aloe vera pulp nanoemulsion in the percentage of 0%, 10%, 20%, and 30% respectively. Serum levels of paraoxynase (POX) and tissue levels of malondialdehyde (MDA), nitric oxide (NO), and catalase (CAT) activity were assessed. Serum levels of nuclear factor kappa B (NF-κB), interleukin-1beta (IL-1ß), matrix metalloproteinase-9 (MMP-9), ceramide, and homocysteine (Hcy) were evaluated. Results indicated that the Aloe vera pulp nanoemulsion was appeared in spherical nano form with droplets diameter around 330 nm. Ethanol induces GU to cause a significant increase in the levels of MDA, NO, NF-κB, IL-1ß, MMP-9, Hcy, and ceramide along with a significant decrease in POX and CAT activities compared to the control group (p < 0.05). Pretreatment with different concentrations of probiotics fortified with Aloe vera pulp nanoemulsion with, especially the 30% concentration, significantly reduce the oxidative stress and ameliorate the release of different inflammatory mediators suggesting it as a promising approach in the protection against GU via scavenging superoxide radicals and inhibiting the activation of the inflammatory signaling cascades.

Influence of irisin on diet-induced metabolic syndrome in experimental rat model.

OBJECTIVE: To evaluate the influence of irisin on the experimental paradigm of non-alcoholic fatty liver (NAFL) as a part of MetS cluster. METHODS: Forty male albino rats were divided into four groups; normal control, standard diet + irisin, high carbohydrate and fat diet (HCHF), and HCHF + irisin. After the experimental period, levels of fasting blood sugar (FBS), insulin, lipid profile, kidney functions, salusin-alpha (Sal-α), adropin, and retinol-binding protein-4 (RBP-4) were evaluated. Peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1α) expression in skeletal muscle was evaluated by quantitative real-time PCR. Aorta, liver, pancreas, and skeletal muscle tissue samples were prepared for histopathological examination. RESULTS: Rats administrated HCHF showed elevated levels of FBS, lipid profile, kidney functions, RBP-4, and downregulation of PGC-1α expression along with a decline in levels of insulin, Sal-α, and adropin while administration of irisin significantly attenuated these levels. CONCLUSIONS: Irisin as based therapy could emerge as a new line of treatment against MetS and its related diseases.

Stimulatory effect of docosahexaenoic acid alone or loaded in zinc oxide or silver nanoparticles on the expression of glucose transport pathway.

The role of glucose transporters (GLUTs) in diabetes mellitus has become more prominent as a possible therapeutic target. In the present study, we aimed to compare the effect of zinc oxide nanoparticles (ZnONPs), silver nanoparticles (AgNPs), and docosahexaenoic acid (DHA) alone or loaded in ZnONPs or AgNPs on insulin signaling pathway and GLUTs expression in diabetic rats. In the experimental part, rats were divided into seven groups; control, diabetic, and the other five groups were diabetic received different treatments. Fasting blood sugar (FBS), serum level of insulin, insulin resistance (IR), and serum level of phosphatidylinositol 3-kinase (PI3K) were evaluated. In addition, insulin expression in pancreatic islets was assessed by immunohistochemical analysis, and the expression of liver GLUTs 1, 2, and 4 and liver insulin receptor substrate-1 (IRS-1) was evaluated by real-time polymerase chain reactions (RT-PCR). The results of the current study showed that ZnONPs, AgNPs, and DHA alone or loaded in ZnONPs or AgNPs attenuated levels of FBS, insulin and decreased IR in diabetic rats through enhancing the expression of GLUTs as well as IRS-1 and PI3K. Furthermore, AgNPs loaded with DHA showed the most significance with high comparability to the control group. In conclusion, this study elucidated the role of GLUTs and IRS-1 in diabetes and introduced novel characteristics of ZnONPs, AgNPs, and DHA alone or loaded in ZnONPs or AgNPs as a therapeutic modality to activate GLUTs and IRS1, which may be beneficial for diabetic patients with IR.

Shoot aqueous extract of Manihot esculenta Crantz (cassava) acts as a protective agent against paracetamol-induced liver injury.

Manihot esculenta Crantz (Euphorbiaceae), known as cassava, is a widely cultivated plant, considered one of the main sources of food in the tropical and subtropical regions of Africa and Asia. The aim of the present study was the evaluation of the antioxidant and anti-inflammatory effects of cassava shoot aqueous extract (CSAE) on liver injury induced by paracetamol and investigation of its effect on hyperhomocysteinemia. CSAE was administered to male albino rats classified into seven groups: control, treated, and prophylactic groups. A significant reduction in liver enzymes, malondialdehyde, and homocysteine were observed when compared to the paracetamol group, together with an increase in paraoxonase-1. Histopathological and histochemical results indicated that CSAE effectively ameliorate these parameters. Two main flavonol glycosides, quercetin 3-O-rutinoside and kaempferol 3-O-rutinoside, in addition to a minor myricetin 3-O-rutinoside, were identified in CSAE. CSAE showed a therapeutic potential against paracetamol-induced liver injury probably through antioxidant activity of its flavonol glycosides.

Curcumin nanoparticles have potential antioxidant effect and restore tetrahydrobiopterin levels in experimental diabetes.

Diabetes is associated with an increase in the production of free radicals, reduction of tetrahydrobiopterin (BH4, THB) levels and reduced bioavailability of nitric oxide (NO) in the vascular walls. In this contribution, we probed the effective role of curcumin nanoparticles (CUR-NPs) that prepared via solvent evaporation nanoprecipitation technique as potential system to attenuate endothelial dysfunction. In this technique, Tween 60 (polysorbate) was used as stabilizing agent for the prepared CUR-NPs and protect such nanoparticles from further agglomeration. BH4 levels and other parameters were estimated in diabetic rats. To this end, we dedicated 48 male albino rats, categorized into six groups; control (healthy rats), diabetic rats, along with four treated groups via oral administration of 0.2 mL/kg body weight/day of solutions of Tween 60 (60 mg/mL), free CUR (60 mg/mL), CUR-NPs1 (30 mg/mL), and CUR-NPs2 (60 mg/mL) for 30 days. Results showed that the mean level of malondialdehyde (MDA) has been significantly increased in diabetic group associated with a reduction of total antioxidant capacity, NO, and BH4 compared to control. These parameters were restored by the delivery of CUR-NPs - both doses in rats, compared with the two control groups that treated with Tween 60 and free CUR.

The efficiency of blackberry loaded AgNPs, AuNPs and Ag@AuNPs mediated pectin in the treatment of cisplatin-induced cardiotoxicity in experimental rats.

Cisplatin (cis-Diaminedichloroplatinum) is one of the most effective chemotherapeutic because of its anti-neoplastic properties against various types of tumor. However, it has a wide variety of side effects such as hepato, gastrointestinal, neuro, nephro, and cardiotoxicity (acute and/or chronic) that highly restricted its usage. Thus, research work was planned to detect the role of gold (AuNPs), silver nanoparticles (AgNPs) and their corepshell (Ag@AuNPs) as a carrier for blackberry extract and to enhance its benifit in treatment of cisplatin-induced cardiotoxicity. In our work, solid-state process was used in order to prepare these nanoparticles using pectin as an ecologically friendly-polymer acting as reductant for ions and at the same time as stabilizing agent for the produced nanoparticles. This nominated method for large-scale preparation of nanoparticles is simple, efficient, and convenient. The presence of individual metallic Ag, Au and both has been proven by UV-vis spectroscopy. Transmission electron microscopy (TEM) and particle size analyzer confirmed the preparation of spherical small size with a main diameter <40 nm. The data obtained from zeta potential evaluation displayed the well stabilization for the produced nanoparticles. Transmission electron microscopy (TEM), scanning electron microscopy (SEM) and particle size analyzer have verified that the spherical small size is <40 nm in diameter. Data from zeta potential assessment revealed the good stability of the produced nanoparticles. To this end, fifty sex rats were used in this study and divided into control, cisplatin (cispt), and five treated groups. After the experimental period, lipid profile was estimated and atherogenic coefficient (AC), atherogenic index (AI), and cardiac risk ratio (CRR) were calculated. Oxidant and antioxidant parameters were also estimated. Cardiovascular disease markers were estimated by ELISA. The mean levels of cholesterol, triglycerides, malondialdehyde (MDA), advanced oxidative protein products (AOPP), and cardiovascular markers were significantly increased in cispt group compared to control; whereas these parameters were attenuated in all treated groups in particular that received blackberry (bb) loaded Ag@AuNPs. Based on these results, it can be concluded that bb has antioxidant and antilipidemic effect that help in protecting against cardiovascular disease specially when loaded with Ag@AuNPs.

Homocysteine and Asymmetrical Dimethylarginine in Diabetic Rats Treated with Docosahexaenoic Acid-Loaded Zinc Oxide Nanoparticles.

Hyperglycemia, the hallmark of diabetes mellitus, is considered one of the endothelial dysfunction risk factors, the main reason of vascular complication. In this study, we aimed to evaluate homocysteine (Hcy) and asymmetrical dimethylarginine (ADMA) levels in diabetic rats and the possibility to attenuate the elevation of these two parameters by supplementation of docosahexaenoic acid (DHA) alone or loaded zinc oxide nanoparticles (ZnONPs) to improve endothelial dysfunction in streptozotocin (STZ)-induced diabetic rats. Forty male albino rats weighing 180-200 g were classified as control, diabetic, diabetic treated with DHA, and diabetic treated with DHA-loaded zinc oxide nanoparticles (DHA/ZnONPs) groups. Fasting blood glucose, insulin, ADMA, Hcy, and nitric oxide (NO) were estimated. Fatty acids (linoleic acid (LA), arachidonic acid (AA), DHA, α-linolenic acid (ALA), and oleic acid (OA)) were also evaluated by reversed phase HPLC using a UV detector. The results showed that fasting blood sugar, insulin resistance, LA, AA, OA, ADMA, and Hcy increased significantly in diabetic rats compared with control while fasting insulin, DHA, ALA, and NO decreased significantly in diabetic rats. In both treated groups, fasting blood sugar, insulin resistance, LA, AA, OA, ADMA, and Hcy significantly decreased as compared with the diabetic group while fasting insulin, DHA, ALA, and NO were significantly increased. In conclusion, DHA and DHA/ZnONP supplementation protect against diabetic complications and improve endothelial dysfunction as well as hyperhomocysteinemia in diabetes. DHA/ZnONP-treated group appeared more efficient than DHA alone.

Hypoxia-induced oxidative stress in high altitude population: impact of coenzyme Q10 supplementation.

OBJECTIVE: The aim of this study was to investigate the effect of coenzyme Q10 (CoQ10) supplementation on oxidative stress engendered from hypoxia in population live at high altitude. METHODS: This is an intervention study in which 50 females of volunteers population-36 of them who live at high altitude compared with the placebo group (14 from the total population that live at sea level). Blood samples were collected in -anticoagulant tubes from control and high altitude before and after CoQ10 supplementation (150 mg/day for 2, 4 and 8 weeks). Plasma was separated and used for the determination of malondialdehyde (MDA), nitric oxide (NOx), total antioxidant capacity (TAC), paraoxonase (PON1) by spectrophotometer, CoQ10 and vitamin E by high performance liquid chromatography (HPLC). RESULTS: Our results appeared that TAC, PON1, vitamin E and CoQ10 concentrations were significantly decreased in population at high altitude at base line compared to placebo group population at sea level. Whereas, administration of CoQ10 attenuated all measured parameters especially after eight weeks of administration. CONCLUSION: We concluded that coenzyme Q10 supplement at a dose of 150 mg/day has a powerful effect in oxidative stress parameters and increased antioxidant parameters included vitamin E in population with hypoxia after 4 and 8 weeks. So that supplementation positively affects oxidative stress and is recommended CoQ10 supplementation in population who live at high altitude.

Effect of Ficus carica L. leaves extract loaded gold nanoparticles against cisplatin-induced acute kidney injury.

BACKGROUND: Cisplatin (CisPt) is one of the most widely used and highly effective drugs for the treatment of various solid tumors, unfortunately acute kidney injury (AKI) is considered one of its side effects through several mechanisms including production of reactive oxygen species (ROS), pro-inflammatory and pro-fibrotic cytokines. Due to the poor effect of AKI therapy, the use of nanoparticles loaded with natural extracts for delivering to the kidney molecules are desirable. AIM: This study aims to investigate the effectiveness of different concentrations of gold nanoparticles (Au-NPs) as a carrier for Ficus carica L. (Fig) leaves extract against CisPt induced AKI. METHODS: Seventy male albino rats were used and divided into seven groups. After the experimental period, blood was withdrawn, serum was separated for determination of urea, creatinine, homocystein (Hcy) and folic acid while reduced glutathione (GSH), nitric oxide (NO), malondialdehyde (MDA), total antioxidant capacity (TAC) and hydroxyproline content (Hyp) were evaluated in kidney tissue homogenate. RESULTS: CisPt induced AKI in rats and results in a significant increase in the levels of serum urea, creatinine, Hcy and kidney Hyp, lipid peroxidation along with a significant reduction of kidney GSH, NO and TAC compared to the control rats. Treatment with Au-NPs and Fig extract particularly in a ratio of (3:2) respectively was shown to improve renal functions with efficient capacity in scavenging ROS and reduced AKI severity. CONCLUSION: Au-NPs enhanced the anti-oxidative properties of the Fig extract in targeting kidney damaged tissue and reduced oxidative toxicity induced by CisPt.

Differential expression of miRNAs regulating NF-κB and STAT3 crosstalk during colitis-associated tumorigenesis.

Inflammatory bowel disease (IBD) is mostly responsible for the development of colitis-associated colon cancer. Of the several signaling pathways involved in colonic inflammation, the activation and crosstalk between NF-κB and STAT3 serve as the pivotal regulatory hubs that regulate epithelial tumorigenesis by linking inflammation with cancer development. Understanding the molecular mechanisms regulating the crosstalk between NF-κB and STAT3 will help in targeting these signaling pathways and halt epithelial tumorigenesis. MicroRNAs (miRNAs) play important role in the regulation of NF-κB and STAT3 and function in a positive- or negative feedback loop to regulate the crosstalk of these transcription factor. In the present study we evaluated the aberrant expression of a selected panel of miRNAs (miR-181b, miR-31, miR-34a, miR-146b, miR-221, and miR-155) that regulate the crosstalk between NF-κB and STAT3 during colitis-associated tumorigenesis. We used the stepwise colorectal carcinogenesis murine model known as Azoxymethane (AOM)/Dextran sodium sulphate (DSS) to recapitulate the different stages of tumorigenesis. Our results revealed that the expression of the selected miRNAs changed dynamically in a stepwise pattern as colonic tissue transforms from normal to actively inflamed to neoplastic state, in accordance with the gradual activation of NF-κB and STAT3, suggesting that the aberrant expression of these miRNAs could function as the epigenetic switch between inflammation and colorectal tumorigenesis. We were able to elucidate the contribution of miRNAs in the NF-κB - STAT3 crosstalk during the stepwise development of colitis-associated carcinoma, and this could improve our understanding of the molecular pathology of colorectal tumorigenesis and even suggesting a therapeutic strategy by modulating the expression of these regulating miRNAs.

Solid state synthesis of docosahexaenoic acid-loaded zinc oxide nanoparticles as a potential antidiabetic agent in rats.

Our goal in this study is to improve the efficiency of docosahexaenoic acid (DHA) toward the enhancement of insulin signaling pathway in vivo via loading with zinc oxide nanoparticles (ZnO NPs). To this end, two consecutive steps were undertaken, preparation of ZnO NPs by one-step solid-state reaction in dry conditions and calcinated followed by loading DHA. Both developed nanoparticles, with and without DHA were then characterized by TEM, SEM, EDX, and Zetasizer. For comparison between free and loaded DHA, four groups of rats were prepared to receive different treatments. Group I; healthy rats (reference), group II; diabetes (streptozotocin-induced), group III and group IV are diabetes orally administered with free DHA and DHA-loaded ZnO NPs (10 mg/kg bw/day), respectively. Blood samples were collected and analyzed where the results demonstrated that fasting blood sugar and insulin resistance were significantly increased in diabetic group along with upgrading in oxidative stress parameters emphasizing the oxidative properties of streptozotocin. HPLC analysis of cell membrane fatty acids resulted in the reduction of omega-6 and 9 and elevation of omega-3 after free DHA and DHA-loaded ZnO NPs streptozotocin treatments. DHA-loaded ZnO NPs had high performance in enhancing insulin signaling pathway as expressed in changes of phosphatidylinositol 3-kinase (PI3K) levels.

Evaluation of urinary 8-hydroxy-2-deoxyguanosine level in experimental Alzheimer's disease: Impact of carvacrol nanoparticles.

The present study aimed to compare the effect of carvacrol essential oil and carvacrol nanoemulsion against experimental Alzheimer's (AD). Forty male albino rats were used and divided into four groups as follow: control, AlCl3 induced AD, carvacrol oil treated and carvacrol nanoemulsion treated groups. Brain nor-epinephrine, serotonin and dopamine were analyzed by high performance liquid chromatography (HPLC). Levels of brain Thiobarbituric acid-reactive substances (TBARS), Superoxide dismutase (SOD), reduced glutathione (GSH), cholinesterase, and advanced oxidation protein product (AOPP) were evaluated. Urinary 8-hydroxyguanosine (8-OHdG) level was evaluated by HPLC. Brain Cyclooxygenase 1 and 2 (COX 1and 2) were analyzed by immunohistochemistry. AD induced by AlCl3 in rats was depicted by the significant increase in the neurotransmitters levels which is accompanied with high degree of oxidative stress that was revealed in the elevated level of urinary 8-OHdG along with significant elevation in AOPP, TBARS, and cholinesterase levels and a significant decrease in SOD and GSH; these results are confirmed by immunohistochemistry analysis of COX 1 and 2. On the other hand, the treatment with carvacrol oil and carvacrol nanoemulsion were capable of mitigate effects mediated by AlCl3 administration in treated rats. While the treatment with both approached succeeded to retract the negative impact of AlCl3; but the effect of carvacrol nanoemulsion was more notable than the essential oil. Carvacrol oil and carvacrol nanoemulsion were eminent to overturn AlCl3 induced brain AD which could be imputed to antioxidant and anti-inflammatory capabilities of carvacrol to alter oxidative stress effect. In extension; carvacrol nanoemulsion were evident to give more effective and efficient way in carvacrol delivery to pass through blood brain barriers and ameliorate brain changes.

Genetically engineered CAR T-immune cells for cancer therapy: recent clinical developments, challenges, and future directions.

Cancer immunotherapy offers tremendous clinical outcomes in cancer management with the potential to induce sustained remission in patients with refractory disease. One of these immunotherapy modalities is the adoptive transfer of autologous T-cells that are genetically engineered ex vivo to express chimeric antigen receptors (CARs). These receptors can direct T-cells to the surface antigens of tumor cells to initiate an efficient and specific cytotoxic response against tumor cells. This review elucidates the structural features of CAR T-cells and their different generations reaching the recent 4th generation (TRUCK). The step-wise treatment process using CAR T-cell therapy and some of the updated prominent clinical applications of this treatment modality in both hematologic and solid malignancies are also covered in the present review. The success of CAR T-cell therapy is still encountered by several limitations for a widespread clinical application of this treatment modality, these challenges along with the recent innovative strategies that have been developed to overcome such drawbacks, as well as, the approaches and future directions aiming for a commercial low cost CAR T-cell immunotherapy modality, are all covered in the present review.

Solvent-free and one-pot synthesis of silver and zinc oxide nanoparticles: Activity toward cell membrane component and insulin signaling pathway in experimental diabetes.

OBJECTIVE: To investigate and compare between the effect of both silver nanoparticles (AgNPs) and zinc oxide nanoparticles (ZnONPs) on insulin signaling pathway and insulin sensitivity in experimental diabetes. Preparation of AgNPs and ZnONPs in their solid state were carried out using pullulan (Natural polymer) as both reducing and stabilizing agent. The synthesis of these nanoparticles in a large scale were carried out without using any solvents. The experimental male albino rats received diluted solutions of AgNPs and ZNONPs. After the experimental period, blood was withdrawn; erythrocyte membrane lipids were extracted and fatty acids were determined by HPLC. Oxidant, antioxidant profile and phosphatidylinositol 3-kinase (PI3K) were estimated. RESULTS: It was observed that the as synthesized AgNPs and ZnONPs have nearly spherical shape with small size due to the stabilization effect of pullulan as proved by UV-vis spectroscopy (UV-vis), Transmission electron microscy (TEM) and Field emission scanning electron microscopy (FESEM), Zeta potential, Dynamic light scattering (DLS) and X-ray diffraction (XRD) techniques. The average hydrodynamic size of the formed AgNPs was 15 nm which is considered as very small size when compared with that of ZnONPs (above 50 nm). Fasting blood sugar was significantly increased in diabetic group along with elevation of MDA and DNA damage indicating the oxidative properties of streptozotocin. Whereas, the treatment with nanoparticles significantly attenuated these elevations. CONCLUSION: AgNPs and ZnONPs represent promising materials in attenuating diabetic complications and insulin resistance in experimental diabetes; no Impressive differences were observed between the effect of ZnONPs and AgNPs in this current research.